37 weeks' gestation, and had primary PPH following vaginal birth. PPH was unresponsive to first-response medical treatment (not described). Women in the intervention group received condom-loaded catheter intrauterine tamponade. Women in the control group received intrauterine packing with roll gauze and vaginal packing with an epipad. All women received antibiotic prophylaxis (drug and dose not described).\nPPH was defined as excessive blood loss from the genital tract, but the method of blood loss estimation was not described. Women were excluded if they had PPH due to perineal, cervical or vaginal tear or episiotomy; PPH due to retained placenta; vaginal birth following previous caesarean section; coagulation disorder.\n\n# Main resource requirements\nStaff trained in recognition and prompt treatment of refractory PPH.\n\n# Equipment and infrastructure\nPlacement of uterine balloon tamponade typically also requires:\nIV fluids Instruments (speculum, forceps)\nAnalgesia or anaesthesia Antibiotics.\nShould uterine balloon tamponade fail, transfer to a surgical theatre or to a health facility able to perform hysterectomy is required to treat unresponsive PPH.\nHowever, typically in high-income countries such as France, the United Kingdom and United States, the uterine balloon tamponade is placed with the woman in the surgical theatre, and after exploration of the uterine cavity to exclude trauma as the cause of the bleeding. Conversely, in LMICs the placement is commonly done in the delivery room, frequently without exploration of the uterine cavity.\n\n# Time -\n\n# Supervision and monitoring\nSupervision and monitoring to ensure appropriate use, stock availability and quality.\nOne study quoted a higher price of $10 for a uterine balloon tamponade kit that included misoprostol tablets: \"Tablets of 200 μg misoprostol and uterine balloon tamponade kits (including Foley catheter size 24, condom, 1-litre bag of solute, needleless suture, 50 mL syringe, compresses, sterile gloves) were implemented in the participating centres (each kit costing US$ 10 but free of charge for the patients)\" (11).\nIs uterine balloon tamponade for PPH treatment acceptable to key stakeholders?\n\n# Research evidence\nIn an update of a qualitative systematic review exploring perceptions of PPH prevention and treatment among women and health-care providers (7), findings from providers indicate that the use of a simple uterine balloon tamponade device is effective as second-line treatment in arresting blood loss associated with PPH (moderate confidence). Findings from providers also suggest that a uterine balloon tamponade is relatively easy to use and, with appropriate training, could be administered by a variety of cadres, including midwives and medical officers (moderate confidence). In addition, providers felt that the use of a uterine balloon tamponade reduced referral rates to secondary facilities and the need for more complicated surgical procedures (hysterectomy) (moderate confidence). A few providers were also aware that some women might be reluctant to have a condom inserted on cultural or religious grounds and that the uterine balloon tamponade should be referred to as a \"tamponade\" rather than a condom for this reason (low confidence).\nThe same review also found that neither women nor providers expressed a preference for a particular type of uterine balloon tamponade; providers in most of the studies utilized a simple \"device\" consisting of a condom, urinary catheter, cotton string and luer lock valve.\nThere was very little direct evidence from women about their experiences of uterine balloon tamponade.\n\n# Additional considerations\n\n# Research evidence\nFindings from an update of a qualitative systematic review on PPH prevention and treatment (7) suggest that a uterine balloon tamponade is a practical and affordable solution in many low-resource settings and could be improvised from readily available items (condoms, surgical gloves) (low confidence). In most of the studies contributing to this review finding, the uterine balloon tamponade consisted of a condom, urinary catheter, cotton string and a luer lock valve. Findings from the same review also suggest that there may be some confusion amongst providers about how long to leave a uterine balloon tamponade in place and they highlighted the need for regular \"handson\" training to maintain their skills (moderate confidence).\nThere was very little direct evidence from women relating to the feasibility of using a uterine balloon tamponade.\n\n# Additional considerations\nIt is commonly accepted that insertion of a uterine balloon tamponade is a relatively simple procedure and that the required level of competence can be achieved after a short training in simulated conditions. For example, trials of uterine balloon tamponade have used a half-day onsite training at participating hospitals (11,18). In these trials, the training sessions were conducted by trained obstetricians, who were trained by experienced obstetricians (using a \"train-the-trainers\" approach). These trials described either concerns with the use of the uterine balloon tamponade, or substantial delays in insertion of the uterine balloon tamponade (11). Whether those factors were related to the training, the type of device, or the previous expertise of the providers is unknown. However, it must be acknowledged that these trials did not include other tamponade interventions as comparisons. Problems with other tamponade interventions might be plausible as well.\nIf commercially available devices were those proven to be more effective, accessing them in low-resource settings may be a challenge based on their more expensive cost."}}},{"rowIdx":80,"cells":{"id":{"kind":"string","value":"dd7041541f9c0070451b79f6ed2d027a11c9a8fd"},"source":{"kind":"string","value":"nice"},"text":{"kind":"string","value":"Pelvic floor dysfunction: prevention and non-surgical management\n\nThis guideline covers the prevention, assessment and non-surgical management of pelvic floor dysfunction in women aged 12 and over. It aims to raise awareness and help women to reduce their risk of pelvic floor dysfunction. For women who have pelvic floor dysfunction, the guideline recommends interventions based on their specific symptoms.\n\n# Recommendations\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\nWhat is pelvic floor dysfunction?\nPelvic floor dysfunction is a condition in which the pelvic floor muscles around the bladder, anal canal, and vagina do not work properly. This guideline covers the following symptoms and disorders when they are associated with pelvic floor dysfunction:\nurinary incontinence\nemptying disorders of the bladder\nfaecal incontinence\nemptying disorders of the bowel\npelvic organ prolapse\nsexual dysfunction\nchronic pelvic pain.\nThe 3 most common and definable symptoms are urinary incontinence, faecal incontinence and pelvic organ prolapse.\nWho does this guideline cover?\nThis guideline covers young women aged 12 to 17 and women aged 18 and over. When recommendations refer to 'women' without specifying an age range, that means they cover this entire population.\n\n# Raising awareness of pelvic floor dysfunction for all women\nWhen producing resources on pelvic floor dysfunction, include:\nthe symptoms of pelvic floor dysfunction\nvisual aids to help identify potential causes of symptoms (for example, by showing the anatomy of pelvic organs)\nwhen to get help\nwhere to go for help (including self-referral to community-based multidisciplinary teams, where available)\nan outline of risk factors, prevention and management options (including non-surgical management and lifestyle changes).\nConsider providing information on pelvic floor dysfunction in the following formats and settings:\nFormats\nprint, broadcast and online adverts\ninformation given alongside over-the-counter continence products\nleaflets in the community (for example, at GP surgeries, family planning clinics and exercise classes)\nvideos and information on social media\ninteractive online resources (for example, the NHS app).\nSettings\nas part of general exercise programmes\nin leaflets on gynaecological cancer treatment or gynaecological surgery (such as hysterectomies)\nas part of existing programmes, for example, cervical screening or national or local NHS health checks\ncontact with a healthcare practitioner with pelvic floor dysfunction knowledge\ngiving advice to people with contacts in the community (such as exercise and fitness instructors and teachers), so they can provide information on pelvic floor dysfunction themselves\n-n community and health trust websites\ninformation provided by healthcare charities.\nTailor information and communication about pelvic floor dysfunction for different age groups and characteristics (for example, pregnancy).\nConsider covering pelvic floor dysfunction in the syllabus for healthcare and other professionals, such as trainee nurses, physiotherapists, doctors, midwives and teachers.\nLocal authorities should consider designing pelvic floor dysfunction information programmes for specific communities when there is evidence of healthcare inequalities (for example, in how services are provided and accessed, or rates of uptake). This can be done by:\nfinding more effective ways to provide information (for example, by attending community meetings)\ninvolving members of the community as champions\nusing webinars to reach women who are unable to attend meetings in person.\nFor women using maternity services, include information on pelvic floor dysfunction, how to prevent it, the symptoms, and how to access local services:\nin the booking information pack or patient portal\nat all midwife consultations and reviews\nat all consultations with an obstetrician\nin hospital postnatal wards.\nHealth visitors, midwives and GPs should discuss pelvic floor dysfunction with women at each postnatal contact.\nTeach young women (between 12 and 17) in education settings about pelvic floor anatomy, pelvic floor muscle exercises and how to prevent pelvic floor dysfunction.\nProvide information on pelvic floor dysfunction for older women within primary and intermediate care services, and within care homes and supported living communities. This could be done:\nwhen women ask for advice about perimenopause and menopause\nas part of general health assessments\nas part of comprehensive geriatric health assessments.\nFor guidance on tailoring communication, information and shared decision making for people using health and social care services, see the:\nNICE guideline on shared decision making\nNICE guideline on patient experience in adult NHS services\nNICE guideline on babies, children and young people's experience of healthcare\nNICE guideline on people's experience in adult social care services\nNHS Accessible Information Standard (in particular, for guidance on making information accessible).\nFor guidance on planning and developing digital and mobile tools to provide tailored information, see the NICE guideline on behaviour change: digital and mobile health interventions.\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on raising awareness of pelvic floor dysfunction for all women .\nFull details of the evidence and the committee's discussion are in evidence review A: community information strategies.\nLoading. Please wait.\n\n# Risk factors for pelvic floor dysfunction\nWhen discussing the risk of pelvic floor dysfunction with women, advise them that their risk is higher with any of the characteristics in box 1.\nModifiable risk factors\nA body mass index (BMI) over 25 kg/m2\nSmoking\nLack of exercise\nConstipation\nDiabetes\nNon-modifiable risk factors\nAge (risk increases with increasing age)\nFamily history of urinary incontinence, overactive bladder or faecal incontinence\nGynaecological cancer and any treatments for this\nGynaecological surgery (such as a hysterectomy)\nFibromyalgia\nChronic respiratory disease and cough (chronic cough may increase the risk of faecal incontinence and flatus incontinence)\nRelated to pregnancy:\nBeing over 30 years when having a baby\nHaving given birth before their current pregnancy\nRelated to labour:\nAssisted vaginal birth (forceps or vacuum)\nA vaginal birth when the baby is lying face up (occipito-posterior)\nAn active second stage of labour taking more than 1 hour\nInjury to the anal sphincter during birth\nFor pregnant women with pelvic floor dysfunction that started before or during their pregnancy, advise them that there is an increased risk that their symptoms will get worse during their pregnancy and that they may persist after this (for preventative and management strategies, see the section on preventing pelvic floor dysfunction and the section on non-surgical management of pelvic floor dysfunction.\nFor more detailed guidance on all the benefits and risks of vaginal and caesarean birth (including urinary incontinence, faecal incontinence and injury to the anal sphincter), see the section on benefits and risks of caesarean and vaginal birth in the NICE guideline on caesarean birth.\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on risk factors for pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in:\nevidence review B: risk factors for pelvic floor dysfunction\nevidence review C: coexisting long-term conditions and pelvic floor dysfunction\nevidence review D: prediction tools for pelvic floor dysfunction.\nLoading. Please wait.\n\n# Preventing pelvic floor dysfunction\n\n## Physical activity and diet\nAdvise women that physical activity and a healthy diet can help prevent pelvic floor dysfunction.\nOn levels of physical activity, advise women to follow the standard advice, as covered by:\nthe UK Chief Medical Officers' physical activity guidelines\nthe NICE guideline on physical activity: brief advice for adults in primary care\nthe NICE guideline on physical activity: walking and cycling.\nOn diet, advise women to:\nhave a balanced diet (following Public Health England's Eatwell Guide), and in particular to eat enough fibre, because this can improve stool consistency and prevent symptoms of faecal incontinence\nensure they have an appropriate fluid intake, increasing or decreasing it if needed.\nFor guidance on training to help health and social care practitioners recognise and respond to diet, physical activity and hydration needs in older people with social care needs and multiple long-term conditions, see the section on training health and social care practitioners in the NICE guideline on older people with social care needs and multiple long-term conditions.\n\n## Weight loss, stopping smoking, managing constipation and diabetes\nFor guidance on weight loss, see the NICE guideline on obesity, and (if relevant) the NICE guideline on weight management before, during and after pregnancy.\nGive advice on stopping smoking, using the NICE guideline on tobacco.\nFor guidance on managing constipation in young people, see the NICE guideline on constipation in children and young people.\nFor guidance on managing diabetes, see the NICE guidelines on:\ntype 1 diabetes in adults\ntype 2 diabetes in adults\ndiabetes (type 1 and type 2) in children and young people.\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on physical activity and diet and other modifiable risk factors .\nFull details of the evidence and the committee's discussion are in:\nevidence review B: risk factors for pelvic floor dysfunction\nevidence review E: lifestyle factors for the prevention of pelvic floor dysfunction.\nLoading. Please wait.\n\n## Pelvic floor muscle training\nEncourage women of all ages to do pelvic floor muscle training, and explain that it helps to prevent symptoms of pelvic floor dysfunction.\nEncourage women to continue pelvic floor muscle training throughout their life, because long-term training continues to help prevent symptoms.\nEncourage women who are pregnant or who have recently given birth to do pelvic floor muscle training, and explain that it helps prevent symptoms of pelvic floor dysfunction.\nConsider a 3‑month programme of supervised pelvic floor muscle training:\nfrom week 20 of pregnancy, for pregnant women who have a first-degree relative with pelvic floor dysfunction\nduring postnatal care, for women who have experienced any of the following risk factors during birth:\nassisted vaginal birth (forceps or vacuum)\na vaginal birth when the baby is lying face up (occipito-posterior)\ninjury to the anal sphincter.\nBefore discharging women from maternity services, and during routine postnatal care, encourage them to do pelvic floor muscle training.\nWhen designing a pelvic floor muscle training programme, see the NICE guideline on behaviour change for relevant recommendations:\nrecommendation 7: use proven behaviour change techniques when designing interventions\nrecommendation 8: ensure interventions meet individual needs.\nPelvic floor muscle training programmes should be supervised by a physiotherapist or other healthcare professional with the appropriate expertise in pelvic floor muscle training.\nSupervision should involve:\nassessing the woman's ability to perform a pelvic floor contraction and relaxation\ntailoring the pelvic floor muscle training programme to the woman's ability to perform a pelvic floor contraction and relaxation, any discomfort felt, and her individual needs and training goals\nencouraging the woman to complete the course, because this will help to prevent and manage symptoms.\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pelvic floor muscle training for preventing pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.\nLoading. Please wait.\n\n# Communicating with and providing information to women with pelvic floor dysfunction\n\n## Communication\nAgree consultation formats (for example, in person, video or telephone) with each woman with pelvic floor dysfunction, taking into account the need for physical examinations.\nWhen discussing pelvic floor dysfunction:\nbe aware of potential cultural sensitivities\nbe aware that women may feel embarrassed discussing their symptoms, and they may believe that healthcare professionals will also be embarrassed\ntake particular care around terminology:\nfor example, avoid using 'faeces' if a woman better understands or prefers 'poo'\nbe aware that women may not use the precise technical terms for parts of their pelvic anatomy\ntailor information to each woman's level of understanding of anatomy and of the causes of pelvic floor dysfunction.\nFor general guidance on communicating with patients, see the:\nsection on communication in the NICE guideline on patient experience in adult NHS services\nsection on communication and information in the NICE guideline on babies, children and young people's experience of healthcare.\nWhen providing information to women with pelvic floor dysfunction and cognitive impairment, ask them if they want their family, carers and other people to be involved, to support them (as appropriate) and to help reinforce and support management plans.\n\n## Information for women with pelvic floor dysfunction\nHelp women with pelvic floor dysfunction to understand their condition by giving clear and concise information. This should include:\nthe anatomy of the pelvic floor and pelvic organs (using visual aids when helpful)\npossible causes of their symptoms\nmanagement options and possible outcomes\nan explanation that interventions will be focused on their symptoms, rather than on pelvic floor dysfunction in general\n-ther medical conditions and treatments that can cause or exacerbate their symptoms (see risk factors for pelvic floor dysfunction).\nTailor information to each woman's age, level of understanding and circumstances, because pelvic floor dysfunction can affect women differently at different stages of life. For example:\nyoung women (between 12 and 17)\nwomen who are pregnant or who have given birth\nwomen in perimenopause or postmenopause\nwomen with comorbidities or frailty.\nConsider digital information sources (for example, apps or videos) to support women with pelvic floor dysfunction (see guidance on developing digital tools in the NICE guideline on behaviour change: digital and mobile health interventions).\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on communicating with and providing information to women with pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in:\nevidence review G: information provision related to the management of pelvic floor dysfunction (people's views and experiences)\nevidence review H: information provision about management of pelvic floor dysfunction (most effective ways).\nLoading. Please wait.\n\n# Assessment in primary care\nAt initial assessment in primary care (which may include assessments by physiotherapists, bladder and bowel team members and continence advisors), take a general history from the woman about current and past symptoms or disorders associated with pelvic floor dysfunction, such as:\nurinary incontinence\nemptying disorders of the bladder\nfaecal incontinence\nemptying disorders of the bowel\npelvic organ prolapse\nsexual dysfunction\nchronic pelvic pain.\nDepending on the symptoms described, carry out a focused history, clinical examination and investigations to exclude other causes, such as:\npelvic masses\nneurological disease\nurinary tract infection\nadverse effects of medication\ndiabetes\ncancer (for further information, see the NICE guideline on suspected cancer: recognition and referral)\nfistula\ninflammatory bowel or bladder conditions\nendometriosis\nmobility and cognitive impairment.\nAsk women who have recently given birth about symptoms of pelvic floor dysfunction during routine postnatal care, in hospital and in the community.\nFor women who are taking multiple medications, conduct a medication review. For guidance on how to do this, see the section on medication review in the NICE guideline on medicines optimisation.\nDepending on the symptoms and the woman's preferences and circumstances, consider other clinical examinations. For example:\ninspecting the woman's vulva and vagina for atrophy\nasking them to bear down, to check for visible vaginal or rectal prolapse\nrectal examination to check for impaction, for women who are at risk of this and who cannot give an accurate history of their symptoms (for example, women with cognitive impairments or dementia).\nFor more guidance on assessing urinary incontinence and pelvic organ prolapse, see the NICE guideline on urinary incontinence and pelvic organ prolapse in women. (The recommendations in this guideline may also be relevant for women under 18.)\nIf the woman has symptoms of faecal incontinence, follow the recommendations on baseline assessment in the NICE guideline on faecal incontinence. (The recommendations in this guideline may also be relevant for women under 18.)\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment in primary care .\nFull details of the evidence and the committee's discussion are in:\nevidence review I: assessment in non-specialist care\nevidence review G: information provision related to the management of pelvic floor dysfunction (people's views and experiences).\nLoading. Please wait.\n\n# Non-surgical management of pelvic floor dysfunction\n\n## Community-based multidisciplinary teams\nAfter initial assessment in primary care, consider a community-based multidisciplinary team approach for the management of pelvic floor dysfunction.\nThe community-based multidisciplinary team (or teams) should have members with competencies related to assessing and managing pelvic floor dysfunction, such as:\ncarrying out initial assessments (see the section on assessment in primary care)\nassessments of mobility and personal care issues related to pelvic floor dysfunction\nawareness of the psychosocial implications of pelvic floor dysfunction\nidentifying risk factors\ninterpreting urinalysis\nconducting and interpreting bladder scans to measure post-void residual volume\nconducting digital assessments of the pelvic floor and pelvic floor muscle contraction and relaxation\ntraining women and their families and carers in behavioural interventions for pelvic floor dysfunction (such as bladder retraining)\nprescribing and reviewing medications, and knowledge of interactions and side effects related to pelvic floor dysfunction\nsupervising a pelvic floor muscle training programme (see the section on supervising pelvic floor muscle training)\nmanaging the use of pessaries and intravaginal devices\ntraining and supporting other care providers to assess and manage pelvic floor dysfunction (for example, carers or care home workers)\nidentifying which women need referral to specialist care or other services (for young women aged 12 to 17, this may include referral to paediatric services or adolescent gynaecology services).\nDiscuss and agree a management plan with women who have suspected or confirmed pelvic floor dysfunction.\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on community-based multidisciplinary teams .\nFull details of the evidence and the committee's discussion are in evidence review R: community-based multidisciplinary teams.\nLoading. Please wait.\n\n## Lifestyle changes\nWhen discussing lifestyle changes with women who have pelvic floor dysfunction:\nmotivate them to make changes by focusing discussions on how this will improve their symptoms\ngive them regular encouragement to keep up the changes, because it may take weeks or months before they notice a benefit.\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on encouraging women to make lifestyle changes .\nFull details of the evidence and the committee's discussion are in evidence review G: information provision related to the management of pelvic floor dysfunction (people's views and experiences).\nLoading. Please wait.\nAdvise women with a body mass index (BMI) over 30 kg/m2 that weight loss can help with the following symptoms associated with pelvic floor dysfunction:\nurinary incontinence\n-veractive bladder\npelvic organ prolapse.\nFor guidance on weight loss, see the NICE guideline on obesity, and (if relevant) the NICE guideline on weight management before, during and after pregnancy.\nRefer women for weight loss support following the NICE guideline on lifestyle services for weight management in overweight or obese adults and the NICE guideline on lifestyle services for weight management in overweight or obese children and young people.\nDo not wait for women to lose weight before starting other pelvic floor dysfunction management options.\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on weight loss .\nFull details of the evidence and the committee's discussion are in evidence review J: weight loss interventions.\nLoading. Please wait.\nFor all women with pelvic floor dysfunction:\nexplain how a balanced diet (following Public Health England's Eatwell Guide) and appropriate fluid intake can improve stool consistency, which can help with their symptoms\nfollow guidance on maintaining healthy bowel habits in recommendation 1.3.2 of the NICE guideline on faecal incontinence in adults (including for women under 18 or with symptoms other than faecal incontinence).\nAdvise women with overactive bladder or urinary incontinence associated with pelvic floor dysfunction to:\nreduce their caffeine intake\nmodify their fluid intake (increasing if it is too low, decreasing if it is too high).\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diet .\nFull details of the evidence and the committee's discussion are in evidence review K: dietary factors for the management of symptoms.\nLoading. Please wait.\nFor women who are doing supervised pelvic floor muscle training and want to be physically active, advise them that supervised exercise (for example, yoga) may help with their symptoms.\nAdvise women with pelvic floor dysfunction that there is no evidence to say that unsupervised physical activity (such as walking or swimming) will improve or worsen their symptoms.\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on physical activity .\nFull details of the evidence and the committee's discussion are in evidence review L: physical activity for the management of symptoms.\nLoading. Please wait.\n\n## Pelvic floor muscle training\nConsider a programme of supervised pelvic floor muscle training for at least 4 months for women with symptomatic pelvic organ prolapse that does not extend greater than 1 cm beyond the hymen upon straining.\nOffer a programme of supervised pelvic floor muscle training for at least 3 months to women (including pregnant women) with stress urinary incontinence or mixed urinary incontinence.\nConsider a programme of supervised pelvic floor muscle training for at least 4 months for women with faecal incontinence and coexisting pelvic organ prolapse.\nFor women who are doing a supervised pelvic floor muscle training programme, offer the choice of group or individual sessions.\nSee the recommendations on supervising pelvic floor muscle training in the section on preventing pelvic floor dysfunction.\nWhen providing a programme of pelvic floor muscle training, offer at least 1 review to assess progress during the programme, and 1 review at the end of the programme.\nFor women who are unable to perform an effective pelvic floor muscle contraction, consider supplementing pelvic floor muscle training with biofeedback techniques, electrical stimulation or vaginal cones.\nIf the programme is beneficial, advise women to continue pelvic floor muscle training after the supervised programme ends.\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pelvic floor muscle training for managing pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review M: pelvic floor muscle training for the management of symptoms.\nLoading. Please wait.\n\n## Intravaginal devices and pessaries\nConsider a trial of intravaginal devices for women with urinary incontinence, only if other non-surgical options have been unsuccessful.\nConsider pessaries for women who have symptomatic pelvic organ prolapse.\nBefore starting treatment with a pessary for women with symptomatic pelvic organ prolapse:\ndiscuss with the woman how a pessary could help, and explain it may not help with their urinary and bowel symptoms\nexplain that a pessary will only help with their pelvic organ prolapse symptoms while it is in place, and the symptoms will come back when it is removed\nexplain that reducing the prolapse with a pessary may cause new stress urinary incontinence.See recommendation 1.7.8 in the NICE guideline on urinary incontinence and pelvic organ prolapse for further discussions to have with women before starting treatment with a pessary.\nIf women using a pessary experience new stress urinary incontinence, offer them a choice of treatment for the incontinence or removal of the pessary.\nFor more guidance on pessaries for women with symptomatic pelvic organ prolapse, see the section on pessaries in the NICE guideline on urinary incontinence and pelvic organ prolapse.\nFor women who are self-managing their intravaginal device or pessary, explain how they can seek advice from a healthcare provider if they have problems.\nFor guidance on reviewing pessaries for women who are at risk of complications, for example because of a physical or cognitive impairment, see recommendation 1.7.9 in the NICE guideline on urinary incontinence and pelvic organ prolapse.\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on intravaginal devices and pessaries .\nFull details of the evidence and the committee's discussion are in evidence review N: physical devices for the management of pelvic floor dysfunction.\nLoading. Please wait.\n\n## Psychological interventions\nDiscuss the psychological impact of their symptoms with women who have pelvic floor dysfunction. Take account of this impact when developing a management plan.\nFor more guidance on psychological management, see the:\nNICE guideline on antenatal and postnatal mental health\nNICE guideline on depression in adults with a chronic physical health problem.\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychological interventions .\nFull details of the evidence and the committee's discussion are in evidence review O: psychological therapy for women with pelvic floor dysfunction.\nLoading. Please wait.\n\n## Behavioural approaches\nOffer supported bladder retraining (combined with other interventions, such as pelvic floor muscle training) to women with urinary frequency, urgency or mixed incontinence.\nFor women with faecal incontinence, see the section on diet, bowel habit and toilet access in the NICE guideline on faecal incontinence in adults. (The recommendations in this guideline may also be relevant for women under 18.)\nWhen choosing a behavioural intervention, take into account that prompted toileting and habit training may be particularly suitable for women with cognitive impairment.\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on behavioural approaches .\nFull details of the evidence and the committee's discussion are in evidence review P: behavioural approaches to the management of symptoms.\nLoading. Please wait.\n\n## Medicines\nDo not offer vaginal diazepam to treat pelvic floor dysfunction, even for women with high muscle tone.\nFor guidance on medicines for urinary incontinence and faecal incontinence associated with pelvic floor dysfunction, see the NICE guideline on urinary incontinence and pelvic organ prolapse in women and the section on medication in the NICE guideline on faecal incontinence in adults. (The recommendations on medicines in these guidelines may also be relevant for women under 18.)\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on medicines .\nFull details of the evidence and the committee's discussion are in evidence review Q: pharmacological management.\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Pelvic floor muscle training\nExercise to improve pelvic floor muscle strength, endurance, power, relaxation, or a combination of these. For more information, see the definition of pelvic floor muscle training in the International Continence Society and International Urogynecological Association's joint report on the terminology for the conservative and non-pharmacological management of female pelvic floor dysfunction.# Recommendations for research\nThe guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## How to provide pelvic floor muscle training\nWhat is the most effective way to provide pelvic floor muscle training (covering the type of training, the timing, and who should supervise it), to improve adherence and prevent pelvic floor dysfunction?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.\nLoading. Please wait.\n\n## Pelvic floor muscle training for preventing pelvic floor dysfunction in young women\nIs pelvic floor muscle training for young women (between 12 and 17 years) effective in preventing pelvic floor dysfunction?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.\nLoading. Please wait.\n\n## Pelvic floor muscle training for preventing pelvic floor dysfunction during pregnancy for women in higher-risk groups\nHow effective is pelvic floor muscle training in preventing pelvic floor dysfunction during pregnancy in women who are in higher-risk groups?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.\nLoading. Please wait.\n\n## Lifestyle factors to reduce the risk of pelvic floor dysfunction\nWhat lifestyle factors reduce the risk of developing pelvic floor dysfunction (diet, reducing carbonated drink and caffeine intake)?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on physical activity and diet and other modifiable risk factors .\nFull details of the evidence and the committee's discussion are in evidence review E: lifestyle factors for the prevention of pelvic floor dysfunction.\nLoading. Please wait.\n\n## Prediction tools\nWhat is the effectiveness of prediction tools for identifying women who are at risk of pelvic floor dysfunction?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on risk factors for pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review D: prediction tools for pelvic floor dysfunction.\nLoading. Please wait.\n\n## Pelvic floor muscle training for preventing pelvic floor dysfunction in older women\nIs pelvic floor muscle training effective in preventing pelvic floor dysfunction for older women (aged 65 and over), and women in the perimenopausal or postmenopausal phases?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.\nLoading. Please wait.\n\n## Coexisting long-term conditions\nWhat coexisting long-term conditions (for example, chronic respiratory disorders) are associated with a higher risk of pelvic floor dysfunction?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on risk factors for pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review C: coexisting long-term conditions and pelvic floor dysfunction.\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Lifestyle factors to reduce the risk of pelvic floor dysfunction\nWhat are the long-term effects of different types, intensities and frequencies of physical activity for preventing symptoms associated with pelvic floor dysfunction?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on physical activity and diet and other modifiable risk factors .\nFull details of the evidence and the committee's discussion are in evidence review E: lifestyle factors for the prevention of pelvic floor dysfunction.\nLoading. Please wait.\n\n## Universal postnatal pelvic floor muscle training for preventing pelvic floor dysfunction\nIs universal postnatal pelvic floor muscle training effective in preventing pelvic floor dysfunction?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.\nLoading. Please wait.\n\n## Pelvic floor muscle training for preventing bowel symptoms associated with pelvic floor dysfunction\nHow effective is pelvic floor muscle training in preventing bowel symptoms associated with pelvic floor dysfunction?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.\nLoading. Please wait.\n\n## Weight loss for managing pelvic floor dysfunction\nCan weight loss reduce symptoms of pelvic floor dysfunction in women who are overweight or obese?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on weight loss .\nFull details of the evidence and the committee's discussion are in evidence review J: weight loss interventions.\nLoading. Please wait.\n\n## Diet for managing pelvic floor dysfunction\nWhat changes in diet can improve symptoms associated with pelvic floor dysfunction?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on diet .\nFull details of the evidence and the committee's discussion are in evidence review K: dietary factors for the management of symptoms.\nLoading. Please wait.\n\n## Weight training to improve symptoms of pelvic floor dysfunction\nHow effective is weight training at improving symptoms associated with pelvic floor dysfunction?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on physical activity .\nFull details of the evidence and the committee's discussion are in evidence review L: physical activity for the management of symptoms.\nLoading. Please wait.\n\n## Unsupervised physical activity to improve symptoms of pelvic floor dysfunction\nHow effective is unsupervised physical activity (such as walking or swimming) at improving symptoms associated with pelvic floor dysfunction?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on physical activity .\nFull details of the evidence and the committee's discussion are in evidence review L: physical activity for the management of symptoms.\nLoading. Please wait.\n\n## Psychological interventions to manage symptoms of pelvic floor dysfunction\nHow effective are psychological interventions (either on their own or combined with other interventions) in the management of pelvic floor dysfunction?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on psychological interventions .\nFull details of the evidence and the committee's discussion are in evidence review O: psychological therapy for women with pelvic floor dysfunction.\nLoading. Please wait.\n\n## Raising awareness about pelvic floor dysfunction\nAre community-based strategies effective in raising awareness about the prevention of pelvic floor dysfunction?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on raising awareness of pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review A: community information strategies.\nLoading. Please wait.\n\n## Information valued by young women with pelvic floor dysfunction\nWhat are the experiences and information needs of young women (between 12 and 17 years) with pelvic floor dysfunction?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on communicating with and providing information to women with pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review G: information provision related to the management of pelvic floor dysfunction (people's views and experiences).\nLoading. Please wait.\n\n## Effective ways of supporting women to start and continue interventions for pelvic floor dysfunction\nWhat is the best way to support women to start and continue interventions for pelvic floor dysfunction (for example, apps, decision aids, or behavioural change techniques)?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on communicating with and providing information to women with pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review H: information provision about management of pelvic floor dysfunction (most effective ways).\nLoading. Please wait.\n\n## Effective ways of providing information to women with pelvic floor dysfunction\nWhat are best ways to provide information about pelvic floor dysfunction to young women (between 12 and 17 years), and to groups defined by protected characteristics under the Equality Act?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on communicating with and providing information to women with pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review H: information provision about management of pelvic floor dysfunction (most effective ways).\nLoading. Please wait.\n\n## Medicines for pelvic floor dysfunction\nIs vaginal oestrogen effective at treating the symptoms of pelvic floor dysfunction?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on medicines .\nFull details of the evidence and the committee's discussion are in evidence review Q: pharmacological management.\nLoading. Please wait.\n\n## Community-based multidisciplinary pelvic floor dysfunction teams\nWhat roles are needed in a community-based multidisciplinary pelvic floor dysfunction team?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on community-based multidisciplinary teams .\nFull details of the evidence and the committee's discussion are in evidence review R: community-based multidisciplinary teams.\nLoading. Please wait.\n\n## Intravaginal devices and pessaries combined with pelvic floor muscle training for managing pelvic floor dysfunction\nHow effective is a pessary or intravaginal device combined with pelvic floor muscle training for managing pelvic floor dysfunction, compared with pelvic floor muscle training alone?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for managing pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review M: pelvic floor muscle training for the management of symptoms.\nLoading. Please wait.\n\n## Virtual and in-person contact time for pelvic floor muscle training\nHow effective is virtual contact with a trainer, compared with in-person contact, for pelvic floor muscle training?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for managing pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review M: pelvic floor muscle training for the management of symptoms.\nLoading. Please wait.\n\n## Anal plug devices and rectal irrigation for the management of bowel symptoms in women with pelvic floor dysfunction\nHow effective are anal plug devices and rectal irrigation for bowel symptoms in women with pelvic floor dysfunction?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on intravaginal devices and pessaries .\nFull details of the evidence and the committee's discussion are in evidence review N: physical devices for the management of pelvic floor dysfunction.\nLoading. Please wait.\n\n## Multiple pregnancy as an independent risk factor for pelvic floor dysfunction\nIs multiple pregnancy an independent risk factor for pelvic floor dysfunction?\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on risk factors for pelvic floor dysfunction .\nFull details of the evidence and the committee's discussion are in evidence review B: risk factors for pelvic floor dysfunction.\nLoading. Please wait.# Rationale and impact\nThese sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Raising awareness of pelvic floor dysfunction for all women\nRecommendations 1.1.1 to 1.1.11\n\n## Why the committee made the recommendations\nThe evidence was limited to 1 study, so most of the recommendations were based on the committee's knowledge and experience. However, this study did show that teaching pelvic floor health in school improved young women's understanding of their pelvic floor anatomy.\nImproving women's knowledge of pelvic floor health is important because this increases the chance they will take action to prevent pelvic floor dysfunction (for example, through lifestyle changes and pelvic floor muscle training). The range of communication formats and strategies recommended is broad, because pelvic floor dysfunction can happen to any woman, so different strategies will be more effective for different groups of women. The committee discussed what the content of this information should be and decided that this would need to be tailored to the individual and the situation in which it is provided (for example, they noted that information provided during school lessons would likely have a different focus to information provided at a local community group). However, to ensure information is accurate and useful, it should include the topics highlighted in recommendation 1.1.1. The committee acknowledged that there can be groups of women that experience inequalities (for example, in access to services). When there is evidence of this, the committee noted that local authorities should consider designing information programmes that increase awareness of the condition with the aim of advancing equality in healthcare provision and fostering good relations with communities.\nHealthcare professionals themselves need to understand enough about pelvic floor dysfunction to discuss it with women. In the committee's experience, this is not consistently taught during training, so they made a recommendation that this should be added to the syllabus for relevant professionals.\nThe committee believed it was particularly important to raise awareness in maternity services; this is when symptoms can first occur, when risk factors can be identified and when prevention strategies can be started. The recommendations could lead to midwives providing information about pelvic floor dysfunction many times during a woman's pregnancy. However, the committee believe this is reasonable, because it gives the midwife an opportunity to normalise the topic and time to discuss it in detail. Normalisation is important, because embarrassment often gets in the way of discussions about pelvic floor dysfunction. The committee also noted that frequent discussions would reinforce the message and improve adherence to prevention or management, which is key to their effectiveness.\nBecause of the sparsity of evidence, and the potential benefits of raising awareness of pelvic floor dysfunction, the committee made a recommendation for research on raising awareness about pelvic floor dysfunction.\n\n## How the recommendations might affect practice and services\nPelvic floor dysfunction is not currently covered in the school curriculum. However, sex and relationship education is already a compulsory part of the curriculum, and pelvic floor dysfunction could be covered as part of these classes.\nSchool nurses and nurses in other education settings could also be involved in raising awareness of pelvic floor dysfunction. There are already resources available on this topic (for example, this video on pelvic floor by NHS Highland).\nReturn to recommendations\n\n# Risk factors for pelvic floor dysfunction\nRecommendations 1.2.1 to 1.2.3\n\n## Why the committee made the recommendations\nInterpreting the evidence was difficult, because there was a lot of variation in how the studies were done, the way risk factors were defined, and which symptom each risk factor affected. However, the evidence did consistently reflect the committee's experience.\nThe evidence suggested a number of modifiable and non-modifiable risk factors. The committee recommended advising women of these, so that they are aware of their risks, and (for modifiable factors) they can take steps to reduce them. For example, the evidence showed that constipation is a risk factor for pelvic floor dysfunction (the committee believe that this is because of the straining involved). For women with constipation, there are recommendations on diet to help with constipation and reduce their risk of pelvic floor dysfunction (see recommendation 1.3.3 and recommendation 1.6.9).\nAlthough some risk factors are non-modifiable (such as age or familial history), the committee agreed that it is still useful for women to be told about these. This is because if women know about their risks, they may be encouraged to reduce any modifiable risk factors and use preventative interventions (such as pelvic floor muscle training). Women with some of these risk factors will also be offered supervised pelvic floor muscle training (see the recommendations on pelvic floor muscle training).\nFor the risk factors related to vaginal birth, the committee discussed whether more information was needed in the recommendations, because these risk factors affect the decision to have a vaginal or caesarean birth. However, women consider many other factors beyond pelvic floor dysfunction when deciding on mode of birth. The committee decided not to make further recommendations on this, because the NICE guideline on caesarean section goes into much more detail on the benefits and risks of caesarean and vaginal birth.\nDue to the evidence being unclear, the committee made a recommendation for research on whether multiple pregnancy is an independent risk factor for pelvic floor dysfunction.\nThere was evidence for a variety of physical coexisting conditions associated with pelvic floor dysfunction. There was variation in the quality of the evidence because in some studies, the inclusion criteria were not clearly described. In addition, although some conditions were shown to increase the risk of pelvic floor dysfunction, there was uncertainty around how large this increase is. Because of this, the committee did not list every condition identified in the studies. Instead, they highlighted the conditions that have a direct impact on the pelvic floor muscles, when the risk of pelvic floor dysfunction in the evidence aligns with their own experience.\nFor some conditions that may increase the risk of pelvic floor dysfunction (such as hypermobility, neurological disease and mental health problems), there was little evidence on their effect. In addition, there was only limited evidence on the effect of respiratory disease and chronic cough on the full range of symptoms, and this is particularly important because of the COVID‑19 pandemic. A recommendation for research on coexisting long-term conditions was made to address these evidence gaps.\nThere are groups of women who have an increased risk of developing pelvic floor dysfunction. There are also interventions that can help prevent pelvic floor dysfunction (see the section on physical activity and diet and the section on pelvic floor muscle training). Because of this, it would be useful to have an effective tool for predicting pelvic floor dysfunction so that women at higher risk can be prioritised for pelvic floor muscle training programmes. However, there was no evidence on the effectiveness of existing tools. The committee agreed this was an important area for further study, and made a recommendation for research on prediction tools.\n\n## How the recommendations might affect practice\nThe recommendations will standardise the information and advice that is provided to women, to enable better shared decision making. There are no significant costs associated with this, because providing information is already standard practice. The costs of the time taken to give this information would be outweighed by better satisfaction with services and the potential for avoiding future pelvic floor dysfunction.\nReturn to recommendations\n\n# Physical activity and diet and other modifiable risk factors\nRecommendations 1.3.1 to 1.3.8\n\n## Why the committee made the recommendations\nThe evidence suggested that physical activity, healthy diet and appropriate fluid intake help to prevent pelvic floor dysfunction. The quality of the evidence was low because some studies did not account for other factors that could potentially explain the findings. However, it reflected the committee's experience in clinical practice and was in line with standard UK diet and physical activity guidance.\nOne of the risk factors for pelvic floor dysfunction is constipation, and in the committee's experience, 1 way this can be addressed is by adjusting fluid intake. Public health guidance does not clearly define ideal levels of fluid intake, and there are differences in the fluid needs of individuals (for example, people need more fluid if they are very physically active). The committee therefore decided not to give their own definition of appropriate fluid intake.\nThe committee recognised that there were other modifiable risk factors: body mass index (BMI) over 25 kg/m2, smoking and diabetes, and they referenced relevant NICE guidance for management strategies for these, which would help prevent pelvic floor dysfunction.\nThere was only limited evidence on specific dietary factors, such as caffeine and carbonated drinks. To address this, the committee made a recommendation for research on lifestyle factors to reduce the risk of pelvic floor dysfunction.\nNo evidence was found on the impact of other lifestyle factors that can prevent symptoms associated with pelvic floor dysfunction (such as pelvic organ prolapse, emptying disorders of the bladder or bowel, sexual dysfunction or chronic pelvic pain syndromes). However, in the committee's experience, physical activity that involves repetitive pelvic floor loading (such as weight training) can improve pelvic floor muscle strength and so prevent symptoms. The committee agreed that more research is needed to support this, particularly in relation to the intensity of physical activity needed, so they made a recommendation for research on long-term effects of different types, intensities and frequencies of physical activity for preventing symptoms associated with pelvic floor dysfunction.\n\n## How the recommendations might affect practice\nCurrently, lifestyle advice is given to women to help with the management of symptoms of pelvic floor dysfunction. However, lifestyle advice is rarely considered as part of pelvic floor dysfunction prevention, because these women are symptom free. Therefore, these recommendations will help standardise the advice women receive on preventing pelvic floor dysfunction.\nReturn to recommendations\n\n# Pelvic floor muscle training for preventing pelvic floor dysfunction\nRecommendations 1.3.9 to 1.3.16\n\n## Why the committee made the recommendations\nThe available evidence covered women in 3 settings: community, antenatal and postnatal. It specifically addressed pelvic floor dysfunction and associated symptoms (including urinary incontinence, pelvic organ prolapse and sexual dysfunction).\nIn addition to the research evidence, the committee also took account of the Independent Medicines and Medical Devices Safety Review and the NHS Long Term Plan, which made recommendations on pelvic floor muscle training.\nPelvic floor muscle training was shown to prevent symptoms of pelvic floor dysfunction in all 3 settings. Evidence was not available for some symptoms (such as faecal incontinence and pelvic pain). The training was most effective in the short term. The committee noted that most studies looked at pregnant women (antenatal and postnatal). However, all healthcare professionals can provide encouragement to all women doing pelvic floor muscle training in all settings (there are already resources available on this, such as the video on pelvic floor by NHS Highland). Because there are particular obstetric risk factors associated with pelvic floor dysfunction (see the section on risk factors), pelvic floor muscle training could be particularly beneficial for pregnant women. The evidence supported this, because pelvic floor muscle training was shown to be effective in preventing pelvic floor symptoms when started during or after pregnancy.\nMost of the evidence was for a narrow age range of women in their twenties or thirties. However, there was a consistent pattern of risk reduction across this group. The committee believed that this supported them in making recommendations for women of all ages.\nAn economic analysis showed that antenatal supervised pelvic floor muscle training is likely to be cost effective for some pregnant women:\nthe evidence suggested that women who have a first-degree relative with pelvic floor dysfunction are at higher risk\nthe committee identified 3 risk factors related to labour that they thought would increase risk.\nHowever, there was some uncertainty about the conclusion generated from the economic analysis, which was based on evidence from only 1 study. Because of these limitations, and the costs of providing supervised pelvic floor muscle training to such a large group, the committee did not recommend routinely offering training to all of these women. The committee still recommended the training as an option, because it is likely to be cost effective for some women in these groups.\nThe committee did not include 'an active second stage labour taking more than 1 hour' in the recommendation on supervised pelvic floor muscle training. This is because it is quite common (so would have a high potential cost), and the evidence on this was inconsistent (some studies showed an increased risk when labour was longer than 1 hour, but others did not show increased risk when it was longer than 20 minutes).\nIn all the studies, pelvic floor muscle training was supervised by a trained healthcare professional. The committee agreed that this is important for ensuring that pelvic floor muscle contraction and relaxation is done correctly. In their experience, it is also important to tailor the training for each woman, to ensure that it is manageable and will meet their training goals.\nThere was limited evidence on long-term effectiveness, because only 2 studies had a longer follow-up period (12 months in 1 study, and 8 years in the other). However, all the studies showed that adherence decreased over time. In the committee's experience, continuing with the training is key for continued prevention of symptoms, and they agreed that low long-term adherence is likely to explain the limited evidence for long-term effectiveness. To address adherence problems, the committee made the recommendation on encouraging women to continue pelvic floor muscle training.\nThe committee made recommendations for research to investigate several gaps in the evidence:\nMost effective ways to provide training: the studies did not give much detail on how training should be done.\nYounger women: there was no evidence on training for young women (between 12 and 17).\nOlder women: there was only 1 study supporting training for women over 60.\nWomen who are pregnant and at particular risk of pelvic floor dysfunction: there was little evidence specific to women who are pregnant and have particular risk factors.\nFaecal incontinence and emptying disorders of the bowel: there was no evidence on whether pelvic floor muscle training improves these symptoms (which can be particularly distressing).\nThe Independent Medicines and Medical Devices Safety Review recommended 'that the NHS adopts the French model for universal postnatal pelvic floor rehabilitation', to help prevent pelvic floor dysfunction. This model includes 10 sessions of routinely prescribed perineal rehabilitation sessions (pelvic floor muscle training with manual internal techniques, biofeedback and electrical stimulation) starting at least 8 weeks after birth, regardless of symptoms. The committee did not think the evidence (in particular the cost-effectiveness evidence) was strong enough to support this for all women during or after pregnancy. Instead, they identified the risk factors that put women at the greatest risk, for which pelvic floor training was most likely to be cost effective. They also made a recommendation for research on universal postnatal pelvic floor muscle training to investigate further.\n\n## How the recommendations might affect practice\nCurrently, pelvic floor muscle training is rarely used for prevention, and is usually only considered and taught to women when they develop symptoms (such as urinary incontinence). There would likely be a significant resource impact if training was provided to all women with the risk factors specified in the recommendation (particularly given the size of the population who would be eligible). Some of this cost is likely to be offset by savings from preventing or delaying pelvic floor dysfunction.\nPregnant women receive information on pelvic floor muscle training. However, this is usually general advice rather than specific instructions or supervised sessions. Women are not routinely told about how pelvic floor muscle training can help prevent sexual dysfunction during and after pregnancy. The recommendations ensure that all women are getting information on the benefits of pelvic floor muscle training to prevent pelvic floor dysfunction. This will standardise practice.\nReturn to recommendations\n\n# Communicating with and providing information to women with pelvic floor dysfunction\nRecommendations 1.4.1 to 1.4.7\n\n## Why the committee made the recommendations\nQualitative evidence showed that women with pelvic floor dysfunction perceived some communication styles as unhelpful. It also indicated that some women are not given enough information to understand their symptoms, diagnosis, investigations or treatment. The quality of the evidence was mixed, because of concerns about methodological limitations in the design of the studies. The committee also made recommendations based on their own experience, in areas where there was no evidence (such as video and telephone consultations).\nThe recommendation on asking women if they want their family, carers or other people involved is particularly important for addressing potential barriers to support for women with cognitive impairments.\nPelvic floor dysfunction is a complex condition, with particular communication issues (such as embarrassment). Based on the evidence and on their experience, the committee highlighted key issues to take into account when discussing pelvic floor dysfunction with women.\nBecause of the COVID‑19 pandemic, many services are being provided remotely. In the committee's experience, this has been well received by some women. A particular benefit of remote services can be reduced embarrassment (both for women and for healthcare professionals), which makes women more willing to discuss problems. However, even though this may be the case for some women, the committee acknowledged that it may be harder for the healthcare professional to identify whether symptoms may not be reported because of embarrassment during a remote consultation.\nThe committee made recommendations for research in areas where there was no evidence:\neffective ways of providing information to young women (between 12 and 17 years) and women with protected characteristics (such as physical or learning disabilities)\neffective ways of supporting women to start and continue interventions for pelvic floor dysfunction\ninformation valued by young women with symptoms of pelvic floor dysfunction.\n\n## How the recommendations might affect practice\nHealthcare professionals already discuss pelvic floor dysfunction with women and provide information on this. However, the information given and how it is communicated can vary, and these recommendations will standardise the process. Because the symptoms of pelvic floor dysfunction are often distressing and embarrassing, communication and sensitivity are very important for all healthcare professionals to ensure good care is provided.\nServices already use translation services as needed to overcome communication barriers. However, there may be an impact in areas where video consultation or digital information aids are not currently available.\nReturn to recommendations\n\n# Assessment in primary care\nRecommendations 1.5.1 to 1.5.7\n\n## Why the committee made the recommendations\nThere are a number of signs and symptoms associated with pelvic floor dysfunction. However, there was no evidence on which assessments are needed in non-specialist care to identify these signs and symptoms. Because of this, the committee made recommendations based on their clinical expertise, highlighting the investigations they use in their practice and the most important signs and symptoms to look out for.\nThere was evidence that healthcare professionals may overlook symptoms of pelvic floor dysfunction in women who have recently given birth. The evidence also highlighted that there are common misconceptions about pelvic floor dysfunction during and after pregnancy, which can prevent women from seeking care early. To address this, the committee emphasised that women who have recently given birth should be asked about symptoms.\nIn the committee's experience, many medications can impact on symptoms of pelvic floor dysfunction. In addition, this impact is often larger for people who are taking multiple medicines. Because of this, a medication review is important.\nA focused history is important for identifying the likely cause of any symptoms, because many of the symptoms of pelvic floor dysfunction can be caused by other conditions as well.\nThe committee highlighted some of the examinations that would be needed to clarify whether symptoms are likely to be associated with pelvic floor dysfunction or not. Because some of these are intimate examinations, they highlighted the importance of checking the woman's preferences and ensuring a private space is available.\nFurther assessments are described in the NICE guideline on urinary incontinence and pelvic organ prolapse in women and the section on baseline assessment in the NICE guideline on faecal incontinence. These guidelines only cover adults, but many of the initial assessments recommended are non-specialist and the committee agreed that they could be relevant for younger women (aged 12 to 17) in primary care.\n\n## How the recommendations might affect practice\nPelvic floor dysfunction is a complex condition, and there is currently variation in how it is assessed. These recommendations will ensure consistency in the initial assessments that are done in primary care.\nReturn to recommendations\n\n# Community-based multidisciplinary teams\nRecommendations 1.6.1 to 1.6.3\n\n## Why the committee made the recommendations\nThere was limited evidence on team-based approaches for managing pelvic floor dysfunction. However, the available evidence reflected the committee's experience in practice. They decided that the range of competencies needed could not be covered by 1 healthcare professional alone, and so a multidisciplinary team approach should be considered. Because pelvic floor dysfunction can happen to any woman, multidisciplinary teams will need a wide range of skills to be able to care for all women who need support. The committee agreed that several teams could be needed (for example, a team for pregnant women and another for older women). These teams would need to be community based, to ensure that care is accessible to all women.\nAdherence and satisfaction with care are important factors in effective management of pelvic floor dysfunction, and the committee agreed that these would also be improved by community-based multidisciplinary teams.\nThe experience and training of multidisciplinary team members is likely to vary widely in different areas. Because of this, the committee made a recommendation on competencies, based on their own experience of the key knowledge and experience that is needed in the team to implement the other recommendations in this guideline.\nThe committee did not recommend including specific roles (such as specialist continence advisors) in the team, because community healthcare professionals can be trained to carry out non-specialist assessment, and because including specific specialists in every team could have substantial costs. The committee made a recommendation for research on the roles needed in community-based multidisciplinary pelvic floor dysfunction teams.\nWhen agreeing a management plan, it is important to involve the woman with pelvic floor dysfunction, to ensure the plan takes account of her needs, preferences and goals.\n\n## How the recommendations might affect practice\nCommunity-based multidisciplinary teams may represent a change to current practice, because there is variation in their availability. Pelvic floor dysfunction is a common condition, and other services (such as community-based continence services) could form the basis of these teams. The committee decided that the benefits of good pelvic floor dysfunction management would outweigh potential costs associated with setting up community-based multidisciplinary teams.\nThere is currently variation in the competencies that community-based multidisciplinary teams have on assessing and managing pelvic floor dysfunction. There would be upfront costs for training healthcare professionals in the competencies recommended in this guideline, but these costs would be outweighed by better long-term outcomes (improved identification of symptoms and better management as a result).\nReturn to recommendations\n\n# Lifestyle changes\n\n## Encouraging women to make lifestyle changes\nRecommendation 1.6.4\nThe evidence showed that positive communication improves patient motivation and adherence to lifestyle changes. This was also consistent with the committee's experience. It can take time for women to see a benefit from lifestyle changes, so the committee believed it was important to emphasise encouraging and motivating women in the recommendation.\nAll healthcare professionals communicate with women and this recommendation will raise awareness that this communication should not be framed only in a negative way but provide positive messages when appropriate.\nReturn to recommendation\n\n## Weight loss\nRecommendations 1.6.5 to 1.6.8\nThe evidence showed that in women with a BMI over 30 kg/m2, weight loss helped with urinary incontinence and overactive bladder. In the committee's experience, excess body weight exacerbates these symptoms by putting pressure on the pelvic floor muscles and organs, so weight loss will be particularly beneficial. The evidence did not show any effect from weight loss on symptoms of pelvic organ prolapse. However, the committee still believe that weight loss may be beneficial in the early stages of pelvic organ prolapse, because less weight would press on the pelvic organs and this could improve symptoms.\nThe committee recommended against delaying other management options until women have lost weight because:\nthere was no evidence on the impact of weight loss for many symptoms of pelvic floor dysfunction and\nthere are other interventions that could benefit women with pelvic floor dysfunction.\nBecause other NICE guidelines cover helping people to lose weight, the committee referred to these guidelines rather than making new recommendations on weight loss interventions.\nThe committee made a recommendation for research to address the lack of evidence on whether weight loss can reduce symptoms of pelvic floor dysfunction.\nWeight loss referral related to pelvic floor dysfunction differs across the country. The recommendations would reduce variation and promote consistency in care.\nReturn to recommendations\n\n## Diet\nRecommendations 1.6.9 and 1.6.10\nThere was some evidence suggesting that reducing caffeine intake helps with urinary incontinence and overactive bladder, and this was supported by the committee's experience in practice.\nNo evidence was found on other symptoms associated with pelvic floor dysfunction. However, the committee agreed that in their experience, addressing fluid intake can help with symptoms by promoting an ideal stool consistency. Public health guidance does not clearly define ideal levels of fluid intake, and there are differences in the fluid needs of individuals (for example, people need more fluid if they are very physically active). The committee therefore decided not to give their own definition of appropriate fluid intake.\nA balanced diet also reduces the risk of constipation and so would indirectly reduce the risk of pelvic floor dysfunction. This is particularly important for women with pelvic organ prolapse, faecal incontinence, emptying disorders of the bowel and chronic pelvic pain syndromes.\nThe committee believed that more research specific to pelvic floor dysfunction related to food rather than fluid intake is needed, and therefore made a recommendation for research on diet to address this.\nThese recommendations are in line with current clinical practice. Clinicians will already be familiar with the practical details of lifestyle changes that can be made to promote pelvic floor health, and lifestyle changes are a common aspect of management for symptoms of pelvic floor dysfunction.\nReturn to recommendations\n\n## Physical activity\nRecommendations 1.6.11 and 1.6.12\nThere was some evidence on urinary incontinence, overactive bladder and pelvic organ prolapse. The evidence showed that physical activity could improve these symptoms, but the physical activity programmes in these studies were supervised and included pelvic floor muscle training as part of the interventions.\nThe physical activity interventions covered were yoga, pilates, weight training and aerobic exercises. However, it was not clear from the studies what type of exercises were beneficial, because they were usually combined with some form of pelvic floor muscle training. Because of this, the committee did not recommend specific activities. The committee know from their own experience that women often ask whether physical activity could improve or worsen their symptoms. Because of the evidence that showed some improvement, they made a recommendation in favour of supervised exercise. 'Supervised' exercise is specified because certain exercises, if done incorrectly, can weaken the pelvic floor by increasing intra-abdominal pressure. This could worsen symptoms of pelvic floor dysfunction.\nThere is no evidence that unsupervised physical activity improved or worsened symptoms of pelvic floor dysfunction. The committee acknowledged that there are general health benefits associated with having an active lifestyle. Therefore, they also made a recommendation for research on unsupervised activities (in particular, common activities such as walking and swimming).\nHeavy lifting has been considered a risk factor for damaging the pelvic floor by increasing intra-abdominal pressure. The NICE guideline on urinary incontinence and pelvic organ prolapse in women recommends minimising heavy lifting. However, a more recent study showed that weight training combined with pelvic floor muscle training could improve symptoms of urinary incontinence. Because there was uncertainty around the evidence and it was not entirely consistent with the committee's experience, they made a recommendation for research on weight training to investigate this further.\nThe recommendations cover providing information, which is part of current practice, so there should be no cost to services. These recommendations will ensure women are educated on exercises they can do to improve their symptoms and exercises that are not harmful. In addition, they will help standardise the information being provided.\nReturn to recommendations\n\n# Pelvic floor muscle training for managing pelvic floor dysfunction\nRecommendations 1.6.13 to 1.6.20\n\n## Why the committee made the recommendations\nThe evidence showed that pelvic floor muscle training improves several symptoms of pelvic floor dysfunction (pelvic organ prolapse, stress and mixed urinary incontinence, and faecal incontinence with coexisting pelvic organ prolapse). There was greater uncertainty around the findings on faecal incontinence with coexisting pelvic organ prolapse, because there was much less evidence in this area.\nFor pelvic organ prolapse, the evidence showed a benefit from pelvic floor muscle training for prolapse that does not extend more than 1 cm beyond the hymen. This matched the committee's experience, because they agreed that more extensive pelvic organ prolapse would be managed in specialist care.\nThe recommended lengths of time for the training programmes are based on the most common time points used in the studies for assessing the benefit of training. This was 16 weeks for pelvic organ prolapse and faecal incontinence, and 3 months for urinary incontinence. The committee noted that this would give enough time to assess whether the training improved symptoms. This is also consistent with the recommendations on pelvic floor muscle training in the NICE guideline on urinary incontinence and pelvic organ prolapse in women.\nIn addition to the research evidence, the committee also took account of the Independent Medicines and Medical Devices Safety Review and the NHS Long Term Plan, which made recommendations on pelvic floor muscle training.\nSee the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction, for an explanation of the recommendations on supervising pelvic floor muscle training.\nFor additional therapies, such as weighted vaginal cones, biofeedback and electrical stimulation, the evidence was inconsistent. Some studies showed benefits, and others showed no effect. Some of the evidence suggested that these interventions could help women with pelvic floor muscle training by improving their ability to contract their pelvic floor muscles. In the committee's experience, effective pelvic floor contractions and relaxations are important for improving pelvic floor dysfunction symptoms and most women are able to do this as part of a supervised pelvic floor muscle training programme. However, the committee believed that supplementing a pelvic floor muscle training programme with biofeedback, electrical stimulation or vaginal cones could be cost effective in the subgroup who make little progress during supervised pelvic floor muscle training. These additional therapies are particularly likely to be cost effective if using them allows women to avoid the need for surgical intervention.\nBased on their experience, the committee thought it would be important that women are advised to continue doing pelvic floor muscle training and that they have the opportunity to discuss progress in regular reviews during the initial training programme. The committee believed that reviews with a healthcare professional improve adherence, which is important for the long-term effectiveness of pelvic floor muscle training.\nThere was some evidence suggesting that training in a group improved adherence and symptoms, but it was not consistently found to be more effective than individual training. This was supported by the committee's experience, because some women benefit from peer support whereas others feel more motivated with one-to-one supervision. To take account of this, the committee recommended giving women a choice of group or individual training. One-to-one supervision is more expensive than group training, but the difference in cost is relatively small and so the approach favoured by each woman is likely to be cost effective.\nIt was unclear whether using a pessary or intravaginal device would be effective when combined with pelvic floor muscle training, so the committee made a recommendation for research on intravaginal devices and pessaries. The development of remote clinical practice during the COVID‑19 pandemic also made the committee curious about the effectiveness of virtual pelvic floor muscle training, so they recommended research into the effectiveness of virtual and in-person contact time for pelvic floor muscle training.\n\n## How the recommendations might affect practice\nThe recommendations will standardise practice. Pelvic floor muscle training is a key intervention for managing the symptoms of pelvic floor dysfunction and is already widely used in the NHS. However, access to group pelvic floor muscle training classes differs across the country. Although some healthcare services may need to change practice, group pelvic floor muscle training classes are less expensive, so the committee did not anticipate a significant resource impact.\nReturn to recommendations\n\n# Intravaginal devices and pessaries\nRecommendations 1.6.21 to 1.6.27\n\n## Why the committee made the recommendations\nThe evidence on intravaginal devices was unclear, with variance across outcomes. For example, there was no measurable reduction in urinary leakage, but women reported that their symptoms improved. However, the committee noted that a subjective improvement in symptoms was still important, because it is an indication of the woman's perception of the device's success. The committee were also aware from their experience that these devices can help to prevent urinary leakage in certain circumstances (for example, during exercise). Based on the limitations of the evidence and the potential complications, the committee recommended trialling intravaginal devices if other non-surgical options have been tried and have been unsuccessful, so that women could decide whether they were beneficial before using them long term.\nThis differs from recommendation 1.4.23 in the NICE guideline on urinary incontinence and pelvic organ prolapse, which recommends against the use of intravaginal devices. However, the committee noted that recommendation 1.4.23 had not been updated since 2006. Most of the evidence they reviewed for this guideline has been published since 2006. Even though the findings from the evidence were not entirely certain, they decided that these devices should not be ruled out if other non-surgical options were unsuccessful. This would provide another option that may prevent the need for more invasive treatment.\nThe evidence on pessaries indicated that they help with symptoms of pelvic organ prolapse while they are in position, and this is in keeping with the committee's clinical experience. However, there was a lack of long-term evidence on the effectiveness and potential complications of pessary use. Because of the uncertainty around pessaries, the committee specified particular benefits and harms to discuss with women, based on the evidence that was available and their clinical experience. This will help women to make an informed decision on whether a pessary is right for them.\nIn the committee's experience, women with physical or cognitive impairments may have difficulty in managing an intravaginal device or pessary and are at higher risk of complications. Because of this, these women should have regular appointments to check for complications. The committee also recommended telling women how to self-refer if they are managing the device themselves, so that they know how to get help if they are having problems or if their intravaginal device or pessary does not help.\nThere was a lack of evidence on the physical devices available for managing faecal incontinence (which is a particularly distressing symptom). The existing evidence consists of studies in mixed populations of men and women, so it could not be used to make recommendations for the population of this guideline. To address this, the committee made a recommendation for research on anal plug devices and rectal irrigation for managing bowel symptoms in women with pelvic floor dysfunction.\n\n## How the recommendations might affect practice\nThese recommendations are in line with current practice on pessaries. There is variation in the use of intravaginal devices, but the recommendations would not involve major changes to practice because it would be an option only if other options had not been successful. Even though this may increase the general use of intravaginal devices, they are already used in some areas. They may also prevent more invasive options (such as surgery) which are more costly.\nReturn to recommendations\n\n# Psychological interventions\nRecommendations 1.6.28 and 1.6.29\n\n## Why the committee made the recommendations\nThe evidence showed a psychological impact from the symptoms of pelvic floor dysfunction. However, the committee noted that there was a lot of uncertainty about this evidence and made recommendations based on their experience and expertise. They made a recommendation emphasising this because women with pelvic floor dysfunction often do not seek help with the psychological impact of their symptoms, and healthcare professionals do not always ask them about it.\nSome therapies were shown to improve distress associated with pelvic floor dysfunction, but the studies were very small. There was also evidence that psychological therapy could help with vaginismus, but it was not clear from the studies whether the participants' symptoms were related to pelvic floor dysfunction. The committee decided that they could not recommend therapies based on this evidence.\nBecause other NICE guidelines cover identifying and managing mental health problems for people with a chronic health condition, the committee referenced these guidelines instead of making new recommendations on specific psychological interventions.\nThere was some evidence showing that psychological interventions improved attendance and adherence to pelvic floor muscle training. However, there were several limitations to this evidence:\nit did not show whether the improvement in attendance and adherence was sustained in the long term\nalthough some of the interventions improved the mental health of participants, it was not clear whether the interventions also had an impact on symptoms (which could mean that the improvement in mental health may not be sustained in the long term)\nthe studies were small.\nThese limitations meant that the committee could not make a practice recommendation. However, they do believe that better attendance and adherence to training improves the benefit of pelvic floor muscle training. Because of this, they made a recommendation for research on ways to improve adherence for women who are having this training.\n\n## How the recommendations might affect practice\nThe committee agreed that there is variation in practice in how well psychological factors related to pelvic floor dysfunction are considered when planning treatment. The recommendations would not involve major changes to practice, but would standardise current good practice.\nReturn to recommendations\n\n# Behavioural approaches\nRecommendations 1.6.30 to 1.6.32\n\n## Why the committee made the recommendations\nThere was evidence about behavioural techniques including bladder retraining and lifestyle education, provided under direct supervision by a trained healthcare professional. The studies usually included pelvic floor muscle training as part of the interventions. The symptoms covered in the studies included urinary incontinence, urinary urgency and frequency, and faecal incontinence. Evidence was not available for some symptoms (such as emptying disorders of the bladder and bowel).\nThe evidence was difficult to interpret because there was variation in the quality of the research and a mixture of different interventions and comparators, which made it difficult to combine results. This meant that it was not clear which aspects of interventions were directly improving the symptoms of pelvic floor dysfunction.\nThe evidence showed that behavioural techniques in combination with pelvic floor muscle training improved these symptoms, which was in keeping with the committee's experience in clinical practice. The committee noted that bladder retraining consists of advice about when or how frequently to go to the toilet to encourage a routine that can help prevent incontinence episodes.\nThere was some limited evidence suggesting that a combination of behavioural techniques and pelvic floor muscle training was associated with improved adherence and satisfaction. The committee agreed that motivation and adherence were key to long-term benefit. The committee were conscious that behavioural techniques should be tailored to the individual, because ability may differ based on other coexisting conditions (such as cognitive impairment).\n\n## How the recommendations might affect practice\nBehavioural techniques involve a wide range of techniques that can be used to change behaviour and teach women skills to reduce symptoms of pelvic floor dysfunction. These techniques are already used by most services, so the recommendations will reinforce current practice.\nBladder training can easily be provided in conjunction with a pelvic floor muscle training programme and would not add significant costs.\nReturn to recommendations\n\n# Medicines\nRecommendations 1.6.33 and 1.6.34\n\n## Why the committee made the recommendations\nThere was limited evidence on medicines for general pelvic floor dysfunction. However, the evidence available did show that intravaginal diazepam was not effective at improving symptoms. Although this evidence was based on a small population, the committee were also concerned about the risk of dependency from diazepam use. Because of this risk and the lack of evidence for any benefit, the committee recommended against intravaginal diazepam.\nWomen with high muscle tone are specifically mentioned in this recommendation because this is the only group diazepam would be considered for in current practice (because diazepam relaxes muscles and relieves muscle spasms). Because the evidence showed that diazepam was not effective, the committee wanted to make sure it was not used even in this group.\nThe NICE guidelines on urinary incontinence and pelvic organ prolapse in women, and faecal incontinence in adults, make recommendations on medicines for symptoms that can be associated with pelvic floor dysfunction. The committee recommended following these recommendations for women with pelvic floor dysfunction, because the medicines recommended are likely to be effective even if the underlying cause of symptoms is different in the other guidelines. They also thought that some of the recommendations in this guideline may also be relevant for women under 18.\nTopical intravaginal oestrogen is currently used in clinical practice for managing pelvic floor dysfunction. However, no evidence was identified for this, so the committee made a recommendation for research on vaginal oestrogen.\n\n## How the recommendations might affect practice\nThe recommendation on intravaginal diazepam will not change current practice, because this is not currently used in the NHS. Because the other recommendation cross refers to other NICE guidance, it will reinforce current guidance and will not have any significant resource impact.\nReturn to recommendations# Context\nPelvic floor dysfunction covers a variety of symptoms. In this guideline, the following symptoms are addressed as long as they are associated with pelvic floor dysfunction: urinary incontinence, emptying disorders of the bladder, faecal incontinence, emptying disorders of the bowel, pelvic organ prolapse, sexual dysfunction and chronic pelvic pain syndromes. The 3 most common and definable conditions are urinary incontinence, faecal incontinence and pelvic organ prolapse.\nPrevalence of pelvic floor dysfunction is high. For example, on examination, prolapse is present in up to 50% of women. This can have a significant impact on quality of life, reducing social engagement and ability to be physically active.\nThis guideline makes recommendations on common risk factors and on preventative interventions. Ideally, women who are most at risk of pelvic floor dysfunction would be identified early and offered interventions to prevent symptoms developing. This would reduce the impact on women and the NHS.\nWhen pelvic floor dysfunction is diagnosed, there is variation in the availability of non-surgical management options, such as pelvic floor muscle training. Women have no clear and effective strategies available to prevent worsening of the condition. This guideline provides a more community-based pathway to address these problems and to reduce the number of women who develop complex symptoms that need specialist care (including surgery)."}}},{"rowIdx":81,"cells":{"id":{"kind":"string","value":"72bfb9678d27e5037245b5402c73ce90ee315f1f"},"source":{"kind":"string","value":"cdc"},"text":{"kind":"string","value":"will be glad to provide the latest information on any changes made to the text, plans for new editions, and reprints and translations already available.# Chikungunya Virus\nThere is no specific treatment for CHIKV infection, nor any commercially available vaccine to prevent it. Pending the development of a new vaccine, the only effective means of prevention are to protect individuals against mosquito bites. It should be noted, however, that the only available method for preventing an ongoing transmission of a possible CHIKV epidemic, namely the control of its vectors, has rarely been achieved and never has been sustained. Given these factors, the Pan American Health Organization (PAHO), with the support of the Division of Vector-borne Diseases of the United States Centers for Disease Control and Prevention (DVBD, CDC), created a working group and convened a meeting in Lima, Peru, on July 21−23, 2010, to discuss the threat this virus represents and to examine measures that might be taken to mitigate this vii threat (see Appendix I for additional details on the meeting). These preparedness guidelines are the result of this collaboration. These guidelines are intended to be adapted by each Member Country. They are designed to increase awareness about the threat and to provide the necessary tools to put in place the best possible strategies to prevent the importation of CHIKV into the Region, or to control it if introduced. These guidelines provide guidance on how to detect an outbreak of the disease, conduct pertinent epidemiological investigations, and prevent or mitigate the spread of the disease throughout the Region.\nWe encourage everyone working to apply these guidelines to take into account all the knowledge available and their own country's capability to cope with the introduction of CHIKV. Steps should be taken now to put in place the necessary measures that will decrease the impact that this new arbovirus could have in our Region. The publication of these guidelines was possible thanks to funding from the U.S.\nCenters for Disease Control and Prevention.\n\n# ABBREviATiONS ANd ACRONymS\nAe. Aedes\n\n# BACKGROUND AND RATIONALE\nSince 2004, Chikungunya virus (CHIKV) has been causing large epidemics of chikungunya fever (CHIK), with considerable morbidity and suffering. The epidemics have crossed international borders and seas, and the virus has been introduced into at least 19 countries by travelers returning from affected areas.\nBecause the virus has been introduced into geographic locations where the appropriate vectors are endemic, the disease could establish itself in new areas of\nEurope and the Americas. The possibility that CHIKV could become established in the Americas has heightened awareness of the need to develop guidelines for the prevention and control of CHIK in PAHO's Member Countries. This document is meant to serve as a guideline that individual countries can use as the basis for their CHIKV surveillance, prevention, and control programs.\n\n# TA R G E T O F T H E S E G U I D E L I N E S :\nThese guidelines are intended to be used by health workers, public health officials, and vector control specialists at the national, district, and sub-district levels.\n\n# O B J E C T I V E S :\nGeneral objectives are the prevention, detection, and timely response to outbreaks of CHIK through surveillance, case detection, investigation, and the launching of public health actions.\n\n# EPidEmiOLOgy\n\n# BACkgROUNd\nCHIKV is an RNA virus that belongs to the Alphavirus genus in the family Togaviridae. The name chikungunya derives from a word in Makonde, the language spoken by the Makonde ethnic group living in southeast Tanzania and northern Mozambique. It roughly means \"that which bends,\" describing the stooped appearance of persons suffering with the characteristic painful arthralgia.\nEpidemics of fever, rash, and arthritis resembling CHIK were reported as early as the 1770s. However, the virus was not isolated from human serum and mosquitoes until an epidemic in Tanzania in 1952−1953. 1 Subsequent outbreaks occurred in Africa and Asia, many of them affecting small or rural communities.\nIn Asia, however, CHIKV strains were isolated during large urban outbreaks in Bangkok, Thailand, in the 1960s and in Calcutta and Vellore, India, during the 1960s and 1970s. 2,3\n\n# Recent Outbreaks\nAfter the initial identification of CHIKV, sporadic outbreaks continued to occur, but little activity was reported after the mid-1980s. In 2004, however, an outbreak originating on the coast of Kenya subsequently spread to Comoros, La Réunion, and several other Indian Ocean islands in the following two years.\nFrom the spring of 2004 to the summer of 2006, an estimated 500,000 cases had occurred.\nThe epidemic spread from the Indian Ocean islands to India, where large outbreaks occurred in 2006. Once introduced in India, CHIKV spread to 17 of the country's 28 states, infecting more than 1.39 million people before the end of the year. The outbreak in India continued into 2010, with new cases appearing in areas that had not been affected in the epidemic's early phase.\nViremic travelers also spread outbreaks from India to the Andaman and Nicobar Islands, Sri Lanka, the Maldives, Singapore, Malaysia, Indonesia. Concern over the spread of CHIKV peaked in 2007, when the virus was found to be spreading autochthonously (human-to-mosquito-to-human) in northern Italy after being introduced by a viremic traveler returning from India. 4 The attack rates in communities that have been affected in the recent epidemics ranged from 38%−63%, and in many of these countries cases continue to be reported, albeit at reduced levels. In 2010, the virus continued to cause illness in India, Indonesia, Myanmar, Thailand, and the Maldives; it also has resurged in La Réunion. In 2010, imported cases also were identified in Taiwan, France, and the United States. These cases were infected viremic travelers returning from Indonesia, La Réunion, and India, respectively.\nDuring the recent outbreaks, individuals viremic with CHIKV were found in the Caribbean (Martinique), the United States, and French Guiana. 5 All of them had returned from areas with endemic or epidemic CHIKV transmission; thus, these cases were not due to autochthonous transmission. All of these areas have competent mosquito vectors and naïve hosts, however, and thus could support endemic transmission of CHIKV in the Americas. Given these factors, CHIKV has the capacity to emerge, re-emerge, and quickly spread in novel areas, which makes heightened surveillance and preparedness a priority.\n\n# EPidEmiOLOgy\n\n# Tr a n s m i s s i o n D y n a m i c s\n\n# Vectors\nThere are two main vectors of CHIKV, Aedes aegypti and Ae. albopictus. Both mosquito species are widely distributed throughout the tropics with Ae. albopictus also present at more temperate latitudes. Given the vectors' distribution throughout the Americas, the entire Region is susceptible to the virus' invasion and spread.\n\n# Reservoirs\nHumans serve as the primary CHIKV reservoir during epidemic periods. During inter-epidemic periods, several vertebrates have been implicated as potential reservoirs, including non-human primates, rodents, birds, and some small mammals.\n\n# Incubation Periods\nMosquitoes acquire the virus from a viremic host. Following an average extrinsic incubation of 10 days, the mosquito is then able to transmit the virus to a naïve host, such as a human. In humans bitten by an infected mosquito, disease symptoms typically occur after an average intrinsic incubation period of threeto-seven days (range: 1−12 days) (Figure 1).\n\n# Susceptibility and Immunity\nAll individuals not previously infected with CHIKV (naïve individuals) are at risk of acquiring infection and developing disease. It is believed that once exposed to CHIKV, individuals will develop long lasting immunity that will protect them against reinfection.\n\n# EPidEmiOLOgy\n\n# Mosquito refeeds / acquires virus\nViremia\n\n# Summary of Epidemiology Section\n- CHIKV is an RNA virus that belongs to the Alphavirus genus in the family Togaviridae.\n- The attack rates in communities that have been affected in the recent epidemics ranged from 38%−63%.\n- The two major vectors of CHIKV are Ae. aegypti and Ae. albopictus;\nboth mosquitoes are widely distributed throughout the tropics and Ae. albopictus is present at more temperate latitudes.\n- CHIK is not known to be circulating in the Americas; however, the risk of introduction is high due to travel importation, competent vectors (same vectors as dengue), and population susceptibility.\n\n# CLiNiCAL\n\n# 3A. Clinical Presentation of Acute disease\nFollowing the bite of a mosquito infected with CHIKV, most individuals will present with symptomatic disease after an incubation period of three to seven days (range: 1−12 days). Not all individuals infected with the virus develop symptoms, however. Serosurveys indicate that between 3% and 28% of persons with antibodies to CHIKV have asymptomatic infections. 6−7 Individuals acutely infected with CHIKV, whether clinically apparent or asymptomatic, can contribute to the spread of the disease if the vectors that transmit the virus are present and active in the same location.\nCHIKV can cause acute, subacute, and chronic disease. Acute disease is most often characterized by sudden onset of high fever (typically greater than 102°F\n) and severe joint pain. 8−10 Other signs and symptoms may include headache, diffuse back pain, myalgias, nausea, vomiting, polyarthritis, rash, and conjunctivitis (Table 1). 11 The acute phase of CHIK lasts for 3−10 days.\n\n# CLiNiCAL\n- Fever typically lasts from several days up to a week. The fever can be continuous or intermittent; a drop in temperature is not associated with worsening of symptoms, however. Occasionally, the fever may be associated with relative bradycardia.\n- Joint symptoms are usually symmetric and occur most commonly in hands and feet, but they can affect more proximal joints. Swelling can also be seen and is often associated with tenosynovitis. Patients are often severely incapacitated due to pain, tenderness, swelling, and stiffness. Many patients cannot perform normal tasks or go to work, and many will be confined to bed due to these symptoms.\n- Rash usually occurs two to five days after onset of fever in approximately half of all patients. It is typically maculopapular, involving the trunk and extremities, but can also include palms, soles, and face. The rash can also present as a diffuse erythema that blanches with pressure. In infants, vesiculobullous lesions are often the most common skin manifestation.\nThere are no significant pathognomonic hematologic findings seen with CHIKV infections. Abnormal laboratory findings can include mild thrombocytopenia (>100,000/mm 3 ), leukopenia, and elevated liver function tests. Erythrocyte sedimentation rate and C-reactive protein are usually elevated.\nRarely, severe forms of the disease can occur with atypical manifestations (see Section 3B). Fatalities related to CHIKV infection are thought to be uncommon.\n\n# 3B. Atypical manifestations\nAlthough most CHIKV infections result in fever and arthralgias, atypical manifestations can occur (Table 2). These manifestations can be due to the direct effects of the virus, immunologic response to the virus, or drug toxicity. Some of the atypical manifestations are more in common in certain groups.\nFor instance, meningoencephalitis and vesiculobullous dermatosis are observed more frequently in children and infants, respectively . . 21,22 3C. High-risk groups CHIKV can affect women and men of all ages. Clinical presentation is thought to vary by age, however, with the very young (neonates) and the elderly being at greater risk for more severe disease. In addition to age, comorbidities (underlying diseases) have also been identified as a risk factor for poor disease outcome. 8,23,24,27 Most CHIKV infections that occur during pregnancy will not result in the virus being transmitted to the fetus. 25,28 There have been rare reports of spontaneous abortions following CHIKV infection in the mother, however. 26 The highest transmission risk appears to be when women are infected during the intrapartum period .29 The vertical transmission rate is as high as 49% during this period.\nInfants are typically asymptomatic at birth and then develop fever, pain, rash, and peripheral edema. Those infected during the intrapartum period may also develop neurologic disease (e.g., meningoencephalitis, white matter lesions, brain swelling, and intracranial hemorrhage), hemorrhagic symptoms, and myocardial disease. 30 Laboratory abnormalities included raised liver function tests, reduced platelet and lymphocyte counts, and decreased prothrombin levels. Neonates who suffer from neurologic disease often develop long-term disabilities. 31 There is no evidence that the virus is transmitted through breast milk. 25 Older adults are more likely to suffer from severe atypical disease and death.\nIndividuals >65 years had a 50-fold higher mortality rate when compared to younger adults (<45 years old). 23 Although it is unclear why older adults are at increased risk for more severe disease, it may be due to the frequency of concomitant underlying diseases or decreased immunlogic response. 23\n\n# 3d. differential diagnosis\nFever with or without arthralgia is a very common manifestation of several other diseases. CHIK may not have the typical manifestations or it may coexist with other infectious diseases such as dengue fever or malaria. Diseases that can be considered in the differential diagnoses may vary based on pertinent epidemiologic features such as place of residence, travel history, and exposure (Table 3).\n\n# Disease or agent Presentation\nPost-infectious arthritis (including rheumatic fever)\nArthritis of one or more, typically larger joints due to an infectious disease such as Chlamydia, shigella, and gonorrhea.\nRheumatic fever is seen more commonly in children as migratory polyarthritis predominantly affecting large joints. CHIK has to be distinguished from dengue fever, which has the potential for much worse outcomes, including death. The two diseases can occur together in the same patient. Observations from previous outbreaks in Thailand and India have characterized the principal features distinguishing CHIK from dengue fever. In CHIK, shock or severe hemorrhage is very rarely observed; the onset is more acute and the duration of fever is much shorter. In CHIK, maculopapular rash also is more frequent than in dengue fever (Table 4). Although people may complain of diffuse body pain, the pain is much more pronounced and localized to the joints and tendons in CHIK, in comparison of dengue fever.\n(Cont.)\n\n# CLiNiCAL\n\n# 3E. Subacute and Chronic disease\nAfter the first 10 days, most patients will feel an improvement in their general health and joint pain. Following this period, however, a relapse of symptoms can occur, with some patients complaining of various rheumatic symptoms, including distal polyarthritis, exacerbation of pain in previously injured joints and bones, and subacute hypertrophic tenosynovitis in wrists and ankles. This is most common two to three months after their illness onset. Some patients can also develop transient peripheral vascular disorders, such as Raynaud's syndrome.\nIn addition to physical symptoms, the majority of patients will complain of depressive symptoms, general fatigue, and weakness. 13 Chronic disease is defined by symptoms that persist for more than three months.\nThe frequency of persons reporting persistent symptoms varies substantially by study and the time that had elapsed between symptom onset and follow-up.\nStudies from South Africa note that 12%−18% of patients will have persistent symptoms at 18 months and up to 2 to 3 years later. 35,36 From more recent studies in India, the proportion of patients with persistent symptoms at 10 months was 49%. 37 Data from La Réunion have found that as many as 80%−93% of patients will complain of persistent symptoms 3 months after disease onset; this decreases to 57% at 15 months and to 47% at 2 years 38,39 (F. Simone, Dept of Infectious Diseases and Tropical Medicine, Laveran Military Hospital, Marseilles, France, personal communication).\nThe most common persistent symptom is inflammatory arthralgias in the same joints that were affected during the acute stages. Usually, there is no significant change in laboratory tests and x-rays of the affected areas. However, some individuals will go onto develop destructive arthropathy/arthritis resembling rheumatoid or psoriatic arthritis. 40 Other symptoms or complaints of the chronic phase of the disease can include fatigue and depression. 6 Risk factors for nonrecovery are older age (> 45 years), pre-existing joint disorders, and more severe acute disease. 38,41\n\n# Summary of Clinical Section\n- Acute stage is symptomatic in most people and causes acute fever, distal polyarthralgias, and occasional rash.\n- Severe and lethal forms are more frequent among patients older than 65 years and/or with underlying chronic diseases.\n- Maternal-fetal transmission is possible among pregnant women, with the highest risk for severe infection in the neonates during the antepartum period.\n- Most patients initially will have severe and incapacitating joint symptoms; many will go on to develop long-lasting rheumatism, fatigue, and depression resulting in an impaired quality of life for months to years.\n\n# Collection of samples for serology, isolation and molecular diagnosis:\nSample: Serum Time of collection: Acute, within the first eight days of illness; convalescent, 10−14 days after acute specimen collection.\nTo collect serum:\n- Aseptically collect 4−5 ml of venous blood in a tube or a vial.\n- Allow blood to clot at room temperature, centrifuge at 2,000 rpm to separate serum. Collect the serum in a clean dry vial.\n- All clinical samples should be accompanied by their clinical and epidemiological information.\n\n# Other types of specimens for laboratory investigation:\nSpecimens:\n- CSF in meningo-encephalitis cases.\n- Synovial fluid in arthritis with effusion.\n- Autopsy material -serum or available tissues.\nTransportation of Samples:\n- Transport specimens to the laboratory at 2°−8°C (icebox) as soon as possible.\n- Do not freeze whole blood, as hemolysis may interfere with serology test results.\n- If a delay greater than 24 hours is expected before specimens can be submitted to the laboratory, the serum should be separated and stored at refrigerated temperature.\n- Serum samples for virus isolation and molecular diagnosis should be stored frozen (at −20°C for short-term storage or at −70°C for long-term storage).\n\n# 4B. Laboratory Surveillance\nPrior to identification of CHIKV in a country, laboratory surveillance should be conducted on three sets of samples, as follows: 1) dengue-negative specimens where the patient exhibits severe joint pain; 2) samples with clinically compatible illness from new geographic areas without active dengue circulation; 3) clusters of febrile illness with severe joint pain. The following table (Table 5) outlines the ideal tests to be performed in various epidemiological settings.\n\n# During the initial introduction of CHIKV into a new region, comprehensive\ntesting should be completed to confirm that CHIKV is the etiological agent.\nAfter CHIKV has been identified, limited testing (not testing all specimens or performing fewer assay types) can be considered depending upon the capacity of the lab and the epidemiological situation.\n\n# 4C. interpretation and Reporting of Results\nFigure 2 shows typical viremia and antibody response in humans and Table 6 describes the typical results of testing samples at various time points. The following laboratory test results would confirm a recent CHIKV infection:\n- Isolation of CHIKV, including confirmatory identification (either IFA, RT-PCR, or sequencing).\n- Detection of CHIKV RNA by real time RT-PCR.\n- Identification of a positive IgM result in a patient with acute symptoms of CHIK, followed by the demonstration of CHIKV-specific antibody determined by PRNT with viruses in the SFV serogroup.\n- Demonstration of seroconversion or a four-fold rise in PRNT, HI, or ELISA titers (again using other SFV serogroup viruses) between acute and convalescent specimens.\nAutochthonous cases should be reported to WHO, in collaboration with an epidemiologist, according to International Health Regulations (IHR) (see section 6F).\n\n# 4d. Laboratory Network for diagnosing CHikv\nCurrently DVBD, CDC can provide diagnostic testing for CHIKV infection.\nReagents and consultations can also be provided by CDC and the Public Health Agency of Canada. Depending on the availability of resources and the epidemiologic situation, PAHO and CDC will be working together in the near future to improve CHIKV detection in the Region by providing training and reagents to existing dengue (RELDA) and other arbovirus laboratories in the Americas. Furthermore, proficiency testing is planned to ensure testing quality in the Region. A contingency plan will be developed to ensure that all laboratories capable of performing testing in the Americas have an adequate supply of reagents and protocols.\n\n# Summary of Laboratory Section\n- Both molecular and serologic techniques are available for the laboratory diagnostic evaluation of CHIKV infection.\n- During an outbreak, laboratories will need to develop, with other public health partners, sample triage plans to avoid laboratory overload.\n- Laboratories have a key role in the surveillance for CHIKV introduction and spread; ongoing training of laboratories for CHIK detection is needed throughout the Region.\n- Collaboration is important, in order for network partner (public health) labs to be able to share materials.\n- Reference laboratories in the Region will play a significant role in reagent production and in providing laboratory confirmation of suspected CHIK cases.\n\n# LABORATORy\n\n# CASE mANAgEmENT 5A. Treatment\nThere is no specific antiviral drug treatment for CHIK. Symptomatic treatment is recommended after excluding more serious conditions like malaria, dengue, and bacterial infections.\n\n# A c u t e D i s e a s e\nTreatment is symptomatic or supportive, comprised of rest and the use of acetaminophen or paracetamol to relieve fever, and ibuprofen, naproxen, or another non-steroidal anti-inflammatory agent (NSAID) to relieve the arthritic component of the disease. Using aspirin is not advised because of the risk of bleeding in small number of patients and the risk of developing Reye's syndrome in children younger than 12 years of age. In patients with severe joint pains that are not relieved by NSAID, narcotics (e.g., morphine) or short-term corticosteroids can be used after evaluating the risk-benefit of these treatments.\nPatients should be advised to drink plenty of fluids to replenish fluid lost from sweating, vomiting, and other insensible losses.\n\n# S u b a c u t e a n d C h r o n i c D i s e a s e\nWhile recovery from CHIK is the expected outcome, convalescence can be prolonged (sometimes up to a year or even more) and persistent joint pain may require pain management, including long-term anti-inflammatory therapy.\nAlthough an older study suggested that chloroquine phosphate offered some benefit, 45 a recent double-blind, placebo-controlled randomized trial found it to be of no real value treating joint symptoms. 46 Disabling peripheral arthritis that has a tendency to persist for months, if refractory to other agents, may occasionally respond to short-term corticosteroids. 38 To limit the use of oral corticosteroids, local injections (intra-articular) of corticosteroids or topical NSAID therapy can be used. In patients with refractory joint symptoms, alternative therapies such as methotrexate can be evaluated. In addition to pharmacotherapy, cases that have prolonged arthralgia and joint stiffness may benefit from a program of graduated physiotherapy. Movement and mild exercise tend to improve morning stiffness and pain, but heavy exercise may exacerbate symptoms.\n\n# 5B. Patient isolation Recommendations\nTo prevent the infection of others in the household, the community, or the hospital, a patient with acute CHIK should avoid being bitten by Ae. aegypti or Ae. albopictus mosquitoes during the viremic phase, which is usually the first week of illness. As these mosquitoes bite during daytime, from dawn to dusk or even after dark in the presence of artificial light, staying under an insecticide-treated (IT) bednet or remaining in place with intact screens is highly recommended.\nFurthermore, physicians or health care workers who visit CHIK-infected patients at home should take care to avoid being bitten by mosquitoes by using insect repellent and wearing long sleeves and pants.\n\n# CASE mANAgEmENT\nOne hospital-associated infection of CHIK has been identified in a healthcare provider who had an accidental needle stick from a patient with CHIK. 47 Several laboratory workers also have contracted CHIKV infection after handling infected blood. 48 These exposures indicate that direct contact transmission can occur. However, other modes of transmission, such as through respiratory droplets or particles, have not been documented.\n\n# 5C. Health Care and Hospital Surge Capacity\nAt the peak of one recent outbreak, 47,000 suspected cases were identified in a single week among a population of 766,000. 27 There also can be an accumulation of patients with symptoms who seek more long-term care. With that potential volume of cases per week, huge demands are likely to be placed on the health care system during outbreaks of the disease. A number of steps similar to those for pandemic influenza preparedness should be considered by health care - Develop and implement methods for identifying and investigating potential introduction of CHIKV within existing surveillance systems (e.g., surveillance system for dengue).\n- Inform health care providers and public health officials about the potential threat of CHIKV, and educate them about the clinical presentation, diagnosis, and management of cases at health care facilities.\n- Develop planning and decision-making structures for responding to a potential outbreak at health care facilities.\n- Develop institutional plans to address disease surveillance, hospital communications, education and training, triage and clinical evaluation, facility access, occupational health, surge capacity (beds and access to care), supply chain, and access to critical inventory needs.\nFollowing the introduction of CHIKV into an area, health care facilities should:\n- Activate institutional plans with assistance from the Ministry of Health.\n- Ensure rapid and frequent communication within health care facilities and between health care facilities and health departments.\n- Implement surge-capacity plans that address staffing, bed capacity, consumable and durable supplies, and continuation of essential medical servic-\n\n# es (see section on Health care Planning in the PAHO and HHS Pandemic\nInfluenza Plan for further considerations 49,50 ).\nEffective triage systems at various levels of health care may help to decrease the potential burden of a CHIK outbreak on the health care system. Regardless of the level of medical care available at the triage location, a key measure that needs to be considered at all levels of health care is the institution of appropriate mosquito control measures in the immediate area. If this is not done, patients acutely ill with CHIK can serve as a source of subsequent infections for other patients and for health care workers via mosquito transmission. Furthermore, consideration should be given to establishing areas where patients with suspected CHIK infection are seen and, if necessary, hospitalized (e.g., establish CHIK wards with screens and/or bednets). Finally, consideration should be given to the safety of health care workers. During a previous outbreak, up to one-third of health care workers became infected, further taxing already overburdened and stretched resources. 9 'Guiding principles for managing acute stage of the disease' has been previously described in detail in WHO's \"Guidelines on Clinical Management of Chikungunya Fever\". 51 Key information, including triage considerations, from that document is summarized here.\n\n# Who should seek medical care?\n- Anyone with neurologic signs or symptoms including irritability, drowsiness, severe headaches, or photophobia.\n- Anyone with chest pain, shortness of breath, or persistent vomiting.\n- Anyone with a fever persisting for more than five days (indicative of another illness like dengue).\n- Anyone who develops any of the following, especially once the fever subsides:\n-intractable severe pain, -dizziness, extreme weakness, or irritability, -cold extremities, cyanosis, -decreased urine output, and -any bleeding under the skin or through any orifice.\n- Women in the last trimester of pregnancy, newborns, and persons with chronic underlying disease, as they or their offsprings are at risk for more severe disease.\n\n# Triage at point of first contact (Primary or ambulatory/urgent care)\n- Rule out other illnesses by history, clinical examination, and basic laboratory investigations, including but not limited to complete blood count (CBC), liver function tests, and electrolytes. Be careful to evaluate if patient has warning signs for severe dengue or malaria. If these signs are present, refer patient immediately to a hospital.\n- Assess for dehydration and provide proper rehydration therapy as needed.\n- Evaluate hemodynamic status and stabilize and immediately refer patients with delayed capillary refill, narrow pulse pressure, hypotension, oliguria, altered sensorium, or bleeding manifestations.\n- Treat symptomatically (paracetamol/acetaminophen).\n- For those with prolonged joint pain (after three days of symptomatic treatment) consider more aggressive pain management, such as morphine and short-term corticosteroids.\n- Consider referral for patients with increased risk of a poor outcome (persons older than 60 years, those with chronic disease, pregnant women, and newborns).\n\n# Triage at the secondary level (district or local hospital)\n- Treat symptomatically (according to previous treatments).\n- Investigate person for renal failure, neurologic signs and symptoms, hepatic insufficiency, cardiac illness, thrombocytopenia, and malaria.\n- Evaluate hemodynamic status and assess for dehydration; provide proper supportive care and rehydration therapy as needed.\n- Consider cerebral spinal tap if meningitis is suspected.\n- Collect blood for serologic testing of CHIK and other diseases in the differential diagnosis (e.g., dengue).\n- Review history of present illness and evaluate if patient has warning signs for severe dengue. If present, administer supportive care in a unit that can monitor vital signs on an hourly basis during the critical phase.\n- Refer patients with any of the following conditions to a higher level health center: pregnancy, oliguria/anuria, refractory hypotension, significant clinical bleeding, altered sensorium, meningoencephalitis, persistent fever of more than one week's duration, and signs of decompensation of underlying diseases.\n\n# Triage at the tertiary care level (advanced care centers or centers with infectious disease specialists)\n- Ensure that all the above-mentioned procedures have been completed and that a comprehensive medical team is available to assist in managing patients with severe or atypical disease.\n- Collect blood sample for serology and/or RT-PCR (see Laboratory section for more specific on CHIK testing).\n- Consider the possibility of other rheumatic (e.g., rheumatoid arthritis, gout, rheumatic fever) or infectious diseases (e.g., viral or bacterial meningoencephalitis).\n- Treat serious complications (e.g., bleeding disorder with blood components, acute renal failure with dialysis).\n- Assess disability and recommend rehabilitative procedures.\n- Given the severity of the pain and the potential long-term pain with CHIK, pain management and psychological assistance should be made available and consideration given to develop chronic pain management protocols, teams, and centers. Autopsies should be considered on all deceased patients, with involvement of pathologists.\n\n# 5d. Blood, Organ, and Tissue Safety\nBlood-borne transmission is possible. There are documented cases that include infection of laboratory personnel handling infected blood and of a health care worker drawing blood from an infected patient. 47,48 These cases support the belief that CHIKV is able to be transmitted through blood products.\nTo determine the impact of CHIKV on blood supply safety consider: 1) incidence of viremia among blood donors (which may vary depending on the time of the outbreak); 2) clinical impact on transfusion recipients who become infected;\n3) availability of measures to reduce transfusion transmission (e.g., nucleic acid amplification testing (NAT) or photochemical pathogen inactivation treatment); 4) availability of an alternative blood supply (from non-affected areas); and 5) the cost incurred by adopting these measures. 52\n\n# CASE mANAgEmENT\nIn addition to asking the local health-care community to promote optimal use of blood components, possible considerations for blood safety in areas with CHIKV introduction could include: 53 - Continue to obtain blood donations from local persons until an unacceptable incidence or prevalence a of infection is reached in the community.\n- Screen blood donors for symptoms prior to donation.\n- Asking donors to report any illness they experience after donating blood, while holding on to the blood donations for several days (e.g, 2-5 days) prior to releasing it.\n- If feasible, cease all blood donations in an area of known CHIKV infections and import blood products from uninfected areas.\n- Institute screening (e.g., NAT) of the blood supply for CHIKV. This will require a preexisting platform and regulatory clearance, and is unlikely to be available in most areas.\nSimilar measures should be considered for organ and tissue (grafts) transplantations.\n\n# CASE mANAgEmENT\na To be determined by blood banks and public health officials in the area.\n\n# Summary of Case Management Section\n- Treatment for CHIK is supportive, using anti-pyretics, optimal analgesics, and fluids.\n- Acutely infected patients need to be protected against mosquito bites to prevent further disease spread at home, in the community, and in the health care facility.\n- Because CHIK will place a large burden on the community, including on all levels of the health care system, well-established protocols and plans need to be developed in advance to assist in the triage, care, and rehabilitation of patients.\n\n# SURvEiLLANCE ANd OUTBREAk RESPONSE\nT he main objective of surveillance is to detect, in a timely manner, cases of CHIK in the Americas. Early detection will allow for proper response and characterization of the outbreak and identification of the viral strains circulating.\n\n# 6A. modes of Surveillance\nMultiple modes of surveillance can be considered to determine if CHIK may have been introduced to an area, to track the disease once introduced, or to follow the disease once it has been established.\n\n# . P r e p a r e d n e s s p h a s e\nReinforce existing febrile syndromic surveillance sentinel sites so they can detect CHIK cases. A percentage of patients presenting with fever and arthralgia or fever and arthritis with no known etiology (e.g., negative test for malaria or dengue), should be tested for CHIK at the national reference laboratory (See Section 4 for more details on proposed laboratory surveillance testing). To ensure adequate laboratory testing and surveillance capacity, laboratories should be aware of the laboratory network set up for testing and eventual distribution of supplies.\n\n# Introduction\nOnce an autochthonous case of CHIK is detected, an in-depth epidemiologic investigation must be conducted to:\n- Track viral spread.\n- Monitor for possible introduction into surrounding areas.\n- Describe key epidemiologic and clinical features.\n- Assess clinical severity and impact on society (e.g., days missed from work, school closures, etc.).\n- Identify risk factors for infection or severe disease.\n- Identify circulating CHIKV lineages.\nThese efforts will be the basis for developing effective control measures.\nActive, passive, and laboratory surveillance should be used to calculate and monitor indicators such as: incidence, rate of spread, rate of hospitalization (per infections), proportion of severe disease, mortality ratios, and disability rates.\n\n# Sustained transmission\nOnce the virus has been identified throughout a country, scaling back of the level of testing and active surveillance can be considered (e.g., testing only a fraction of suspect cases or testing severe or atypical cases, newborns, cases identified in new regions) to avoid unnecessary costs in resource-limited settings.\nHowever, ongoing surveillance should be continued to monitor changes in the epidemiology and ecology of CHIKV transmission. Any changes in surveillance at the national level should be readily communicated to other surveillance and prevention partners, such as vector control specialists, to ensure the quality and uniformity of the data collected. Public health authorities should be alerted to small clusters of disease (fever and arthralgia or arthritis) associated with a traveler returning from a CHIK endemic area or an increase in the number of hospital visits for fever and arthralgia or arthritis occurring in a localized area in a short time.\n\n# 6B. Case detection\n\n# 6C. Case definition\nSuspect case: a patient with acute onset of fever >38.5ºC (101.3ºF) and severe arthralgia or arthritis not explained by other medical conditions, and who resides or has visited epidemic or endemic areas within two weeks prior to the onset of symptoms.\nConfirmed case: a suspect case with any of the following CHIK specific tests:\n- Viral isolation.\n- Detection of viral RNA by RT-PCR.\n- Detection of IgM in a single serum sample (collected during acute or convalescent phase).\n- Four-fold increase in CHIKV-specific antibody titers (samples collected at least two to three weeks apart).\nDuring an epidemic, all patients need not be subjected to confirmatory tests as above.\nAn epidemiologic link can be sufficient.\nAn evaluation of the sensitivity and specificity for clinical criteria for CHIKV infection was done during a large outbreak of the disease. 54 The combination of fever and polyarthralgias had the best sensitivity and specificity at 84% and 89%, respectively, and allowed for the correct classification 87% of individuals with serologically confirmed CHIKV infection.\n\n# 6d. Case Reporting\nCHIK is not a notifiable disease in most countries. However, depending on the epidemiologic situation, each country must determine independently when CHIK should be a disease of mandatory reporting. Occurrence of suspect cases could indicate a possible outbreak and, therefore, should be immediately reported to the nearest health authority in accordance with the IHR guidelines.\nPrior to the introduction of CHIK into an area, clinicians should report any suspect or confirmed travel-related cases to local public health officials who, in turn, should report them to a regional level and then on to a national level, where the information should be summarized and shared with stakeholders (Figure 3). In addition, other key partners, such as vector control management teams, should be notified.\n\n# 6E. Epidemiologic Reports\nIdeally, epidemiologic reporting should be established at the national level, with the support of local and regional public health officials. The types and number of epidemiologic reports will likely evolve during the course of the outbreak to reflect the types of surveillance that are performed in an area. terms of presenting and closing the data on a daily basis. In addition to case count by location and timing, reporting on disease severity (hospitalization, mortality), number of hospital beds occupied per day, and trends in cases based on syndromic surveillance can be considered as ways to present the data. The national level data should be communicated back to the collecting districts, as well as to the press and other public health and partner agencies that participate in the control efforts (see Section 8, \"Risk and Outbreak Communication\" for more detail). Once a country has identified autochthonous transmission within its borders, it should activate its emergency operations center (\"sala de situación\") to serve as a source for rapid communication and decision making.\n\n# 6F. international Health Regulations\nand Border measures I n t e r n a t i o n a l H e a l t h R e g u l a t i o n s A single imported case (i.e., a traveler) of CHIKV into the Americas would not necessarily constitute a public health emergency of international concern (PHEIC) under IHR, 55 although this case should be thoroughly investigated to minimize the risk of CHIK establishment in the country. However, suspicion of autochthonous CHIKV transmission in the Americas will meet PHEIC criteria and should be reported per IHR (see Appendix E for an example). Such an event would have a serious public health impact because of its potential to cause an epidemic with high attack rates among an immunologically naïve population, and because vectors are sufficiently abundant to potentially support permanent establishment of the virus and year-round transmission. The event would also be unusual for the Americas, since it would signal the appearance of a previously absent pathogen and a significant risk of international spread given the amount of travel between countries in the Region. Although CHIKV does not have a high mortality rate, it has high morbidity rates associated with persistent arthralgias that can lead to disability and a reduction in productivity. Even disregarding the issue of cost and complexity of implementation, port of entry screening activities are unlikely to prevent or delay the importation of CHIKV.\nThere is no evidence to support that requiring pilots or ship captains to complete health declarations, asking passengers to complete screening questionnaires, taking temperature measurements and engaging in other entry screening modalities effectively prevent CHIKV introduction and spread into the Americas. Member\nCountries should use their scarce public health resources on activities more likely to achieve intended results, including implementing sustainable vector control efforts, enhancing clinical surveillance for CHIKV disease, educating the public, and considering assisting affected Member Countries. For similar reasons, exit screening is not recommended if Member Countries in the Americas confront CHIKV outbreaks within their borders.\nSome jurisdictions outside the Americas have instituted mosquito abatement activities at international airports and spraying adulticides in the passenger cabins of arriving international flights as part of efforts aimed at preventing dengue importation. However, virus-infected mosquitoes arriving in passenger aircraft are not considered as significant sources of most arboviral importations.\nFor arboviruses with a human-mosquito-human transmission cycle, the most important source of viral importation is the viremic traveler. In a region like the Americas, where competent vectors are already present in the majority of countries, mosquito abatement and vector surveillance efforts predominantly focused on international airports and seaports can be implemented by national authorities to prevent CHIKV importation, but PAHO does not recommend them.\nThe exception would be if cases were being detected close to an international airport or seaport, or if suspected cases worked in or around these ports of entry.\nRoutine vector control efforts consistent with IHR Article 22, which calls for eliminating vectors at facilities used by travelers at points of entry, should be implemented, but are not intended as a principal means of preventing CHIKV importation.\nSimilarly, in the presence of CHIK cases and local virus transmission, there is no need to place any restrictions on baggage, cargo, containers, goods, or postal parcels beyond usual practices; this will avoid unnecessary interference with international traffic in the absence of any identified public health benefit.\nIt is advisable, however, to establish communications between public health authorities and conveyance operators (sea and air, cargo and passenger) and other port-based organizations, in case there is a need to implement a CHIKV communication campaign.\nCountries may elect to distribute Travel Health Alert Notices (THANs) to international travelers if there is concern that CHIKV transmission is likely or if ongoing transmission has been detected. This information would offer guidance to travelers on how to reduce their risk of contracting CHIKV, steps to take for reducing the likelihood that they will be bitten by mosquitoes, or seeking early diagnosis if they develop signs and symptoms compatible with CHIK fever.\nThese messages could be relayed through online reservation systems, travelers' health clinics, travelers' health Web sites, and postings at international ports when outbreaks are occurring.\nIt will be important to monitor air travel patterns between countries where CHIKV is circulating and every other country or area in the Americas, in order to identify locations most at risk to virus introduction. In a preliminary analysis that was limited exclusively to direct flight data, scheduled commercial flight data shows that countries importing CHIKV had 23 times more total scheduled passenger seats originating from countries with CHIKV activity than did nonimporting countries (CDC, unpublished). Subsequent analyses using passengerspecific data, which includes travel connections and actual passenger volume, could provide more accurate information on which to base a risk assessment of CHIKV importation.\n\n# Summary of Surveillance and Outbreak\n\n# Response Section\n- Epidemiological surveillance is key to the timely detection of cases and appropriate and rapid response with active participation from all stakeholders.\n- CHIK surveillance should be built upon existing dengue surveillance (highlighting differences in clinical presentation).\n- If autochthonous transmission of CHIK is identified, it must be reported immediately as a PHEIC under IHR.\n\n# vECTOR SURvEiLLANCE ANd CONTROL\nI n the absence of an effective CHIKV vaccine, the only tool available to prevent infection is reduction of human-vector contact. The primary vectors of CHIKV are Ae. aegypti and Ae. albopictus. Ae. aegypti is the principal vector in areas of Africa where the virus is considered to be endemic. However, Ae. albopictus was incriminated during recent epidemics, following introduction of the virus into temperate Europe 17 and some tropical areas of the Indian\nOcean .27, 57 These outbreaks were associated with an adaptation of CHIKV strains to Ae. albopictus. 58,59 Both Ae. aegypti and Ae. albopictus are present in the Americas (Figures 4 and 5). Ae. aegypti will likely be the most important vector in urban areas, and Ae. albopictus will likely play a more significant role in There are some significant differences between Ae. aegypti and Ae. albopictus that must be considered in developing surveillance and control procedures.\nAe. aegypti is more closely associated with humans and their homes, and feeds preferentially on humans. Adult Ae. aegypti rest indoors, and its larval habitats are most frequently containers on the household premises. Ae. albopictus feeds readily on humans, but also utilizes a broader range of bloodmeal hosts; 62 its larvae occur in peridomestic habitats as well as surrounding natural habitats.\nAe. albopictus can overwinter in the egg stage and, therefore, can occupy more temperate climates 63 than Ae. aegypti. These species have distinct morphological features, and the identification of specimens collected during surveillance and control programs in the Americas can be readily accomplished. 64,65 An effective, operational dengue control program provides the basis for CHIKV preparedness, because the biology and control procedures for Ae. aegypti are similar to those for Ae. albopictus. Surveillance and control recommendations developed for dengue management 66 as a component of the Integrated\nManagement Strategy for Dengue Prevention and Control (IMS-Dengue) may be utilized and intensified in order to respond to a CHIKV introduction.\nSuccessful control programs require well trained professional and technical staff and sufficient funding. In addition, an independent quality assurance program should be incorporated into the integrated vector management (IVM) scheme.\nTo be successful, the CHIKV IVM program must include intersectoral participation (collaboration) at all levels of government and among health, education, environment, social development, and tourism agencies. IVM programs also benefit from participation of non-governmental organizations (NGOs) and private organizations. CHIKV control program must communicate with and mobilize the entire community. 67 In fact, the community's participation is an essential component of IVM. 68 To be effective, an IVM strategy must be developed and in place before CHIKV is introduced.\n\n# vECTOR\n\n# 7A. Reducing the Risk of CHikv\nComponents of an IVM program to reduce CHIKV risk include:\n\n# Vector Surveillance and Identification of High Risk Areas\nIn areas where dengue is endemic, a retrospective analysis of Dengue virus transmission during previous years should be conducted during the CHIKV planning phase to indicate the areas where CHIKV is expected to circulate (given the similarity in transmission cycles of these viruses). Areas can be stratified in terms of risk of transmission. 69 Stratification is then used to assign resources and priorities. For example, controlling or preventing CHIKV transmission in neighborhoods that traditionally have produced many cases of dengue should inhibit virus amplification and virus spread to nearby neighborhoods.\nThe program must have the ability to systematically collect surveillance data on relative densities of Ae. aegypti and Ae. albopictus. Surveillance methods for Ae. aegypti and Ae. albopictus are varied and include methods to monitor egg production, larval sites, pupal abundance, and adult abundance. These methods are reviewed in Chapter 5 of the WHO Dengue Guidelines. 66 New traps and sampling methods are being developed that may provide more accurate surveillance data. 70,71 Programs must be able to detect and identify hidden and difficult to control larval sites (e.g., cryptic locations such as septic tanks, storm drains, sump pumps, and vacant lots) and other productive sites, as well as the readily identified and commonly found larval habitats.\n\n# Personal Protection\nIndividuals may reduce the likelihood of infection by the use of personal repellents on skin or clothing. DEET (N,N-diethyl-m-toluamide) and picaridin (also known as KBR3023 or Bayrepel™) are effective repellents widely available in the Americas. Infants and others sleeping or resting during the day should use bednets to avoid infection from Ae. aegypti and Ae. albopictus, both of which are day biting mosquitoes. It is of particular importance that individuals who are vECTOR potentially infected with CHIKV during an outbreak rest beneath an IT bednet to avoid mosquito bites and further spread of infection. Use of IT bednets has the additional benefit of killing mosquitoes that come into contact with the net, which may reduce vector-human contact for other household members. 72 A number of pesticide products may be used to safely treat bednets (Table 6), or long-lasting pretreated nets can be obtained commercially.\n\n# Household Prevention\nThe use of intact screens on windows and doors will reduce entry of vectors into the home, and mosquito proofing water storage vessels will reduce oviposition sites and local production. Within a household, use of IT bednets 72 and IT curtains 73 also reduce vector-human contact.\nThe number of adult mosquitoes in a home may be reduced by using commercially available pyrethroid-based aerosol sprays and other products designed for the home, such as mosquito coils and electronic mat vaporizers. Aerosol sprays may be applied throughout the home, but areas where adult mosquitoes rest (dark, cooler areas) must be targeted, including bedrooms, closets, clothing hampers, etc. Care should be taken to emphasize proper use of these products when advocating their application to the public, in order to reduce unnecessary exposure to pesticides.\n\n# Neighborhood and Community Prevention\nNeighborhood and community prevention for a CHIKV introduction in the Americas should be based on methods developed for dengue control, utilizing effective strategies to reduce the densities of vector mosquitoes. 66 A fully operational dengue control program will reduce the probability that a viremic human arriving in the Americas will be fed upon by Ae. aegypti or Ae.\nalbopictus mosquitoes, thereby leading to secondary transmission and potential establishment of the virus.\nDengue programs for controlling Ae. aegypti have traditionally focused on control of immature mosquitoes, often through the community's involvement in environmental management and source reduction. It is essential that community involvement be incorporated into an IVM program. 74,75\n\n# Ve c t o r C o n t r o l P r o c e d u r e s\nThe WHO Dengue Guidelines 66 provide information on the main methods of vector control, and they should be consulted when establishing or improving existing programs. The program should be managed by experienced professional vector control biologists to assure that the program uses current pesticide recommendations, incorporates new methods of vector control, and includes resistance testing. Prevention programs should utilize the methods of vector control found in Appendix F, as appropriate. 66, 74\n\n# 7B. Response to CHikv introduction\nImmediately upon confirmation of the first autochthonous CHIKV case, the health department should inform the IVM program regarding the onset date and location of the case. Vector control procedures must be intensified to effectively reduce the abundance of infected vectors in order to halt transmission in the areas of the case(s).\nvECTOR Simultaneously, emergency response committees at local and national levels should be informed of the situation and activated. Initial efforts should focus on containing virus transmission and preventing expansion (Appendix G). If virus containment fails, or if cases are not detected until the outbreak has spread over a large geographic area, intensive vector control efforts will need to be expanded to a larger scale program.\n\n# Summary of Vector Surveillance and Control Section\n- Epidemiological surveillance is key to the timely detection of cases Early detection of disease will increase the likelihood of containing transmission of CHIKV in the area.\n- Successful IVM for CHIKV requires trained experts in medical entomology and vector control, sufficient resources, and a sustained commitment.\n- Current dengue control programs in the Region should be utilized and improved to prevent CHIKV transmission.\n- Vector surveillance and control activities and methodologies must be validated and continually evaluated to measure efficacy. As CHIKV is new to the Americas, the media, the public, and many officials will need to be educated about the disease, its mode of transmission, the lack of specific therapeutic treatment, means of symptomatic and supportive treatment, and the adoption of control measures.\nRisk communication messaging can emphasize that the risk of CHIKV infection can be reduced, and that it is typically a self-limiting disease.\n\n# 8B. Risk Communication Strategies by Phase and Target Audience\nAppendix H gives an example of a model risk communication plan with strategies organized by preparedness, response, and recovery phases of an emergency. The plan defines various target audiences that should be considered in developing a country-specific risk communication plan.\nRisk communication should be organized across multiple agencies and should target the media, the public health community, community-based organizations, the private sector, and civil society institutions.\n\n# S t r u c t u r e a n d C o o r d i n a t i o n\nIdeally, an emergency response to a CHIKV outbreak will use an Incident\nCommand System that provides structure for collaboration. In Latin America, the equivalent is the Emergency Operational Committee (or COE in Spanish).\nA key component in emergency operations is the establishment of a Joint Lack of coordination on these points will help create confusion and undermine confidence in the management of the response.\n\n# S t r a t e g i e s b y P h a s e : P r e p a r e d n e s s P h a s e\nThe primary activities during the preparedness phase are to develop a communications plan and to create strategic partnerships. During this phase, potential activities may include:\n- Informing key stakeholders about preparedness materials, such as these guidelines.\n- Developing basic response materials, such as fact sheets and frequently asked questions, will facilitate a rapid response to a CHIKV introduction and reduce misinformation. Information channels may include printed materials, websites and other electronic and social media, the mass media, short message service (SMS) text messages, inter-personal communication through group meetings, schools, and utilization of traditional or folk media.\n- Working with partners to develop strategies to guide care seeking, travel (national and international), and prevention/risk reduction.\n- Communication with journalists and news agencies to provide baseline information on CHIKV and on the national preparedness and response plan.\n- Networking with key personnel at potential information points, such as arrivals and departure locations (airports, ports, borders) and public facilities (health care facilities, educational centers, workplaces, nursing homes, shopping malls, churches, public transport sites, stadiums, among others).\n- Anticipating sensitive issues can allow for preemptive preparation of responses and strategies. Sensitive topics related to CHIKV may include concern over safety of community and household pesticide use, any restrictions involved in a containment response, large numbers of persons seeking care at health care facilities, and the cost of control measures.\n\n# S t r a t e g i e s by P h a s e : T h e R e s p o n s e P h a s e\nDuring the response phase, the communication plan is put into action; in particular, communications with the mass media, health care providers, and other key audiences are intensified.\n\n# The Mass Media\nEffective communication through the mass media can help maintain clear information regarding the outbreak and the public health response. Information should be communicated via an appropriate, trained national-level spokesperson.\nUse of a consistent spokesperson can build trust and avoid the release of potentially conflicting messages from various sources. Information in the mass media can also reinforce the key behavioral outcomes that can help reduce risk during an outbreak. Content in the electronic and print media should be regularly monitored (on a daily basis during an intense outbreak), in order to make any necessary adjustments to the strategies and messages conveyed to the population.\n\n# 8C. Specific Behavioral Strategies for CHikv Risk Reduction\nSpecific strategies for effective personal, household, and community primary Advance research into knowledge, attitudes, and practices regarding repellent and household control measures may yield benefits in understanding barriers to use and potential for misapplication. Even if it is not feasible to conduct this research in advance, rapid qualitative assessment in affected areas can yield insights to increase the effectiveness of prevention messages.\nCommunication on prevention should target specific behaviors that offer the best likelihood of reducing risk. Feasible strategies will vary by location, depending on a given community's resources, attitudes, control program capacity, and ecology. Key messages for personal and household prevention can include:\nC o m m u n i t y S t r a t e g i e s\n- Encouraging support of and compliance with governmental control efforts such as environmental sanitation, larviciding and adulticiding.\n- Advocacy for household and neighborhood source reduction (e.g., trash clean-up, control of water storage, etc.). - Use of personal prevention such as clothing, repellents, and insecticidetreated materials:\n-Encouraging the use of long sleeves and pants may be reasonable in areas where temperatures are moderate, particularly during evening when Aedes mosquitoes are often still seeking a bloodmeal. This recommendation may be less practical in tropical zones.\n-Repellents for use on skin and clothing are now sold widely throughout the Americas. A significant outbreak may increase interest in these tools, and authorities should be prepared to provide guidance and to rely on creative strategies to increase use.\n- Methods to reduce human-vector contact include use of household insecticides and installation of screening. Where feasible, screening material can be installed over windows even without the use of expensive frames (stapling in place or using wooden frames).\n- It may be useful to specify active ingredients or even brand names for recommended repellent and/or household insecticides, as a way to reduce use of ineffective and possibly dangerous materials.\n\n# Summary of Risk and Outbreak Communication Section\n- Communications are an integrated, coordinated effort involving all disciplines and components for preparation and response.\n- Timely communication with stakeholders is crucial for enlisting the community's participation and to avoid confusion and misinformation.\n- As CHIKV is novel in the Americas, the media, the public and many officials will need to be educated about the disease, the mode of transmission, the lack of specific therapeutic treatment, means of symptomatic and supportive treatment, and effective control measures.\n\n# CONCLUSiON\nC urrently, CHIKV is not known to be circulating in the Americas. The risk of introduction is high, however, due to travel importation, competent vectors (same vectors as dengue), and population susceptibility. Given the likelihood that CHIKV will be introduced in the Region, advance preparation is essential. The timely detection of cases and an appropriate and rapid response with active participation of all stakeholders will be necessary to minimize the risk of importation and sustained transmission in the Region.\nThese guidelines for the preparedness and response CHIKV introduction in the Americas were developed to increase awareness of the disease and to provide the necessary information to institute the most appropriate strategies to prevent the importation and spread of CHIKV in the Region. Each Member Country is encouraged to use and adapt these guidelines to detect an outbreak of the disease early, to conduct pertinent epidemiologic investigations, and to prevent or mitigate the expansion of the disease in the Americas.\n\n# APPENdiCES\n\n# Introduction\nThe optimal method for determining specific etiology of an arbovirus infection requires isolation of the virus from a specimen obtained from the patient during the acute stage of the disease and the demonstration of a rise in titer of an antibody to the isolate during convalescence. For a number of reasons, the successful isolation of most arboviruses from patient specimens is the exception, whether because the specimen to be examined is not collected early enough, is not properly handled, or is not expeditiously transmitted to the virus laboratory for inoculation. The viremia for many arbovirus infections in humans, if detectable at any stage, ceases by the time of or soon after onset of symptoms⎯a stage when antibody is often demonstrable. Because some circulating virus\n\n# Introduction\nFor isolation from brain, samples should be taken from several areas, including the cortex, brain nuclei, cerebellum, and brain stem. Neurotropic arboviruses sometimes can be isolated from CSF obtained by lumbar puncture during the acute stages of encephalitis or aseptic meningitis. Alphaviruses, like CHIKV, have been isolated from joint fluid of patients with acute polyarthritis. Under certain circumstances arboviruses have been recovered from urine, milk, semen, and vitreous fluid.\n\n# Principle\nSusceptible cell culture systems are available for the attempted isolation of the presumed etiologic agent of an illness or disease. Following successful isolation, the isolate may be positively identified and an antigen prepared from this isolate or the virus itself may be used to test the patient's serum for the presence of antibodies to the viral isolate. If antibodies are detected, this exercise confirms that the isolate was the causative agent of the illness or disease. In certain instances, serum from a patient may not be available. Under those circumstances, one relies on reisolation of the causative virus from the same original specimen. Reisolation should always be attempted, however, whether serum is available from the patient or not.\n\n# Materials and Reagents\nVero cell culture monolayers or other suitably susceptible cell cultures C6/36 cell cultures-cloned Ae. albopictus mosquito cell.\n\n# Procedure\nAvailable tissues or fluids should be divided for viral isolation, electron microscopy, and for immunohistochemical examination. Tissues should be collected aseptically and rapidly transported to the laboratory in viral transport.\nThe aliquot for viral isolation should be immediately frozen at −70° C in a mechanical freezer or stored on dry ice. Samples for viral isolation should be kept frozen continuously, avoiding freeze-thaw cycles that inactivate virus.\nAppendix A. Viral Isolation Protocol (for Cell Culture)\n(Cont.)\n\n# Procedure\nThe aliquot for electron microscopy should be minced and place directly in glutaraldehyde. Autolytic changes occur rapidly and tissues should be fixed as quickly as possible. A portion of the sample should be fixed in buffered formalin or, preferably, embedded in freeze-media and frozen, to prepare sections for immunohistochemical examination. Processed specimens should be inoculated into cell cultures with a minimum of delay. Sera from patients with acute febrile illnesses can be used undiluted for virus isolation or at dilutions of 1:10 and 1:100 in a protein containing diluent. It is important to inoculate unknown specimens at two or preferably more dilutions (undiluted to 10-2 ). Shell vial cultures or 25cm 2 flask cultures of Vero are inoculated and observed for the production of CPE during 10−14 days. For shell vials, a total volume of 400 µl is inoculated, followed by centrifugation at 100 x g for one hour at 37°C. A portion of the cell supernatant can be collected and tested for the presence of virus by either targeted RT-PCR or consensus RT-PCR assays. Alternatively cells are harvested and spot slides are prepared for IFA examination using monoclonal dengue type-specific antibodies.\n\n# Controls Uninoculated Vero and C6/36 cells\n\n# Interpretation\nPositive virus isolation, reisolation, and definitive identification define the etiologic agent of the patient's illness.\nIf paired sera or a convalescent serum from that patient are available, the identified viral isolate is tested serologically with the patient's sera to verify antibody response to that virus.\nRNase free water Prepare a reagent \"master mix\" according to the number of reactions desired. The master mix should be prepared in a \"clean room\" that is physically separated from all other laboratory activities and that has dedicated reagents and equipment (e.g., pipettes). For 10 samples make a 10X master mix (see above) by multiplying the volumes of all individual reagents by 10. Combine the reagents in the above order in an RNase free centrifuge tube on ice. Divide the master mix into 10 portions of 40 µl each into either 0. Master mix production.\n- Utilize dedicated or separate equipment within pre-and post-amplification areas, especially pipets and centrifuges.\n- Always wear gloves, even when handling unopened tubes.\n- Quickly open and close tubes and avoid touching any inside portion.\n- Use RNase free plastic disposable tubes and pipet tips.\n- Use aerosol block pipet tips.\n- Use RNase free water.\n- Prepare all reagents on ice. 1. Solid phase samples (mosquitoes or tissues) are first homogenized in an isotonic buffer to produce a liquid homogenate. RNA is extracted from liquid specimens (CSF or serum) without any pre-treatment as described below. Tissue specimens (\n) are homogenized in 1 ml of BA-1 diluent using TenBroeck tissue grinders. Mosquito specimens are homogenized in TenBroeck tissue grinders or by using the copper clad steel bead (BB) grinding technique. With both techniques the homogenates are clarified by centrifugation in a microcentrifuge (e.g., Eppendorf) at maximum speed for 5 minutes to pellet any particulate material.\n(Continued)\n\n# Introduction\nAssays that detect viral specific immunoglobulin M (IgM) are advantageous because they detect antibodies produced during the first few days after onset of clinical symptoms in a primary infection. This obviates the need for convalescent-phase specimens in many cases. IgM capture is the optimal approach to IgM detection: it is simple, sensitive, and is applicable to serum and cerebrospinal fluid (CSF) samples from a variety of animal species (e.g., human, equine, avian). False-positive reactions due to rheumatoid factor are minimized.\n\n# Principle\nIgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) provides a useful alternative to immunofluorescence for documentation of a serologic response. ELISA is less subjective than immunofluorescence and large numbers of samples can be processed. The principle of ELISA is similar to that of immunofluorescence. Anti-IgM (the capture antibody) is coated on 96-well plates in the Arboviral Diagnostic Laboratory at DVBD, CDC. This is followed sequentially by the patient's serum, then known non-infectious viral antigen. The presence of antigen is detected by using enzyme-conjugated anti-viral antibody, and a colorimetric result is generated by the interaction of the enzyme and a chromogenic substrate. This constitutes the MAC-ELISA.\n\n# Safety\nThe procedure should be performed under laboratory safety conditions that take into consideration the potential infectious nature of the serum specimens involved. Lab coat, gloves, and a laminar flow hood is recommended.\n\n# Materials and Reagents Incubator\nSingle and multi-channel pipettors Reagent reservoirs Ziploc bags, paper towels Clinical specimens Acute and convalescent human serum and/or cerebrospinal fluid (CSF) specimens Previously tested antibody-positive and antibody-negative human sera for controls Note: Store all diagnostic specimens at 4°C prior to testing, and -20°C after all anticipated testing has been completed. Avoid repeated freeze-thaw cycles.\n\n# Procedure\nNote: The following procedure includes information on quality control and interpretation. Each serum specimen is tested in triplicate on both viral and normal antigens. Eight test specimens can be analyzed per plate. CSF specimens are usually tested only singly.\n1. Using a fine-tipped permanent marker, number and label the plates. Identify the location of each clinical specimen (S1−S8) by using the appropriate laboratory code number. To keep timing of reagent addition consistent, process plates in the order that they are numbered during all steps of the procedure. Plates should be kept in an enclosed, humidified environment during all incubation times with the exception of the coating step. A large ziploc bag containing a moist paper towel works well for this purpose. Procedure 9. Add 50µl per well of horseradish peroxidase-conjugated monoclonal antibody, broadly cross-reactive for the appropriate viral antigenic group, diluted in blocking buffer, according to a previous titration.\n\n# Incubate for\n-ne hour at 37°C in a humid chamber. 10. Turn on plate reader to warm up, and remove TMB-ELISA from refrigerator. 11. Wash plates 5X twice. Turn the plates 180 o in the washer after the first series of five cycles. This promotes consistent results.\n12. While the plate is at room temperature, add 75µl per well of TMB substrate to all wells. Immediately cover plates to block out light. Incubate at room temperature for 10 minutes. A blue color will develop in antibody-positive wells.\n13. Add 50µl per well of stop solution to all wells, including the outer rows of wells on the plate (the plate reader itself should be set to zero on some of these wells). The wells that were blue will now change to a yellow color. Allow plates to sit at room temperature for one minute. Read plates in microtiter plate reader by using a 450 nm filter. C for an undefined period of time.\n4. Test and control sera can be diluted to the working dilutions and refrigerated one day prior to use. Antigens and conjugate must be diluted to the working dilutions immediately prior to use.\nThe MAC-ELISA should be restandardized periodically. This should occur when new lot numbers of reagents are introduced, and at the very least, once a year. It is recommended that the mean optical density of the positive control serum reacted on the viral antigen be set to approximately at 1.0. The normal control serum reacted on the viral antigen should be around 0.2 (this varies). The standardization of reagents is normally achieved via titration, always comparing the optical densities of the reagents when reacted on viral and normal antigen.\n\n# Results\nBefore the results can be calculated for each clinical specimen, the test must be determined to be valid. For a valid test the following must be true:\n\n# Results\nMean OD of the positive control serum reacted on viral antigen (P) Mean OD of the negative control serum reacted on viral antigen (N) must be greater than or equal to 2.0. This is the P/N of the positive control.\nTest validity must be determined for each plate. Results for the clinical specimens may only be determined if the test is valid. If the test is not valid, then that plate must be repeated. If the test still fails after a repeat, then one or more of the reagent or test parameters was likely in error, and troubleshooting should be performed.\nTo determine whether the clinical specimens (S1−S8) contain IgM to the viral antigen (which would indicate recent infections with that virus) the following must be calculated:\nMean OD of the test specimen reacted on viral antigen (P) Mean OD of the negative control serum reacted on viral antigen (N) This is the P/N of the test specimen. For a specimen to be considered IgM-positive to the test virus, the P/N must be greater than or equal to 2.0. In addition the value of P for the test specimen must be greater than or equal to twice the mean OD of the test specimen reacted on normal antigen. If this requirement is not met, non-specific background is being generated, and the result must be reported as uninterpretable.\n\n# Interpretation\nIt is further recommended that for sera, all positive results should be confirmed by titration using 6, 2-fold dilutions of the serum specimens compared to a similar titration of the negative control serum. Linear curves indicate true seropositivity. Flat or undulating titration curves indicate false-positive results.\n\n# Procedure\nNote: The following procedure includes information on quality control and interpretation. Each serum specimen is tested in triplicate on both viral and normal antigens. Eight test specimens can be analyzed per plate.\n1. Using a fine-tipped permanent marker, number and label the plates. Identify the location of each clinical specimen (S1−S8) by using the appropriate laboratory code number. To keep timing of reagent addition consistent, process plates in the order that they are numbered during all steps of the procedure. Plates should be kept in an enclosed, humidified environment during all incubation times with the exception of the coating step. A large ziploc bag containing a moist paper towel works well for this purpose.\n2. Coat the inner 60 wells of 96 well plates with 75µl/well of the appropriate group-reactive monoclonal antibody diluted in coating buffer according to prior titration. Incubate at 4°C overnight.\n3. Dump out the coating antibody and blot plates on paper towels. Block plates with 200µl blocking buffer per well.\nIncubate at room temperature for 30 minutes.\n4. Wash wells 5X with wash buffer by using an automatic plate washer. Wells should be filled to the top each cycle. 5. Dilute viral antigen in wash buffer according to a previous titration. Add 50µl per well to the left three wells of each serum block. To the right three wells of each block, add 50µl per well of normal antigen diluted in wash buffer to the same concentration as the viral antigen.\nIncubate overnight at 4°C in a humidified chamber.\n6. Wash 5X. 10. Turn on plate reader to warm up and dissolve substrate tablets in tris buffer about 15 minutes prior to adding it to the plates.\n\n# Wash plates 5X\ntwice. Turn the plates 180 o in the washer after the first series of five cycles. This promotes consistent results.\n12. While the plate is at room temperature, add 75µl per well of Sigma 104 substrate to all wells. Immediately cover plates to block out light. Incubate at room temperature for 30 minutes. A yellow color will develop in antibody-positive wells.\n13. Add 35µl per well of stop solution to all wells, including the outer rows of wells on the plate (the plate reader itself should be set to zero on some of these wells). Reactive wells will remain a yellow color. Allow plates to sit at room temperature for one minute. Read plates in microtiter plate reader by using a 405 nm filter.\nPractical considerations 1. Plates can be coated and kept at 4 o C for up to a week. C for an undefined period of time.\n4. Test and control sera can be diluted to the working dilutions and refrigerated one day prior to use. Antigens and conjugate must be diluted to the working dilutions immediately prior to use.\nThe IgG-ELISA should be restandardized periodically. This should occur when new lot numbers of reagents are introduced, and at the very least, once a year. It is recommended that the mean optical density of the positive control serum reacted on the viral antigen be set to approximately. 1.0. The normal control serum reacted on the viral antigen should be around 0.2 (this varies). The standardization of reagents is normally achieved via titration, always comparing the optical densities of the reagents when reacted on viral and normal antigen.\n\n# Results\nBefore the results can be calculated for each clinical specimen, the test must be determined to be valid. For a valid test the following must be true: Mean OD of the positive control serum reacted on viral antigen (P) Mean OD of the negative control serum reacted on viral antigen (N) must be greater than or equal to 2.0. This is the P/N of the positive control.\nAppendix C. IgM and IgG Serologic Assay Protocols (Cont.)\n\n# IgG ENZYME-LINKED IMMUNOSORBENT ASSAY PROTOCOL\n\n# Results\nTest validity must be determined for each plate. Results for the clinical specimens may only be determined if the test is valid. If the test is not valid, then that plate must be repeated. If the test still fails after a repeat, then one or more of the reagent or test parameters was likely in error, and troubleshooting should be performed.\nTo determine whether the clinical specimens (S1-S8) contain IgG to the viral antigen (which would indicate either recent or past infections with that virus) the following must be calculated: Mean OD of the test specimen reacted on viral antigen (P) Mean OD of the negative control serum reacted on viral antigen (N) This is the P/N of the test specimen. For a specimen to be considered IgG-positive to the test virus, the P/N must be greater than or equal to 2.0. In addition the value of P for the test specimen must be greater than or equal to twice the mean OD of the test specimen reacted on normal antigen. If this requirement is not met, non-specific background is being generated, and the result must be reported as uninterpretable.\n\n# NOTIFICATION_____________Region______________\nA Note: The immediate notification must include whatever is possible to complete the learning of the outbreak. Once investigated, it is sent back the full format to regional World Health Organization office.\n\n# Appendix E. Report for an Event or Outbreak of Public Health Importance\nThere are a number of vector control procedures that should be considered to mitigate the risk of CHIKV expansion in an area (Table F1).\nAppendix F. Vector Control Procedures C h e m i c a l C o n t r o l o f L a r v a l H a b i t a t s\nIf potable water vessels cannot be screened or covered, they should be cleaned regularly or treated to stop larval production according to WHO Pesticide Evaluation Scheme (WHOPES) recommended practices for potable water. 66 Potential larval habitats that do not contain water intended for human consumption may be treated with larvicides listed in Table F2. Adapted from: Pesticides and their application for the control of vectors and pests of public health importance. 77 Label instructions must always be followed when using insecticides.\nb\nThe strength of the finished formulation when applied depends on the performance of the spraying equipment used. Traditionally, Indoor Residual Sprays (IRS) have been used most successfully against malaria vectors (Table F4). IRS treatment should be effective against Ae.\naegypti, which rests indoors, though it may be difficult to apply operationally.\nGenerally, all interior walls and ceilings of a house are treated. For control of Ae. aegypti, it is important to treat bedrooms, closets, the undersides of beds, and other dark areas where Ae. aegypti adults rest before and after taking a bloodmeal. Residents should be informed that IRS are safe when applied according to the label, but that individuals with health concerns, such as those with asthma or allergies, should take measures to reduce or eliminate exposure during the application process.\n\n# R e s i s t a n c e Te s t i n g\nFrequent application of the same insecticide or class of insecticide may select for individual mosquitoes that are able to survive pesticide applications. 78 Resistance is a heritable change in the sensitivity of a mosquito population to an insecticide that may lead to failure of the pesticide to yield the expected degree of control.\nThe insecticides available for use as adulticides are limited, and fall into three chemical classes: organophosphates, carbamates, and pyrethroids. Some products for larviciding have different modes of actions, such as insect growth regulators and microbials tools. 78 However, the most commonly used product for controlling larvae of Ae. aegypti in containers is the organophosphate temephos. Resistance to temephos has been detected in multiple Ae. aegypti populations in the Americas 79,80 and poses a serious threat to Ae. aegypti control. Little information is available about resistance in Ae. albopictus populations in the Region.\nControl programs must include a resistance monitoring program 81−83 (additional references are available at / en/) to assess efficacy and to establish a pesticide rotation plan to mitigate the development of resistance. 5. Monitor houses and buildings in the neighborhoods that are being treated and implement special control rounds after working hours, weekends, and holidays to assure that nearly 100% of homes and businesses are treated.\n\n# O u t b r e a k I n t e r v e n t i o n\nControlling an epidemic of CHIKV or a series of outbreaks over a larger geographic scale requires the following:\n1. Activating a command center (Emergency Operations Center), either physical or virtual, where epidemiologists, entomologists and vector control specialists, educators, media communicators, etc., can jointly plan, work, and evaluate progress throughout the epidemic. Epidemiological services need to be organized so that daily, detailed reports are sent to all authorized personnel in the affected areas (states, municipalities). To be successful, it will be necessary to establish an efficient system of communications, allowing for feed-back reports and the receipt of acknowledgements (by e-mail, fax, telephone, etc.).\nOrienting the population at large through the media on the possibility of resulting infection with CHIKV and on how families and communities can contribute to the abatement of the epidemic. Educational materials on specific actions to prevent or control CHIKV transmission should be elaborated and distributed by various media (TV, radio, newspapers, local organizations, schools, clinics, etc.). It is important to report daily (to the press) which communities or neighborhoods are being affected by CHIKV, so that residents and local authorities are aware of imminent risk of infection and can take appropriate actions (e.g., proper use of repellents, elimination of all standing water, organizing clean-up campaigns, etc.). Dissemination of this information needs to be done in a way that no personal information or identifiers are released to the public at any time.\n3. Ensuring that infected and febrile persons are protected from mosquito bites by using bednets at home and in hospitals.\n\n# Orienting vector control operations through real-time epidemiological\nand entomological assessments of CHIKV transmission, indicating the specific areas that need to be treated. In areas where dengue is endemic, knowledge from a retrospective analysis of dengue virus transmission or previous experience with dengue viruses should be used to guide vector control operations.\n5. Applying effective vector control measures. An epidemic is generally a series of smaller outbreaks occurring simultaneously in several different places within a country (neighborhoods, cities, municipalities, states), where the number of disease cases is unusually large. This means that epidemic control measures may need to be applied concurrently in several locations.\nLarge-area control of mosquito populations over short periods by spraying insecticides from truck-or aircraft-mounted equipment has not proven effective in reducing dengue transmission. Large-scale outdoor application of pesticides may be beneficial when used in conjunction with other control measures as part of an integrated mosquito control program. 76 Therefore, effective vector control measures to be applied during an epidemic are similar to those recommended for area-wide CHIKV containment (above)\nand dengue virus outbreaks. 66 The main difference is that they should be simultaneously applied in many areas to abate individual outbreaks.\na. Geo-reference each CHIKV case to the level of operational control areas.\nIn the case of endemic areas, conduct the retrospective epidemiological study at this level, so that stratification serves operational purposes.\nUse Geographical Information System (GIS) to map operational units, make and distribute maps of disease incidence, and spatially monitor the epidemic.\nb. Divide the target area (e.g., state, municipality) into relatively uniform areas (operational control areas) that will be treated using an area-wide approach (neighborhoods with 2,000−5,000 persons; census areas, zip-codes, etc.). All premises, businesses and other areas (parks, cemeteries, abandoned lots, areas along creeks, illegal dumps, etc.) will be simultaneously treated within a few days. This operational division of the space should be conducted well in advance of an eventual introduction of CHIKV.\nc. Area-wide vector control measures imply having sufficiently trained personnel, equipment, and supplies to treat the environment where Aedes mosquitoes are being produced. By significantly reducing mosquito adults (using adulticides) and the production of new adult mosquitoes (source reduction and elimination, larvicides) in a particular area, the transmission cycle could be interrupted, and CHIKV could be driven to extinction. This scenario is possible only if the number of biting mosquitoes is dramatically reduced for the length of time it takes for humans and vectors to become clear of CHIKV. For this reason, vector control measures need to achieve a very high efficiency, as measured by the elimination of an extremely large proportion of vector mosquitoes.\n\n# L i m i t a t i o n s o f Ve c t o r C o n t r o l\nVector population reduction and the associated reduction of vector-human contact should be correlated with reduced virus transmission and reduced human disease. In order to interrupt an outbreak, however, vector population reduction must be immediate, substantial, and sustained. Adult mosquitoes will continue to emerge and replace adult mosquitoes killed by adulticides.\nTherefore, it is essential to maintain IVM programs with complete coverage and repeated treatments. In addition to the presence of mosquito control professionals and an active IVM program, it is important to maintain the support and cooperation of all members of society. 67\n\n# Medical personnel\n- Develop and provide information via websites, booklets, pamphlets, and pocket guides.\n- Participate in conferences addressing risk factors, case presentations, diagnostics, and risk factors.\n- Develop frequently addressed questions (FAQs) addressing differences between CHIKV and dengue, if applicable.\n- Establish hotline infrastructure for clinical support.\n- Implement response plan(s).\n- Provide updated, easy-toaccess information concerning epidemiology of outbreak, risk factors, case definition, diagnostics, etc.\n- Update information flow as necessary.\n- Activate and staff an information hotline for clinical support. - Continue to provide updates.\n- Continue to support the clinical hotline.\n- Provide information concerning sequelae.\n- Evaluate communication with the clinical community; gather \"lessons learned\".\n- Provide final response report. - Continue to gather information from laboratories.\n- Gather \"lessons learned\".\n(Continued) Local and regional health department personnel; epidemiologists - Health department staff, epidemiologists, and communicators work together to develop and provide information to be used by public health partners and the media to address the surveillance methods, analysis of data, and development of messages for the general population.\n- Activate information channels for the timely gathering of information to support decision cycles at the operational level, including the health care services. - Evaluate communications with health departments and epidemiologists.\n- Gather \"lessons learned\".\n(Continued)\nTravelers associations, businesses, and organizations - Outreach to those traveling to regions at risk for CHIKV, describing symptoms and prevention of the disease, using official and business websites and factsheets, and other means (such as closed circuit TV, message boards, and public service announcements). - Request travel and tourism industry operators to intensify the communication activities included in the travelers information plan.\n- Provide updates concerning disease status and preventive and protective actions.\n- Evaluate the timeliness of response by the travel industry.\n- Gather \"lessons learned\".\nMaritime, land, and air transportation industry and authorities (ports) - Develop THANs before the event for use by port authorities, customs and transportation security agencies.\n- Provide the industry and authorities with information concerning IHR requirements. - Request maritime, land, and air industry and port representatives to intensify their communications activities as appropriate for the response.\n- Provide updates concerning disease status and preventive and protective actions.\n- Evaluate the timeliness of response by the travel industry.\n- Gather \"lessons learned\".\nGeneral population - Use multiple channels to inform the general public of the potential for CHIKV risk and means of prevention and protection.\n- Plan for use of hotlines; support local hotlines as appropriate.\n- Develop health education materials, such as website pages, posters, pamphlets, handbills, billboards, SMS text messaging and social media, and on-line social networking.\n- Consider the use of interpersonal communication through group meetings, in schools; make optimal use of traditional/folk media.\n- Special campaigns may be carried out via the mass media, including in local newspapers/ magazines, radio, and TV, as well as through outdoor publicity, such as billboards.\n- Monitor communication channels. Assess delivery of the messages.\n- Increase efforts to garner support of insecticide use and other control measures, as needed.\n- Develop location-specific messaging and update as appropriate.\n- Open hotlines, and support local hotlines as appropriate.\n(Continued)\nFaith-based communities - Develop and provide information for use within religious media networks, during services, and among outreach groups.\n- Collaborate with leadership to advance protection and prevention efforts and vector management. addressing protection and prevention efforts and vector management.\n- Provide updates to the private sector concerning the response.\n- Evaluate involvement of private sector in the communication plan for preparation and response to CHIKV.\n- Gather \"lessons learned\".\nReal time RT-PCR can be performed using a number of commercially available kits. Either the BioRad iScript 1 Step RT-qPCR (#170-8895) or the QIAGEN QuantiTect Probe RT-PCR kit (#204443) is currently used by the Arboviral Diagnostic Laboratory at DVBD, CDC. The two kits are nearly identical in the reaction setup, with one exception: the volume of enzyme used in the QIAGEN kit is 0.5 µl per reaction, instead of 1.0 µl; the volume of water in the master mix is adjusted by 0.5 µl to account for this. The setup shown below is for the QIAGEN kit. Note also that the volume of RNA added per reaction below is 10 µl but can be increased or decreased with the appropriate adjustment of total volume with water.\n\n# Component\nVol. per reaction Appendix B. Real-Time Reverse Transcriptase-Polymerase Chain Reaction Protocol (Cont.)\n\n# Interpretation\nThe following algorithm is used by the Arboviral Diagnostic Laboratory at DVBD, CDC to evaluate the TaqMan results.\nPositive:\n- Cutoff (Ct) value 38 in duplicate wells Equivocal:\n- Ct value 38 in one of two wells Negative:\n- Ct values >38 in duplicate wells\nAll positive and equivocal samples are repeated with a second set of primer/probes for confirmation. A positive result in any of the negative controls invalidates the entire run. Failure of the positive control to generate a positive result also invalidates the entire run.\nAppendix B. Real-Time Reverse Transcriptase-Polymerase Chain Reaction Protocol (Cont.)\n2. Extract RNA from 140 µl of the liquid specimen (CSF, serum, or clarified homogenate) using the QiAmp viral RNA kit (QIAGEN part # 52904). Follow the manufacturer's protocol exactly.\n\n# NOTE:\nFor mosquito specimens add one additional wash with AW1. Extract at least two negative controls and two positive controls along with the test specimens. The positive controls should differ in the amount of target RNA present (i.e., a pre-determined high positive and a low positive).\nThe volume of sample extracted can be greater or less than the standard volume stated in the QIAGEN protocol (140 µl) with the appropriate adjustments to all other volumes in the protocol. 4. Wash wells 5X with wash buffer by using an automatic plate washer. Wells should be filled to the top each cycle. 5. Add 50µl per well of the patient's serum (S) diluted 1:400 in wash buffer to a block of six wells, or add patient's CSF undiluted to two wells only, so that the CSF will be tested singly against the viral and normal antigens. Note: CSF can be diluted to a maximum of 1:5 in wash buffer if necessary. Add positive control human serum (Ref) diluted in wash buffer according to a previous titration, and a negative human serum control (N) diluted 1:400 in wash buffer to a block of six wells each. Incubate plates for 1 hour at 37°C in a humidified chamber.\n6. Wash 5X. 7. Dilute viral antigen in wash buffer according to a previous titration. Add 50µl per well to the left three wells of each serum block. To the right three wells of each block, add 50µl per well of normal antigen diluted in wash buffer to the same concentration as the viral antigen.\nIncubate overnight at 4°C in a humidified chamber.\n8. Wash 5X.\nAppendix C. IgM and IgG Serologic Assay Protocols (Cont.)\n\n# IgM ANTIBODY CAPTURE ENZYME-LINKED IMMUNOSORBENT ASSAY PROTOCOL\nInterpretation All patient P/N values greater than or equal to 2.0 should be reported as presumptive IgM-positive (see paragraph below), as long as they meet the requirements listed above. In the event that an early acute CSF or serum is negative by this test, a convalescent serum specimen must be requested and tested before that patient is reported as negative for serological evidence of recent viral infection. Without testing of a convalescent specimen, a negative result may reflect testing of an acute-phase specimen obtained before antibody has risen to detectable levels. In most patients, IgM is detectable eight days post-onset of symptoms from an alpha-, flavi-, or California group virus infection. IgM persists for at least 45 days, and often for as long as 90 days. The positive P/N cut-off value of 2.0 is empirical, based on experience and convention. P/N values that lie between 2.0 and 3.0 should be considered suspect false-positives. Further tests should be performed to determine the status of these specimens.\nIt should be stressed that the P/N value for a specimen at the screening dilution of 1:400 is not an indication of absolute antibody concentration, i.e., the P/N value is not quantitative.\n\n# Principle\nThe IgG-ELISA provides a useful alternative to immunofluorescence for identification of a viral isolate or documentation of a serologic response. IgG-ELISA is less subjective than immunofluorescence and large numbers of samples can be processed. Viral group-reactive monoclonal antibody is coated on a 96-well plate, followed sequentially by known viral antigen, patient serum, enzyme-conjugated human IgG, and lastly substrate for the conjugate used. This constitutes the IgG-ELISA used at the Arboviral Diagnostic Laboratory, DVBD, CDC.\n\n# Safety\nThe procedure should be performed under laboratory safety conditions that take into consideration the potential infectious nature of the serum specimens involved. Lab coat, gloves, and a laminar flow hood is recommended.\n\n# Materials and Reagents\nA negative IgG-ELISA result plus a negative MAC-ELISA result indicates the lack of any recent or past infections with the test virus if the sample was collected >7 days post illness onset. These results on a more acute sample cannot rule out the infection as the antibody response may not have had time to form.\nThe positive P/N cut-off value of 2.0 is empirical, based on experience and convention. P/N values that lie between 2.0 and 3.0 should be considered suspect false-positives. Further tests should be performed to determine the status of these specimens.\nIt should be stressed that the P/N value for a specimen at the screening dilution of 1:400 is not an indication of absolute antibody concentration, i.e., the P/N value is not quantitative. - Train spokespersons on this subject.\n\n# Appendix D. Example of a Case Report Form\n- Develop a plan for risk and crisis communication. - Provide the associations with FAQ sheets.\n- Work with associations to provide prevention messages to the general population.\n- Intensify communication with the medical sciences and health-professional associations with respect to health care services and look for disease patterns and trends.\n- Evaluate the timeliness of information provided to the associations, as well as the timeliness of transfer of the information to the association's membership.\nAppendix H. Model of Risk and Outbreak Communication Plan (Cont.)\n\n# Target audience\n\n# Preparation phase\nResponse phase\n\n# Recovery phase\nVector control personnel - Vector control personnel and communicators work together to develop and provide information concerning possible CHIKV vectors and integrated vector management, in both electronic and hardcopy formats via video conferences, workshops, etc. - Activate communication plan with health professionals and other entities.\n- Gather information concerning the effectiveness of ongoing integrated vector management activities, if appropriate.\n- Provide updated information to health professionals concerning protection and prevention. - Evaluate communications actions for vector control and gather \"lessons learned\".\n- Gather information concerning best practices for vector management.\nAppendix H. Model of Risk and Outbreak Communication Plan (Cont.)\n\n# Target audience\n\n# Preparation phase\nResponse phase\n\n# Recovery phase\nBlood banks - Provide information to blood bank managers concerning risks associated with CHIKV.\n- Develop and provide information concerning blood-product management and risks, as well as preparation for donor shortages.\n- Develop donor screening guidelines and procedures.\n- Develop fact sheets for donors and prospective donors for distribution in the blood banks. - Establish active communication with blood banks to address shortages of supplies and of donors within restricted areas, in order to inform the general population as well as the media.\n- Coordinate with implementation of donor screening guidelines and procedures in areas affected by CHIKV emergence.\n- Evaluate the effectiveness of recommendations that blood banks provide to blood donors.\n- Develop a communications plan to support lifting of restrictions for donations within a previously restricted area.\nAppendix H. Model of Risk and Outbreak Communication Plan (Cont.)\n\n# Target audience\n\n# Preparation phase\nResponse phase\n\n# Recovery phase\nCivil authorities, government officials - Engage in advocacy to gain the support needed for effective preparation and response.\n- Keep channels open with local, regional, and national levels of government.\n- Designate and train spokespersons, providing function-specific information appropriate for the level of responsibility. - Implement the communications plan with the other government authorities, updating spokespersons information.\n- Include appropriate representatives in the JIC. - Evaluate the effectiveness of preparation and response communications activities conducted with authorities and officials.\n- Gather \"lessons learned\".\nAppendix H. Model of Risk and Outbreak Communication Plan (Cont.)\n\n# Target audience\n\n# Preparation phase\nResponse phase\n\n# Recovery phase\nThe media - Develop and maintain relationships with the media that will support communications activities.\n- Provide training, participate in interviews, and develop public service announcements to advice media partners and prepare them for potential CHIKV activity.\n- Prepare spokespersons. Spokespersons must be technically and politically credible and willing to interact with the press on short notice.\n- Establish a permanent channel of information with the media for regular communications, including briefings and interviews.\n- Disseminate regular reports from the JIC concerning the status of outbreak to provide a consistent message.\n- Monitor press reports and coverage. Conduct analysis of reports for appropriateness and relevance and adjust messaging/ strategies accordingly.\n- Continue to provide updates to the media, including appropriate messaging as the risk of transmission is reduced.\n\n# O b j e c t i v e s\nThe aim of this meeting was to assemble a technical advisory group to review and adapt a preliminary draft of \"Preparedness and Response for Chikungunya Virus Introduction in the Americas\". The technical advisory group included experts in various fields from the Americas, including epidemiologists, clinicians, entomologists, laboratory personnel, and communication specialists.\nAfter discussing the document's various chapters, these experts submitted changes, additions, and rewrites that they considered appropriate to make the guidelines factual and relevant to all countries in the Region. The guidelines are meant to be a useful tool that can be adapted and applied by each Member Country in establishing the most appropriate strategies for the prevention and control of Chikungunya virus in the Americas. -Communications (Communications Chapter)\n16:15 -17:45 Groups meet to decide on approach (Coordinator, Presenter)"}}},{"rowIdx":82,"cells":{"id":{"kind":"string","value":"30bfde21e4cbd38f27cc786eb8e3c3f8711156aa"},"source":{"kind":"string","value":"nice"},"text":{"kind":"string","value":"Vortioxetine for treating major depressive episodes\n\nEvidence-based recommendations on vortioxetine (Brintellix) for treating major depressive episodes in adults.\n\n# Guidance\nVortioxetine is recommended as an option for treating major depressive episodes in adults whose condition has responded inadequately to 2 antidepressants within the current episode.\nPeople whose treatment with vortioxetine is not recommended in this NICE guidance, but was started within the NHS before this guidance was published, should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.# The technology\nVortioxetine (Brintellix, Lundbeck) is an antidepressant that is thought to exhibit its clinical effect through direct modulation of receptor activity and inhibition of the serotonin transporter. Vortioxetine has a marketing authorisation in the UK 'for the treatment of major depressive episodes in adults'.\nThe summary of product characteristics lists the following 'common' and 'very common' adverse reactions for vortioxetine: abnormal dreams, constipation, diarrhoea, dizziness, itching, nausea and vomiting. For full details of adverse reactions and contraindications, see the summary of product characteristics.\nVortioxetine is administered orally. The recommended starting dosage is 10 mg once daily in adults younger than 65 years, and 5 mg once daily in adults 65 years and older. Depending on how the symptoms respond, the dose may be increased to a maximum of 20 mg once daily or decreased to a minimum of 5 mg once daily. Treatment for at least 6 months is recommended after the symptoms resolve. The price of a pack (28 tablets) of 5 mg, 10 mg or 20 mg tablets is £27.72 (excluding VAT; company's submission). Costs may vary in different settings because of negotiated procurement discounts.# The company's submission\nThe Appraisal Committee (section 7) considered evidence submitted by Lundbeck and a review of this submission by the Evidence Review Group (ERG; section 8).\n\n# Clinical effectiveness\nThe company conducted a systematic review of the literature to identify studies evaluating the clinical effectiveness and safety of vortioxetine for treating adults having a moderate‑to‑severe major depressive episode. These adults included those who had not tolerated initial antidepressant treatment or whose condition had responded inadequately to it, and who needed further antidepressant therapy (hereafter referred to as the 'second‑line population'). Therefore, in its original submission, the company did not include in its analyses all adults with major depressive disorder, as specified in NICE's final scope and vortioxetine's marketing authorisation. In its original submission, it identified 2 phase III randomised controlled trials, REVIVE and TAK318.\nREVIVE was an international (14 European countries including the UK), double‑blind, randomised, active‑control trial. It included 501 adults with a single episode of moderate‑to‑severe major depressive disorder or recurrent major depressive disorder whose condition had inadequately responded to monotherapy with a selective serotonin reuptake inhibitor (SSRI) or a serotonin–norepinephrine reuptake inhibitor (SNRI). Patients were randomised 1:1 to flexible doses of vortioxetine (10–20 mg daily; starting dose 10 mg daily), or agomelatine (25–50 mg daily; starting dose 25 mg daily). Patients were assessed weekly during the first 4 weeks of treatment and then every 4 weeks until the end of the 12‑week treatment period. A further safety assessment was scheduled 4 weeks after completing or withdrawing from the study. Most patients enrolled into REVIVE were women (74.7%), most were white (99.8%), the mean age was 46.3 years and they had a mean of 2.5 previous major depressive episodes. The company stated that both groups had comparable baseline Montgomery–Åsberg Depression Rating Scale (MADRS) scores and previous antidepressant use. Most patients received the maximum dosage of vortioxetine (20 mg, 64.7%) and agomelatine (50 mg, 71.7%) from weeks 4 to 12.\nThe primary outcome measure in REVIVE was change in MADRS score from baseline to week 8 (MADRS is a rating scale consisting of 10 items, each rated 0 to 6 , contributing to a total score from 0 to 60; the higher the score, the more severe the condition). A 'full analysis set' population (that is, people who were randomised into the study and had a baseline assessment and at least 1 further assessment) was used to analyse the efficacy outcomes. The company tested a primary hypothesis of non‑inferiority. Non‑inferiority was considered established if the upper bound of the two‑sided 95% confidence interval of the difference between treatment groups in MADRS total score at week 8 did not exceed +2 MADRS units compared with agomelatine. The mean change from baseline in MADRS total scores at week 8 were −16.5 and −14.4 points in the vortioxetine group and the agomelatine group respectively. This resulted in a mean difference of −2.16 points in favour of vortioxetine (95% confidence interval −3.51 to −0.81; see table 1).\nPre-specified subgroup analyses of the primary outcome were carried out by the company for sex, age, baseline severity, baseline anxiety and class of prior antidepressant. The company stated that these analyses suggested that vortioxetine improved the MADRS score compared with agomelatine across all pre‑specified subgroups.\nThe company stated that vortioxetine statistically significantly improved outcomes compared with agomelatine across the analyses of outcomes reflecting response and remission measured by MADRS score (see table 2). Response is defined as a 50% or more decrease from baseline in the MADRS. Remission is defined as a MADRS total score of 10 or less.\n\n## Table 1 Company's analysis of primary outcome in REVIVE\nOutcome\nVortioxetine: difference compared with agomelatine\nWeek 8\nWeek 12\nMMRM\nLOCF, ANCOVA\nMMRM\nLOCF, ANCOVA\nΔ MADRS total score\n(−3.51 to −0.81)\n(−3.45 to −0.60)\nΔ=mean change from baseline.\nPrimary efficacy analysis.\n*p<0.01; p<0.001 compared with agomelatine.\nVortioxetine: baseline n=252, week 8 n=220, week 12 n=200.\nAgomelatine: baseline n=241, week 8 n=190, week 12 n=178.\nAbbreviations: ANCOVA, analysis of covariance; LOCF, last observation carried forward; MADRS, Montgomery–Åsberg Depression Rating Scale; MMRM, mixed model for repeated measures; n, number.\n\n## Table 2 Response and remission in REVIVE\nResponse (MADRS)\nRemission (MADRS)\nWeek 8\nVortioxetine\nAgomelatine\nAdjusted odds ratio (95% CI)\n(1.26 to 2.60)\n(1.17 to 2.52)\nWeek 12\nVortioxetine\nAgomelatine\nAdjusted odds ratio (95% CI)\n(1.26 to 2.65)\n(1.39 to 2.90)\n*p <0.05; p <0.01; *p <0.001 compared with agomelatine.\nAbbreviations: CI, confidence interval; MADRS, Montgomery–Åsberg Depression Rating Scale.\nHealth-related quality of life was measured at baseline and at weeks 4, 8 and 12 in the REVIVE trial using the EuroQol‑5 dimensions survey (EQ‑5D, see table 3).\n\n## Table 3 EQ‑5D summary scores and changes in EQ‑5D score from baseline\nAssessment\nVortioxetine\nAgomelatine\np value\nn\nMean (SD)\nChange from baseline\nn\nMean (SD)\nChange from baseline\nBaseline\nWeek 4\nWeek 8\nWeek 12\nBased on a mixed model for repeated measures analysis.\nAbbreviations: n, number; SD, standard deviation.\nTAK318 was a multicentre (62 centres in USA and Canada), double‑blind, randomised, active‑control trial including 447 adults with stable major depressive disorder experiencing treatment‑emergent sexual dysfunction. Patients were randomised 1:1 to flexible doses of vortioxetine (10–20 mg daily; starting dose 10 mg daily), or escitalopram (10–20 mg daily; starting dose 10 mg daily). Patients were assessed at the end of the 8‑week treatment period and had an additional safety assessment 3 weeks after study completion.\nThe primary outcome measure in TAK318 was change from baseline in the Changes in Sexual Functioning Questionnaire Short‑Form 14 (CSFQ‑14) total score after 8 weeks of treatment (total score ranges from 14 to 70; higher scores reflect higher sexual functioning). A 'full analysis set' population was used to analyse the efficacy outcomes. Sexual functioning improved in both the vortioxetine and escitalopram groups, with a mean difference of 2.2 points in favour of vortioxetine compared with escitalopram (p=0.013).\nThe company conducted both a Bayesian indirect treatment comparison and a frequentist indirect treatment comparison using the Bucher method for 2 outcomes: probability of remission, and the proportion of people who stop treatment because of adverse events. The company systematically searched the literature and identified the REVIVE trial plus 3 additional multicentre, blinded, randomised, controlled trials comparing: agomelatine with sertraline (Kasper et al. 2010); venlafaxine with citalopram (Lenox‑Smith et al. 2008); and bupropion with sertraline or venlafaxine (STAR*D). The company excluded:\nRosso et al. (2012), which compared bupropion with duloxetine, because it considered the method of randomisation (by day of the week) and blinding (single‑blind) inadequate\nplacebo‑controlled trials because the company's clinical advisers suggested that people who enrol in placebo‑controlled trials may be different from those in active‑controlled studies, but the company included these trials in a sensitivity analysis.The company stated that its searches did not identify any evidence to include on 2 other relevant comparators (fluoxetine or mirtazapine) in the indirect treatment comparison.\nKasper et al. (2013) was a post‑hoc analysis of the 'pre‑treated' population from 2 trials of agomelatine in people with major depressive disorder. The number of patients enrolled in each of the 4 trials ranged from fewer than 100 (Kasper) to 789 (STAR*D). The mean age of patients was reported for 3 of the 4 trials and ranged from 41.8 years (STAR*D) to 46.3 years (REVIVE). Baseline severity measured by Hamilton Depression Rating Scale (HAM‑D) was between 18.9 (STAR*D) and more than 31.0 (Lenox‑Smith et al. 2008), but the company considered that the differences between the trials would not have had an impact on the treatment effect. In general, STAR*D enrolled a higher proportion of men who were younger and whose depression was less severe than the populations in the other trials. Outcomes were assessed at different time‑points in the trials, from 6 weeks (Kasper) to 14 weeks (STAR*D). Each study measured depressive symptoms (and hence remission) using different scales: MADRS (REVIVE), HAM‑D17 (Kasper, STAR*D) and HAM‑D21 (Lenox‑Smith). However, the company stated that each trial used clinically accepted cut‑off rates for remission, which are generalisable regardless of the scale used.\nThe company stated that the results of its indirect treatment comparison suggested that vortioxetine works better and is better tolerated than the comparators. The results of the company's indirect treatment comparison are presented in tables 4 and 5. The company stated that it did not assess heterogeneity because of the small number of studies included in the network.\n\n## Table 4 Summary of results of company's frequentist indirect treatment comparison\nTreatment\nRemission rate\nPeople stopping treatment because of adverse events (withdrawal)\nRate (%)\nRisk difference versus vortioxetine (%)\n% CI\nRate (%)\nRisk difference versus vortioxetine (%)\n% CI\nVortioxetine\nn/a\nn/a\nn/a\nn/a\nAgomelatine\n−19.4 to −2.6\n−1.1 to 8.3\nSertraline\n−29.9 to 1.1\nto 21.1\nVenlafaxine\n−24.3 to 9.9\nto 23.8\nBupropion\n−27.8 to 6.4\nto 30.1\nCitalopram\n−41.1 to 7.5\n−0.3 to 24.5\nAbbreviation: CI, confidence interval; n/a, not applicable.\n\n## Table 5 Summary of results of company's Bayesian indirect treatment comparison\nTreatment\nRemission rate\nPeople stopping treatment because of adverse events (withdrawal)\nRate (%)\nOdds ratio vortioxetine versus comparator (%)\n% CrI\nRate (%)\nOdds ratio vortioxetine versus comparator (%)\n% CrI\nVortioxetine\nn/a\nn/a\nn/a\nn/a\nAgomelatine\nto 2.37\nto 1.17\nSertraline\nto 4.24\nto 0.62\nVenlafaxine\nto 3.07\nto 0.65\nBupropion\nto 3.77\nto 0.46\nCitalopram\nto 6.60\nto 0.86\nAbbreviation: CrI, credible interval; n/a, not applicable.\nThe company presented short‑term safety data from REVIVE. About half of patients in each treatment group had 1 or more adverse reaction over the 12‑week treatment period. Adverse reactions with an incidence of 5% or more for vortioxetine or agomelatine respectively were: nausea (16.2% and 9.1%), headache (10.3% and 13.2%), dizziness (7.1% and 11.6%) and somnolence (4.0% and 7.9%). Fewer patients in the vortioxetine group (1.2%) compared with the agomelatine group (1.7%) experienced serious adverse events. Fewer patients stopped treatment because of adverse events in the vortioxetine group (5.9%) than in the agomelatine group (9.5%).\nThe company also presented safety data from 5 open‑label long‑term extension studies including a total of 2587 patients, of which 54% received vortioxetine for 52 weeks or more. The overall incidence of adverse reactions was 74.6%, and was higher in the 15–20 mg dose group (78.9%) than in the 2.5–10 mg group (71.2%).\n\n# Cost effectiveness\nThe company did not identify any published studies of the cost effectiveness of vortioxetine for treating the second‑line population. It submitted a decision tree model with a Markov component to include subsequent treatment switches to third and later lines. It assumed that a patient can be offered 1 of 5 treatments: vortioxetine, agomelatine, citalopram, sertraline and venlafaxine. The company conducted the economic analysis from an NHS and personal social services perspective and chose a time horizon of 12 months so did not discount costs and health effects. A half‑cycle correction was applied to the health effects but not the costs in the Markov part of the model (cycle length 2 months).\nThe company stated its economic model represented a single major depressive episode. Hypothetical patients entered the model with major depressive disorder that had not responded to initial therapy. The decision tree included:\nan acute phase of treatment of 8 weeks (months 0–2)\na maintenance phase of 6 months (months 2–8) and\na recovery phase of 4 months' duration (months 8–12).The time that patients spent in the decision tree varied and depended on whether treatment was successful in each phase. If treatment succeeded in all 3 phases, with remission achieved and sustained to recovery, a hypothetical patient spent the entire 12 months in the decision tree model. The company's economic model also included events in which treatment was not successful (lack of remission or adverse events). These events led to a further treatment, that is, to third and subsequent lines of treatment. Patients who did not complete the acute or maintenance phase left the decision tree model and entered the Markov component. In a given cycle of the Markov component, a patient's condition could either remit or not. In its original economic model, the company assumed that patients remained on treatment for 6 months after their condition had remitted in the acute phase unless they experienced a long‑term adverse reaction (insomnia, sexual dysfunction or weight gain).\nThe company took data on the probability of remission after 8 weeks of treatment (acute phase) from its indirect treatment comparison (see table 4). The company assumed that a person's probability of relapse depended on the line of treatment rather than a specific drug: initial second‑line treatment (14.2%, from Limosin et al. 2004), third‑line treatment (25.0%, from STAR*D), and fourth- plus fifth‑line treatment (42.6%, from STAR*D). STAR*D was a prospective, sequentially randomised controlled trial of outpatients with nonpsychotic major depressive disorder who received 1 (n=3671) to 4 (n=123) successive acute treatment steps, including treatment combinations and augmented therapies. Patients who relapsed during the maintenance phase (which the company assumed occurred halfway through this phase) could switch to third and subsequent lines of treatment. The company assumed that clinicians then assessed these patients for remission 2 months after starting third‑line treatment. It took the data reflecting the proportion of patients whose condition was in remission after each line of treatment from STAR*D: third- (13.7%), fourth- (13.0%) and fifth‑line treatment (13.0%). The company considered that patients who had not relapsed after 6 months of maintenance treatment had recovered. These patients stopped treatment and the company assumed that they could not experience recurrent depression.\nResource use and costs in the company's economic model included those for treatment (drug), adverse events and each health state (that is, monitoring, inpatient and outpatient admissions). The company based drug costs on the list prices from the 'Monthly Index of Medical Specialities'. Dosages in the acute phases were based on the World Health Organization Defined Daily Dose (for example, 10 mg daily for vortioxetine), and dosages in the maintenance phase were based on the mean dose reported at the end of trials included in the company's indirect treatment comparison. The company took data for health state resource use for the acute phases from an unpublished interim analysis of the PERFORM study (n=226, which included people previously untreated) and, for the maintenance phase, from Byford et al. (2011; the General Practice Research Database 2001/06 – 88,935 people with depression and at least 2 antidepressant prescriptions). The company took data for the health state costs from Unit Costs of Health and Social Care (2013) and NHS Reference Costs. The company assumed that no treatments were prescribed to manage adverse events, but that around one‑third of people would incur an additional GP visit. Therefore, the company costed all adverse events based on an assumed 0.3 GP visits per patient per adverse event (£13.50).\nTo estimate health‑related quality of life in the acute phase, the company used EQ‑5D data from REVIVE (see table 6). However, in its original economic model for the maintenance phase, the company used EQ‑5D data from Sapin et al. (2004). Sapin was a French study that included 250 people with major depressive disorder in primary care, and assessed health‑related quality of life at baseline and after 8 weeks of treatment. The company noted that the mean MADRS score at baseline was 32.7 in Sapin compared with 29.1 in REVIVE, which may explain why the baseline EQ‑5D score from Sapin was lower than that in REVIVE. The company included disutility values associated with adverse events from Sullivan et al. (2004), and applied them for 3 weeks in the company's base case analysis.\n\n## Table 6 Summary of utility values used in company's economic model\nEvent\nUtility value\nComment\nSource\nAcute phase (0–8 weeks)\nDepression (baseline)\nNone\nREVIVE\nRemission\nNo remission\nWeighted average of people whose depression had not responded to treatment and people whose depression had responded but not remitted at 8 weeks\nMaintenance phase (after 8 weeks)\nRemission\nEQ‑5D score for people whose depression had remitted or responded to treatment\nSapin et al. 2004\nRelapse/no remission\nEQ‑5D score for people whose depression had not responded to treatment\nRecovery\nAssumed equal to remission\nDisutility values (decrements) of adverse events\nSexual dysfunction\nNone\nSullivan et al. 2004\nHeadache\nDiarrhoea\nSomnolence\nAssumed equal to drowsiness\nNausea\nAssumed average of gastrointestinal adverse events\nInsomnia\nAssumed equal to anxiety\nDry mouth\nNo data available, so company assumed no decrement\nNot applicable\nDizziness\nSweating\nWeight gain\nCompany calculation\nDixon et al. 2004 and REVIVE\nThe company's deterministic cost‑effectiveness results for vortioxetine compared with the comparators in the second-line population are presented in table 7.\n\n## Table 7 Company's base‑case cost‑effectiveness results for vortioxetine in people having second‑line treatment\nTechnology\nTotal costs (£)\nTotal QALYs\nIncremental costs (£)\nIncremental QALYs\nICER (£/QALY)\nVenlafaxine\nn/a\nn/a\nn/a\nVortioxetine\nCitalopram\nDominated\nSertraline\nDominated\nAgomelatine\nDominated\nDominated: fewer QALYs at greater cost than comparator.\nAbbreviations: ICER, incremental cost‑effectiveness ratio; n/a, not applicable; QALY, quality‑adjusted life year.\nThe company explored parameter and structural uncertainty in its economic model by presenting the results of 1‑way sensitivity analyses, scenario analyses and a threshold analysis. The 1‑way sensitivity analyses suggested the company's cost‑effectiveness results were most sensitive to:\nthe difference in remission rates at 8 weeks (acute phase) between vortioxetine and each comparator\nGP consultation costs\nthe utility value for remission at 8 weeks\nthe utility value for relapse after 8 weeks.However, in all but 2 of the company's 1‑way sensitivity analyses, vortioxetine dominated other treatments (was more effective and cost less) or had an incremental cost‑effectiveness ratio (ICER) below £15,670 per quality-adjusted life year (QALY) gained. Vortioxetine was dominated by venlafaxine and by citalopram when the lower bound of the 95% confidence interval was included for the differences in remission rates at 8 weeks. The company commented that its scenario analyses showed that its economic model was robust to all of the structural assumptions and remained the most cost‑effective treatment. Because the remission rate at 8 weeks was the most influential driver of the company's cost‑effectiveness results, it explored a threshold analysis around this parameter for vortioxetine, see table 8.\n\n## Table 8 Company's threshold analysis of remission rate for vortioxetine\nTreatment\nRemission rate at 8 weeks\n£20,000 per QALY gained threshold\nRemission rate at 8 weeks\n£30,000 per QALY gained threshold\nVortioxetine (base case)\nn/a\nn/a\nVortioxetine\nn/a\nn/a\nVenlafaxine\nVortioxetine\nn/a\nn/a\nAgomelatine\nVortioxetine\nn/a\nn/a\nSertraline\nVortioxetine\nn/a\nn/a\nCitalopram\nFigures in bold are base case remission rates.\nThreshold ICERs between vortioxetine and agomelatine are based on lower cost and fewer QALYs for vortioxetine, so the ICERs should be interpreted as willingness to accept QALYs lost, not willingness to pay for QALYs gained.\nAbbreviations: ICER, incremental cost‑effectiveness ratio; n/a, not applicable; QALY, quality‑adjusted life year.\n\n# ERG's critique of clinical effectiveness\nThe ERG stated that the reporting of the company's searches were clear and appropriate. The ERG noted that the company presented no evidence to suggest that the relative efficacy between non‑SSRIs may vary between first- and second‑line use (and beyond). It stated that it would be more appropriate to include the full evidence base for vortioxetine and its comparators, rather than restricting the evidence base from the outset to the second‑line population, so excluding 22 of the 24 completed studies of vortioxetine.\nThe ERG commented that REVIVE and TAK318 appeared well conducted but raised the following concerns:\nBoth trials included comparators of limited relevance to clinical practice in England (NICE has not issued any guidance for agomelatine).\nBoth trials were short considering the duration of treatment recommended by NICE to achieve and consolidate remission, so evidence of long‑term efficacy was uncertain.\nBoth trials evaluated the efficacy of vortioxetine 10–20 mg daily, so the efficacy of the licensed 5 mg daily regimen was uncertain.\nThe ERG commented that the population enrolled into REVIVE was broadly representative of the second‑line population in England. For example, baseline MADRS scores ranged from 22–43 points, which is consistent with people with moderate‑to‑severe major depressive disorder. However, the ERG noted that:\nmost patients were white (99.8%), which is unlikely to be reflective of the second‑line population in England\n% of patients had received an SNRI as initial treatment, which is not reflective of clinical practice in England, where first‑line SNRI use is negligible\nmost patients were recruited from an outpatient psychiatric setting (97.2%)\nthe proportion of patients from the UK was small (about 7%).\nThe ERG noted that, although the efficacy analyses in REVIVE and TAK318 used a modified intention‑to‑treat analysis (that is, full analysis set rather than including all randomised patients), the risk of bias was likely to be low because relatively few patients randomised were excluded.\nThe ERG commented that the results from the company's analysis of the primary and secondary outcomes from REVIVE had relatively wide confidence intervals, so the size of the difference in efficacy between vortioxetine and agomelatine was uncertain (see tables 1 and 2).\nThe ERG agreed with the company's assessment of bias for Rosso et al. (2012), so considered it was reasonable to exclude it, but noted it was the only trial that indirectly compared vortioxetine with duloxetine. The ERG stated that it was questionable whether Kasper et al. (2013) was suitable for inclusion in the indirect treatment comparison. It stated that it was unclear whether the population consisted entirely of patients receiving second‑line treatment, or whether it also included those who had been treated for a previous depressive episode in the last 12 months but were starting first‑line treatment for a current major depressive episode.\nThe ERG stated that it had significant concerns over the validity of the company's indirect treatment comparison because of the differences in the baseline patient characteristics and severity of depression of the populations across the 4 trials. It also stated that time of outcome assessment between trials (varying from 6–14 weeks) may also affect the results because rates of remission and withdrawal are likely to be time-dependent. The ERG concluded that the heterogeneous nature of data included in the network meant that the results may not be reliable.\nThe ERG highlighted that there was little evidence of a statistically significant improvement in the efficacy for vortioxetine compared with the comparators, given that the results from the company's indirect treatment comparison had wide confidence intervals. It stated that the findings in each specific trial drove the results of the company's indirect treatment comparison because of the sparse evidence network (that is, each arm of the network was informed by 1 trial). The ERG noted that basing results on risk differences was potentially inappropriate because they may be sensitive to the heterogeneity across trials (see table 4). However, it acknowledged that the company's results based on odds ratios were largely consistent (see table 5). The ERG also commented that the results from the company's sensitivity analysis including the 2 placebo‑controlled trials were broadly similar to those that excluded them.\nThe ERG stated that there was no evidence to suggest the relative efficacy between drugs that were not classified as SSRIs (for example, SNRIs) vary between first- and second‑line treatment (and beyond) (see section 3.21). Therefore, it sought further evidence from the company on a first‑line population during the clarification stage:\nThe ERG re-analysed data from a published meta‑analysis of placebo‑controlled trials with active reference treatment arms (Pae et al. 2015). Pae compared vortioxetine with agomelatine (1 trial), duloxetine (5 trials) and venlafaxine (1 trial). The ERG noted that both the European Medicines Agency and the company have criticised the use of trials including active references because they are not true randomised comparisons, given that patients whose condition is known to be non‑responsive to the reference treatment are excluded, possibly biasing results in favour of the active reference. The ERG accepted the potential for such bias, but did not consider it substantial enough to exclude these trials. The ERG stated that Pae found no evidence of any difference in efficacy between vortioxetine and venlafaxine, and that vortioxetine was less effective than duloxetine in reducing depression scores, or achieving response and remission.\nLlorca et al. (2014) published an indirect treatment comparison that included 57 placebo controlled trials of the following drugs: vortioxetine, agomelatine, desvenlafaxine, duloxetine, escitalopram, sertraline, venlafaxine, vilazodone. Llorca found no evidence of any difference in efficacy between vortioxetine and its comparators. The ERG commented that there was evidence to suggest fewer people stop vortioxetine because of adverse events than other treatments, including sertraline and venlafaxine. The ERG considered that Llorca may represent the most reliable evidence for comparing vortioxetine with other treatments.\nThe ERG concluded that, based on all the evidence, vortioxetine is likely to be similar in efficacy to other antidepressants, but may be superior to agomelatine and inferior to duloxetine.\nThe ERG agreed that vortioxetine appears generally safe and tolerable in people with major depressive disorder. The ERG stated that, although the incidence of adverse events was high in people taking vortioxetine, most were mild to moderate in nature, and there was no conclusive evidence that they were dose‑dependent.\nThe ERG also concluded that vortioxetine may have a better overall safety profile than other antidepressants, but sparse comparative data for adverse events prevented the ERG making a firm conclusion.\n\n# ERG's critique of cost effectiveness\nThe ERG stated that the company developed an unnecessarily complicated model structure, and that it was unclear why:\nThe company used different modelling approaches in the maintenance and recovery periods, rather than an initial decision tree for the acute phase and then a separate Markov component for all people in the subsequent 10‑month period.\nThe company assumed different time-points for relapse (after 3 months) and stopping treatment in the maintenance phase because of adverse reactions (after 1 month), which favoured those treatments with higher acquisition costs. The ERG noted that this introduced inconsistency between the timing of relapse for people within the decision tree and Markov components.\nThe ERG commented that basing the decision to change treatments solely on remission data at 8 weeks was an important limitation of the company's original economic model. It stated that the company's model therefore excluded people whose condition responded to treatment partially but had not remitted and that, in clinical practice, clinicians use response in deciding whether to continue treatments. The ERG commented that the company also used the 8‑week remission data in its original economic model to inform decisions to change treatment at 4 weeks in the model. The ERG explained that this ignored the costs of additional treatment for people whose disease responded but did not remit. It also explained that it may have overestimated health benefits for people whose disease remits because it assigned a utility value based on health improvements demonstrated over 8 weeks rather than 4 weeks. The ERG concluded that the company's base case may have underestimated vortioxetine's costs and overestimated vortioxetine's benefits.\nThe ERG noted that:\nBecause the company had assumed that a person's depression was not at risk of recurrence in the recovery phase, it introduced a potential bias in favour of the most effective initial treatment. The ERG agreed that the risk of relapse (or recurrence) may be different in later phases than in earlier phases of the condition, but that assuming no risk of recurrence seemed overly optimistic.\nThe company had assumed that people remain on treatment for 6 months after remission in the maintenance phase. The ERG considered that this was reasonable and consistent with NICE's guideline on depression in adults, but was aware that NICE recommends 2 years of continued treatment in people considered to be at high risk of relapse.The ERG acknowledged that the company explored both of these assumptions in the response to clarification by varying the time‑horizon of the model from 8 months (no recovery period) up to 2 years (treatment and monitoring costs continued in the recovery period). The ERG concluded that, although the company's base‑case analysis was robust to these scenarios, the ICER for vortioxetine compared with the next most cost‑effective treatment was higher than in the company's base‑case analysis, suggesting that including the original assumptions had potentially favoured vortioxetine.\nThe ERG stated that a half‑cycle correction for both costs and utility values would have been appropriate, rather than for utility values only, because different health states are associated with different costs for consultation or hospitalisation.\nThe ERG highlighted that using a 12‑month time horizon was reasonable for the 'average' patient because an untreated major depressive episode is estimated to last 5–6 months (World Health Organization 2008). However, the ERG noted that some people may be treated for longer than 12 months and therefore 12 months may not have been sufficient to capture all of the relevant costs and benefits.\nThe ERG highlighted that there was uncertainty around whether STAR*D was an appropriate study to inform the prognosis of people with depression whose condition had not remitted after second‑line treatment. The ERG considered that STAR*D included treatments that did not reflect the comparators in the model, and that the population of STAR*D was different from the population of REVIVE. It explained that using data from STAR*D for third- and later lines of treatment imposed a poorer prognosis (that is, lower remission rates and higher relapse rates) than expected for a population with the same characteristics as in REVIVE. The ERG stated that using STAR*D may have made the most effective second‑line treatment look even better (that is, vortioxetine in the company's base case analysis).\nThe ERG disagreed with the company's decision to use the same utility value for relapse, and for people whose condition was not in remission after 3 or more treatments. This was because they are very different health states. It highlighted that the utility value from Sapin et al. (2004), used by the company for people whose condition had not remitted, was lower than the utility value reported for people whose condition had not remitted at week 8 in the REVIVE trial. The ERG considered that it was not necessary to use a different source for the utility values in the maintenance phase, and that using these 2 sources (REVIVE and Sapin et al. 2004) favoured vortioxetine in the company's base‑case analysis. It also felt that the relapse health state should have reflected the recurrence of moderate‑to‑severe major depression and so the baseline level of utility (that is, 0.54). The ERG proposed alternative utility values for the company's model, see table 9.\n\n## Table 9 ERG's preferred utility values\nHealth state\nCompany's utility\nCompany's source\nERG's utility\nERG's source\nNo remission (0–8 weeks)\nREVIVE\nREVIVE (FAS, MMRM)\nNo remission (after 8 weeks)\nSapin (2004)\nRelapse (after 8 weeks)\nSapin (2004)\nREVIVE (baseline depression)\nAbbreviations: ERG, Evidence Review Group; FAS, full analysis set; MMRM, mixed model for repeated measures.\nGiven the issues highlighted by the ERG around the company's indirect treatment comparison (see sections 3.26 to 3.28), the ERG stated that there was considerable uncertainty associated with the ICERs. It concluded that the company's base‑case analysis can only be reliably used for comparisons of vortioxetine with agomelatine.\nThe ERG was aware from the World Health Organization (2008) that an untreated major depressive episode lasts on average 5–6 months. The ERG calculated the average duration of a major depressive episode for each treatment included in the company's model based on approximating the mean number of months not spent in the remission and recovery health states. The ERG highlighted that the lowest estimated duration for a major depressive episode for any given treatment in the company's model was for vortioxetine (6.73 months; longer than the 5–6 months stated by the World Health Organization). The ERG explained that this assumed implicitly that people who change treatment have a poorer prognosis compared with the broader major depressive disorder population. This therefore highlighted that the sources used to inform the parameters for remission and relapse for third- and later lines of treatment in the company's model were crucially important (for example, STAR*D).\nThe ERG presented deterministic ICERs for several exploratory analyses for second‑line treatment using the company's original economic model. These exploratory analyses used alternative sources of evidence for the relative effectiveness of vortioxetine compared with its comparators (see section 3.29 and table 10) and used the ERG's preferred utility values (see table 9).\nExploratory analysis 1 (see table 11):\nThe dosage of treatment was up‑titrated after 8 weeks (maintenance phase).\nSTAR*D was used to inform remission and relapses rates for third- and later lines of treatment.\nExploratory analysis 2 (see table 12):\nThe same dosage of treatment was used for the acute and mainanteance phases rather than up‑tritrated after 8 weeks.\nSTAR*D was used to inform remission and relapses rates for third- and later lines of treatment.\nExploratory analysis 3 (see table 13):\nThe dosage of treatment was up‑titrated after 8 weeks.\nThe remission rate for all treatments used third and subsequent lines of treatment was assumed to be equal to the average of the remission rates of the second‑line comparators. Therefore, the ERG assumed that the absolute rate of remission did not change from third and subsequent lines of treatment.\nThe same rate of relapse was applied for second and subsequent lines of treatment rather than based on the line of treatment (relapse rate taken from Limosin et al. 2004).\nExploratory analysis 4 (see table 14):\nThe dosage of treatment was up‑titrated after 8 weeks\nFor third and subsquent lines of treatment, all treatments had the same remission rates. However, the remission rates declined after each line of treatment. The ERG took the average of the remission rates of the second‑line comparators and calculated the remission rates for third and subsequent lines of treatment by applying a proportionate reduction based on the STAR*D trial.\nThe same rate of relapse was applied for second and subsequent lines of treatment rather than based on the line of treatment (relapse rate taken from Limosin et al. 2004).\n\n## Table 10 ERG's alternative scenarios for relative effectiveness: proportion of remitters at 8 weeks\nTreatment\nProbability of remission\nCompany submission\n(from ITC)\nERG scenario 1 (Llorca et al. 2014)\nERG scenario 2 (Pae et al. 2015)\nERG scenario 3 (equal effectiveness)\nVortioxetine\nAgomelatine\nSertraline\nn/a\nn/a\nn/a\nVenlafaxine (XR)\nDuloxetine\nn/a\nCitalopram\nn/a\nn/a\nn/a\nEscitalopram\nn/a\nn/a\nAbbreviations: ERG, Evidence Review Group; ITC, indirect treatment comparison; n/a, not applicable; XR, extended release.\n\n## Table 11 ERG exploratory analysis 1 using STAR*D data (with up‑titration)\nCosts\nQALYs\nIncremental\nICER\nCosts\nQALYs\nwith SSRI\nwithout SSRI\n(incremental analyses, in relation to next best)\nERG scenario 1: Llorca et al. (2014)\nVenlafaxine (XR)\nRef\nRef\nRef\nRef\nEscitalopram\nDominated\nn/a\nVortioxetine\nDominated\nDominated\nDuloxetine\nDominated\nDominated\nAgomelatine\nDominated\nDominated\nERG scenario 2: Pae et al. (2015)\nVenlafaxine (XR)\nRef\nRef\nRef\nRef\nVortioxetine\nDuloxetine\nAgomelatine\nDominated\nDominated\nERG scenario 3: Equal effectiveness\nEscitalopram\nRef\nRef\nRef\nn/a\nVenlafaxine (XR)\nDominated\nRef\nVortioxetine\nDuloxetine\nDominated\nDominated\nAgomelatine\nDominated – fewer QALYs at greater cost than comparator.\nAbbreviations: ERG, Evidence Review Group; ICER, incremental cost‑effectiveness ratio; n/a, not applicable; QALY, quality‑adjusted life year; Ref, reference comparator; SSRI, selective serotonin re‑uptake inhibitor; XR, extended release.\n\n## Table 12 ERG exploratory analysis 2 using STAR*D data (without up‑titration)\nCosts\nQALYs\nIncremental\nICER\nCosts\nQALYs\nwith SSRI\nwithout SSRI\n(incremental analyses, in relation to next best)\nERG scenario 1: Llorca et al. (2014)\nVenlafaxine (XR)\nRef\nRef\nRef\nRef\nEscitalopram\nDominated\nn/a\nVortioxetine\nDominated\nDominated\nDuloxetine\nDominated\nDominated\nAgomelatine\nDominated\nDominated\nERG scenario 2: Pae et al. (2015)\nVenlafaxine (XR)\nRef\nRef\nRef\nRef\nDuloxetine\nVortioxetine\nDominated\nDominated\nAgomelatine\nDominated\nDominated\nERG scenario 3: Equal effectiveness\nEscitalopram\nRef\nRef\nRef\nn/a\nVenlafaxine (XR)\nDominated\nRef\nVortioxetine\nDuloxetine\nDominated\nDominated\nAgomelatine\nDominated – fewer QALYs at greater cost than comparator.\nAbbreviations: ERG, Evidence Review Group; ICER, incremental cost‑effectiveness ratio; n/a, not applicable; QALY, quality‑adjusted life year; Ref, reference comparator; SSRI, selective serotonin re‑uptake inhibitor; XR, extended release.\n\n## Table 13 ERG exploratory analysis 3 assuming same relapse rate and average remission rate of second‑line treatments (with up‑titration)\nCosts\nQALYs\nIncremental\nICER\nCosts\nQALYs\nwith SSRI\nwithout SSRI\n(incremental analyses, in relation to next best)\nERG scenario 1: Llorca et al. (2014)\nEscitalopram\nRef\nRef\nRef\nn/a\nVenlafaxine (XR)\nRef\nVortioxetine\nDuloxetine\nDominated\nDominated\nAgomelatine\nDominated\nDominated\nERG scenario 2: Pae et al. (2015)\nVenlafaxine (XR)\nRef\nRef\nRef\nRef\nVortioxetine\nDuloxetine\nDominated\nDominated\nAgomelatine\nDominated\nDominated\nERG scenario 3: Equal effectiveness\nEscitalopram\nRef\nRef\nRef\nn/a\nVenlafaxine (XR)\nDominated\nRef\nVortioxetine\nDuloxetine\nDominated\nDominated\nAgomelatine\nDominated – fewer QALYs at greater cost than comparator.\nAbbreviations: ERG, Evidence Review Group; ICER, incremental cost‑effectiveness ratio; n/a, not applicable; QALY, quality‑adjusted life year; Ref, reference comparator; SSRI, selective serotonin re-uptake inhibitor; XR, extended release.\n\n## Table 14 ERG exploratory analysis 4 assuming same relapse rate and average remission rate with second‑line use with proportionate reduction based on STAR*D (with up‑titration)\nCosts\nQALYs\nIncremental\nICER\nCosts\nQALYs\nwith SSRI\nwithout SSRI\n(incremental analyses, in relation to next best)\nERG scenario 1: Llorca et al. (2014)\nEscitalopram\nRef\nRef\nRef\nn/a\nVenlafaxine (XR)\nRef\nVortioxetine\nDominated\nDominated\nDuloxetine\nDominated\nDominated\nAgomelatine\nDominated\nDominated\nERG scenario 2: Pae et al. (2015)\nVenlafaxine (XR)\nRef\nRef\nRef\nRef\nVortioxetine\nDuloxetine\nAgomelatine\nDominated\nDominated\nERG scenario 3: Equal effectiveness\nEscitalopram\nRef\nRef\nRef\nn/a\nVenlafaxine (XR)\nDominated\nRef\nVortioxetine\nDuloxetine\nDominated\nDominated\nAgomelatine\nDominated – fewer QALYs at greater cost than comparator.\nAbbreviations: ERG, Evidence Review Group; ICER, incremental cost‑effectiveness ratio; n/a, not applicable; QALY, quality‑adjusted life year; Ref, reference comparator; SSRI, selective serotonin re-uptake inhibitor; XR, extended release.\n\n# Company's additional evidence\nThe company provided additional evidence in its response to the appraisal consultation document. The company focused its additional evidence submission on people who had not tolerated, or whose major depressive episode had responded inadequately to, 2 antidepressants (hereafter referred to as the 'third-line population'). The company stated that there was no clinical-effectiveness evidence available for vortioxetine in people having third-line treatment. The company did not carry out any additional searches for comparators, and so the available clinical‑effectiveness evidence for vortioxetine and its comparators included: its original indirect treatment comparison for people having second‑line treatment (see section 3.11), Pae et al. (2015), Llorca et al. (2014) and the SOLUTION trial provided with the response to the appraisal consultation document.\nSOLUTION was an international, double‑blind, randomised, active‑control trial. It included 410 East Asian adults with recurrent moderate‑to‑severe major depressive disorder and did not exclude any people based on the line of treatment used for their current major depressive episode. Patients were randomised 1:1 to fixed doses of vortioxetine (10 mg daily) or venlafaxine (150 mg daily). They were assessed weekly during the first 2 weeks of treatment and then every 2 weeks until the end of the 8‑week treatment period. The primary outcome measure in SOLUTION was change from baseline in MADRS score at week 8. A 'full analysis set' population was used to test a primary hypothesis of non‑inferiority. Non‑inferiority was considered established if the upper bound of the two‑sided 95% confidence interval of the difference between treatment groups in MADRS total score at week 8 did not exceed +2.5 MADRS units compared with venlafaxine. The mean change from baseline in MADRS total scores at week 8 were −19.4 points in the vortioxetine group and −18.2 points in the venlafaxine group. This resulted in a mean difference of −1.2 points in favour of vortioxetine (95% CI −3.0 to 0.6). At week 8, 43.1 and 41.4% of the people's major depressive episode had remitted in the vortioxetine group and venlafaxine group respectively. The company considered that the SOLUTION trial was relevant to the decision problem because it directly compared vortioxetine with venlafaxine.\nThe company noted that, as a third‑line treatment, SSRIs were not offered in clinical practice in England and so were not relevant comparators for vortioxetine. The company revised its economic model structure so that it:\ndefined treatment success, and decisions to switch treatment, by remission and response (rather than remission alone)\nused the time point when patients changed to another treatment because their condition did not respond to treatment from the trials for the time point in the model (8 weeks rather than 4 weeks)\nincluded a risk of relapse or recurrence at all stages of depression (rather than only in the acute or maintentance phase)\nused utility values from REVIVE (rather than using utility values from REVIVE for the acute phase and utility values from Sapin et al. 2004 for the maintenance and recovery phases)\nincluded a 24‑month time horizon (with discounting of costs and health effects after 12 months).\nThe company adjusted the second‑line remission rates used in its original economic model to reflect third‑line remission rates used in its revised economic model using the proportional reduction observed in STAR*D between second- and third‑line treatment. For fourth and subsequent lines of treatment, the company used the absolute remission reported for third- and fourth‑line treatment in STAR*D.\nThe company presented probabilistic pairwise ICERs, as well as a fully incremental analysis, for several scenarios using its revised economic model:\nScenario 1a (see table 15): Primary care setting, up to 6 months' maintenance treatment and assuming equal use of healthcare resources for people whose condition was in remission and for people whose condition responded but was not in remission.\nScenario 1b (see table 16): Secondary care setting, up to 6 months' maintenance treatment and assuming equal use of healthcare resources for people whose condition was in remission and for people whose condition responded but was not in remission.\nScenario 1c (see table 17): Primary care setting, up to 6 months maintenance treatment and assuming that use of healthcare resources is 30% higher between weeks 8 and 12 in people whose condition was not in remission but responded compared with people whose condition was in remission.\nScenario 2a (see table 18): Primary care setting, up to 22 months' maintenance treatment and assuming equal use of healthcare resources for people whose condition was in remission and for people whose condition responded but was not in remission.\nScenario 2b (see table 19): Secondary care setting, up to 22 months' maintenance treatment and assuming equal use of healthcare resources for people whose condition was in remission and for people whose condition responded but was not in remission.\nScenario 2c (see table 20): Primary care setting, up to 22 months' maintenance treatment and assuming that use of healthcare resources is 30% higher between weeks 8 and 12 in people whose condition was not in remission but responded compared with people whose condition was in remission.In the company's revised base case, it assumed that all treatments were equally effective. The company also presented cost‑effectiveness results for scenarios using alternative sources of data on efficacy (see section 3.43).\n\n## Table 15 Company's cost‑effectiveness results for people having third‑line treatment for treating a major depressive episode (scenario 1a)\nCosts (£)\nQALYs\nPairwise ICERs (vortioxetine versus comparator)\nIncremental ICERs\nScenario: Equal efficacy\nVortioxetine\nn/a\nRef\nVenlafaxine\nDominant\nDominated\nDuloxetine\nDominant\nDominated\nAgomelatine\nScenario: Llorca et al. (2014)\nVenlafaxine\nDominated\nRef\nVortioxetine\nn/a\nDominated\nDuloxetine\nDominant\nDominated\nAgomelatine\nDominant\nDominated\nDominant – vortioxetine gave more QALYs at less cost than comparator; dominated – treatment gave fewer QALYs at greater cost than comparator.\nSouth west ICER (£ saved per QALY lost; vortioxetine less costly and less effective)\nAbbreviations: ICER, incremental cost‑effectiveness ratio; n/a, not applicable; QALY, quality‑adjusted life year; Ref, reference comparator.\n\n## Table 16 Company's cost‑effectiveness results for people having third-line treatment for treating a major depressive episode (scenario 1b)\nCosts (£)\nQALYs\nPairwise ICERs (vortioxetine versus comparator)\nIncremental ICERs\nScenario: Equal efficacy\nVortioxetine\nn/a\nRef\nVenlafaxine\nDominant\nDominated\nAgomelatine\nDuloxetine\nDominant\nDominated\nScenario: Llorca et al. (2014)\nVenlafaxine\nDominated\nRef\nVortioxetine\nn/a\nDominated\nDuloxetine\nDominant\nDominated\nAgomelatine\nDominant\nDominated\nDominant – vortioxetine gave more QALYs at less cost than comparator; dominated – treatment gave fewer QALYs at greater cost than comparator.\nSouth west ICER (£ saved per QALY lost; vortioxetine less costly and less effective)\nAbbreviations: ICER, incremental cost‑effectiveness ratio; n/a, not applicable; QALY, quality‑adjusted life year; Ref, reference comparator.\n\n## Table 17 Company's cost‑effectiveness results for people having third‑line treatment for treating a major depressive episode (scenario 1c)\nCosts (£)\nQALYs\nPairwise ICERs (vortioxetine versus comparator)\nIncremental ICERs\nScenario: Equal efficacy\nVenlafaxine\nRef\nVortioxetine\nn/a\nDuloxetine\nDominant\nDominated\nAgomelatine\nScenario: Llorca et al. (2014)\nVenlafaxine\nDominated\nRef\nVortioxetine\nn/a\nDominated\nDuloxetine\nDominant\nDominated\nAgomelatine\nDominant\nDominated\nDominant – vortioxetine gave more QALYs at less cost than comparator; dominated – treatment gave fewer QALYs at greater cost than comparator.\nSouth west ICER (£ saved per QALY lost; vortioxetine less costly and less effective)\nAbbreviations: ICER, incremental cost‑effectiveness ratio; n/a, not applicable; QALY, quality‑adjusted life year; Ref, reference comparator.\n\n## Table 18 Company's cost‑effectiveness results for people having third‑line treatment for treating a major depressive episode (scenario 2a)\nCosts (£)\nQALYs\nPairwise ICERs (vortioxetine versus comparator)\nIncremental ICERs\nScenario: Equal efficacy\nVenlafaxine\nRef\nVortioxetine\nn/a\nDuloxetine\nDominant\nDominated\nAgomelatine\nScenario: Llorca et al. (2014)\nVenlafaxine\nDominated\nRef\nVortioxetine\nn/a\nDominated\nDuloxetine\nDominant\nDominated\nAgomelatine\nDominant\nDominated\nDominant – vortioxetine gave more QALYs at less cost than comparator; dominated – treatment gave fewer QALYs at greater cost than comparator.\nSouth west ICER (£ saved per QALY lost; vortioxetine less costly and less effective)\nAbbreviations: ICER, incremental cost‑effectiveness ratio; n/a, not applicable; QALY, quality‑adjusted life year; Ref, reference comparator.\n\n## Table 19 Company's cost‑effectiveness results for people having third‑line treatment for treating a major depressive episode (scenario 2b)\nCosts (£)\nQALYs\nPairwise ICERs (vortioxetine versus comparator)\nIncremental ICERs\nScenario: Equal efficacy\nVenlafaxine\nRef\nVortioxetine\nn/a\nDuloxetine\nDominant\nDominated\nAgomelatine\nScenario: Llorca et al. (2014)\nVenlafaxine\nDominated\nRef\nVortioxetine\nn/a\nDominated\nDuloxetine\nDominant\nDominated\nAgomelatine\nDominant\nDominated\nDominant – vortioxetine gave more QALYs at less cost than comparator; dominated – treatment gave fewer QALYs at greater cost than comparator.\nSouth west ICER (£ saved per QALY lost; vortioxetine less costly and less effective)\nAbbreviations: ICER, incremental cost‑effectiveness ratio; n/a, not applicable; QALY, quality‑adjusted life year; Ref, reference comparator.\n\n## Table 20 Company's cost‑effectiveness results for people having third‑line treatment for treating a major depressive episode (scenario 2c)\nCosts (£)\nQALYs\nPairwise ICERs (vortioxetine versus comparator)\nIncremental ICERs\nScenario: Equal efficacy\nVenlafaxine\nRef\nVortioxetine\nn/a\nDuloxetine\nDominant\nDominated\nAgomelatine\nScenario: Llorca et al. (2014)\nVenlafaxine\nDominated\nRef\nVortioxetine\nn/a\nDominated\nDuloxetine\nDominant\nDominated\nAgomelatine\nDominant\nDominated\nDominant – vortioxetine gave more QALYs at less cost than comparator; dominated – treatment gave fewer QALYs at greater cost than comparator.\nSouth west ICER (£ saved per QALY lost; vortioxetine less costly and less effective)\nAbbreviations: ICER, incremental cost‑effectiveness ratio; n/a, not applicable; QALY, quality‑adjusted life year; Ref, reference comparator.\n\n# ERG's critique of the company's additional evidence\nThe ERG did not agree with the company that the results of Llorca et al. (2014) were biased because the rates of response and remission from several trials were not reported. The ERG noted that the results for the mean change in depression score from Llorca (no missing data) were consistent with the results for the rates of response and remission.\nThe ERG stated that SOLUTION was a well‑conducted randomised controlled trial but did not reflect the population in England. However, the ERG stated that the relative effectiveness between vortioxetine and venlafaxine was unlikely to differ substantially between people treated in East Asia and England. The ERG considered that the results from SOLUTION supported the ERG's original conclusions (and of Llorca et al. 2014) that vortioxetine is similarly effective to other non‑SSRIs, but may be better tolerated.\nThe ERG stated that the company's revised economic model more accurately reflected whether a person should continue or change treatment for their major depressive disorder in clinical practice in England (see section 3.45). The ERG considered that the company's revised economic model had used the most appropriate available data.\nThe ERG explained that, in most cases, the conclusions about vortioxetine's cost effectiveness depends on which source of efficacy data is chosen (for example, assumption of equal efficacy, Llorca et al. 2014, Pae et al. 2015, company's indirect treatment comparison in people having second‑line treatment, SOLUTION) rather than the scenario chosen (for example, primary or secondary care setting, length of maintenance treatment).\nFull details of all the evidence are available.# Consideration of the evidence\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of vortioxetine, having considered evidence on the nature of major depressive disorder and the value placed on the benefits of vortioxetine by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\nThe Committee heard from the clinical and patient experts about the nature of major depressive disorder. The Committee understood from the patient expert that treatment success was measured by a broad range of outcomes including time to remission, reduced incidence of relapse, and improvements in sexual function, sleep quality and cognitive function. The patient expert highlighted that the current options for treating major depressive disorder are associated with different adverse reactions, so having access to a range of treatments is important. The clinical and patient experts commented that major depressive disorder can impair a person's social life and ability to work, and impacts the lives of their families and carers. The patient expert explained that some people may stop treatment early because of a perceived lack of response and adverse reactions, and therefore considered that increasing available information about options would encourage people to seek or continue treatment. The Committee recognised the importance of having a range of treatment options for people with major depressive disorder.\nThe Committee discussed the management of major depressive disorder in adults. The Committee understood that major depressive disorder often has a remitting and relapsing course. It heard from the clinical expert that, in general, clinical practice reflects the recommendations in NICE's guideline on depression in adults. These include initial treatment in primary care with a generic selective serotonin reuptake inhibitor (SSRI) such as citalopram and high‑intensity psychological support. NICE's guideline further recommends that if a person's episode of major depression does not adequately respond, or if the person does not tolerate first‑line treatment, they and their clinicians should consider a different SSRI or a better‑tolerated, newer‑generation antidepressant. The clinical expert stated that most people in the NHS would receive escitalopram (also an SSRI) second line, but treatment choice is influenced by treatment history (for example, number of previous therapies, first or recurrent episode of depression) and presence of specific signs and symptoms. The Committee understood from the responses received to the appraisal consultation document that SSRIs are not an option for people having third‑line treatment for a major depressive episode in England. The clinical expert explained that, in clinical practice, people with:\nlow energy levels may receive venlafaxine (the Committee was aware that the company stated that venlafaxine is the most commonly used serotonin‑norepinephrine reuptake inhibitor at second line)\nagitation may receive mirtazapine because of its sedative effect (but mirtazapine is associated with weight gain so people may instead receive agomelatine).The Committee was aware that the NICE's guideline depression in adults gave GPs the option to prescribe second‑line treatments in primary care (for example, escitalopram or an SNRI) and that GPs may also manage depression in people for whom third‑line treatment is needed. The Committee further heard from the clinical expert that people with difficult‑to‑treat, severe depression who need second- or third‑line treatment with an antidepressant from another pharmacological class are often referred to secondary care (for example, psychiatric outpatient clinics).\nThe Committee considered the likely position of vortioxetine in the treatment pathway. It noted that vortioxetine has a marketing authorisation in the UK for treating 'major depressive episodes in adults'. However, it noted that the company had not submitted clinical- and cost‑effectiveness evidence for this population, but only for people with moderate‑to‑severe major depressive disorder whose condition had responded inadequately in terms of efficacy or tolerability to first‑line treatment (that is, second‑line treatment) in its original submission. The Committee heard from the clinical expert that vortioxetine would not be used first line, but was likely to be used second line or third line for treating a major depressive episode. The clinical expert explained that this was because vortioxetine's tolerability and efficacy are comparable with other antidepressants categorised in NICE's guideline on depression in adults as 'better‑tolerated newer generation antidepressants'. The clinical expert expressed the view that vortioxetine was more likely to be prescribed in secondary than primary care because its price is higher than other antidepressants. The Committee understood that clinicians would like to use vortioxetine for people whose major depressive episode is likely to benefit from second- or third‑line treatment (that is, after SSRI therapy) with a 'newer‑generation, better tolerated antidepressant'.\n\n# Clinical effectiveness\nThe Committee reviewed the clinical trial evidence submitted by the company, and agreed that the REVIVE trial comparing vortioxetine with agomelatine was of good quality. However, it noted that a key issue highlighted by the Evidence Review Group (ERG) was the generalisability of the results from REVIVE to people whose major depressive episode had responded inadequately to a course of SSRI antidepressants (that is, the second‑line population on which the company focused its original evidence submission). The Committee heard from the clinical expert that agomelatine was a reasonable comparator for vortioxetine in a trial setting because it is not sedative. The Committee understood that agomelatine is not widely used in clinical practice in the NHS, but is used as an alternative treatment for some people for whom mirtazapine is not appropriate because it is associated with weight gain. The Committee agreed that, because of agomelatine's limited use, the comparison of vortioxetine with agomelatine was of limited relevance to clinical practice in England. The Committee considered whether the previous treatments received by the REVIVE population were generalisable to clinical practice in England. The Committee was aware that over 20% of patients in REVIVE received initial treatment with an SNRI rather than an SSRI as recommend by NICE's guideline on depression in adults, and agreed that this did not reflect clinical practice in England. The Committee noted that the proportion of people recruited to the REVIVE trial from the UK was small (about 7%), and agreed that the variation in managing major depressive disorder across countries may limit the applicability of the trial results to patients in England. The Committee concluded that the results from the REVIVE trial were not generalisable to most patients in routine clinical practice in England.\nThe Committee considered the results from the REVIVE trial. The Committee heard from the company that it used a 'full analysis set' rather than an intention‑to‑treat analysis to assess the outcomes, in accordance with the Committee for Medicinal Products for Human Use guidelines for non‑inferiority trials. The Committee commented that it preferred to see outcomes analysed using an intention‑to‑treat analysis but it was aware that few patients were excluded from the 'full analysis set' analysis in the REVIVE trial. The Committee noted that the primary outcome in REVIVE was the change in severity of depressive symptoms measured by the mean change from baseline in the Montgomery–Åsberg Depression Rating Scale (MADRS) at 8 weeks, and that this was 2.16 points lower with vortioxetine than with agomelatine. The Committee also noted that vortioxetine showed a statistically significant improvement in both response and remission rates (secondary outcomes) compared with agomelatine. The Committee discussed what size of changes in depressive symptom severity scores clinicians and patients consider clinically important. The Committee heard from the clinical expert that the mean change from baseline in total MADRS score was not a useful outcome measure for judging whether a clinically important difference was observed because the MADRS included 10 items for measuring depressive symptoms. The clinical expert explained that a reduction in 1 item of the MADRS by 2 or more points would generally be considered clinically meaningful in clinical practice. The Committee noted that this was disputed in some comments it received on the appraisal consultation document. However, the Committee agreed that achieving remission and avoiding relapse were much more useful outcomes than the mean change in a person's depressive symptom severity score for measuring success of treatment in clinical practice.\nThe Committee discussed the company's indirect treatment comparison presented for the second‑line population. It was concerned that the evidence network only consisted of 4 trials and only included 1 trial for each treatment comparison. The Committee was also aware that 1 of these trials (Kasper et al. 2013) included people who may not have been changing to another treatment for a major depressive episode but starting first‑line treatment for a recurrent major depressive episode. The company acknowledged that the population in Kasper may not be comparable with the other populations in the evidence network, or consistent with the population specified in its decision problem. The Committee considered that the patient populations in the trials differed in baseline severity of depression. It was aware that the company's indirect treatment comparison reported remission rates and the proportion of people stopping treatment because of adverse events, both of which depend on trial duration, which differed between the trials in the network. The Committee concluded that, because of the evidence base, the company's indirect treatment comparison was not sufficiently robust for estimating the clinical effectiveness of vortioxetine compared with other antidepressants for second‑line treatment.\nThe Committee discussed whether evidence from the first‑line treatment population was relevant for informing the relative effectiveness of vortioxetine compared with other antidepressants for people having second and subsequent lines of treatment. The Committee heard from the company that, although there is a paucity of evidence for vortioxetine used second line, the company chose not to include data from its trials of vortioxetine as a first‑line treatment, because it claimed that the relative effectiveness changes across lines of treatment. The Committee was aware that the ERG considered that the company did not provide sufficient evidence that the relative effectiveness differs between non‑SSRIs within each line of treatment, but the ERG accepted that the absolute effectiveness may change between each line of treatment. This was confirmed by the clinical expert who stated that, in clinical practice, the absolute effectiveness of each antidepressant is likely to decline with each subsequent line of treatment because there are people whose major depressive episode is difficult‑to‑treat (that is, treatment‑resistant) and therefore unlikely to remit or respond. However, the clinical expert noted that the relative effectiveness of the antidepressants compared with one another may also change at each subsequent line of treatment. The clinical expert explained that depression which does not respond to 1 or 2 SSRIs may be mediated by different receptors, so the relative effectiveness of treatments with a different mechanism may differ across subsequent lines of treatment. The ERG acknowledged that the relative effectiveness may reduce in clinical practice at second or later lines of treatment compared with first‑line treatment, particularly for SSRIs compared with antidepressants of a different class. However, it emphasised that the company had not provided sufficient evidence, either in its original submission or in its response to the appraisal consultation document, to support a declining relative effect of treatment between non‑SSRIs within each line of treatment. The Committee was also aware that NICE's guideline on depression in adults concluded that 'the evidence for the relative advantage of switching either within or between classes is weak' and 'that evidence from primary efficacy studies of existing treatments should also be considered' when making decisions about second and subsequent lines of treatment. On balance, the Committee concluded that evidence from trials in the first‑line population was relevant to informing the relative effectiveness of vortioxetine compared with other antidepressants for second and subsequent lines of treatment.\nThe Committee discussed alternative sources (Pae et al. 2015 and Llorca et al. 2014) to estimate the relative effectiveness of vortioxetine compared with other antidepressants. The Committee was aware that these meta‑analyses included populations being treated first line. It noted that the absolute remission rates for vortioxetine were lower than for some of the other antidepressants included in Pae and Llorca (see table 10). It noted that this was not consistent with the company's indirect treatment comparison, which estimated vortioxetine to be the most effective treatment option (see table 10). The Committee appreciated that the 2 studies took different methodological approaches (see section 3.29). It heard from the ERG that each analysis had a number of biases (for example, Pae included trials with active reference arms), and that the ERG considered Llorca to be the most credible. The Committee was aware that Llorca included more treatment options and trial evidence than Pae, and also used indirect evidence to inform the estimates of relative effectiveness (rather than only direct evidence as carried out by Pae). The Committee was aware from the response to the appraisal consultation document that the company was concerned that the results from Llorca for remission and response were potentially biased because several of the included trials did not present data for these outcomes. The Committee heard from the ERG that there was no evidence to suggest that the Llorca analysis was affected by reporting bias (see section 3.48). The Committee concluded that the estimates of relative effectiveness in each analysis were subject to uncertainty but, of the available sources, Llorca had the fewest weaknesses for informing the relative effectiveness of vortioxetine compared with other antidepressants.\nThe Committee discussed the relative effectiveness evidence available for vortioxetine compared with other antidepressants. The Committee noted that the published meta‑analyses were consistent with the interpretation that vortioxetine was neither better nor worse than other treatments. Specifically, the Committee acknowledged that none of the analyses it had seen (that is, the company's indirect treatment comparison, Pae et al. 2015, Llorca et al. 2014), showed statistically significant differences between vortioxetine and the other antidepressants for achieving remission (other than compared with agomelatine, a comparator not widely used in the NHS). The Committee was aware that Pae (not sponsored by the company) concluded that vortioxetine was 'more effective than placebo but the difference was of doubtful clinical significance', and that Llorca (sponsored by company) concluded that vortioxetine had 'comparable or favourable' efficacy and tolerability compared with other antidepressants. Furthermore, the Committee noted that the evidence for vortioxetine in people having second‑line treatment included trials only of short duration, so the treatment effect of vortioxetine after 12 weeks was uncertain. The Committee concluded that no convincing evidence existed to show that vortioxetine was more or less effective than other antidepressants.\nThe Committee discussed the adverse effects associated with vortioxetine and the other antidepressants. It noted that the company's indirect treatment comparison, Pae et al. (2015), and Llorca et al. (2014) measured the odds of stopping treatment because of adverse events. The Committee was aware that some patients may stop treatment for reasons other than adverse events, and that some patients tolerate adverse events and do not stop treatment. The Committee understood that vortioxetine's recommended starting dose may be increased and that the long‑term safety data suggested that the overall incidence of adverse reactions was higher in people taking 15–20 mg of vortioxetine daily compared with 5 mg of vortioxetine daily. The Committee was aware that the TAK318 trial, which the company did not include in its indirect comparison or modelling, showed that vortioxetine improved sexual function in people with sexual dysfunction more than escitalopram. The Committee agreed that the long‑term adverse effect profile of vortioxetine compared with commonly used antidepressants in England was uncertain. However, it accepted that the available evidence suggested vortioxetine leads to a lower probability of stopping treatment and fewer adverse effects than most other antidepressants in the short term. The Committee concluded that, based on the available (albeit sparse) evidence, vortioxetine may have a better overall safety profile than other antidepressants.\n\n# Cost effectiveness\nThe Committee discussed the company's revised economic model received in response to the appraisal consultation document. The Committee highlighted that it could not make a recommendation for vortioxetine to treat all people included in the marketing authorisation. At the first Appraisal Committee meeting, the Committee was not convinced that vortioxetine offered a cost‑effective use of NHS resources as a second‑line treatment option. The Committee was also concerned about the structure of the company's original economic model. The company's revised cost‑effectiveness results were for vortioxetine as a third‑line treatment and the Committee was satisfied that the company's revised economic model had addressed several structural uncertainties. The Committee concluded that it was now able to assess the cost effectiveness of vortioxetine compared with other antidepressants for people whose condition has responded inadequately to 2 antidepressants within the current major depressive episode.\nThe Committee discussed the costs and resource‑use included in the company's economic model. The Committee noted that the dose of third‑line treatment was increased after the acute phase in the company's economic model, and was aware that this may reflect clinical practice in people who tolerate, and whose depression responds to, treatment. Moreover, the Committee understood from the ERG's exploratory analysis that assuming that the dose of third‑line treatment did not increase after the acute phase had little impact on the incremental cost‑effectiveness results. The Committee noted that continuing treatment in the company's revised model was based on whether a person's depression remits, responds (but does not remit) or does not respond. The Committee understood from the clinical expert that this reflected how clinicians decide when to continue treatment in clinical practice. The clinical expert explained that people with a major depressive episode whose condition responds after 8 to 10 weeks of treatment, but does not remit, would generally be treated for a further 4 weeks. The Committee considered that, because people whose condition responds to treatment but does not remit have a lower health‑related quality of life, it was appropriate for the company to assume that their condition costs more to treat than people whose condition does remit. The Committee concluded that the company appropriately modelled continuing treatment. The Committee also accepted that the company appropriately modelled the time at which people change treatments. The Committee acknowledged that people who switch treatment because of adverse reactions were likely to switch earlier than people who switch treatment because of a lack of response, in line with the company's approach. The Committee was also aware that the company had provided scenarios with either 6 or 22 months maintenance therapy (that is, continued treatment for up to 2 years in people at high risk of relapse), in line with the recommendations in NICE's guideline on depression in adults and clinical practice. The Committee was also aware that the company had provided separate scenarios for people being treated either in primary care or in secondary care. The Committee understood from the clinical expert that vortioxetine is likely to be used predominantly in secondary care. It noted a comment received on the appraisal consultation document, which highlighted that people treated for major depressive disorder in primary care were likely to be completely different from those treated in secondary care. The Committee commented that the company's approach to only changing the unit cost of a healthcare professional visit from a GP visit (primary care) to a psychiatrist visit (secondary care) was unlikely to reflect the change in healthcare resource use between primary and secondary care. The Committee therefore noted that the company's cost‑effectiveness results for the secondary care analysis should be interpreted with caution. However, the Committee concluded that overall the cost and resource use included in the company's model generally reflected the pathway of care for people for whom vortioxetine would be considered appropriate.\nThe Committee was aware that the company did not assume that treating depression lowered the risk of suicide, so any modelled gains in quality‑adjusted life years (QALYs) reflected only a difference in health‑related quality of life. The Committee agreed it was appropriate for the company to use the utility values from REVIVE for all phases of the economic model, rather than using 2 separate sources of evidence for the utility values as applied in its original economic model. The Committee concluded that it preferred the EQ‑5D data from REVIVE because it represented the best evidence available and was more internally consistent.\nThe Committee discussed the company's approach to modelling adverse events. The Committee was aware that the company based adverse event rates for vortioxetine and its comparators on absolute rates reported from individual trials. The Committee noted that it accepted that safety data would be transferable across lines of treatment. However, it was uncertain whether the company's approach to modelling adverse events was appropriate, given differences in the baseline severity of depression in the trials' populations for vortioxetine and its comparators. On balance, the Committee recognised from the evidence currently available that vortioxetine was likely to lead to fewer adverse events than other antidepressants. The Committee noted that the company assigned no decrease in health‑related quality of life because of several adverse events (for example, dry mouth, dizziness), and agreed that this was unlikely to reflect reality. However, the Committee was aware that, for these adverse events, the incidence rates were generally lower for vortioxetine than the other antidepressants, so the company's approach underestimated the benefits of vortioxetine. The Committee also noted that the company had not considered adverse events in people receiving fourth and subsequent lines of treatment. The Committee agreed that, because a substantial proportion of people receive therapy after third‑line use in the company's model, this led to further uncertainty around the cost‑effectiveness results. The Committee concluded that it would have preferred the company to justify its approach for modelling adverse reactions, but appreciated that data for antidepressants in comparable populations were likely to be sparse.\nThe Committee discussed the company's approach to modelling remission and relapse rates for people having fourth and subsequent lines of treatment. The Committee heard from the clinical expert that there was limited evidence available on the prognosis for people having subsequent lines of treatment, and that the STAR*D trial provided the best available data. The Committee accepted this, but understood that STAR*D included treatments that did not reflect those commonly used in England, and that the population was different from the population in REVIVE. The Committee also appreciated that the effectiveness of subsequent lines of treatment was independent of the initial treatment strategy, but the proportion of people that subsequently switched to fourth‑line treatment differed depending on the effectiveness of the third‑line treatment. The company noted that the company used the absolute rates of remission from the STAR*D trial for subsequent lines of treatment. However, the Committee considered it more appropriate to apply a proportionate reduction in the rates of remission for fourth and subsequent lines of treatment, as seen in the STAR*D trial, to the remission data used for third‑line treatment. The Committee noted that the company assumed that the rate of relapse did not differ between initial treatments but did differ between subsequent lines of treatment. The Committee considered it more appropriate to assumed that the rate of relapse was independent of treatment line. The Committee concluded that fuller exploration of alternative scenarios for modelling remission and relapse rates for people having subsequent lines of therapy would have been helpful.\nThe Committee discussed the cost‑effectiveness results presented by the company and the ERG's exploratory analyses. The Committee noted that the company's base‑case results were not sensitive to changes to most parameters. The Committee was aware that, when relative effectiveness was estimated by Llorca et al. (2014) or Pae et al. (2015), or when vortioxetine was assumed to be as effective as other antidepressants, the incremental cost-effectiveness ratios (ICERs) for vortioxetine were extremely unstable because of the very small differences in incremental QALYs (that is, highly sensitive to the parameters used for the rates of remission and relapse). The Committee understood from the ERG that the small differences between the incremental QALYs were driven partly by the short time horizon of the model and partly by the data suggesting that vortioxetine was not more or less effective than other antidepressants (but reflecting the small observed differences in absolute effects). The ERG explained that, given that there were no substantial differences in depressive severity symptoms scores between the antidepressants reported in the trials included in the company's indirect treatment comparison (or Pae or Llorca), it was not surprising that the incremental QALYs were equally small. The Committee concluded that it needed to take into account the instability of the ICERs in its decision‑making.\nThe Committee noted that the company's revised ICERs were estimated from probabilistic analyses based on pairwise comparisons. The Committee concluded that it preferred probabilistic ICERs estimated for all comparators simultaneously, but acknowledged that the company had addressed other structural uncertainties in the economic model.\nThe Committee discussed whether it could recommend vortioxetine as a third‑line treatment option for treating major depressive episodes. The Committee acknowledged that the company's revised economic model generally reflected the pathway of care for people for whom vortioxetine would be offered, and had used EQ‑5D utility data as preferred by NICE in its Guide to the methods of technology appraisal (2013). Furthermore, the Committee emphasised that there was no convincing evidence to show that vortioxetine was more or less effective than other antidepressants (see section 4.10). The Committee noted that the results of the SOLUTION trial provided by the company in its response to the appraisal consultation document supported the general conclusion of Llorca et al. (2014) that vortioxetine's effectiveness was comparable with that of other antidepressants (in this trial, venlafaxine). The Committee stated that there were likely to be small differences between the antidepressants, but it was satisfied based on all the evidence that a scenario assuming equal efficacy could be considered for the purposes of assessing the cost effectiveness of vortioxetine compared with other third‑line antidepressants. The Committee noted that, although the emerging evidence on adverse effects for vortioxetine compared with other antidepressants was relatively immature, the available evidence suggested that people tolerate vortioxetine better than other options. The Committee based its decision‑making on the company's cost‑effectiveness analyses that excluded SSRIs (see sections 4.3 and 4.4). The Committee highlighted that, across all of the company's scenarios using its revised economic model, and when assuming equal efficacy between treatments, the ICERs for vortioxetine compared with other antidepressants were £9000 per QALY gained or below. Therefore, the Committee agreed that treatment with vortioxetine was a cost‑effective use of NHS resources compared with other antidepressants. The Committee concluded that vortioxetine could be recommended as an option for treating major depressive episodes in adults whose condition has responded inadequately to 2 antidepressants within the current episode.\nThe Committee was aware that the company's evidence included people with first and recurrent major depressive episodes. It recognised that it was appropriate to change treatments between the first episode and any subsequent episodes, and to not use any drug, or a specific sequence of drugs, for a recurrent episode that had not worked during a previous episode. The Committee also noted that NICE's guideline on depression in adults states that 'treatment choice should be influenced by: previous treatment history, including the consequences of a relapse, residual symptoms, response to previous treatment, any discontinuation symptoms, and the person's preference'. The Committee therefore agreed that a flexible approach was needed in clinical practice when treating recurrent episodes of depression.\nThe Committee discussed whether vortioxetine could be considered innovative, and whether the company's economic analysis had captured all changes in health‑related quality of life. The Committee noted that the company considered vortioxetine innovative because: it reduces cognitive dysfunction independent of its effect on MADRS; it minimises impact on social relationships; it reduces symptoms associated with stopping treatment; and it provides benefits related to health‑related quality of life underestimated by the EQ‑5D instrument. The Committee acknowledged that vortioxetine may be a valuable treatment option for people with a major depressive disorder experiencing cognitive dysfunction. However, it noted that the EQ‑5D data from REVIVE reported for the vortioxetine and agomelatine groups did not suggest that the average utility for remission and non‑remission was notably different between treatments. The Committee also acknowledged that, in general, the benefits of mental health conditions relative to other conditions may be underestimated by the EQ‑5D instrument. However, the Committee considered that any shortcomings in the EQ‑5D would impact each treatment option included in the company's economic analysis similarly, particularly because there was no convincing evidence to suggest that vortioxetine was more or less effective than its comparators. The Committee concluded that all benefits were sufficiently captured in the company's economic modelling.\n\n# Summary of Appraisal Committee's key conclusions\nTA367\nAppraisal title: Vortioxetine for treating major depressive episodes\nSection\nKey conclusion\nVortioxetine is recommended as an option for treating major depressive episodes in adults whose condition has responded inadequately to 2 antidepressants within the current episode.\nThe Committee emphasised that there was no convincing clinical‑effectiveness evidence to show that vortioxetine was more or less effective than other antidepressant.\nThe Committee was satisfied, based on all the evidence, that a scenario assuming equal efficacy could be considered for the purposes of assessing the cost effectiveness. The Committee highlighted that, across all of the company's scenarios using its revised economic model, and when assuming equal efficacy between treatments, the incremental cost‑effectiveness ratios (ICERs) for vortioxetine compared with other antidepressants were £9000 per quality‑adjusted life year (QALY) gained or below. Therefore, the Committee agreed that treatment with vortioxetine was a cost‑effective use of NHS resources.\nThe Committee agreed that a flexible approach was needed in clinical practice when treating recurrent episodes of depression.\nCurrent practice\nClinical need of patients, including the availability of alternative treatments\nThe Committee recognised the importance of having a range of treatment options for people with major depressive disorder.\nThe clinical expert stated that treatment choice was influenced by treatment history (for example, number of previous therapies, first or recurrent episode of depression) and presence of specific signs and symptoms\nThe technology\nProposed benefits of the technology\nHow innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?\nThe Committee noted that the company considered vortioxetine innovative because: it reduces cognitive dysfunction independent of its effect on the Montgomery–Åsberg Depression Rating Scale; it minimises impact on social relationships; and it reduces symptoms associated with stopping treatment.\nWhat is the position of the treatment in the pathway of care for the condition?\nThe Committee understood that clinicians would like to use vortioxetine for people whose major depressive episode is likely to benefit from second- or third‑line treatment (that is, after selective serotonin reuptake inhibitor therapy) with a 'newer‑generation, better tolerated antidepressant'.\nAdverse reactions\nThe Committee concluded that, based on the available (albeit sparse) evidence, vortioxetine may have a better overall safety profile than other antidepressants.\nEvidence for clinical effectiveness\nAvailability, nature and quality of evidence\nThe Committee agreed that the REVIVE trial comparing vortioxetine with agomelatine was of good quality.\nThe Committee concluded that, because of the evidence base, the company's indirect treatment comparison was not sufficiently robust for estimating the clinical effectiveness of vortioxetine compared with other antidepressants for second‑line treatment.\nOn balance, the Committee concluded that evidence from trials in the first‑line population was relevant to informing the relative effectiveness of vortioxetine compared with other antidepressants for second and subsequent lines of treatment.\nThe Committee concluded that the estimates of relative effectiveness in each analysis were subject to uncertainty but, of the available sources, Llorca et al. (2014) had the fewest weaknesses.\nRelevance to general clinical practice in the NHS\nThe Committee concluded that the results from the REVIVE trial were not generalisable to most patients in routine clinical practice in England.\nUncertainties generated by the evidence\nThe Committee was concerned that the evidence network only consisted of 4 trials and only included 1 trial for each treatment comparison. It considered that the patient populations between the trials differed in baseline severity of depression.\nThe Evidence Review Group (ERG) emphasised that the company had not provided sufficient evidence, either in its original submission or in its response to the appraisal consultation document, to support a declining relative effect of treatment between non‑SSRIs within each line of treatment.\nThe Committee heard from the ERG that Pae et al (2015) and Llorca comparisons were subject to several biases, but that the ERG considered Llorca to be the most credible.\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\nNot applicable\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\nThe Committee concluded that no convincing evidence existed to show that vortioxetine was more or less effective than other antidepressants.\nEvidence for cost effectiveness\nAvailability and nature of evidence\nThe company's revised cost‑effectiveness results were for vortioxetine as a third‑line treatment.\nUncertainties around and plausibility of assumptions and inputs in the economic model\nThe Committee was satisfied that the company's revised economic model had addressed several structural uncertainties.\nThe Committee commented that the company's approach to only changing the unit cost of a healthcare professional visit from a GP visit (primary care) to a psychiatrist visit (secondary care) was unlikely to reflect the change in healthcare resource use between primary and secondary care. The Committee therefore noted that the company's cost‑effectiveness results for the secondary care analysis should be interpreted with caution.\nThe Committee concluded that fuller exploration of alternative scenarios for modelling remission and relapse rates for people having subsequent lines of therapy would have been helpful.\nIncorporation of health‑related quality‑of‑life benefits and utility values\nHave any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?\nThe Committee concluded that it preferred the EQ‑5D data collected in REVIVE, because it represented the best evidence available and more closely reflected the population included in the company's model.\nThe Committee concluded that vortioxetine's benefits were sufficiently captured within the company's economic modelling.\nAre there specific groups of people for whom the technology is particularly cost effective?\nNot applicable\nWhat are the key drivers of cost effectiveness?\nThe Committee noted that the company's base‑case results were not sensitive to changes in most parameters. The Committee was aware that, when relative effectiveness was estimated by Llorca or Pae, or when vortioxetine was assumed to be as effective as other antidepressants, the incremental cost‑effectiveness ratios for vortioxetine were shown to be extremely unstable because of the small differences in incremental QALYs.\nMost likely cost‑effectiveness estimate (given as an ICER)\nThe Committee highlighted that, across all of the company's scenarios using its revised economic model, and when assuming equal efficacy between treatments, the ICERs for vortioxetine compared with other antidepressants were £9000 per QALY gained or below.\nAdditional factors taken into account\nPatient access schemes (PPRS)\nNot applicable\nEnd‑of‑life considerations\nNot applicable\nEqualities considerations and social value judgements\nPotential equality issues raised during the appraisal could not be addressed through NICE technology appraisal guidance.\n–# Review of guidance\nThe guidance on this technology is considered for review by the Guidance Executive 3 years after publication of the guidance. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew DillonChief ExecutiveNovember 2015# About this guidance\nNICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS.\nThis guidance was developed using the NICE single technology appraisal process.\nWe have produced information for the public explaining this guidance. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\nNICE produces guidance, standards and information on commissioning and providing high‑quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\nCopyright© National Institute for Health and Care Excellence 2015. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\nISBN: 978-1-4731-1555-2"}}},{"rowIdx":83,"cells":{"id":{"kind":"string","value":"6e724c0b3c9be4d66e7ed99cac367b20eb8bace6"},"source":{"kind":"string","value":"who"},"text":{"kind":"string","value":"- 1 Background 1\n- 2 Scope and purpose 3 1.3 Objectives 5\n- 4 Target audience 5\n\n# How this guideline was developed 6\n- 1 Contributors to guideline development 6\n- 2 Guideline development process 7\n- 3 Management of conflicts of interest 11\n\n# Summary of evidence\nEvidence on the nature, extent and impact of food marketing 13\n- 2 Evidence on effectiveness of policies to restrict food marketing to which children are exposed 16\n\n# Evidence on contextual factors 20\n\n# Objective, scope and methods\nIn 2010, the Sixty-third World Health Assembly unanimously endorsed the World Health Organization (WHO) Set of recommendations on the marketing of foods and non-alcoholic beverages to children, and urged Member States to take the necessary measures to implement the set of recommendations.\nIn response to Member State requests, WHO developed this guideline to strengthen and streamline support for Member States in developing and implementing new, or strengthening existing, policies to protect children from the harmful impact of food marketing.\nThis guideline builds on the 2010 WHO Set of recommendations on the marketing of foods and non-alcoholic beverages to children, and takes into consideration more recent evidence specific to children and to the context of food marketing. The guideline's objectives are to:\nprovide evidence-based recommendations and implementation considerations for policies to protect all children from the harmful impact of food marketing; enable evidence-informed advocacy to advance policy action to restrict food marketing to which children are exposed;\nguide future research to further strengthen the evidence base for policy action; and contribute to the creation of healthy food environments that enable healthy dietary practices among children.\nIn this guideline, policies were defined as all measures to regulate marketing to which children are exposed, whether through legal instruments mandating compliance (such as legislation and regulations), government-led measures with which compliance is voluntary (such as codes of conduct and standards), or measures by which industry actors voluntarily undertake to restrict marketing (such as pledges and codes).\nThis guideline was developed using the procedures outlined in the WHO handbook for guideline development. These procedures include a review of systematically gathered evidence by an international, multidisciplinary group of experts (the Nutrition Guidance Expert Advisory Group (NUGAG) Subgroup on\nxii Policies to protect children from the harmful impact of food marketing: WHO guideline best interests of the child a primary consideration when regulating marketing that is addressed and accessible to children (14,15).\n\n# WHO recommendation\nWHO suggests implementation of policies to restrict marketing of foods high in saturated fatty acids, trans-fatty acids, free sugars and/or salt to which children are exposed, and that such policies: ¡ be mandatory;\n¡ protect children of all ages;\n¡ use a government-led nutrient profile model to classify foods to be restricted from marketing;\n¡ be sufficiently comprehensive to minimize the risk of migration of marketing to other media, to other spaces within the same medium or to other age groups; and ¡ restrict the power of food marketing to persuade.\n\n# Recommendation remarks\nThese remarks provide context for the recommendation and are to facilitate interpretation and implementation.\n'Children' refers to all human beings below the age of 18, as defined by the Convention on the Rights of the Child, unless, under the law applicable to children, majority is attained earlier.\nThe impact of marketing is a function of both exposure and power.\n-Exposure is the reach (percentage of people in a target market who are exposed) and frequency (the number of times an average person is exposed) of a marketing communication, message or action. Policies should address children's exposure to food marketing, irrespective of timing, venue or intended audience, and should therefore go beyond children's media.\n-Power refers to the extent to which a marketing communication, message or action achieves its communications objectives. Power is influenced by the creative content and strategies used. The power of food marketing to persuade children relates to techniques appealing to children, including promotional characters, branding, emotional appeals, games, engagement techniques, interactive or downloadable content, and celebrity endorsements (9); these techniques impact dietary intake (10).\nMigration of marketing refers to the movement of marketing from restricted to unrestricted mediums or spaces (e.g. if a policy restricts marketing on television but not digital marketing, digital marketing may increase).\nA nutrient profile model is a tool for classifying foods according to their nutritional composition for reasons relating to preventing disease and promoting health. Nutrient profile models in the context of food marketing help define foods to be restricted from marketing and should align with national dietary guidelines.\n\n# Recommendation rationale\nThe recommendation was formulated by the NUGAG Subgroup on Policy Actions based on several key considerations (below and Table 2, p. 24).\nBased on evidence from a systematic review that assessed the effectiveness of policies to restrict food marketing to which children are exposed (8), the group judged policies to have moderate desirable effects and trivial undesirable effects and judged the overall balance between desirable and undesirable xiii effects to favour the intervention. Following application of the GRADE approach (see section 2.2), the certainty of the evidence from the systematic review was considered very low, therefore the group made a conditional recommendation. The group noted that the relevant policy evaluations were all observational studies, leading to lower certainty of evidence when applying the GRADE system, and that the inconsistency of effect, which led to downgrading of the certainty of evidence for some outcomes, was partly due to variation in policy design elements.\nThe group judged policies to be cost-effective, feasible and generally acceptable to government, policy-makers and the public, but less so to industry. Further, implementation of policies supports the realization of human rights and will probably support improved health equity.\nSome policy design elements are likely to be effective in protecting children from marketing of HFSS foods, but others are more likely to lead to unfavourable effects. The recommendation therefore specifies elements that maximize the effectiveness of policies, as identified in the systematic review (8).\n-Of studies evaluating voluntary policies, significantly more studies showed undesirable effects than desirable effects on exposure to, and power of, food marketing. This was not the case for studies evaluating mandatory policies (8).\n-Of studies evaluating policies designed to restrict food marketing to children that included only children aged 12 years or younger, significantly more studies showed undesirable effects than desirable effects on exposure to, and power of, food marketing. This was not the case for studies evaluating policies that included children older than 12 (8).\n-Of studies evaluating policies that used a company-led nutrient profile model to define foods to be restricted from marketing more studies showed undesirable effects than desirable effects on exposure to food marketing. This was not the case for studies evaluating policies that used a government-led nutrient profile model.\n-Some studies indicated that policies that were too narrow in scope (i.e. not comprehensive) may have led to migration of marketing (e.g. from children's television programmes to non-children's television programmes, from younger to older age groups) (16,17).\n-Food marketing uses strategies that appeal to young audiences (9), and marketing using such strategies affects food choice and dietary intake (10). Studies indicated that mandatory policies result in reductions in use of powerful marketing strategies, such as the use of promotional characters and other persuasive techniques that appeal to children (8).\n\n# Key considerations for implementation\nIn line with the good-practice statement, policies should be formulated in the best interests of children.\nTheir design should also consider the policy design elements specified in the recommendation. The WHO/ UNICEF publication Taking action to protect children from the harmful impact of food marketing: a child rights-based approach provides step-by-step guidance through the four main stages of the policy cycle (preparation; development; implementation; monitoring and evaluation).\nRecommendations should be adapted to the local contexts of WHO regions and Member States. Considerations about the local context include: available resources, including for policy implementation, enforcement and continued monitoring for compliance;\nstructures and mechanisms, including mechanisms to manage conflicts of interest and to safeguard public health policies and enforcement mechanisms; the policy context, including the country's legal system and potential regulatory pathways and the overall political economy; and the stakeholders to consult or engage with at different stages of the policy cycle.\nOther considerations include actions to reduce children's exposure to cross-border marketing, and restrictions on the promotion of brands (as distinct from products and services).\nUnhealthy diets are a leading global public health risk, contributing to all forms of malnutrition (i.e. undernutrition; micronutrient deficiencies; and overweight, obesity, and diet-related noncommunicable diseases (NCDs)) (18,19). Globally, 38.9 million children under the age of 5 were estimated to have overweight or obesity in 2020 -41% of whom lived in low-and lower-middle-income countries (20). 45.4 million were estimated to be wasted, and 149.2 million to be stunted (20). Of children aged 5-19 in 2016, 337 million were estimated to have overweight or obesity (18). Virtually no progress has been made in reducing the spread of childhood overweight in two decades (20). Worldwide, dietary risks 1 were responsible for 11.61% of all disability-adjusted life years (DALYs) lost to NCDs and nearly 8 million deaths from NCDs in 2019 (21).\nEvery country in the world is affected by one or more forms of malnutrition. Malnutrition threatens the survival, growth and development of children and adolescents, as well as economies and nations (22).\nCombating malnutrition in all its forms is one of the greatest global health challenges (23,24). The causes of malnutrition are complex, and action is required on many fronts (25)(26)(27)(28). There is wide recognition that structural changes (i.e. changes to social, cultural, political and physical environments) are required to promote healthy diets (29). Behaviour change interventions on their own have had limited success in reducing disease risk factors (30). Following the work of the World Health Organization (WHO) on creating supportive environments for health (31)(32)(33), key actions to improve diets include those that focus on the food environment -that is, the surroundings that influence and shape consumers' food behaviours, preferences and values, and prompt consumer decisions (34,35).\nGovernments play a leading role in addressing malnutrition in all its forms and reducing the burden of diet-related NCDs, including through public policies that create food environments conducive to healthy diets (36)(37)(38)(39) and through effective regulation of private sector activities that influence health -that is, the commercial determinants of health (33,40). The private sector, however, continues to influence public health policy and regulation through lobbying and other actions (40).\nFood marketing (Box 1) is one commercial activity that shapes the food environment and marketing of HFSS foods has long been recognized as having an especially harmful impact on the diets of children (41)(42)(43). Marketing is a recognized means to promote products that are harmful to health, such as HFSS foods (44). Arguments in defence of marketing fade when the marketed products harm health and when marketing poses a threat to children's rights. In 2009, a review on the extent, nature and effects of food promotion to children found that food marketing affects children's nutrition knowledge, food preferences and consumption patterns, and that the foods promoted by food marketing represented a \"very undesirable dietary profile, with heavy emphasis on energy dense, high fat, high salt and high sugar foods\" (41). More recent evidence has echoed these findings, showing that exposure to food marketing affects children's food preference, food choice and food intake in undesirable ways (45), and that food marketing continues to be predominantly for HFSS foods (9). Numerous studies have documented the wide variety of media used for food marketing, including television, packaging, magazines, outdoor media, digital and sponsorship media, and promotions in and around schools (9,(41)(42)(43). The advent and growth of digital marketing has raised new concerns, including the use of novel marketing techniques (e.g. food-themed apps, influencer marketing, user-generated content) (46). Another concern is the collection of copious personal data from internet users and the use of these data to target marketing to users (46).\nPolicies to protect children from the harmful impact of food marketing: WHO guideline\n\n# Box 1. What is marketing?\nThe definition of marketing used in this guideline builds on that used in the 2012 WHO publication A framework for implementing the set of recommendations on the marketing of foods and non-alcoholic beverages to children (47), with the explicit addition of marketing of brands. The 2012 framework refers to marketing of products and services, and states that efforts to restrict marketing need to consider how brands are marketed (47). Marketing, in this guideline, is therefore defined as:\nAny form of commercial communication, message or action that acts to advertise or otherwise promote a product or service, or its related brand, and is designed to increase, or has the effect of increasing, the recognition, appeal and/or consumption of products or services.\nThe definition of marketing in the 2012 framework is intended to be comprehensive in its coverage (47). For example, the framework explains that examples of marketing include not only advertising, but also product placement and branding, sponsorship, direct marketing, product design and packaging, and point-of-sale marketing (47). \"Commercial\" is also intended to be broadly interpreted to include all forms of direct and indirect promotion (47). The definition of marketing used in this guideline should be similarly interpreted to be comprehensive in its coverage.\nFig. 1 illustrates the cascade of effects by which exposure to food marketing is likely to ultimately influence children's weight status and likelihood of developing diet-related NCDs (48), and highlights the commercial drivers of food marketing.\nFood marketing is also increasingly recognized as a children's rights concern, particularly in relation to the Convention on the Rights of the Child (12). The Convention on the Rights of the Child articulates the rights of children, including the rights to health, adequate and nutritious food, privacy and freedom from exploitation. Countries that are State Parties to the Convention have legal obligations to respect, protect\n\n# Fig. 1. Cascade of effects of food marketing\nSource: Adapted from Kelly et al. (48). and fulfil these rights, and are required to take immediate action to implement these obligations as a matter of priority (12). Countries that are State Parties to the Convention are therefore obliged to take action toward the fulfilment and realization of children's rights. This should include actions to protect children from marketing of HFSS foods as such marketing negatively affects children's rights, such as the rights to health, adequate and nutritious food, privacy and freedom from exploitation (12). The Committee on the Rights of the Child, in a 2013 general comment on the right of the child to the enjoyment of the highest attainable standard of health, stated that the marketing of foods that are high in fat, sugar or salt, and are energydense and micronutrient-poor should be regulated (49). The general comment articulated core obligations relating to children's right to health, which include reviewing the national and subnational legal and policy environment and, where necessary, amending laws and policies; providing an adequate response to the underlying determinants of children's health; and developing, implementing, monitoring and evaluating policies and budgeted plans of action that constitute a human rights-based approach to fulfilling children's right to health (49). In a 2021 general comment on children's rights in relation to the digital environment, the Committee on the Rights of the Child reinforced that marketing of \"unhealthy products, including certain food and beverages\" should be regulated to prevent children's exposure to such marketing and stated that regulations relating to the digital environment \"should be compatible and keep pace with regulations in the offline environment\" (15).\n\n# Responsiveness to cues at point of sale\n\n# Awareness of products and brands\nRecognizing the harmful impact of food marketing on children, numerous global and regional calls to action have been made. As part of implementation of the Global Strategy on Diet, Physical Activity and Health (2004) (50), the World Health Assembly in May 2010 endorsed the WHO Set of recommendations on the marketing of foods and non-alcoholic beverages to children (resolution WHA63.14) (51). The resolution called for policies to reduce the impact on children of marketing of HFSS foods. In response to WHA63.14, a framework was developed for implementing the WHO set of recommendations (47). Implementing policies to restrict food marketing to which children are exposed has also been proposed in various other WHO documents adopted by the World Health Assembly, including the Comprehensive Implementation Plan on Maternal, Infant and Young Child Nutrition (52) in 2012, and the Global Action Plan for the Prevention and Control of Noncommunicable Diseases 2013-2020 1 (53) in 2013. In 2016, the report of the WHO Commission on Ending Childhood Obesity similarly recommended implementation of the Set of recommendations on the marketing of foods and non-alcoholic beverages to children (54).\n\n# Scope and purpose\nDespite growing evidence of the harmful impact of food marketing on children and increasing recognition of food marketing as a children's rights concern, as of May 2022, only 60 2 countries have adopted policies that restrict food marketing to which children are exposed. Of these, one third (20 countries) have mandatory policies. Additionally, in the second global nutrition policy review, undertaken in 2016-2017, responding countries that had measures in place to restrict food marketing to which children are exposed reported a mix of approaches used to define which foods are covered by such measures (55). Of 17 countries that provided detailed information, fewer than half used nutrient profile models to define the foods covered by the policies (55). Marketing restrictions differed not only in relation to the foods included but also the marketing media covered -of 28 countries that provided detailed information, 93% covered television, but only 29% covered social media (55). Overall, an important omission in existing measures was that, of the 18 countries that had defined the age of children covered by the policy, most had policies that covered children only up to the age of 12 years (55).\nIn response to Member State requests, and to strengthen and streamline support for Member States in developing and implementing new, or strengthening existing, public policies to protect children from the harmful impact of food marketing, WHO began developing this guideline, taking new evidence into consideration (Box 2).\n\n# Box 2. How does this guideline relate to other published WHO guidance on policies to restrict food marketing to which children are exposed?\nThis guideline builds on the 2010 WHO Set of recommendations on the marketing of foods and nonalcoholic beverages to children (51), endorsed by the Sixty-third World Health Assembly in May 2010 (51).\nSince then, the evidence on the harmful impact of food marketing has grown; however, country action remains limited, and children continue to be exposed to marketing for HFSS foods. New marketing media have also evolved, most notably digital marketing, which poses a growing concern.\nThe development of this guideline followed a transparent process, outlined in the WHO handbook for guideline development (56). This guideline considers a more recent evidence base than the set of recommendations was based on, including more recent evidence on the effectiveness of policies to restrict food marketing to which children are exposed and on the effectiveness of different policy approaches.\nThe 2012 WHO publication A framework for implementing the set of recommendations on the marketing of foods and non-alcoholic beverages to children (47) remains a useful resource for the development and implementation of policies to protect children from the harmful impact of food marketing, noting that evidence continues to accumulate, especially on the effectiveness of different policy approaches and on the evolution of new marketing media and techniques.\nIn view of the increasing recognition of food marketing as a children's rights concern, the 2012 framework should be used in conjunction with the 2023 WHO/United Nations Children's Fund (UNICEF) publication Taking action to protect children from the harmful impact of food marketing: a child rightsbased approach (57). See Chapter 5 for further details.\nBecause no single intervention can ensure that all aspects of the food environment support healthy diets, a comprehensive package of policy actions is required. Therefore, guidelines are being developed for multiple policy actions in addition to policies to protect children from the harmful impact of food marketing, including nutrition labelling policies (58), fiscal policies (59) and school food and nutrition policies (60). Prioritization of policies will depend on the country context. The scope of this guideline relates to policies to protect children from the harmful impact of food marketing, with a focus on marketing of HFSS foods. The systematic reviews undertaken to address the key questions for the guideline (see section 2.2) excluded studies on the impacts of marketing and marketing restrictions more broadly, and were restricted to direct evidence on food marketing and its impact on children. Although this limits the ability to extrapolate from evidence on marketing of other products, services or brands or on the impact of marketing on adults, the direct evidence was considered a workable subset of the evidence for developing this guideline. Finally, this guideline is not an implementation manual. It does not describe how countries can implement and monitor policies to protect children from the harmful impact of food marketing, but rather recommends what measures to take. While some implementation considerations are highlighted in Chapter 5, detailed implementation guidance can be found in the WHO/UNICEF publication Taking action to protect children from the harmful impact of food marketing: a child rights-based approach (57).\nThe WHO guidelines on policies to improve the food environment are in line with other WHO guidelines and recommendations, including guidelines on sodium intake (61) and sugars intake (62); forthcoming guidelines on total fat, saturated fatty acids and trans-fatty acids, polyunsaturated fatty acids, carbohydrates, use of non-sugar sweeteners and use of low-sodium salt substitutes; and the recommendations of the WHO Commission on Ending Childhood Obesity (54). The guidelines on policies to improve the food environment can be used in conjunction with available tools and frameworks, including the nutrient profile models and guidance developed by the WHO regional offices for restricting food marketing to which children are exposed (2-7).\nComplementing global and regional guidance on restricting food marketing to which children are exposed, and recognizing that there is considerable evidence on the impacts of marketing and marketing restrictions outside the food context, the objectives of this guideline are to: provide Member States with recommendations and some key implementation considerations on policies to protect all children from the harmful impact of food marketing; enable evidence-informed advocacy to advance policy action to restrict food marketing to which children are exposed; guide future research to further strengthen the evidence base for policy action to restrict food marketing to which children are exposed; and contribute to the creation of food environments that enable healthy dietary practices among children.\nAs noted above, this WHO guideline is one of several on policies to improve the food environment. The overarching objective of these guidelines is to contribute to the achievement of healthier populations, in line with the WHO Thirteenth General Programme of Work (2019-2023) (63). The WHO guidelines on policies to improve the food environment will also contribute to implementation of additional calls to action relating to nutrition and health (Annex 1).\n\n# Target audience\nThe guideline is intended for a wide audience involved in the development, design, implementation, monitoring and evaluation of policies to protect children from the harmful impact of food marketing, as well as those involved in compliance with, and advocacy for, such policies. The end users for this guideline are thus: national and local policy-makers and food regulators involved in developing, designing, implementing, monitoring or evaluating policies restricting food marketing to which children are exposed; implementers and managers of national and local health and nutrition programmes, including school administrators, teachers and educators; organizations (including nongovernmental organizations) and professional societies involved in advocating for, developing and evaluating policies restricting food marketing to which children are exposed; health professionals, including managers of health and nutrition programmes and public health policymakers in all settings; scientists and other academic actors involved in relevant research (including policy evaluation); and representatives of the food industry, marketing/advertising agencies and related associations involved in implementing, or complying with, policies to restrict food marketing to which children are exposed.\n\n# How this guideline was developed\nThis guideline was developed in accordance with the WHO process for development of evidence-informed guidelines outlined in the WHO handbook for guideline development (56). This chapter describes the contributors to the guideline development process and the steps taken.\n\n# Contributors to guideline development\nThe guideline was developed by the WHO Department of Nutrition and Food Safety and other members of the WHO Secretariat (Annex 2), together with the contributors described below.\n\n# WHO Steering Committee\nAn internal steering committee (Annex 3) provided input to development of the guideline. The WHO Steering Committee included representatives from relevant departments in WHO with an interest in the provision of advice on food environment policies, determinants of health, health promotion, and maternal and child health.\n\n# External resource people\nVarious external resource people, including methods experts and members of the systematic review teams, attended the meetings of the NUGAG Subgroup on Policy Actions (Annex 5). The systematic review team was led by Dr Emma Boyland, University of Liverpool. It undertook two systematic reviews (8,10) and a narrative review (9) to support development of the guideline.\n\n# External peer review group\nSeven external peer reviewers were identified in consultation with WHO regional nutrition advisers from all WHO regions, representing academia, civil society and government (Annex 6). The external peer review took place between June and August 2022.\n\n# Public consultation\nA public consultation on the draft guideline was held in July 2022. Stakeholders were invited to provide comments on the overall clarity of the guideline, considerations and implications for adaptation and implementation of the guideline, context-and setting-specific issues that may not have been captured, any errors of fact and missing data. The consultation was open to everyone. Declaration of interest forms were collected from all those submitting comments, which were assessed by the WHO Secretariat following procedures for management of conflicts of interest (see section 2.3). The comments were reviewed and considered in finalizing the guideline. A summary of the comments, together with WHO responses, was posted on the WHO website. 1 Comments were received from 46 individuals and organizations.\n\n# Guideline development process\nScoping of the guideline A scoping review of existing evidence was prepared by Dr Emma Boyland, University of Liverpool. The scoping review included a review of newly available evidence on:\nthe impact of food marketing to children on food behaviours and health outcomes among children; and the impact of policies to restrict food marketing to which children are exposed on exposure to food marketing, the power of food marketing, and food behaviours and health outcomes among children.\n\n# Formulation of key questions and prioritization of outcomes\nA policy to protect children from the harmful impact of food marketing is a priority policy option for creating food environments that contribute to healthy diets, and is implemented within complex systems (including the food system), that are country-specific, and influenced by political, legal, economic, cultural and ethical contexts. As proposed in the WHO handbook for guideline development, logic models can be used during guideline planning to show interventions of interest and elements of the system in which they are implemented to help formulate guideline questions (56). Fig. 2 shows a logic model depicting pathways from policies to protect children from the harmful impact of food marketing to behavioural and health outcomes. It shows country context policy inputs and considerations, including potential interactions with other, complementary food environment policies, which can amplify the policy of interest's impact.\nConsidering the scoping review and the logic model, research questions were formulated using the population, intervention, comparator and outcome (PICO) format. Draft PICO questions were first discussed and reviewed by the WHO Secretariat, the WHO Steering Committee and the NUGAG Subgroup on Policy Actions. The final PICO questions were determined by the NUGAG Subgroup on Policy Actions. All potentially important outcomes were first identified and discussed by the group, followed by an anonymous online rating of outcomes on a scale from 1 to 9. Outcomes rated 7-9 were considered critical for decision-making, and those rated 4-6 were considered important. Those rated 1-3 were dropped from the PICO questions.\nThe NUGAG Subgroup on Policy Actions noted several challenges to assessing longer-term health outcomes.\nThe policies under consideration may have been only recently introduced, whereas changes to outcomes such as body weight/body mass index (BMI)/obesity and diet-related NCDs occur gradually.\nThere are methodological challenges in disentangling the impact of food marketing and policies to restrict food marketing to which children are exposed from the complex array of factors that contribute to outcomes such as body weight/BMI/obesity and diet-related NCDs.\nThere is a need to be realistic about the extent to which any one intervention can be expected to impact outcomes such as body weight/BMI/obesity and diet-related NCDs on its own. Instead, policies to restrict marketing are intended to contribute to such outcomes as part of a comprehensive package of policy actions.\nNonetheless, the group ranked several longer-term health outcomes as important, to ensure that the breadth and depth of current evidence were captured and considered in the guideline, and to highlight potential research and knowledge gaps and data challenges to strengthen the evidence base for future updates to this guideline. The selection of outcomes of interest when defining research questions should not be based on outcomes for which evidence is known to be available, but rather should provide the opportunity to explore the unknown and highlight data gaps. Complementary food environment policies: For example: nutrition labelling policies, fiscal policies, school food and nutrition policies, procurement policies.\nThe two PICO questions were as follows.\nWhat is the effect on the outcomes of interest of exposure of children to food marketing, compared with no marketing?\nWhat is the effect on the outcomes of interest of implementing a policy that aims to restrict children's exposure to food marketing and its persuasive power, compared with not implementing a policy?\nTable 1 provides details of the key questions in PICO format. As the WHO Set of recommendations on the marketing of foods and non-alcoholic beverages to children proposed that policies could be implemented through a variety of approaches, including statutory regulation, industry-led self-regulation and co-regulatory mechanisms (51), the definition of policies used in the second key question included both\nPolicies to protect children from the harmful impact of food marketing: WHO guideline mandatory and voluntary measures, to ensure that the effects of all policy approaches were considered.\nThe second key question included disaggregation by target population, target marketing media, approach to defining target foods, voluntary or mandatory approach, and degree and quality of implementation and enforcement, to enable consideration of policy design elements that may affect policy effectiveness.\nThe nature of food marketing has evolved since a previous review, in 2009, on the impact of food marketing (41) -on which the 2010 WHO Set of recommendations on the marketing of foods and non-alcoholic beverages to children (51) was based. Further, the scoping review identified a growing evidence base on the impact of food marketing. Consequently, a new systematic review on the impact of food marketing on the outcomes of interest was commissioned. A second systematic review -to assess the evidence on the effectiveness of implemented policies to restrict food marketing to which children are exposed, including to determine their potential desirable and undesirable effects, and explore policy design elements -was also commissioned, as none of the reviews identified by the scoping review adequately answered the formulated research question.\nThe NUGAG Subgroup on Policy Actions requested an additional review to provide information on contextual factors that would be considered in the formulation of the recommendations, such as resource implications, equity and human rights, acceptability and feasibility. The contextual factors in the review included those outlined in the WHO handbook for guideline development (Chapters 10 and 18) (56). Extra questions were formulated to guide the review of contextual factors (Annex 7).\n\n# Evidence gathering and grading\nEvidence gathered for this guideline included: a systematic review on the impact of food marketing on children (10); a narrative literature review on exposure to, and power of, food marketing, and their associations with food-related attitudes, beliefs and behaviours (9); a systematic review on the effectiveness of policies to restrict food marketing to which children are exposed (8); and a review of contextual factors (values, resource implications, equity and human rights, acceptability, and feasibility) (11).\nThe systematic review team conducted the two systematic reviews to address the two key questions in PICO format (Table 1). The systematic review searches were conducted in March and April 2019 and updated in March 2020. Studies that were retrieved in the systematic review searches and were considered relevant for the formulation of the guideline but did not meet eligibility criteria for either of the two systematic reviews were synthesized into a narrative review on exposure to, and power of, food marketing, and their associations with food-related attitudes, beliefs and behaviours (9). Reasons for excluding studies from the systematic reviews included ineligible study design or absence of a comparator group (9). Opinion pieces, studies that discussed marketing but did not report any primary data, and studies published before 2009 were excluded from the narrative review (9). The review of contextual factors was conducted by WHO and involved literature searches for systematic reviews, primary studies and grey literature that provided information on values, resource implications, equity and human rights, acceptability, and feasibility (11). Detailed descriptions of the methods for each review are available in the review publications.\nIn line with the guideline development process, the certainty of the body of evidence for each outcome gathered through each systematic review was assessed by the systematic review team using the GRADE approach. GRADE provides a transparent approach to grading the certainty of evidence for each outcome included in key questions. The certainty of evidence indicates the level of confidence that the effects of an intervention as observed in a body of evidence (i.e. a set of scientific studies) reflect the true effects that would occur in real-world settings.\nUsing the GRADE approach, there are four possible assessments for the overall certainty of the evidence for an outcome (65):\nvery low (very low level of confidence in the effect estimate -the true effect is likely to be substantially different from the effect estimate); low (low level of confidence in the effect estimate -the true effect may be substantially different from the effect estimate); moderate (moderate level of confidence in the effect estimate -the true effect is likely to be close to the effect estimate, but there is a possibility that it is substantially different); and high (high level of confidence in the effect estimate -the true effect is likely to be close to the effect estimate).\nThe starting point for assessing the overall certainty of the evidence for an outcome depends on the design of the studies that contribute to the evidence base: evidence from observational studies starts at low certainty, because of residual confounding, whereas evidence from randomized controlled trials (RCTs) starts at high certainty. Most studies that assess the effectiveness of policies to restrict food marketing to which children are exposed are observational, which means that the certainty of evidence often starts at low. The overall certainty of evidence for each outcome in the systematic reviews was assessed by considering five factors for potentially downgrading the certainty (risk of bias, inconsistency, indirectness, imprecision and publication bias) as defined and used in the GRADE approach, and three factors for potentially upgrading the certainty (large effect size, all plausible confounding would reduce the demonstrated effect, and doseresponse gradient).\nFor each GRADE factor for each systematic review, judgements were made by the systematic review team leader, and discussed and cross-checked with the systematic review team. The judgements and their rationale were recorded in a GRADE evidence profile table (see Annex 8 for the GRADE evidence profile table for the systematic review on the effectiveness of policies to restrict food marketing to which children are exposed).\nThe certainty of evidence was not assessed for the narrative review or the contextual factors review.\n\n# Formulation of the recommendations\nThe NUGAG Subgroup on Policy Actions discussed and assessed the evidence, drafted recommendations, and reached consensus on the direction and strength of the recommendations using the GRADE approach.\nAfter reviewing the ratings for the certainty of evidence for each critical and important outcome, the NUGAG Subgroup on Policy Actions made a judgement on the overall certainty of evidence by reflecting on the validity, precision, consistency and applicability of the measures of effect, taking into consideration the pathway of effect of the entire body of evidence. The GRADE approach explicitly separates the process of assessing the level of certainty in the evidence from the process of making recommendations. The latter process takes into consideration several additional contextual factors (resource implications, equity and human rights, acceptability and feasibility) (65). The level of certainty of evidence does not imply a particular strength of recommendation; high certainty evidence does not necessarily mean that a strong recommendation will be made, and a strong recommendation can be made with low or very low certainty evidence, depending on additional considerations.\nEvidence-to-decision tables were used to structure and document the discussion, and anonymous online voting was used to arrive at an initial judgement for each factor. Following the voting, initial judgements were discussed until the group reached consensus. Based on the evidence of effectiveness and additional contextual factors, the NUGAG Subgroup on Policy Actions developed the recommendations and associated remarks by consensus.\n\n# Management of conflicts of interest\nAccording to the rules in the WHO Basic documents (66), whenever an expert or an individual provides independent advice to WHO, including participating in WHO meetings, a declaration of interest form must be submitted, and all declarations must be analysed. In the case of guideline development, this includes all members of the guideline development group (for this guideline, the NUGAG Subgroup on Policy Actions), individuals who prepare systematic reviews and evidence profiles, and any other experts (including external peer reviewers) who participate in the process of guideline development in an individual capacity. Declaration of interest forms were reviewed by the WHO Secretariat in consultation with the WHO Office of Compliance, Risk Management and Ethics when finalizing the composition of the NUGAG Subgroup on Policy Actions. Before every meeting, the members of the NUGAG Subgroup on Policy Actions, the members of the systematic review team and other experts who would be participating in the meeting were asked to submit their updated declaration of interest forms. In addition to distributing the declaration of interest form, the WHO Secretariat described the declaration of interest process and provided an opportunity during meetings for guideline development group members to declare any interests not provided in written form. All declared interests were reviewed by the WHO Secretariat in consultation with the Office of Compliance, Risk Management and Ethics, as necessary. A summary of declared interests and the assessment of these interests is provided in Annex 9.\nSimilarly, declaration of interest forms from external peer reviewers were assessed by the WHO Secretariat, following the procedures for management of interests outlined in the Guidelines for declaration of interests for WHO experts (67).\n\n# Summary of evidence\nEvidence was gathered via a systematic review of studies on the impact of food marketing on children (10), a narrative review on food marketing exposure and power and their associations with food-related attitudes, beliefs and behaviours (9), a systematic review on the effectiveness of policies to restrict food marketing to which children are exposed (8), and a review of contextual factors (11). The evidence gathered was specific to food marketing and does not include broader evidence on the impact of marketing of other products, services or brands, or on the effectiveness of policies to restrict marketing of these. Policy-makers may draw upon such broader evidence to further support marketing restrictions.\n\n# Evidence on the nature, extent and impact of food marketing\nThe evidence summarized in this section is from two reviews: the narrative review on exposure to, and power of, food marketing, and their associations with food-related attitudes, beliefs and behaviours (9); and the systematic review on the impact of food marketing on children (10).\n\n# Narrative review\nA total of 179 studies, published from 2009 onwards, were included in the narrative review, which found that marketing of HFSS foods remains pervasive and persuasive across the globe (9).\nAs mentioned in section 2.2, articles that were retrieved in the searches for the two systematic reviews but were not eligible for inclusion in those reviews (e.g. because of unsuitable study design or comparator) were considered for inclusion in the narrative review. The findings should be interpreted as a thorough overview rather than an exhaustive account of the available evidence.\nThe studies were grouped as those related to:\nchildren's exposure to food marketing; the power of food marketing; and associations between food marketing and eating-related attitudes, beliefs and behaviours among children.\nA total of 118 studies (43 solely on exposure and 75 on both exposure and power) provided evidence on children's exposure to food marketing. The majority of studies were conducted in high-income countries (HICs) only (89 studies, compared with 26 conducted in low-and middle-income countries (LMICs) only, and three conducted in both HICs and LMICs). Studies assessed exposure to food marketing via television, digital media, product packaging, magazines and sports sponsorship; and in store, in schools, outdoors, on public transport and in restaurants. Findings of studies showed that, across marketing media, food marketing was prevalent and predominantly promoted HFSS foods. 1 The proportion of food marketing that was identified as being for HFSS foods generally ranged from 31.0% to 93.0%. The most frequently marketed foods (as defined by the study authors) included \"fast food\", sugar-sweetened beverages, chocolate and confectionery, salty/savoury snacks, sweet bakery items and snacks, breakfast cereals, dairy products, and desserts. The studies showed that food marketing continues to be directed at children -one study reported that as many as 95.2% of television advertisements for food were child oriented -and that child-directed marketing is generally for HFSS foods. Studies from the United Kingdom, Australia, the United States of America and New Zealand indicated that exposure to food marketing varied by socioeconomic status (SES), with greater exposure among those of lower SES.\nA total of 100 studies (25 solely on power and 75 on both exposure and power) provided evidence on the power of food marketing. The majority of studies were conducted in HICs only (74 studies, compared with 23 conducted in LMICs only, and three conducted in both HICs and LMICs). Studies considered food marketing via television, digital media, product packaging, magazines and sports sponsorship; and in store, in schools, outdoors and in restaurants. The studies showed that, across marketing media, a wide variety of strategies that are likely to appeal to children were used in food marketing. These included celebrity/ sports endorsements; promotional characters; product claims; promotions, gifts/incentives and tie-ins; competitions; games; colour, visual imagery and novel designs; animation, dynamic elements and special effects; prominent food cues; branding; product association; salient themes or contexts; persuasive appeals; emotional appeals; health/nutrition claims and disclaimers; depiction of physical activity; engagement techniques; interactive or downloadable content; children's language and voices, and childrelated messages and fonts; and large portion sizes. Some of these strategies were more frequent in food marketing directed at children than in general marketing, and in marketing of HFSS foods than in marketing of healthier foods.\nA total of 36 studies (16 studies on associations between food marketing and outcomes of interest, and 20 qualitative studies on the impact of food marketing) provided evidence on the effect of food marketing. Of these, 22 studies were from HICs and 14 from LMICs. Studies considered food marketing via television, video games, billboards, the internet, social media, in store and in print.\nThe studies on associations between food marketing and outcomes of interest covered a range of outcomes.\nFor example, one study showed that exposure to marketing for HFSS foods was positively associated with descriptive norms about the consumption of such foods among adolescents. In another study, the frequency of consumption of such foods was affected by the entertaining dimension of advertising and the level of emotional arousal that children experienced after exposure to food marketing. Studies also reported a positive association between frequency or level of exposure to food marketing and habitual consumption of marketed foods. Two studies indicated that engagement with food marketing (e.g. liking, sharing or commenting on social media posts; actively watching brand videos on YouTube) was associated with a greater impact on consumption than exposure to food marketing on its own. One study reported a positive correlation between the amount of time spent watching television and the prevalence of dental caries. Another reported a significant association between commercial television viewing at time 1 and BMI at time 2 (5 years later), which persisted after adjusting for exercise and eating while viewing television; no association was found for non-commercial television viewing.\nThe qualitative studies also reported on a wide range of impacts of food marketing. For example, one study reported that children could recognize advertised food in the supermarket, while another reported that adolescents could identify energy drink products by brand name. Several studies identified strategies that were likely to appeal to children in food marketing, including promotional characters, toys, playful visuals, colourful packaging, brand imagery and fun themes. Adolescents in one study reported that product packaging, the use of humour and the product's projected image were important. In another study, young adults reported that advertisements that they considered credible, entertaining, informative or relevant to them, or that contained offers, were of more interest to them. In a different study, young adults reported more positive feelings towards brands after exposure to brand websites and social media pages, and particularly content related to corporate social responsibility initiatives, community involvement and sponsorship. In multiple studies, parents reported concern about children's exposure to food marketing and support for regulation of such marketing. Children in one study believed that \"junk food\" should not be advertised to them. In terms of the impact of food marketing, studies generally reported a belief among participants that food marketing influenced eating and related behaviours among young people; these included studies of children, adolescents and parents. In one of these studies, parents reported that their children wanted to purchase food shown in advertisements; in another, children reported that they had chosen a cereal because of a toy and regardless of its taste. Children also reported being influenced by advertisements that their Facebook friends had liked or commented on. In contrast, in one study, parents believed that advertising for food had no effect on preferences or requests, and children did not believe they had learned about food from food advertising.\n\n# Systematic review\nA total of 96 studies, reported in 100 records, were included in the systematic review on the impact of food marketing on children (10). Table 1 outlines the population, intervention, comparator and outcomes that guided the review. Because the review was an update of a previous review conducted in 2009 (41), studies were limited to those with a publication date from January 2009 onwards. The search was conducted in April 2019 and updated in March 2020. Of the 96 included studies, 64 were RCTs and 32 were non-randomized studies (21 experimental and 11 observational). The majority of studies were conducted in HICs; only six took place in LMICs.\nPooled analyses were completed for three of the four critical outcomes -food preferences, food choice or intended choice, and dietary intake -and none of the four important outcomes. For the pooled analyses, moderator analyses assessed the possible impact on the effect sizes of study design type (RCT or nonrandomized study), marketing manipulation type (exposure or power), marketing medium (television, digital or packaging) and risk of bias. The possible impact of different marketing techniques (e.g. promotional characters, toys, celebrities) could not be assessed because of the small number of effect sizes for each technique within each outcome. For food choice or intended choice and dietary intake, the possible impact of mean age and BMI z-score of children on effect sizes was also assessed -this was not possible for food preferences because of the small number of effect sizes. Analyses by SES, sex, gender, rurality or region (i.e. HICs and LMICs) were not possible.\nA total of 20 studies (12 RCTs and eight experimental non-randomized studies) provided evidence on the impact of exposure to food marketing on the critical outcome of food preferences. Pooled analysis of 14 effect sizes from 12 studies found a standardized mean difference in food preferences of 0.30 (95% confidence interval (CI): 0.12-0.49; Z = 3.21; P = 0.001; I 2 = 90.0%), indicating a significant effect of exposure to food marketing on food preference compared with exposure to no, less or less powerful food marketing.\nThere was no statistical evidence that study design type, marketing manipulation type or marketing medium significantly moderated the effect size. Eight studies lacked the required data to be included in the pooled analysis -four of these found a significant association, two reported an association but did not report statistical testing, one showed apparently similar preferences between the exposure and control, and one found no significant association. According to the GRADE assessments for both the pooled analysis and all data, there is very low certainty evidence from RCTs and very low certainty observational evidence about the effect of food marketing on food preferences (10).\nA total of 37 studies (27 RCTs and 10 experimental non-randomized studies) provided evidence on the impact of exposure to food marketing on the critical outcome of food choice 1 or intended choice. Pooled analysis of 27 effect sizes from 27 studies found an odds ratio of 1.77 (95% CI: 1.26-2.50; Z = 3.27; P < 0.001; I 2 = 77.5%), indicating that exposure to food marketing was associated with 1.77 times the odds of choice of the test item compared with exposure to no, less or less powerful food marketing. There was no statistical evidence that study design type, marketing manipulation type, marketing medium, risk of bias or mean age of children significantly moderated the effect size. Ten studies lacked the required data to be included in the pooled analysis -six of these found a significant association, two found no significant association, one reported greater choice of the test item in the control condition but did not report test statistics (the authors suggested that this was due to issues with the demographic targeting of characters to children, with liking of characters very dependent on the age and sex of children), and one reported an association but did not report statistical testing. According to the GRADE assessments for both the pooled analysis and all data, there is moderate certainty evidence from RCTs that food marketing likely increases choice of marketed foods and very low certainty observational evidence about the effect of food marketing on food choice or intended choice (10).\nPolicies to protect children from the harmful impact of food marketing: WHO guideline A total of 46 studies (31 RCTs and 15 non-randomized studies -seven experimental and eight observational) provided evidence on the impact of exposure to food marketing on the critical outcome of dietary intake. Pooled analysis of 43 effect sizes from 41 studies found a standardized mean difference in dietary intake of 0.25 (95% CI: 0.15-0.35; Z = 4.88; P < 0.001; I 2 = 76.6%), indicating a significant effect of exposure to food marketing on dietary intake compared with no, less or less powerful food marketing. There was no statistical evidence that study design type, marketing manipulation type, marketing medium, risk of bias, mean age of children or mean BMI z-score significantly moderated the effect size. Five studies lacked the required data to be included in the pooled analysis -three of these studies found a significant association, and two found no significant association. According to the GRADE assessments for both the pooled analysis and all data, there is moderate certainty evidence from RCTs that food marketing likely increases dietary intake slightly and very low certainty observational evidence about the effect of food marketing on dietary intake (10).\nAs pooled analysis could not be completed for the important outcome of product requests or intended requests, because of a small number of studies and lack of reporting of relevant statistics, P value combination was used. Six studies (five RCTs and one observational non-randomized study) provided evidence. The combination of P values was significant in all model iterations (P < 0.001), indicating an effect of food marketing on product requests or intended requests. According to the GRADE assessment, there is moderate certainty evidence from RCTs that food marketing likely increases product requests or intended requests and very low certainty observational evidence about the effect of food marketing on product requests or intended requests (10).\nAs a result of the limited availability of P values, vote counting by direction of effect was used for the remaining critical outcome of food purchasing/sales or intended purchasing and the important outcomes of dental caries/erosion and body weight/BMI/obesity. The five effect directions were clear effect of public health harm, unclear effect of potential public health harm, no difference in effect, unclear effect of potential public health benefit, and clear effect of public health benefit. No relevant studies were identified for the important outcome of diet-related NCDs (or validated surrogate indicators).\nFive studies (one RCT and four non-randomized studies -one experimental and three observational) provided evidence on the impact of exposure to food marketing on the critical outcome of food purchasing/ sales or intended purchasing. Of the five studies, one reported a clear effect of public health harm, one an unclear effect of potential public health harm, two no significant association, and one a clear effect of public health benefit (a significantly higher proportion of orders for fruit desserts on days when fruit desserts were promoted). According to the GRADE assessment, there is very low certainty evidence from RCTs and very low certainty observational evidence about the effect of food marketing on food purchasing/sales or intended purchasing (10).\nTwo studies (both observational non-randomized studies) provided evidence on the impact of exposure to food marketing on the important outcome of dental caries/erosion. One study reported a clear effect of public health harm, whereas the other study reported no significant association. According to the GRADE assessment, there is very low certainty observational evidence about the effect of food marketing on dental caries/erosion (10).\nA single observational non-randomized study provided evidence on the impact of exposure to food marketing on the important outcome of body weight/BMI/obesity. The study reported no significant association. According to the GRADE assessment, there is very low certainty observational evidence about the effect of food marketing on body weight/BMI/obesity (10).\n\n# Evidence on effectiveness of policies to restrict food marketing to which children are exposed\nA total of 44 observational studies, reported in 47 records, were included in the systematic review on the effectiveness of policies to restrict food marketing to which children are exposed (8). Table 1 outlines the population, intervention, comparator and outcomes that guided the review, and Annex 8 provides the GRADE evidence profile. The search was conducted in March 2019 and updated in March 2020. The 44 included studies assessed the impact of 14 policies (including two subnational policies 1 and one regional policy 1 implemented in 10 countries 2 and one region (the European Union) (see Annex 10 for details of included policies). Seven policies were voluntary measures. Only one study used a natural experiment design; 3 all others had cross-sectional designs. All but one of the studies were conducted in HICs; the one study conducted in an LMIC was from Mexico.\nBecause of the nature of the available evidence, comparators were not consistent for all studies. Studies were therefore considered according to five comparisons: comparison 1 -any policy compared with no policy (includes all studies from comparisons 2 and 3); comparison 2 -mandatory policy compared with no policy (i.e. post-implementation compared with pre-implementation); comparison 3 -voluntary policy compared with no policy (i.e. post-implementation compared with preimplementation, or signatory companies compared with non-signatory companies); comparison 4 -mandatory policy compared with voluntary policy; 4 and comparison 5 -fully implemented mandatory policy compared with partially implemented mandatory policy.\nPooled analysis could not be completed for any of the outcomes of interest, because of the heterogeneity in effect measures 5 and the lack of data required for computation of effect sizes. Because of the lack of effect estimates and limited number of P values, vote counting using five effect directions was used to synthesize results for the critical outcomes of exposure to food marketing, power of food marketing, food purchasing/ sales or intended purchasing and dietary intake, and the important outcomes of product changes and unintended consequences to wider society by outcome of interest for the five comparisons described above.\nThe five effect directions were clear effect favouring the intervention, unclear effect potentially favouring the intervention, no difference in effect, unclear effect potentially favouring the control, and clear effect favouring the control. Fig. 3 shows the results of the vote counting for each outcome and each comparison.\nNo evidence was found for the critical outcomes of food preferences and food choice or intended choice, and the important outcomes of product requests or intended requests, dental caries/erosion, body weight/ BMI/obesity and diet-related NCDs (or validated surrogate indicators).\nWhere possible, subgroup analyses compared findings based on the target age group, marketing medium, approach to determining foods restricted from marketing, and marketing technique. 6 As pooled analyses could not be completed, formal sensitivity analyses were not possible -instead, results were synthesized narratively. Because of data limitations, it was not possible to complete subgroup analyses for children by body weight/BMI/obesity, SES, age group, sex, gender, rurality or region (i.e. HICs and LMICs).\nOverall, 37 studies provided evidence on the effect of food marketing policy on the critical outcome of exposure to food marketing. Of these, four studies reported effects clearly favouring the intervention (i.e. considered desirable for public health), 11 reported unclear effects potentially favouring the intervention, seven reported no effects of the intervention, 11 reported unclear effects potentially favouring the control (i.e. considered undesirable for public health), and four reported effects clearly favouring the control. As shown in Fig. 3, however, the distribution of studies varied between the comparisons -studies comparing mandatory policy with no policy were more likely to report effects clearly or potentially favouring the intervention (five out of seven studies -71% of studies) than studies comparing voluntary policy with no policy (eight out of 26 studies -31% of studies). Additionally, studies comparing voluntary policy with no 18\nPolicies to protect children from the harmful impact of food marketing: WHO guideline policy were significantly more likely to show effects on exposure to, and the power of, food marketing that were unfavourable to public health than effects that were favourable; this was not the case for studies comparing mandatory policy with no policy. Of studies comparing any policy with no policy, subgroup analyses of other policy design elements showed that some studies were more likely than others to report effects clearly or potentially favouring the intervention.\nStudies of policies designed to restrict food marketing to children including those older than 12 showed benefits on exposure more often (six out of eight studies) than studies evaluating policies designed to restrict food marketing to children that included only children aged 12 or younger (seven out of 25 studies). Additionally, studies evaluating policies designed to restrict food marketing to children that included only children aged 12 or younger were significantly more likely to report unfavourable than favourable effects on exposure; this was not the case for studies evaluating policies designed to restrict food marketing to children including those older than 12 years.\nStudies of policies that addressed exposure to television food marketing and to packaging more often found a beneficial impact on exposure (12 out of 29 studies and one of one studies, respectively) than did studies of policies that addressed exposure to digital marketing (zero of three studies; all three assessed policies were voluntary).\nStudies of policies that used a government-led nutrient profile model more often found a beneficial impact on exposure (five out of six studies) than did studies of policies that used a company-led nutrient profile model (eight out of 25 studies). Additionally, studies evaluating policies that used a company-led nutrient profile model were more likely to report unfavourable than favourable effects on exposure; this was not the case for studies evaluating policies that used a government-led nutrient profile model. Some studies reporting on exposure to marketing also provided information about the potential migration of marketing following policy implementation. For example, a study included in the systematic review demonstrated that after the prohibition in the United Kingdom of Great Britain and Northern Ireland of television advertising of HFSS foods on all children's channels and on non-children's channels during or around programmes \"of particular appeal\" to children, children's relative exposure to television advertising of HFSS foods did not change because of an apparent migration of such advertising to other times and channels that children also viewed (17). Another study included in the systematic review demonstrated that, following the implementation of a policy focused on children younger than 12 in the United States of America, there was a decrease in in the average food and beverage television advertisements 2-11 year-olds viewed per year, but an increase for 12-17 year-olds, suggesting migration of marketing to non-restricted spaces (16).\nA total of 18 studies provided evidence on the effect of food marketing policy on the critical outcome of power of food marketing. Of these, three studies reported effects clearly favouring the intervention, two reported unclear effects potentially favouring the intervention, one reported no effects of the intervention, six reported unclear effects potentially favouring the control, and six reported effects clearly favouring the control. As with exposure to food marketing, the distribution of studies varied between the comparisons (Fig. 3) -studies comparing mandatory policy with no policy were far more likely to report effects clearly or potentially favouring the intervention (three out of three studies -100% of studies) than studies comparing voluntary policy with no policy (one out of 13 studies -8% of studies). Additionally, studies comparing voluntary policy with no policy were significantly more likely to show effects on the power of food marketing that were unfavourable to public health than effects that were favourable; this was not the case for studies comparing mandatory policy with no policy. Of studies comparing any policy with no policy, subgroup analyses of other policy design elements showed that some studies were more likely than others to report effects clearly or potentially favouring the intervention.\nStudies evaluating policies designed to restrict food marketing to children including those older than 12 years more often reported favourable effects on power (in three out of four studies) than studies evaluating policies designed to restrict food marketing only to children that included only children aged 12 or younger (one out of 12 studies). Additionally, studies evaluating policies that were designed to restrict food marketing to children that included only children aged 12 or younger were significantly more likely to report unfavourable than favourable effects; this was not the case for studies evaluating policies designed to restrict food marketing to children including those older than 12 years.\nStudies evaluating policies (most of which were voluntary) that restricted the use of promotional characters more often reported favourable effects on power (in three out of 10 studies) than studies evaluating policies that restricted a broader range of child-appealing persuasive techniques (one out of five studies) or animation techniques (zero out of one study). Most of the studies included in this analysis evaluated voluntary policies.\nStudies evaluating policies that addressed power of television food marketing or packaging were more often reported to have favourable effects on power (in three out of 10 studies, and in one out of three studies, respectively) than were policies that addressed power of digital marketing (zero out of three studies; all three assessed policies were voluntary).\nFive studies provided evidence on the effect of food marketing policy on the critical outcome of food purchasing. Of these, four studies reported effects clearly favouring the intervention, and one study reported effects clearly favouring the control.\nOne study provided evidence on the effect of food marketing policy on the critical outcome of dietary intake; the study reported effects clearly favouring the intervention.\nTwo studies provided evidence on the effect of food marketing policy on the important outcome of product change. Of these, one study reported no effects of the intervention, and one study reported effects clearly favouring the control.\nThree studies provided evidence on the effect of food marketing policy on the important outcome of unintended consequences to wider society. Of these, one study reported effects clearly favouring the intervention (a statistically significant reduction in expenditure on television advertising of HFSS foods), and two reported unclear effects potentially favouring the intervention (a reduction in spending on television advertising of HFSS foods, and a reduction in net food and drink advertising revenue on children's channels). These changes were considered favourable to public health.\n\n# Evidence on contextual factors\nA total of 244 publications were included in the review of contextual factors relevant to policies to protect children from the harmful impact of food marketing (11). The overall aim of the review was to search for, identify, summarize and present information on the impact of contextual factors on implementation of policies to protect children from the harmful impact of food marketing.\nFifty-eight publications provided evidence related to values. Study populations varied in their values about body weight status. In HICs, overweight and obesity were generally perceived as a serious health problem.\nWomen were more likely than men to perceive overweight and obesity (especially childhood obesity) as a serious health problem, as were people of lower SES compared with their higher SES counterparts. In contrast, in many studies from LMICs, overweight and obesity were perceived as indicating good health or interpreted as \"normal weight\". However, in some countries that have perceived overweight and obesity as indicating good health, values are changing, and normal-weight BMI is increasingly considered healthy.\nIn contrast to values about body weight status, there was no variability in values about diet-related NCDs, or dental caries and erosion in children, which were perceived negatively in all identified studies. Limited information was identified on the potential impact of food marketing on values or whether consumers value \"non-misleading\" information.\nNine publications provided evidence related to resource implications. Evidence was identified in modelling studies and impact assessments, from both HICs and LMICs. The expected costs of such policies, expected health gains, expected health care cost savings and cost-effectiveness differed depending on country context, and the design and regulatory nature of policies. All identified modelling studies, however, found that policies to protect children from the harmful impact of food marketing would be cost-effective or costsaving. Studies noted that, like other interventions targeting children, policies to protect children from the harmful impact of food marketing may take some time to have an impact. Costs included in various studies included planning, implementation and compliance costs; savings typically included health care cost savings. One study estimated that self-regulation would be less costly than government regulation, but that its effects would also be less because of presumed lower compliance.\nFifty-nine publications provided evidence related to human rights and equity. Policies to protect children from the harmful impact of food marketing are in accordance with human rights standards. The Universal Declaration of Human Rights; the International Covenant on Economic, Social and Cultural Rights; and the Convention on the Rights of the Child provide the legal framework for a child rights-based approach to optimal nutrition and health. Publications included in the review outlined how unregulated food marketing may jeopardize the fulfilment of the Convention on the Rights of the Child, including in relation to Article 24 (the right to health) and Article 17 (protection from material injurious to well-being). The Convention on the Rights of the Child articulates the rights of children, including those to health, adequate and nutritious food, privacy and freedom from exploitation. Countries that are State Parties to the Convention on the Rights of the Child have legal obligations to respect, protect and fulfil these rights and are required to take immediate action to implement these obligations as a matter of priority (12). State Parties to the Convention on the Rights of the Child are therefore obliged to take action toward the fulfilment and realization of children's rights, which should include actions to protect children from marketing of less-healthy foods, which inhibits children's rights, such as the rights to health, adequate and nutritious food, privacy and freedom from exploitation (12). The Committee on the Rights of the Child, in a 2013 general comment on the right of the child to the enjoyment of the highest attainable standard of health, stated that the marketing of HFSS foods should be regulated (49). An area of increasing focus in relation to children's rights and food marketing is marketing through online media. In a 2021 general comment on children's rights in relation to the digital environment, the Committee on the Rights of the Child noted that State Parties should \"make the best interests of the child a primary consideration when regulating advertising and marketing addressed to and accessible to children\" (15). The general comment specifically addresses food marketing to which children are exposed by noting that State Parties \"should regulate targeted or age-inappropriate advertising, marketing and other relevant digital services to prevent children's exposure to the promotion of unhealthy products, including certain food and beverages, alcohol, drugs, tobacco and other nicotine products\" (15). The general comment also notes that \"such regulations relating to the digital environment should be compatible and keep pace with regulations in the offline environment\" (15). Special Rapporteurs on the right of everyone to the enjoyment of the highest attainable standard of health and the right to food have also emphasized the need for regulation of food marketing.\nLimited evidence was identified on the impact on health equity of policies to protect children from the harmful impact of food marketing. However, research in HICs shows that children of lower SES are more exposed to food marketing than children of higher SES, and this can lead to, or worsen, health inequities. As such, policies to protect children from the harmful impact of food marketing can be expected to reduce health inequities. Reflecting this, a modelling study from Australia found that restrictions on food marketing to children on television were likely to have greater health benefits and greater health care cost savings for children of lower SES than for those of higher SES.\nA total of 118 publications provided evidence related to acceptability. The evidence showed that acceptability of policies to protect children from the harmful impact of food marketing varied greatly by stakeholder. The existence of policies, or national action plans that recommend implementation of policies, indicates acceptability to government and policy-makers. For example, 40% of the 167 participating countries in the most recent global nutrition policy review reported including the regulation of food marketing to which children are exposed as an action area in national nutrition policies. However, few countries have implemented comprehensive policies to restrict food marketing to which children are exposed -42 countries reported in the second global nutrition policy review that they have measures in place, which included guidelines or codes (voluntary or mandatory); few measures were integrated into national law. Evidence identified from HICs indicates that policies to protect children from the harmful impact of food marketing are largely acceptable to the public. Women were consistently more supportive than men. Support also varied by age, ethnicity and SES. There was a lack of evidence from LMICs. Industry generally opposed government-led restrictions, but offered voluntary self-regulatory policies as an alternative. When initiated by industry, such policies can be considered a strategy to prevent the introduction of strong, legally enforceable government regulations. Limited evidence was found relating to environmental acceptability.\nThirty-two publications provided evidence related to feasibility. The existence of policies in some countries to protect children from the harmful impact of food marketing points to their feasibility, although many countries are yet to develop or implement such policies. Evidence identified on feasibility showed that facilitators of the development and implementation of policies include strong political leadership, supporting evidence, intersectoral collaboration and community support. Barriers to development and implementation include complexity of regulatory processes, conflicting interests, a lack of financial and human resources, industry interference, a weak evidence base, and ambiguous categorization of, or lack of criteria for, foods for which marketing is to be restricted or banned. Facilitators of monitoring and enforcement include clear guidelines and protocols, independent monitoring, transparency and monetary penalties. Barriers to monitoring and enforcement include a lack of transparency and accountability, conflicting interests in reporting of compliance, methodological difficulties, and inadequate human and financial resources.\n\n# Good-practice statement and recommendation\n\n# Good-practice statement\nChildren of all ages should be protected from marketing of foods that are high in saturated fatty acids, trans-fatty acids, free sugars and/or salt.\n\n# Statement rationale\nThe good-practice statement was formulated by the NUGAG Subgroup on Policy Actions based on several key considerations.\nChildren continue to be exposed to powerful marketing of HFSS foods, consumption of which is associated with negative health effects (8,9). Such marketing is prevalent (including on packaging, in settings where children gather (e.g. schools and sports clubs), during children's viewing times and on children's channels, in youth magazines, and on social media) and uses many techniques appealing to young audiences (9). Digital marketing is of growing concern because it facilitates engagement, which can amplify the marketing message and overall impact of marketing (9).\nFood marketing negatively affects children's food choice or intended choice (odds ratio 1.77; 95% confidence interval (CI): 1.26-2.50) and dietary intake (standardized mean difference 0.25; 95% CI: 0.15-0.35) (10). It also affects children's product requests to adults for marketed foods (10), and negatively influences the development of children's norms about food consumption (9).\nEnabling children of all ages to achieve their full developmental potential is a human right and a critical foundation for sustainable development. Children's rights, including their rights to health, adequate and nutritious food, privacy, and to be free from exploitation, are threatened by the marketing of HFSS foods (11)(12)(13).\nCountries that are State Parties to the Convention on the Rights of the Child have a legal obligation to ensure that children's rights are respected, protected and fulfilled. According to general comments on the Convention, countries that are State Parties to the Convention should use appropriate regulation to ensure that marketing does not have adverse impacts on children's rights, and should make the best interests of the child a primary consideration when regulating marketing that is addressed and accessible to children (14,15).\n\n# WHO recommendation\nWHO suggests implementation of policies to restrict marketing of foods high in saturated fatty acids, trans-fatty acids, free sugars and/or salt to which children are exposed, and that such policies: ¡ be mandatory;\n¡ protect children of all ages;\n¡ use a government-led nutrient profile model to classify foods to be restricted from marketing;\n¡ be sufficiently comprehensive to minimize the risk of migration of marketing to other media, to other spaces within the same medium or to other age groups; and ¡ restrict the power of food marketing to persuade.\n\n# Recommendation remarks\nThese remarks provide context for the recommendation and are to facilitate interpretation and implementation.\n'Children' refers to all human beings below the age of 18, as defined by the Convention on the Rights of the Child, unless, under the law applicable to children, majority is attained earlier.\nThe impact of marketing is a function of both exposure and power.\n-Exposure is the reach (percentage of people in a target market who are exposed) and frequency (the number of times an average person is exposed) of a marketing communication, message or action. Policies should address children's exposure to food marketing, irrespective of timing, venue or intended audience, and should therefore go beyond children's media.\n-Power refers to the extent to which a marketing communication, message or action achieves its communications objectives. Power is influenced by the creative content and strategies used. The power of food marketing to persuade children relates to techniques appealing to children, including promotional characters, branding, emotional appeals, games, engagement techniques, interactive or downloadable content, and celebrity endorsements (9); these techniques impact dietary intake (10).\nMigration of marketing refers to the movement of marketing from restricted to unrestricted mediums or spaces (e.g. if a policy restricts marketing on television but not digital marketing, digital marketing may increase).\nA nutrient profile model is a tool for classifying foods according to their nutritional composition for reasons relating to preventing disease and promoting health. Nutrient profile models in the context of food marketing help define foods to be restricted from marketing and should align with national dietary guidelines.\n\n# Recommendation rationale\nThe recommendation was formulated by the NUGAG Subgroup on Policy Actions based on several key considerations (below and Table 2).\nBased on evidence from a systematic review that assessed the effectiveness of policies to restrict food marketing to which children are exposed (8), the group judged policies to have moderate desirable effects and trivial undesirable effects and judged the overall balance between desirable and undesirable effects to favour the intervention. Following application of the GRADE approach (see section 2.2), the certainty of the evidence from the systematic review was considered very low, therefore the group made a conditional recommendation. The group noted that the relevant policy evaluations were all observational studies, leading to lower certainty of evidence when applying the GRADE system, and that the inconsistency of effect, which led to downgrading of the certainty of evidence for some outcomes, was partly due to variation in policy design elements.\nThe group judged policies to be cost-effective, feasible and generally acceptable to government, policy-makers and the public, but less so to industry. Further, implementation of policies supports the realization of human rights and will probably support improved health equity.\nSome policy design elements are likely to be effective in protecting children from marketing of HFSS foods, but others are more likely to lead to unfavourable effects. The recommendation therefore specifies elements that maximize the effectiveness of policies, as identified in the systematic review (8).\n-Of studies evaluating voluntary policies, significantly more studies showed undesirable effects than desirable effects on exposure to, and power of, food marketing. This was not the case for studies evaluating mandatory policies (8).\n-Of studies evaluating policies designed to restrict food marketing to children that included only children aged 12 years or younger, significantly more studies showed undesirable effects than desirable effects on exposure to, and power of, food marketing. This was not the case for studies evaluating policies that included children older than 12 (8).\n-Of studies evaluating policies that used a company-led nutrient profile model to define foods to be restricted from marketing more studies showed undesirable effects than desirable effects on exposure to food marketing. This was not the case for studies evaluating policies that used a government-led nutrient profile model.\n-Some studies indicated that policies that were too narrow in scope (i.e. not comprehensive) may have led to migration of marketing (e.g. from children's television programmes to non-children's television programmes, from younger to older age groups) (16,17).\n-Food marketing uses strategies that appeal to young audiences (9), and marketing using such strategies affects food choice and dietary intake (10). Studies indicated that mandatory policies result in reductions in use of powerful marketing strategies, such as the use of promotional characters and other persuasive techniques that appeal to children (8).\n\n# Table 2. Additional considerations by the NUGAG Subgroup on Policy Actions to determine the direction and strength of the recommendation\n\n# Decision criteria and judgement Additional considerations\nMagnitude of desirable effects of implementing a policy: moderate\nThe policies included in the systematic review on the effectiveness of policies to restrict food marketing to which children are exposed varied greatly in their design. When comparing any policy with no or other policies, the group judged the magnitude of the desirable effects to be variable. Following discussions on the results of additional comparisons and of subgroup analysis, the magnitude of the desirable effects was judged as moderate. The group agreed that the policy design elements that were more likely to result in effects favourable to public health should be clearly listed in the recommendation; these included the policy approach used, target age group, and approach to defining foods whose marketing was to be restricted.\nMost evidence is from HICs, but the group considered it unlikely that the effects of the intervention would be substantially different in low-and middle-income countries (LMICs).\nFood environment policies are complex interventions. Many factors influence the relevant outcomes of interest (Fig. 2). The intervention's impact on the outcomes of interest could be amplified if it is implemented alongside complementary food environment policies.\n\n# Decision criteria and judgement Additional considerations\n\n# Magnitude of undesirable effects of implementing a policy: trivial\nNo undesirable effects on health outcomes of implementing policies to restrict food marketing to which children are exposed were identified in the reviews.\nBased on the results of the systematic review and experience in countries, the group noted that policies that are too narrowly defined could have undesirable effects, including: migration of marketing to other media; migration of marketing to other spaces within the same medium or to other age groups; and risk of increased marketing of brands in place of marketing of specific products.\nOverall, the magnitude of the undesirable effects of implementing a policy to restrict food marketing to which are children are exposed was judged as trivial, if the approach to marketing restrictions is comprehensive and if policy design uses elements identified by the additional comparisons and subgroup analyses as favourable to public health.\n\n# Balance of desirable and undesirable effects: probably favours the intervention\nBased on the available evidence, country experience and discussions on the results of additional comparisons and of subgroup analyses, the balance of desirable and undesirable effects was judged to probably favour the intervention.\n\n# Overall certainty of evidence: very low\nThere was a high level of heterogeneity in the evidence.\nThe inconsistency of effect was partly due to variation in policy design elements (i.e. the policy approach, target age group and approach to defining foods to be restricted from marketing).\nThe relevant policy evaluations were all observational studies, leading to lower certainty of evidence when applying the GRADE system.\n\n# Cost-effectiveness: favours the intervention\nEvidence was based on modelling studies and showed the intervention was costeffective.\n\n# Resources required: moderate costs\nThe costs should be considered in the context of, and relative to, total government expenditure on health and preventive health.\nBoth one-off costs (e.g. policy drafting and enactment) and ongoing costs (e.g. monitoring and enforcement) should be considered.\nThe costs considered should be costs to government and not costs to other actors (e.g. industry).\nCountry experience showed that some countries may previously have underestimated the resources required.\n\n# Impact of policy implementation on equity: probably increased\nResearch, mainly from HICs, shows that children of lower SES are more exposed to food marketing than children of higher SES, which can lead to, or worsen, health inequities.\nLow-agency public health interventions (i.e. public health interventions that do not rely on, or rely less on, the conscious actions of individuals) are likely to increase health equity.\n\n# Impact of policy implementation on human rights: increased\nChildren's rights are an important consideration for country action to restrict marketing. New marketing media and techniques, particularly digital marketing, are of increasing concern.\nCurrent safeguarding mechanisms permitting advertising in the digital space (e.g. age-appropriate videos on social media platforms) are unlikely to work in practice.\nAdditional challenges arise with increased digital marketing, including respecting the right to privacy.\nPolicies to protect children from the harmful impact of food marketing: WHO guideline\n\n# Decision criteria and judgement Additional considerations\nPeople's values related to the outcomes of policy implementation: probably no important uncertainty or variability\nThe group noted the importance of valuing children's health, the need to protect the health of the vulnerable, and the role of governments in enabling decisionmaking that protects health.\n\n# Acceptability of the policy to key actors: varies\nGenerally, policies are acceptable to government, policy-makers and the public, but less so to industry.\nAcceptability to industry depends on the type of policy proposed. Industry generally prefers voluntary to mandatory policies.\nAcceptability to government may vary between ministries. This could relate to industry being a core stakeholder for some ministries (e.g. industry, commerce and communications), and to concerns about potential economic impacts on related sectors.\nMost evidence is from HICs. It is unclear whether acceptability would be different in LMICs.\n\n# Feasibility of implementing the policy: yes\nCountries that have successfully implemented policies have shown that policies can be implemented, and that well-designed policies do not pose substantive trade concerns.\nThe nutrient profile models developed by the WHO regional offices can be adapted by countries; they help identify foods to be restricted from marketing and may increase feasibility.\nIndustry influence may be a barrier to implementation of effective policies.\nProviding clear guidance to countries may remove fears of complexity and increase feasibility.\nHIC: high-income country; LMIC: low-and middle-income country; SES: socioeconomic status.\n\n# Implementation considerations\nThis chapter is not intended to provide an exhaustive list of implementation considerations. Instead, it aims to highlight some key considerations. These considerations:\nemerged from the systematic review on the effectiveness of policies to restrict food marketing to which children are exposed (8);\nwere mentioned by the NUGAG Subgroup on Policy Actions in the development of this guideline; and/or come from existing implementation resources -particularly the 2023 WHO/UNICEF publication Taking action to protect children from the harmful impact of food marketing: a child rights-based approach (57) and the 2012 WHO publication A framework for implementing the set of recommendations on the marketing of foods and non-alcoholic beverages to children (47).\nThe WHO/UNICEF publication Taking action to protect children from the harmful impact of food marketing: a child rights-based approach provides step-by-step guidance through the four main stages in the policy cycle (preparation; development; implementation; and monitoring and evaluation) -integrating both a public health lens and a child rights lens -as summarized in Table 3 (57). In line with this guideline's goodpractice statement, policies should be formulated in the best interests of children, and apply the policy design elements specified in this guideline's recommendation.\nDuring the preparation stage, it is important to consider the country context. This includes the country's: nutritional situation; cultural context; locally available foods; dietary customs; available resources and capacities; existing governance structures and mechanisms (including mechanisms to identify and manage conflicts of interest and to safeguard public health policies and enforcement mechanisms); policy context (relevant legal and policy frameworks, potential regulatory pathways and the overall political economy); and stakeholders with an interest in the policy outcome and whether, or at what stage, they may be engaged in the policy process to optimise policy effectiveness and implementation while protecting public health objectives (see Fig. 2).\nThe review of contextual factors highlighted factors that may facilitate the development and implementation of policies to protect children from the harmful impact of food marketing. These include strong political leadership, supporting evidence, community support, intersectoral collaboration, and mechanisms to protect the public interest and avoid conflict of interest (11). Factors that hinder development and implementation include complex regulatory processes, conflicts of interest, lack of financial and human resources, industry interference, a weak evidence base, and ambiguous categorization of (or a lack of criteria for categorization of) foods for which marketing is to be restricted or banned (11).\nGiven that marketing and regulatory landscapes are complex, a situation analysis of both is a useful tool for policy development (47). Reviewing existing laws and policies is important to identify gaps, and potential regulatory pathways and mechanisms for the implementation of marketing restrictions. Potentially relevant controls and agencies to include in a regulatory landscape situation analysis vary between countries, but could include: public health policies, legislation and institutions; media controls and regulating authorities; child protection legislation and agencies; regulation and enforcement agencies relevant to food labelling, composition and distribution; regulations and institutions relevant to consumer protection and consumer rights;\nplanning and zoning controls on food retailing, catering and outdoor marketing; and school regulations and education authorities (47).\nTo implement the recommendation in this guideline, countries may choose to strengthen existing policies and/or develop and implement new policies.\nDuring the preparation stage, it is also important for policy developers to anticipate opposition (57). The 2023 WHO/UNICEF publication Taking action to protect children from the harmful impact of food marketing: a child rights-based approach lists common arguments and legal challenges against policies to protect\n\n# Communicate results of evaluation\nRevise and revisit children from the harmful impact of food marketing. It provides counterarguments based on a child rightsbased approach and the available scientific evidence, and gives steps to strengthen the government's legal position in the event of challenge (57). Clear, transparent and robust conflict of interest guidelines and mechanisms that cover all stages of the policy cycle should also be adopted during the preparation stage (57).\nDuring the development stage, when a government is deciding on key design issues, some factors should be borne in mind to maximize effectiveness. These include:\nthe instrument to be used to implement restrictions on food marketing to which children are exposed;\nthe regulatory objectives;\nthe scope and definitions of the key components of the policy (57);\nthe policy design elements specified by the recommendation in this guideline (i.e. taking a mandatory approach, protecting children of all ages, using a government-led nutrient profile model, being sufficiently comprehensive, restricting the power of food marketing to persuade).\nThe nutrient profile models for regulating food marketing to which children are exposed developed by the WHO regional offices (2-7) provide an existing tool that countries can use.\nAs highlighted by the 2012 WHO report A framework for implementing the set of recommendations on the marketing of foods and non-alcoholic beverages to children, efforts to restrict marketing must consider how brands are marketed (47). If brand marketing is not included within a policy's scope, a possible unintended consequence may be an increase in brand advertising and sponsorship by brands synonymous with less-healthy products (in place of marketing for the products themselves) (57). Possible approaches that countries could use to restrict brand marketing include classifying brands as permitted or not permitted based on whether their top-selling products are classified as healthy or unhealthy (47) and restricting marketing of brands that are synonymous with less-healthy products (69).\nWhen agreeing on the scope and defining the key components of a policy, an additional key consideration is the incorporation of provisions for cross-border marketing (i.e. marketing via material that is produced in one country and sold, shared, downloaded or consumed in others) (57). Cross-border marketing presents some challenges to national policies. However, government lawyers can help policy-makers to find entry points for incorporating and enforcing such provisions within domestic jurisdictions (57). Recommendation 8 of the 2010 WHO Set of recommendations on the marketing of foods and non-alcoholic beverages to children noted that, to ensure significant impact of national actions, effective international collaboration is essential (51). Also important is regional collaboration, in which cross-border marketing is shared between neighbouring countries or those with close cultural and commercial ties.\nDuring the development stage, the resources required for policies to protect children from the harmful impact of food marketing should be considered. Like other interventions targeting children, policies to protect children from the harmful impact of food marketing may take considerable time to have an impact on population health (11). Long-term political commitment to such policies -including resource allocation for enforcement, and continued monitoring for compliance and achievement of objectives -is therefore needed if policies are to be effective. Such commitment should be across all relevant ministries, because policy implementation may involve ministries other than health (e.g. food regulators, consumer affairs, media and communications, trade).\nDuring the implementation stage, a monitoring and enforcement system should be established to assist in identifying violations and enforcing compliance (57). The enforcement system should be both proactive (acting on infringements identified through monitoring) and reactive (open to receiving notification of possible infringements) (57) and apply enforceable sanctions that are sufficiently meaningful to deter noncompliance. The monitoring for compliance during the implementation stage should be accompanied by monitoring and evaluation of the policy impact during the monitoring and evaluation stage (57). Additional information on considerations for evaluation design is provided in section 6.2.\nFinally, a comprehensive policy approach is needed to create enabling and supportive food environments.\nThe recommendation in this guideline should be considered together with those in other WHO guidelines on 5. Implementation considerations policies to improve the food environment, including WHO guidelines on school food and nutrition policies (60), nutrition labelling policies (58) and fiscal policies (59). Also relevant for improving the food environment and promoting healthy diets are the WHO guideline on school health services (70); the global standards for health-promoting schools (71); WHO guidelines on sodium intake (61) and sugars intake (62); and the recommendations of the WHO Commission on Ending Childhood Obesity (54). WHO guidelines on total fat, saturated fatty acids and trans-fatty acids, polyunsaturated fatty acids, carbohydrates, use of non-sugar sweeteners and use of low-sodium salt substitutes are all forthcoming.\nMore detailed guidance on the implementation of policies to protect children from the harmful impact of food marketing should be consulted before implementing the recommendation in this guideline. Selected existing global and regional implementation resources are listed in Box 3.\n\n# Box 3. Resources for development and implementation of policies to protect children from the harmful impact of food marketing\nGlobal ¡ A child rights-based approach to food marketing: a guide for policy makers (12) ¡ A framework for implementing the set of recommendations on the marketing of foods and nonalcoholic beverages to children (47) ¡ Implementing policies to restrict food marketing: a review of contextual factors (11) ¡ Protecting children from the harmful impact of food marketing: policy brief (72) ¡ Taking action to protect children from the harmful impact of food marketing: a child rights-based approach (57)\n¡ Monitoring and restricting digital marketing of unhealthy products to children and adolescents: report based on the expert meeting on monitoring of digital marketing of unhealthy products to children and adolescents, Moscow, Russian Federation, June 2018 (73)\n¡ Regional action framework on protecting children from the harmful impact of food marketing in the Western Pacific (74) ¡ Tackling food marketing to children in a digital world: trans-disciplinary perspectives -children's rights, evidence of impact, methodological challenges, regulatory options and policy implications for the WHO European Region (46) Nutrient profile models\n\n# Research gaps\nBased on the results of the systematic reviews, the narrative review, the review of contextual factors, the discussions of the NUGAG Subgroup on Policy Actions, and input received during peer review and the public consultation, a number of research gaps and considerations were identified. They reflect understudied thematic areas and geographic locations, as well as methodological issues. These will be important when updating this guideline, and for further advocacy and action to protect all children from the harmful impact of food marketing.\nAs noted previously, the evidence on which this guideline is based is specific to food marketing. Accordingly, it does not include evidence on the broader question of the impact of marketing, or on the broader question of the effectiveness of policies to restrict marketing. It is inherent in the search strategy and selection criteria used in the systematic reviews that broader evidence on marketing and evidence specific to adults is excluded from the evidence underpinning the guideline. This evidence is also not used for purposes of triangulation or checking the conclusions drawn against the broader body of evidence on the impacts of marketing and marketing restrictions.\n\n# Overarching research gaps\nOverall, most research was from HICs. High-quality studies from LMICs would improve the representativeness of evidence underlying this guideline and provide additional information on contextual factors that may affect the implementation of policies to protect children from the harmful impact of food marketing.\n\n# Impact of food marketing\nMuch of the research identified in the systematic review on the impact of food marketing on children focused on proximal outcomes (e.g. food preferences, food choice or intended choice, dietary intake); few suitable studies were available for more distal outcomes (e.g. dental caries/erosion, body weight/BMI/ obesity, diet-related NCDs) (10). Long-term studies that consider the impact of food marketing on more distal outcomes would be valuable when updating this guideline. Given the substantial methodological challenges -for example, disentangling the impact of food marketing from the complex array of other factors that contribute to outcomes such as body weight/BMI/obesity and diet-related NCDs that develop gradually over time -high-quality studies on proximal outcomes will remain valuable. As well, most studies on the impact of food marketing on dietary intake focused on the impact of acute exposure to marketing on acute dietary intake; studies that consider the sustained effects of food marketing on dietary intake would also be valuable.\nMuch of the research on the impact of food marketing to date has focused on food marketing via television.\nAs the marketing landscape continues to evolve, additional research could improve understanding of the impact of food marketing via other marketing media (e.g. outdoor advertising, digital marketing, sponsorship), as well as of the combined effect of different types of marketing.\nAdditional studies on the impact of brand marketing -including on possible brand spillover and health halo effects -would be beneficial in closing loopholes in some policies to restrict food marketing to which children are exposed that permit the marketing of brands (as distinct from products and services).\nThe potential impact of food marketing on adults, including those who are caregivers and who purchase food for children, was outside the scope of this guideline. However, research in this area may be important when updating this guideline.\nPolicies to protect children from the harmful impact of food marketing: WHO guideline\n\n# Effectiveness of policies\nAs with the systematic review on the impact of food marketing on children, much of the research identified in the systematic review on the effectiveness of policies to restrict food marketing to which children are exposed focused on proximal outcomes (e.g. exposure to marketing, power of marketing); no suitable studies were available for more distal outcomes (e.g. dental caries/erosion, body weight/BMI/obesity, dietrelated NCDs) (8).\nStudies on the effectiveness of policies on more distal outcomes would be valuable when updating this guideline. The same methodological challenges discussed above apply, as well as a need to be realistic about the extent to which any one intervention can be expected to affect these outcomes on its own.\nStudies included in the systematic review reported on the effect of policies on exposure to, or power of, food marketing via a single marketing medium only (e.g. television, packaging). To ensure the effectiveness of policies and mitigate unintended consequences, there is a need for studies that monitor the possible migration of food marketing within one medium (e.g. from child-focused to family-focused television content) or to other marketing media (e.g. outdoor advertising, sponsorship). Current research on the impact of policies largely focuses on changes to food marketing on children's television programmes, or marketing of food products of appeal to children -changes to overall exposure to food marketing are a knowledge gap. The use of indirect evidence on policies to restrict marketing of products or services beyond food could also be explored to further support policy actions to protect children from the harmful impact of food marketing.\nComparative studies that include multiple countries would be beneficial when updating this guideline. Information on the scope of current national policies and whether they cover cross-border food marketing would also be useful.\n\n# Contextual factors\nAlthough the review of contextual factors found evidence that children of lower SES are more exposed to food marketing than children of higher SES, it found few studies that directly examined the impact on health equity of policies to protect children from the harmful impact of food marketing (11). Future studies should therefore include data disaggregated by characteristics such as SES, sex, gender and rurality (see section 6.2).\nDuring the discussions of the NUGAG Subgroup on Policy Actions, an expert noted that, in some countries, there may be concerns that prohibition of sponsorship of children's sport might reduce children's opportunity to play sport. The review of contextual factors found some evidence relating to this. For example, an impact assessment of a draft policy that included restrictions on sponsorship of children's events noted a possible \"public outcry\" if events stopped as a result of funding limitations due to restrictions on marketing (11). Further research on the acceptability and feasibility of restrictions on sports sponsorship would be beneficial.\n\n# Considerations for design of future evaluations\nFor many of the outcomes of interest in the systematic reviews on the impact of food marketing on children (10) and the effectiveness of policies to restrict food marketing to which children are exposed (8), the certainty of the evidence was low or very low. Following application of the GRADE approach (see section 2.2), the certainty of the evidence was often downgraded because of a serious or very serious risk of bias in the included studies, or serious or very serious inconsistency of effect. The certainty of the evidence could be improved by ensuring that future studies address common issues related to risk of bias -for example, for studies on the impact of food marketing on children, not providing information on non-respondents or not controlling for confounding factors. The inconsistency of effect for studies on the effectiveness of policies to restrict food marketing to which children are exposed also reflects differences in study design, sampling approach and effect measure. Use of standardized monitoring procedures could potentially reduce the inconsistency of effect between studies and thereby improve the certainty of the evidence. A diverse array of tools has been used in research that assesses the extent of policy implementation, and implementation processes for food environment policies (75). Although guidance on appropriate study designs and methods for policy evaluation remains limited, results from current research projects can be used to strengthen policy evaluations (76). Potential standardized monitoring procedures include those proposed by the WHO Regional Office for Europe (77) and the International Network for Food and Obesity/ Non-communicable Diseases Research, Monitoring and Action Support (INFORMAS) (78). As the use of digital marketing (including programmatic advertising and user-generated content) increases, tools for monitoring such marketing, such as the CLICK tool for monitoring digital food marketing developed by the WHO Regional Office for Europe (73) should also be considered.\nA number of studies in the systematic review on the effectiveness of policies to restrict food marketing to which children are exposed lacked effect estimates and/or P values. This prevented pooled analysis; instead, vote counting based on direction of effect was used, which provided no information on the magnitude of effect and did not account for differences in the relative size of included studies. Future studies should include effect estimates and P values.\nIn both systematic reviews, analyses by SES, sex, gender and rurality were not possible, because data on these characteristics were either reported by too few studies for each outcome or not reported by exposure groupings. Where possible, future studies should include data disaggregated by these characteristics to enable analysis of the impact on health equity of food marketing and of policies to protect children from its harmful impact.\nOther considerations for the design and reporting of future evaluations of policies to restrict food marketing to which children are exposed include a need for more detailed information on policies (e.g. enforcement mechanisms); this would allow more detailed examination of policy design elements that may impact effectiveness.\nImplementation research addresses both policy implementation processes and relevant contextual factors (79). Integrating implementation research into policy and programmatic decision-making processes from the start can support collaboration between policy implementers and researchers to ensure that such research is useful (79). Qualitative comparative analysis can provide further insights into regulatory governance conditions that lead to food environment policies that can improve population nutrition outcomes (80). Systems thinking can be useful in generating robust evidence about which policies are the most effective. This applies to the policy-making process, problem identification and policy analysis and, after a policy is implemented, policy evaluation (81).\n\n# Uptake, monitoring and updating of the guideline\nThis guideline will be disseminated to Member States through the networks of WHO regional offices and country offices, WHO collaborating centres, United Nations partner agencies and civil society agencies, relevant nutrition webpages on the WHO website 1 and the electronic mailing lists of the WHO Department of Nutrition and Food Safety, among others. The guideline will also be disseminated at relevant global, regional and national meetings. Specifically, it will be used to support policy dialogues being held as part of the WHO's work to accelerate action to stop obesity. The guideline is an important part of the technical package to support implementation of the recommendations for the prevention and management of obesity over the life course, and related targets adopted by the 75th World Health Assembly. 2 The impact of this guideline can be evaluated by assessing its adoption and adaptation across countries.\nEvaluation at the global level will be through the periodically conducted Global Nutrition Policy Review and the WHO NCD Country Capacity Survey, published through the WHO Global database on the Implementation of Nutrition Action (GINA) 3 and will also consider independent researcher input. GINA is a centralized platform developed by the WHO Department of Nutrition and Food Safety for sharing information on nutrition actions in public health practice implemented around the world. GINA currently contains information on thousands of policies (including legislation), nutrition actions and programmes in more than 190 countries. It includes data and information from many sources, including the first and second WHO global nutrition policy reviews conducted in 2009-2010 and 2016-2017, respectively (55,82). By providing programmatic implementation details, specific country adaptations and lessons learned, GINA serves as a platform for monitoring and evaluating how policy guidelines are being translated and adapted in various countries. The WHO NCD Country Capacity Survey is a global survey of all Member States that provides a periodic assessment of national capacity for NCD prevention and control, including in several nutrition-related areas.\nIn line with the WHO handbook for guideline development (56), the recommendation in this guideline will be regularly updated, based on new data and information. The WHO Department of Nutrition and Food Safety will be responsible for coordinating updates of the guideline, following the formal procedure described in the WHO handbook for guideline development (56). When the guideline is due for review, WHO will welcome suggestions for additional questions that could be addressed in the guideline.\nIf there are concerns that the guideline's recommendation may no longer be valid, the Department of Nutrition and Food Safety will communicate this information, together with plans to update the guideline, to relevant actors via announcements on the Department of Nutrition and Food Safety website and electronic mailing lists, as well as communicating directly with actors, as necessary.\n\n# GRADE evidence profile\nPICO: What is the effect in children on the outcomes of interest of implementing a policy to restrict food marketing to children, compared with implementing no policy -or a different policy? Population: Children Intervention: All policies that aim to restrict food marketing to children, comprising mandatory, legally enforceable measures (including statutory approaches, regulations, legislation or orders used by a jurisdiction's legal system) and voluntary measures (including self-regulatory measures, pledges or codes), but excluding action plans, strategies, programmes and initiatives Comparison: Varied by intervention. For voluntary measures, the comparison was before implementation of the measure or by non-signatory companies after implementation of the measure; for mandatory policies, the comparison was marketing activity under a previous voluntary measure, at the point of partial implementation of the mandatory policy, or before implementation of the policy. Key characteristics of policies evaluated by studies included in the systematic review on the effectiveness of policies to restrict food marketing to which children are exposed\nThe following table provides the key characteristics of the policies evaluated by studies included in the systematic review on policies to restrict food marketing to which children are exposed (1). Some of the policies and/or their characteristics may no longer be current. Regulates (does not prohibit) use of promotions, popular characters and premium offers promoted to children in advertisements for food: \"If a premium is offered, any reference to the premium must be incidental to the main product or service advertised\". Premiums are defined as anything offered with or without additional cost that is intended to induce the purchase of an advertised product or service.\nPolicies to protect children from the harmful impact of food marketing: WHO guideline"}}},{"rowIdx":84,"cells":{"id":{"kind":"string","value":"ac465c8454d457f8dd8ca38e2fe172d64ba29494"},"source":{"kind":"string","value":"nice"},"text":{"kind":"string","value":"Physical activity: walking and cycling\n\nThis guideline covers encouraging people to increase the amount they walk or cycle for travel or recreation purposes.\n\n# What is this guidance about?\nThis guidance aims to set out how people can be encouraged to increase the amount they walk or cycle for travel or recreation purposes. This will help meet public health and other goals (for instance, to reduce traffic congestion, air pollution and greenhouse gas emissions). The recommendations cover:\npolicy and planning\nlocal programmes\nschools, workplaces and the NHS.\nThis guidance does not cover:\nEnvironmental changes to encourage walking or cycling. (see the NICE guideline on physical activity and the environment covers the physical infrastructure and planning needed to make non-motorised transport an easier option.)\nNational actions to support walking and cycling, such as fiscal measures and other policy interventions to alter the balance between active and motorised travel in terms of cost and convenience.\nMeasures to reduce the risk of unintentional injuries from walking and cycling. (See the NICE guideline on strategies to prevent unintentional injuries among under-15s.)\n\n# Who is this guidance for?\nThe guidance is for commissioners, managers and practitioners involved in physical activity promotion or who work in the environment, parks and leisure or transport planning sectors. They could be working in local authorities, the NHS and other organisations in the public, private, voluntary and community sectors. It is also aimed at:\nemployers\nestate managers\nhighways authorities\nthose involved in land use planning and development control\nprivate developers\npublic transport operators\nthose involved in carbon reduction or sustainability planning\n-thers responsible for workplace travel, carbon reduction or sustainability plans.\nIn addition, it will be of interest to people who promote walking and cycling in an unpaid capacity, those who want to walk or cycle and other members of the public.# Recommendations\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\nThe guidance complements NICE guidance on physical activity and the environment.\nThe evidence statements underpinning the recommendations are listed in appendix C.\nThe Programme Development Group (PDG) considers that the recommended approaches are highly cost effective.\nSee also the recommendations for research, gaps in the evidence and the evidence reviews, supporting evidence statements and economic modelling report.\n\n# Background\nThis guidance considers walking and cycling as forms of transport, for example, to get to work, school or the shops. It also considers them as recreational activities, for example, as a means of exploring parks or the countryside.\nWalking and cycling are distinct activities which are likely to appeal to different segments of the population. A range of factors may be important in helping or restricting people from taking part. These will vary according to whether someone is walking or cycling for transport purposes, for recreation or to improve their health. Wherever the term 'walking and cycling' is used in this guidance, these variations should be kept in mind.\nIn the context of this guidance, walking and cycling includes the use of adapted cycles (such as trikes, tandems and handcycles), wheelchairs and similar mobility aids.\nThe action needed to increase levels of walking and cycling will vary according to people's local and personal circumstances. For instance, it will differ according to whether someone lives or works in an urban or rural area, the local traffic conditions and their perceptions of safety.\n'Local' may refer to an area defined by geography or for administrative purposes. It may comprise an area larger than that covered by a single local authority such as Greater London, Manchester or Merseyside. It may also refer to a housing estate, a small town or a village.\n\n# Benefits of walking and cycling\nIncreasing how much someone walks or cycles may increase their overall level of physical activity, leading to associated health benefits. These include:\nReducing the risk of coronary heart disease, stroke, cancer, obesity and type 2 diabetes.\nKeeping the musculoskeletal system healthy.\nPromoting mental wellbeing.\nAn increase in walking or cycling can also help:\nReduce car travel, leading to reductions in air pollution, carbon dioxide emissions and congestion.\nReduce road danger and noise.\nIncrease the number of people of all ages who are out on the streets, making public spaces seem more welcoming and providing opportunities for social interaction.\nProvide an opportunity for everyone, including people with an impairment, to participate in and enjoy the outdoor environment.\n\n# Encouraging people to walk and cycle\nEncouraging and enabling people to walk or cycle requires action on many fronts – and by many different sectors. A range of issues have to be addressed, including environmental, social, financial and personal factors.\nIn addition to the recommendations made in this (and related) NICE guidance, other measures are needed to tackle the wider influences on walking or cycling. This includes measures to reduce road dangers and to reallocate road space to create a more supportive environment (see the scope for further detail). Action in these areas is particularly important in tackling inequalities in health, including with regard to people with impairments.\n\n# Whose health will benefit?\nUnless otherwise stated, the recommendations will benefit everyone.\n\n# Policy and planning\n\n## Recommendation 1 High-level support from the health sector\nDirectors of public health.\nPublic health portfolio holders in local authorities.\nClinical commissioning groups.\nEnsure a senior member of the public health team is responsible for promoting walking and cycling. They should support coordinated, cross-sector working, for example, by ensuring programmes offered by different sectors complement rather than duplicate each other (see recommendation 2). The senior member should also ensure the recommendations in NICE's guideline on physical activity and the environment are implemented.\nEnsure the joint strategic needs assessment, the joint health and wellbeing strategy and other local needs assessments and strategies take into account opportunities to increase walking and cycling. They should also consider how impediments to walking and cycling can be addressed.\nEnsure walking and cycling are considered, alongside other interventions, when working to achieve specific health outcomes in relation to the local population (such as a reduction in the risk of cardiovascular disease, cancer, obesity and diabetes, or the promotion of mental wellbeing). These include outcomes identified through the joint strategic needs assessment process. Descriptions of the links between physical activity and health outcomes can be found in the Department of Health's start active, stay active.\nEnsure walking and cycling are included in chronic disease pathways.\nEnsure all relevant sectors contribute resources and funding to encourage and support people to walk and cycle.\nWhere appropriate, ensure walking and cycling are treated as separate activities which may require different approaches.\nEnsure walking and cycling projects are rigorously evaluated. This includes evaluating their impact on health inequalities.\nFor more on the role of the NHS in promoting walking and cycling, see recommendations 9 and 10.\n\n## Recommendation 2 Ensuring all relevant policies and plans consider walking and cycling\nLocal authorities, in particular, portfolio holders, lead members and directors responsible for:\nadult and older people's services\nchildren and young people's services\ncommunity safety\ncountryside management\ndisability\neducation\nenvironment\nhealth and wellbeing (including mental health)\nland use, planning and development control\nparks and leisure\nplanning (including district planning)\nregeneration and economic development\nsocial services\ntransport.\nNational parks authorities.\nIntegrated transport authorities.\nLocal enterprise partnerships.\nChief constables, police authorities and elected police commissioners.\nAgencies with an interest in walking and cycling.\nAgencies with an interest in health and wellbeing or that work with population groups such as older people or people with disabilities.\nEnsure local, high-level strategic policies and plans support and encourage both walking and cycling. This includes a commitment to invest sufficient resources to ensure more walking and cycling – and a recognition that this will benefit individuals and the wider community. Relevant policies and plans include those on:\nair quality\ncommunity safety\ndisability\neducation\nenvironment (including sustainability and carbon reduction)\nhealth and wellbeing\nhousing\nland use, planning and development control\nphysical activity\nregeneration and economic development\ntransport.\nEnsure the walking and cycling aspects of these plans are developed in conjunction with relevant voluntary and community organisations.\nEnsure strategies to promote walking and cycling address factors which influence activity at various levels – from policy down to the individual. This includes ensuring the recommendations in NICE's guideline on physical activity and the environment are implemented.\nAssess the impact of relevant policies and decisions on people's ability to walk and cycle. Where necessary, amend them to ensure support for walking and cycling.\nEnsure plans relevant to walking and cycling are implemented and evaluated. Further advice on evaluation can be found in the National Obesity Observatory guide to evaluation.\n\n# Local action\n\n## Recommendation 3 Developing programmes\nLocal authority directors and portfolio holders for:\ncountryside management\nenvironment (including sustainability)\nleisure services\nparks\npublic health\nregeneration and economic development\ntransport.\nPolice traffic officers and neighbourhood policing teams.\nDevelop coordinated, cross-sector programmes to promote walking and cycling for recreation as well as for transport purposes, based on a long-term vision of what is achievable and current best practice. Ensure the needs of all sections of the population are addressed. Incorporate public health goals to increase the prevalence of people cycling and walking, as well as the distance covered by those who already walk and cycle regularly.\nAim to shift attention away from focusing on individual risk factors and isolated, small-scale interventions and ensure programmes comprise an integrated package of measures, implemented by all relevant sectors and stakeholders. Where appropriate, they should link to existing national and local walking and cycling initiatives, and incorporate actions in specific settings, such as workplace or schools (see recommendations 8 and 9).\nEnsure walking and cycling programmes form a core part of local transport investment planning, on a continuing basis. In line with the Department for Transport's manual for streets and the Chartered Institution of Highways and Transportation's manual for streets 2 – wider application of the principles, pedestrians and cyclists should be considered before other user groups in the design process – this helps ensure that they are not provided for as an afterthought.\nDraw on data, including the transport and physical activity elements of the joint strategic needs assessment, to ensure programmes are based on an understanding of:\nthe local population and the journeys people take using all modes of transport (the aim is to assess the potential for a 'modal change' towards walking and cycling)\nthe opportunities available to increase people's level of walking and cycling, given the right circumstances\nthe behaviour and preferences of existing walkers and cyclists\nthe needs of people with impairments\ngeneral factors influencing people's behaviour such as their attitudes, existing habits, what motivates them and their barriers to change, taking into account the recommendations in NICE's guideline on behaviour change: general approaches.\nEnsure programmes address the behavioural and environmental factors that encourage or discourage people from walking and cycling. These include measures to reduce road danger or the perception of danger. (Environmental factors can be tackled by implementing NICE's guideline on physical activity and the environment.)\nEnsure local expertise is available so that programmes are based on a realistic understanding of the scale of changes needed to encourage the population to change its behaviour.\nEnsure programmes take account of recommendations on developing local and regional programmes (recommendations 13–18) in NICE's guideline on preventing cardiovascular disease, in particular those relating to the need for long-term action.\nEnsure programmes take account of the geography of the surrounding area (for instance, connections with neighbouring local authority areas), as well as local factors such as major road and rail routes, rivers and hills.\nEnsure programmes include communications strategies to publicise the available facilities (such as walking or cycle routes) and to motivate people to use them. Include information that people with impairments will require, such as where dropped kerbs are located, the location and design of barriers at access points to cycle paths, and where public transport links and disabled toilets can be found.\nEnsure programmes, including specific elements within them, are evaluated. Assess how much walking and cycling people are doing. Also assess the number of trips undertaken, using different modes of transport, by different groups within the local population. Where appropriate, control groups should be used. (See, for example, the National Obesity Observatory's evaluation tool.)\nUse an appropriate tool to establish the cost effectiveness of initiatives. For instance, use the World Health Organization's health economic assessment tool (HEAT) for cycling and walking.\nConsider providing specific support for people at a 'transition point' in their lives, for instance, when they are changing job, house or school. At these times people may be open to trying a new mode of transport or new types of recreation. Note: some people may be considering motorised transport, instead of walking or cycling – and support may be needed to help them maintain their active travel habits.\n\n## Recommendation 4 Personalised travel planning\nTransport planners.\nDirectors of public health.\nHelp those interested in changing their travel behaviour to make small, daily changes by commissioning personalised travel planning programmes. These should be based on current best practice (see the Department for Transport's making personal travel planning work: practitioners' guide). Staff running these programmes should:\nIdentify those willing to make changes, for example, people at transitional points in their life (such as when moving house, job or school).\nProvide people with information and help, such as tickets, maps, timetables and, if required, more support to make different travel choices. This includes people with impairments who may rely on wheelchairs or adapted cycles.\nConsider implementing NICE's guideline on physical activity and the environment to create a supportive environment to encourage and sustain walking or cycling.\n\n## Recommendation 5 Cycling programmes\nAdult and child disability services.\nClinical commissioning groups.\nLocal authority transport leads, transport planners and other transport department staff.\nLocal education services.\nOrganisations with an interest in cycling.\nPublic health practitioners.\nPublic transport operators.\nAddress infrastructure and planning issues that may discourage people from wanting to cycle. Take into account NICE's guidelines on physical activity and the environment and unintentional injuries on the road. For example, ensure local facilities and services are easily accessible by bicycle and make changes to existing roads, where necessary, to reduce traffic speeds.\nImplement town-wide programmes to promote cycling for both transport and recreational purposes. These should be linked to existing national and local initiatives. (Note: 'town-wide' in this case could include cities or suburban areas.) Programmes could include:\nprovision of information, including maps and route signing\nfun rides, recreational and sponsored group rides and school sports promotions\nuse of leisure routes on and off roads\nuse of off-road mountain bikes, BMX courses, circuits and parks\ncar-free events or days, virtual cycle races and links with cycle sports events\ncycle hire schemes\nintensive sessions in particular settings or aimed at particular groups, such as: 'Bike to work' weeks and workplace challenges; activities aimed at children and families (such as 'Bike it', 'Bike club' and other school programmes); and activities for people with impairments who may use specially adapted cycles\nactivities and campaigns to emphasise the benefits of cycling (including the health benefits, the reliability and ease of access to local facilities and services).\nEnsure programmes are based on an accepted theoretical framework for behaviour change and take into account NICE's guideline on behaviour change: general approaches. They should also be based on an understanding of the needs of existing and potential cyclists, including those with impairments (see recommendation 3).\nEnsure cycle parking and residential storage issues are addressed.\nEnsure travel by cycle and public transport is integrated to support longer journeys. This includes providing secure cycle parking at public transport sites as well as support to transport adapted cycles and tandems for people with disabilities.\nEnsure training is available for those who are interested in cycling, either as a form of transport or as a recreational activity. An example of a cycle training programme is the Department for Transport's bikeability.\nEnsure all training is sensitive to cultural issues, for instance, by providing women-only groups with female trainers, where appropriate. Also ensure it includes an understanding of the needs of people with impairments\nConsider providing free cycle safety checks (such as Dr Bike sessions) and cycle maintenance training.\nUse local media to publicise activities and to clarify the links between different elements of the programme (for instance, the programme may include the provision of maps, local cycling classes and local challenges and events). In addition, use local media to raise awareness of any new or improved infrastructure. Also provide success stories from different elements of the programme to create momentum.\n\n## Recommendation 6 Walking: community-wide programmes\nAdult and child disability services.\nClinical commissioning groups.\nLocal transport leads, transport planners and other transport department staff.\nLocal authority leisure services.\nOrganisations with an interest in walking.\nPublic health practitioners.\nAddress infrastructure issues that may discourage people from walking, for example, motor traffic volume and speed, lack of convenient road crossings, poorly maintained footways or lack of dropped kerbs, where needed. Take into account NICE's guidelines on physical activity and the environment and unintentional injuries on the road.\nDevelop walking programmes for adults who are not active enough, based on an accepted theoretical framework for behaviour change and taking into account NICE's guideline on behaviour change: general approaches. Ensure groups that are likely to be the least active are encouraged to participate, by addressing issues that may act as a barrier.\nEnsure walking programmes for all adults link to existing national and local walking initiatives.\nEnsure all programmes address safety, cultural and disability issues.\nEnsure all programmes offer a variety of routes, paces and distances at different times of the day (including evenings and on different days of the week or at the weekend). Local people with different preferences, time constraints and physical abilities should all be able to participate. Programmes could include:\ncommunity-wide events, such as mass participation walking groups, community challenges and 'walkathons'\nwalks led by suitably trained walk leaders (paid or voluntary) and aimed at people who are currently inactive.\nEnsure walking routes are integrated with accessible public transport links to support longer journeys. Signage should give details of the distance and/or walking time, in both directions, between public transport facilities and key destinations.\nProvide information tailored for individuals who want to go walking without joining a group or club. Offer continued support in line with recommendation 7.\nDevelop and implement a publicity strategy to let the local community know about the walking routes and events and how accessible they are.\nProvide support to help people who have started walking as a leisure activity to also consider walking as a means of transport.\n\n## Recommendation 7 Walking: individual support, including the use of pedometers\nAdult and child disability services.\nClinical commissioning groups.\nDirectors of public health and public health specialists with responsibility for physical activity.\nLocal authority leisure services.\nOrganisations with an interest in walking.\nEnsure individual support is available for anyone who is walking on their own, walking informally with others in a group, or participating in local walking programmes. This includes helping to assess their activity levels and to set goals which build on this. The aim should be to increase the distance walked gradually, rather than providing them with a set target to aim for.\nEnsure additional, one-to-one support is offered at regular intervals to help people develop a long-term walking habit. This could be provided face-to-face, via the telephone or by using print-based materials, email, the Internet or text messaging. The support could include:\nindividual, targeted information\ngoal-setting (which may or may not include the use of pedometers), monitoring and feedback.\nProvide general information including:\nmaps, signs and other details about walking routes\nhow to visit places of interest on foot (such as shops, educational or recreational facilities)\ndetails on surface quality and accessibility.\nOnly use pedometers as part of a package which includes support to set realistic goals (whereby the number of steps taken is gradually increased), monitoring and feedback.\n\n# Schools, workplaces and the NHS\n\n## Recommendation 8 Schools\nPupils, siblings, their parents and carers.\nSchool staff.\nVisitors to schools.\nHead teachers and school governors.\nLocal authority PHSE coordinators, school travel advisers and transport planners.\nPolice traffic officers and neighbourhood policing teams.\nRoad danger reduction and/or road safety officers.\nFoster a culture that supports physically active travel for journeys to school (for all staff, parents and students) and during the school day. For example, promote the health benefits of cycling and walking and provide sufficient, secure cycle parking. Also ensure it is easy to get into the school grounds by foot or by bike. In addition, schools should provide suitable cycle and road safety training for all pupils.\nDevelop and implement school travel plans that encourage children to walk or cycle all or part of the way to school, including children with limited mobility. Integrate these plans with those produced by other local schools and other travel plans available for the local community. Involve pupils in the development and implementation of plans.\nMap safe routes to school and to local play and leisure facilities, taking into account the views of pupils, parents and carers. Also consult with the local community, including people with expertise in accessibility issues (such as those with mobility difficulties or community groups that work with them).\nDevelop programmes to ensure the local environment around schools and the nearby catchment area provide opportunities for all children to cycle or walk. This should include addressing motor vehicle speed, parking and dangerous driving practices.\nIntroduce regular 'walking buses' and other activities, such as 'Walk once a week' projects, which support and encourage walking and cycling to school.\nSet performance targets for school travel plans which are audited annually and which form part of delivery plans. Remedial action should be taken when agreed targets are not reached.\nEnsure all children can take part in Department for Transport's bikeability training. Ensure cycle training is age-appropriate and timed to allow cycling to school to become a habit. In addition, ensure it is appropriate for those with limited mobility who may need additional support.\nSchools should develop parents' and carers' awareness of the wider benefits of walking and cycling and other physically active modes of travel. For example, they should explain how it can improve children and young people's movement skills, social wellbeing, self-confidence and independence. They should also explain how it can help children to explore and become more familiar (and at ease) with their local environment while, at the same time, being physically active.\nHead teachers should identify a walking or cycling champion (or champions) with sufficient senior support to coordinate activities. The champion/s should liaise with the local authority and other potential partners to address any environmental or organisational barriers to walking and cycling to school.\n\n## Recommendation 9 Workplaces\nStaff and others who use workplaces.\nEmployers, including the NHS and local authorities.\nDirectors and senior staff including managers, health and safety staff, estates managers and human resources professionals.\nActive travel champions.\nDevelop strategies in consultation with staff (and other relevant stakeholders, for example, students in universities and colleges) to promote walking and cycling in and around the workplace. Ensure activities are developed in line with wider local activities (see recommendations 2, 3 and 4) and are linked to existing national and local initiatives.\nLiaise with local authority transport departments, neighbouring businesses and other partners to improve walking and cycling access to workplace sites. (Also see NICE's guidelines on physical activity and the environment and physical activity in the workplace.)\nIdentify an 'active travel champion' (or champions) within the workplace, at a sufficiently senior level. They should coordinate activities such as led and informal walking groups, workplace 'challenges' and promotional competitions (for example, using pedometers), bicycle user groups and walking interest groups. The active travel champion/s should also develop (or promote) schemes that give staff access to a pool of bicycles for short-distance business travel, or access to discounted cycle purchases (such as cycle to work schemes).\nEnsure workplace walking and cycling programmes are developed using an evidence-based theoretical model of behaviour change (see NICE's guideline on behaviour change: general approaches).\nProvide information tailored for the specific workplace on walking and cycling routes and circuits. This should include details on the distances involved, maps, routes and safety information.\nSee the NICE guideline on physical activity in the workplace for further recommendations.\n\n## Recommendation 10 NHS\nClinical commissioning groups.\nNational commissioning board.\nPrimary and secondary healthcare professionals.\nIncorporate information on walking and cycling into all physical activity advice given by health professionals. (See also NICE's guidelines on physical activity: brief advice for adults in primary care and exercise referral schemes to promote physical activity.)\nEnsure walking and cycling are among the options provided by the Let's get moving physical activity care pathway.\nEnsure people who express an interest in walking or cycling as a way of being more physically active are given information about appropriate national and local initiatives. Also provide individual support and follow-up (see recommendation 7).\nDirect people with limited mobility to specialist centres where adapted equipment, assessment and training are available for walking and cycling.\nEnsure walking and cycling programmes link to existing national and local initiatives.\nFor more on the role of the NHS in promoting walking and cycling, see also recommendations 1 and 9.# Public health need and practice\n\n# Introduction\nPhysical activity is essential for good health. It can help reduce the risk of coronary heart disease, stroke, cancer, obesity and type 2 diabetes (Chief Medical Officers of England, Scotland, Wales and Northern Ireland 2011). It also helps keep the musculoskeletal system healthy and promotes mental wellbeing.\nAs well as a direct benefit from physical activity, walking and cycling offer pleasure, independence and exposure to outdoor environments. These benefits may be particularly significant for people with disabilities whose participation in other activities may be more restricted.\nNew national physical activity guidelines were issued in 2011 (Chief Medical Officers of England, Scotland, Wales and Northern Ireland 2011) for: the under-5s, those aged 5–18, adults aged from 19–64 and for those aged 65 plus. Key points include the need to:\nbe physically active at all ages\nbe flexible (combining moderate and vigorous-intensity activity can be effective)\nparticipate in daily activity\nminimise sedentary behaviour\nconsider strength and balance activities for adults and older adults.\nDepending on factors such as speed and the terrain, walking and cycling can both be moderate or vigorous activities. Moderate intensity activities will make the participant breathe faster, experience an increase in heart rate and feel warmer. They may sweat on hot or humid days. The amount of activity needed to reach this varies from one person to another.\n\n# Physical activity levels in England\nBased on self-reporting, 61% of men (71% of women) in England aged 16 and over did not meet the national recommended physical activity levels (Craig et al. 2009). (These figures refer to the pre-2011 guidelines for physical activity; that is: adults should be active for at least 30 minutes at least five times a week at moderate intensity or greater.)\nThe proportion of men who are physically active enough decreases markedly as they get older (from 53% at age 16–24 to 16% at 65-plus). The level of activity among women was considerably lower once they reach 65-plus, from a lower base. (Around 12% of women over 65 met the recommended levels compared to 28–36% of younger women.) (Craig et al. 2009).\nBlack African and Asian adults and black Caribbean women were less likely to achieve the recommendations than the general population (Sproston and Mindell 2006).\nSixty three per cent of girls (72% of boys) aged between 2 and 15 report being physically active for 60 minutes or more on 7 days a week (girls' activity declines after the age of 10) (Craig and Shelton 2008).\nHowever, objective data suggest the above self-reporting data is an overestimate. Based on accelerometry, only 6% of men and 4% of women achieved at least 30 minutes of moderate or vigorous activity on at least 5 days (Craig et al. 2009). Only 2.5% (5.1% of boys and 0.4% of girls) actually did more than 60 minutes of moderate-to-vigorous physical activity daily (Riddoch et al. 2007).\nThere is a lack of information on the levels of physical activity among people with disabilities, although they are likely to be low for those with limited mobility.\nThe Chief Medical Officers' 2011 report notes: 'there is a clear causal relationship between the amount of physical activity people do and all-cause mortality. While increasing the activity levels of all adults who are not meeting the recommendations is important, targeting those adults who are significantly inactive (that is, engaging in less than 30 minutes of activity per week) will produce the greatest reduction in chronic disease' (Chief Medical Officers of England, Scotland, Wales, and Northern Ireland 2011).\n\n# Walking and cycling\nWalking is reported to be the most common – and cycling the fourth most common – recreational and sporting activity undertaken by adults in Britain (Fox and Rickards 2004). Walking (for any purpose) accounted for between 37% and 45% of the time that women of all ages spent doing moderate or vigorous-intensity physical activity. It also accounted for between 26% and 42% of the time devoted to such activities by men of all ages (Belanger et al. 2011). As a result, it is the most likely way all adults can achieve the recommended levels of physical activity.\nBicycles are used for around 2% of journeys in Britain – compared to about 26% in the Netherlands, 19% in Denmark and 5% in France (Ministry of Transport, Public Works and Water Management 2009). Yet of all trips made in Great Britain in 2009, 20% covered less than 1 mile and more than half (56%) of car journeys covered less than 5 miles (Department for Transport 2010a).\nIn England on average, 10% of adults cycle at least once a week (this figure varies from over 50% to less than 5% according to the area) (Department for Transport and Sport England 2012). On average, 11% of adults cycle for at least half an hour, at least once a month (again, this figure varies from 4% to 35% according to the area (Department for Transport and Sport England 2012). Today, on an average day in London, it is estimated that around 4.3 million trips are 'potentially cyclable' (Transport for London 2010).\nThe majority (85.8%) of adults claim they can ride a bicycle (around 92.9% of men and 79% of women) (Department for Culture Media and Sport 2011). However, the average time spent travelling on foot or by bicycle in Britain has decreased from 12.9 minutes per day in 1995/97 to 11 minutes per day in 2007 (Department for Transport 2010a). More starkly, the average distance walked, per person per year, has fallen from 255 miles in 1975/76 to 201 miles in 2006. Bicycle mileage for the same years fell from 51 to 39 miles per person per year (Department for Transport 2007).\n\n# Air pollution and climate change\nMotorised transport in urban areas of England is associated with poor air quality, congestion, collisions and physical inactivity – each costing society around £10 billion a year (Department for Transport 2009a). The cost of greenhouse gas emissions and the annoyance associated with noise are smaller, but still significant. In the case of greenhouse gases, costs are expected to rise sharply in future years (Department for Transport 2009a).\nExposure to air pollution is a significant cause of mortality in England. The House of Commons environmental audit report on air quality noted that: 'poor air quality reduces the life-expectancy of everyone in the UK by an average of 7 to 8 months and up to 50,000 people a year may die prematurely because of it' (House of Commons Environmental Audit Committee 2010).\nAir pollution is caused by a range of factors and people's exposure depends on the level of emissions, dispersion and other factors. Particulate matter, especially small particles less than 10 or 2.5 microns (PM10 or PM2.5) in diameter, has a significant impact on health. Other significant pollutants include nitrogen oxides (NOx) and ozone.\nIndustrial sources produce a larger percentage of PM10 and NOx than road transport (46% and 30% respectively for NOx and 36% and 18% for PM10). However, road transport is responsible for up to 70% of air pollution in urban areas where most human exposure to air pollution occurs (House of Commons Environmental Audit Committee 2010).\nGreenhouse gas emissions from domestic transport in Great Britain stayed at the same level between 1990 and 2009 (around 120 million tonnes of carbon dioxide equivalent ; different gases have a different impact on the warming of the atmosphere so converting to MtCO2e enables a direct comparison of the impact of different gases or mixtures on the atmosphere). Over this period, an improvement in the fuel economy of new cars was offset by increases in mileage. At the same time, the overall emission of greenhouse gases from all sources in this country has decreased. As a result, as a percentage, the proportion from transport has increased from 16% to 22%. Ninety per cent of these emissions are from road transport (58% from cars and around 30% from heavy goods vehicles and light vans) (Department for Transport 2010a).\nThe transportation of goods and general travel in urban areas accounts for around 20% of the distance travelled by motor vehicle, but the contribution to air pollution and climate change is greater, because of driving conditions and frequent cold starts (Favez et al. 2009).\nClimate change, driven by human emissions of gases such as carbon dioxide, will lead to higher temperatures, more frequent extreme weather events, changes in rainfall and weather patterns, food and waterborne diseases and changes in distribution of vector-borne diseases. This will all have a significant impact on health in England (and globally). Changes associated with migration, following events such as flood or famine and higher levels of stress from extreme events are also likely to have a negative effect (World Health Organization 2009).\nReducing transport-related carbon emissions, by supporting a shift to walking and cycling, will help to address these adverse effects. It will also help ensure people are more physically active, so improving their health (Vardoulakis and Heaviside 2012).\n\n# Wider economic impacts\nThe wider economic impact of supporting walking and cycling are difficult to identify with certainty.\nExcess delays from traffic congestion in English urban areas are estimated to cost the economy around £10.9 billion a year (based on 2009 prices and values) (Department for Transport 2009a).\nA Living Streets report highlights that improvements to the walking environment can increase the economic value of, and economic activity within, an area. This can be reflected by the sale price of residential properties and the rental price of retail premises (Sinnett et al. 2011). The report points out that local retailers may overestimate the proportion of shoppers arriving by car (41% compared with the actual proportion of 22%, in a study in Bristol).\nTransport for London's 'Town centre study' (Transport for London 2011) found that people walking to a town centre spent an average of £93 per week there, compared with £56 for car drivers or passengers. Bus users spent £70 per week.# Considerations\nThe Programme Development Group (PDG) took account of a number of factors and issues when developing the recommendations.\n\n# General\nThe PDG noted that encouraging people to walk or cycle for recreation purposes is different from encouraging them to walk or cycle as a mode of transport.\nThe PDG considered walking and cycling as two separate activities.\nMost people should be able to fit these activities into their daily lives and both are relatively cheap or may save money.\nThe PDG is aware of the volume of work and guidance available that is relevant to walking and cycling. It is also aware of the range of examples of good practice, both in this country and abroad. This guidance is intended to support, rather than replace that information.\nPeople with disabilities are less likely to be physically active and more likely to face barriers to being active than those without impairments. Many of this group can walk or cycle. However, they may require additional support, for example, involving specially adapted equipment or changes to the physical environment.\nThe PDG noted that local authority structures and roles vary across the country and that this will affect who has responsibility for specific actions. As a result, the recommendations tend to refer to general areas of responsibility, rather than to specific job titles. Similarly, as different administrative areas may produce plans on similar issues under a different title, the recommendations refer to generic plans.\nAchieving change is likely to be a long-term task and will involve participation by many professionals. This includes those working in local authorities and the NHS, as well as those working in communities (such as voluntary and faith sector organisations). The actions needed include those recommended in this and related NICE guidance.\nThe PDG noted that in the 'Cycle cities and towns' where cycling and walking had increased, the level of spending to encourage walking and cycling for transport purposes had been in the region of £5–10 per head per year. This had been maintained for a prolonged period. The PDG noted that this level of funding could be achieved by changing investment priorities within existing budgets rather than requiring additional funds.\n\n# Evidence\nEvidence related to walking and cycling comes from a number of different professional sectors, in particular, transport and health. Each sector has its own approach to research and evaluation which can lead to difficulties in identifying and interpreting the evidence.\nHealth sector evidence tends to involve controlling for as many factors as possible to help identify and explain any causal links between a given activity and health. While this provides greater certainty about cause and effect, it has tended to limit investigation to topics which lend themselves to this strict approach. Examples include promotional work with individuals to encourage them to walk or cycle, or within a limited setting, such as a school. Transport and other professional sectors are more likely to address population-level factors – and are more likely to have a range of outcomes or intentions in mind. For instance, both public health and transport professionals might have an interest in the benefits of cycling. However, the former might want to know how it impacts on levels of physical activity (and hence health), particularly among those who were previously inactive. Transport professionals, meanwhile, might want to know which particular journey would be cycled (and hence, the impact on motor traffic and congestion levels). They would tend to have less interest in who has changed their mode of transport. As a result, while both groups might have a legitimate interest in activities to increase cycling levels, the outcomes of evaluations might be different.\nThe PDG noted that different professionals have different reasons for wanting to encourage people to walk and cycle. For instance, transport professionals may aim to reduce the volume of motorised traffic (by identifying and influencing people who are most likely to move from motorised transport to cycling). From a public health point of view, the goal might be to encourage people who are currently inactive to take up walking or cycling in order to increase the amount of physical activity they do. While the 2 goals are very closely related (and can be complementary) they may focus on different groups and involve different approaches and outcomes.\nThe evidence identified was predominantly from an urban perspective, so rural issues are under-represented in the recommendations.\nIt is difficult to apply the findings of non-UK cycling studies to England because of the cultural and legal differences – and the fact that levels of cycling are considerably higher in many other countries. Equally, the value of findings from older literature may be of limited relevance because of the social and environmental changes that have since taken place.\nThere is evidence that interventions tailored to people's needs and aimed at either the most sedentary groups – or at those who are most motivated to change – can encourage people to walk more. Evidence showed that interventions could work if aimed at individuals, households or groups.\nEvidence showed that community-wide promotional activities, combined with an improved infrastructure, had the potential to increase cycling rates by modest amounts. Studies of marketing activities aimed at individuals reported a consistent, positive effect on cycling behaviour. However, the PDG noted that more robust study designs were needed to generate more detailed evidence of the best way to achieve this improvement. (For instance, detail is needed on whether the increases are sustained over time or are limited to certain subgroups such as young men.)\nPractical experience indicates that two particular factors play a key role in increasing walking and cycling rates: having a 'champion' who is committed to promoting walking or cycling, and effective local authority support.\nFour interventions, including two multi-component interventions (Cycling Demonstration Towns and Sustainable Travel Towns) were included in the economic modelling. Using cost per quality-adjusted life year (QALY) gained, the interventions were highly cost effective, even when the effect disappeared after year 1. The PDG noted that the key factors influencing the outcome of the economic model were: threshold cost, level of effects, decay in effects and costs related to initial effects. Members also noted the importance of offering the most appropriate interventions for different local settings and needs.\nData from a UK randomised control trial (RCT) were used to model the cost-effectiveness of led walks. The PDG raised concerns because the RCT showed no difference in effect between led walks and the provision of advice only. The results were not used for the recommendations. Using evidence from an evaluation of 'Get walking, keep walking', a large UK study, produced a cost per QALY of around £2700.\nIn addition to a cost–utility analysis, cost–benefit ratios were also calculated for environmental and traffic outcomes. These considered a range of benefits associated with increased walking or cycling and a consequent change in motor vehicle miles driven. The methodology was based on that used by the Department for Transport. However, health benefits (which account for most of the benefits calculated using the Department for Transport methodology) were not included, as these had been calculated in the cost–utility analysis.\nThe PDG recognised the importance of considering children. However the modelling did not consider under-18s due to a lack of direct evidence on children's behaviour in many of the studies.\n\n# Pedometers\nPedometers are cheap, effective and 'user-friendly'. The PDG noted that they may play an important role in helping people to walk more, provided they are used within a programme involving monitoring, support and goal setting. However, the PDG also noted that the use of set targets (such as 10,000 steps a day) was unlikely to be helpful if it did not take into account someone's current level of activity. In addition, some people may be put off if pedometers are used as part of a competition.\nThe PDG discussed the role of other technologies that might replicate pedometers, including mobile phone apps. While these may have a role to play in getting people to walk more, there is a lack of robust evidence to indicate whether or not they are effective.\n\n# Wider influences\nA wide range of factors influence whether or not people walk or cycle. Many were outside the scope of this guidance. In particular, the PDG noted that environmental factors such as the quality, accessibility and availability of walking and cycling networks are likely to be important. Other issues, such as the relative costs and convenience, are also likely to be significant. As a result, it recommended that this guidance should be implemented in conjunction with other related NICE recommendations, in particular NICE's guideline on physical activity and the environment.\nThe scope for this guidance included an adapted logic model (Sallis et al. 2006) which sets out local factors and interventions which can impact on walking and cycling rates. It demonstrates the conceptual link between local interventions targeting the physical or social environment (or individuals) and intermediate outcomes in relation to walking and cycling. These outcomes, in turn, link to impacts on health, the environment and other areas (such as the economy). The model also highlights how local policy, resources and other factors influence the effectiveness of local interventions to improve rates if walking and cycling. For example, a decision to use cycling as a form of transport can be influenced by the level and speed of motor traffic, attitudes to safety, the ability to plan and execute a route, and the ability to carry baggage. (Please note: although national factors such as legislation and fuel duty also have an important impact, these are not included here as they fall outside the scope of the guidance.)\nA number of legal issues differentiate England from parts of continental Europe, where levels of cycling are significantly higher. In parts of continental Europe, 'strict liability' means that pedestrians or cyclists injured in a collision involving a motor vehicle do not have to prove fault in seeking compensation. In addition, drivers have a civil responsibility to have insurance that will pay vulnerable victims independently of fault, while not changing criminal responsibility (see 'Expert paper 2'). Such legal requirements may act as an incentive for drivers to behave in a way that protects the most vulnerable road users.\nThe PDG noted that relatively few people in England cycle on a regular basis for transport purposes. This is not the case in other parts of Europe. For example, in Denmark and the Netherlands, it is considered the norm to use a bicycle for many journeys. Age is not necessarily a barrier. In the Netherlands, 26% of all journeys –and 19% of all the journeys made by people over 75 – are by bike (Ministry of Transport, Public Works and Water Management 2009). The PDG considered these examples as possible aspirational goals for England.\nThe PDG noted that moving towards the higher levels of cycle use seen in some Northern European countries is a process that will involve change over a prolonged period. It also noted that some of these changes are beyond the scope of this guidance. However, it felt that substantial public health benefits (such as increased levels of physical activity and reduced emissions of air pollutants) could be achieved as a result of such a process.\nThe PDG noted a range of issues which, if tackled in isolation, are unlikely to lead to a significant increase in walking or cycling. It also noted that tackling such issues could, nevertheless, provide a necessary foundation for interventions which will have a significant impact. For example, a key factor preventing people from walking and cycling is the danger as well as the perceived danger (including personal security fears) facing them on or near roads, paths or trails. The PDG discussed a range of measures that may help overcome this problem. These included:\nAwareness-raising of the comparatively low risks posed on the roads and contextualising these in terms of other risks (such as the potential risks caused by having a sedentary lifestyle).\nAwareness-raising among motorists and cyclists of the needs of pedestrians (for instance, the need to avoid causing a hazard by pavement parking).\nAwareness-raising among motorists of the needs of cyclists (for instance, by making motorists aware that they should give way, where appropriate, and should give cyclists a wide berth when overtaking them).\nAppropriate enforcement of road traffic law.\nThe potential role of engineering measures such as chicanes or raised junctions and 20 mph limits in helping to restrict motor traffic speed.\nThe needs of children and older people (see NICE guidelines on strategies to prevent unintentional injuries among under-15s and unintentional injuries on the road)\nThe needs of people with mobility difficulties or other impairments which may increase their vulnerability on the road.\nAction to increase walking and cycling rates may reduce motor traffic volume and the PDG was concerned that the resulting benefits (of reduced congestion and reduced air pollution) should not be lost. For example, less traffic could lead to increases in vehicle speed, or may encourage some people to drive for journeys previously undertaken using other modes of transport. Members noted that action to ensure this does not happen could include a reallocation of road space or a reallocation of time at junctions to favour walkers or cyclists, or restricted motor vehicle access.\nLocal roads may act as a barrier to walking and cycling for children. Although it is not a panacea (addressing road conditions is vital), achieving 'Bikeability' level 3 would mean they could deal with all types of road conditions and more challenging traffic situations. This may be important, at least, for older children. The PDG noted that cycling off-road, where there is no exposure to motor vehicles may be appropriate for those who find road cycling too challenging.\n\n# Physical activity\nMost people can walk, including groups such as older people and those with some functional difficulties. While the majority of adults (85.8%) in the UK say they can ride a bicycle (Department of Culture, Media and Sport 2011), cycling as a means of transport is a minority activity. It accounts for a small percentage of all journeys – and for a small part of overall physical activity in this country. Nevertheless, 43% of adults own a bicycle and 14% use it at least monthly (Department for Transport 2009b). Cycling remains popular among children and young people, with 41% of those aged 5–16 years cycling at least weekly (Department for Transport: unpublished data 2012).\nIn London, an estimated 4.3 million trips a day (around two thirds taken by car, the remainder mainly by bus) could be cycled. For this survey, trips were assessed according to a set of criteria designed to reflect trips currently made by bicycle (Transport for London, 2010).\n\n# Inequalities\nOverall physical activity levels vary across the population (see section 2). This is also the case with specific activities, particularly cycling.\nMost adult cyclists in most areas of England are male. The highest number of cyclists are among people who are middle-aged. Black and minority ethnic groups cycle the least. Cycling participation is roughly equal across income quintiles but the biggest growth has come among the more wealthy.\nThe variation in levels of walking among groups in terms of gender, race or socioeconomic status is probably the smallest for any type of physical activity.\nPeople in households without a car walk, on average, 284 miles per year, compared to 176 miles per year walked by people in households with a car (Department for Transport 2010b). People who are most physically active do not necessarily walk or use a bicycle as a mode of transport. For some, the fact they have access to a car may have a positive influence on their physical activity levels.\nThe distance walked in Great Britain varies per person per year. In the quintile with the lowest household income, the distance walked is 223 miles, then it is 202, 182 and 177 miles respectively for people in the next 3 quintiles. In the quintile with the highest household income, people walk an average 201 miles per year. For cycling, the distance increases across the spectrum. Miles cycled per person per year is 32 in the lowest 2 quintiles, then 39, 49 and 77 miles respectively (Department for Transport 2010b).\nOne way of encouraging people to walk or cycle, as a form of transport, might be to apply greater levels of restraint on car usage in urban areas. This could be achieved, for instance, by introducing restricted parking and higher parking charges. However, there is a need to consider how this would impact on car owners living in areas where the environment is not conducive to walking or cycling, or where there is little real alternative to driving.\nThe guidance recommends an integrated package of measures which address a range of barriers to walking and cycling. It should be noted that reducing car use may have a beneficial influence on the environment by reducing traffic volume and air pollution and this may have a positive impact on the health of the whole population.\nThe PDG discussed the impacts that the recommendations may have on health inequalities. It acknowledged that those who are better off may have more opportunity to respond to the choices on offer. It also acknowledged that some transport interventions may deliberately target those most likely to change their mode of transport, rather than those who are least active. In addition, it noted that people with disabilities have specific needs. Taking these issues into account, the PDG emphasised that the recommendations should be accompanied by action to address factors such as a hostile and degraded environment, restricted access points, poor surfaces and the availability of disabled toilets. The Group also noted that some people with, for example, sensory or cognitive impairments, may need specially adapted equipment or information.\nInterventions which reduce motor traffic will reduce air pollution and road danger (assuming the benefits of a reduction in motorised traffic are 'locked in' and not accompanied by, for instance, an increase in traffic speeds). Planners may be reluctant to apply traffic reduction measures in one locality for fear of 'gridlock' on other, neighbouring roads. However, in most cases, the overall level of motorised traffic will be reduced. This is likely to have a positive impact on health inequalities because people from deprived groups, who are exposed to the greatest risks from air pollution and traffic injuries, are most likely to benefit. The very old and the very young, as well as those with pre-existing respiratory or circulatory problems, will also benefit from a reduction in overall exposure to air pollutants.\n\n# Barriers and facilitators\nWhen making transport choices, habit is important for most people, most of the time. Choosing to use a different mode of transport from usual is also likely to require more planning and thought. For instance, making a decision to start cycling might mean obtaining appropriate clothing, preparing the bike, route planning and allowing time for a trip of an unknown duration. The PDG noted that these factors are unlikely to remain as significant barriers once walking or cycling becomes the norm. For instance, both will usually involve reliable and more predictable journey times. Many journeys may be quicker, as well as being more healthy. There are also wider community benefits from reduced congestion and pollution.\nThe PDG noted that changing travel mode might require stopping old habits, such as using the car for short trips. Or it might involve an even more fundamental lifestyle choice, such as deciding to give up having a car altogether.\nThe PDG felt it was important that, where possible, health professionals (and others) set a positive example through their own behaviour in relation to walking and cycling.\nThe PDG noted that the times when someone has to reconsider their transport choices (such as when changing job or school, retiring or moving house) may offer important opportunities to influence their behaviour.\nDespite walking and cycling being different activities, sometimes they are grouped together. The PDG felt this was often unhelpful, as barriers and facilitators to walking and cycling vary – and, in turn, they differ according to whether the activity is chosen for transport or recreational purposes. They can also be specific to the purpose and location of the trip – and to the person undertaking it. Successful interventions to increase cycling and walking need to take into account this wide range of factors.\nWalking and cycling, like any form of transport, involve exposure to a certain level of risk. This includes the risk of injury from falls or from collisions and exposure to air pollution. These risks are not unique to transport involving physical activity. However, evidence shows that the health benefits of being more physically active outweigh these disbenefits.\nThe whole population benefits from less exposure to polluted air and congested streets when there is a general shift away from motorised vehicles.\nRisk of injury or collision is a key consideration when walking and cycling in places where there are other people. As well as the actual level of risk, perception of risk is important. The PDG noted that cyclists and pedestrians are more vulnerable in the event of a collision than those in a motor vehicle. At the same time, they are much less likely to cause injury in the event of a collision, due to their lower mass and lower speed of travel.\nThere is evidence to support the hypothesis (usually called 'safety in numbers') that areas where there are higher numbers of cyclists have better safety records than others. One of the reasons for this may be increased driver awareness of the likelihood of encountering a cyclist – and the fact that they modify their driving as a result.\nThe PDG concurred that transport planning could be a way to reduce road dangers for all users. These dangers relate to motorised traffic volumes and speeds. They are also caused by a lack of driver awareness of the risks of poor driving and the need to fully consider pedestrians and cyclists, including those with restricted mobility.\nAttitudes to walking and cycling are generally positive or neutral, with walking generally regarded more favourably. However, a combination of factors discourages people from taking up either if it is a question of choice, rather than necessity. These include:\nConcerns about the physical environment, in particular, with regard to perceptions of and actual safety. Motor traffic is a major deterrent for many cyclists (potential and current) and pedestrians in rural areas – and for children in all areas. Fear of violence or robbery is another deterrent. Many potential walkers restrict their journeys on foot because of their perception that empty streets, particularly at night, are dangerous.\nComplex household routines (especially for those with young children). For many people it is a combination of circumstances that prevent them from walking or cycling for everyday travel. These include: the logistics of organising and travelling with children, pressures of time and other commitments, and parental concerns about safety.\nThe perception that walking and cycling are not things to do as a matter of routine.\n\n# Wider impacts\nTraffic volume and speed act as barriers to walking and cycling (for recreation, as well as for transport purposes). The PDG noted that the level of motor traffic creates congestion which, in turn, imposes costs on the economy, through loss of productive time. Motor vehicles are also major contributors to air and noise pollution, as well as to carbon dioxide emissions.\nIncreasing the amount people walk or cycle, particularly in urban areas, results in a change in exposure to air pollution. Moving journeys from motorised transport to walking or cycling may alter individual exposure to air pollution, while reducing the total emissions of pollutants. Modelling by De Hartog et al. (2010) suggests that an individual's risk from increased exposure to air pollutants is modest in comparison with the benefits of them being more physically active. In addition, the overall decrease in air pollutant emissions benefits the health of the whole population. The PDG noted that a range of other potential benefits might accrue from a shift to physically active travel. These include reductions in road danger, noise, congestion and emissions of carbon dioxide. Walking and cycling can also benefit local communities by encouraging more people of all ages to be out on the streets, so making streets appear less threatening.\nPersonal exposure to air pollution is influenced by route choice. Routes which avoid busy roads may have much lower levels of air pollutants. This can be a much more significant influence on personal exposure than the mode of transport used.\nCost–utility calculations were based on the increased longevity associated with walking and cycling. They incorporate the effects of deaths from collisions. In addition, the economic modelling included an assessment of the cost–benefit ratios associated with environmental pollution and congestion. In most cases, interventions to promote walking and cycling led to greater benefits than costs, when considering their impact on congestion, infrastructure, collisions, local air quality, noise, greenhouse gases and indirect taxation. Costs associated with collisions were included, based on the expected reduction in car kilometres. Changes in levels of injury, based on changes in walking and cycling behaviour, are difficult to predict, partly because the relationship is not linear (see 3.50). Large increases in cycling and walking, especially if accompanied by interventions to increase safety, could reduce the absolute number of related accidents. As a result, the model did not include an additional modelled effect on injuries. Only for Cycling Demonstration Town interventions were the costs greater than the benefits. However, the modelling did not include the substantial benefits (likely to be in excess of 80% of the total) to be gained from reducing the range of health conditions associated with not being physically active enough. (These were calculated separately.)\nThe PDG agreed that both walking and cycling provide a wide range of health, social, environmental and economic benefits. Members also agreed that there is significant scope to increase the levels of walking and cycling in England – and that this would result in gains across society.# Recommendations for research\nThe Programme Development Group (PDG) recommends that the following research questions should be addressed. It notes that 'effectiveness' in this context relates not only to the size of the effect, but also to cost effectiveness and duration of effect. It also takes into account any harmful/negative side effects.\nAll the research should aim to identify differences in effectiveness among groups, based on characteristics such as socioeconomic status, age, gender and ethnicity.\n. How could existing guidance on evaluating complex, population-wide interventions be most usefully adapted and applied to approaches that aim to increase rates of walking and cycling? Issues to consider include: population-level health outcomes such as pollution emissions and exposure, the impact of an intervention on risk and danger and other, wider outcomes of interest such as the impact on the local economy. Approaches should be developed to take account of the backgrounds and needs of the different professional groups involved in helping to influence walking and cycling for transport or recreation. This includes professionals working in public health, transport, environment, economic development and regeneration.\n. What key factors influence the effectiveness of population-level or whole-area approaches to encouraging walking or cycling? How do these factors interact? (Specifically, how do infrastructure changes, promotion of these changes, promotion of walking and cycling generally, the provision of individual support and approaches in specific settings interact?) How does effectiveness vary between different geographical areas?\n. How do individual and local factors influence the effectiveness of specific approaches to encouraging walking or cycling? (This includes people's level and perception of risk, the degree of connectivity for cycling trips, and the local 'visibility' of cycling or walking as a mode of transport.) How do these factors interact with personal factors (such as willingness to try walking or cycling) and how do these personal factors influence effectiveness? In particular, do local factors influence the effectiveness of cycle training and personalised travel planning?\n. What key factors ensure people continue to walk or cycle in the long term (over a year)? How do individual interventions (such as follow-up or goal-setting) interact with environmental factors (such as distance, perception of danger or provision of facilities) in encouraging people to continue to walk or cycle?\n. What key factors influence differences in walking and cycling behaviour among different groups – and what are the implications for interventions aiming to achieve population-level change and reduce inequalities? This should take into account transport-related variables such as level of car ownership.\nSee also the detail on the gaps in the evidence identified during development of this guidance.# Glossary\n\n# Dr Bike\nGenerally, Dr Bike sessions are basic safety and maintenance checks provided free to the cyclist. They cover topics such as brakes, steering, mechanical integrity and the overall condition of the bicycle. Minor adjustments are carried out free of charge. Sessions may also include security marking, visibility and cycling tips. They may be provided by local authorities, cycling groups or employers.\n\n# Handcycles\nHandcycles are two or three-wheeled bikes powered by the arms rather than the legs. They come in a variety of styles which make them suitable for many people with disabilities.\n\n# Local enterprise partnerships\nLocal enterprise partnerships are led by local authorities and businesses. They provide the vision, knowledge and strategic leadership needed to drive sustainable private sector growth and job creation in their area.\n\n# Mode\nTransport mode refers to the form of transport used (such as by car, lorry, bicycle, public transport or on foot).\n\n# Moderate-intensity physical activity\nModerate-intensity physical activity requires a degree of effort and noticeably increases the heart rate. Examples include brisk walking, cycling and gardening.\n\n# Moderate-to-vigorous physical activity\nModerate-to-vigorous physical activity requires a large amount of effort, causes rapid breathing and a substantial increase in heart rate. Examples include running and climbing briskly up a hill.\n\n# Personalised travel planning\nPersonalised travel planning aims to encourage people to change their travel habits by providing them with detailed information on possible alternatives. People running these schemes provide individuals (usually across a specified geographical area) with information on, and encouragement to use, alternatives to a car for the trips they make.\n\n# Portfolio holder\nA portfolio holder is a local authority member with a specific responsibility delegated by the leader of the local authority.\n\n# Quality-adjusted life year (QALY)\nA quality-adjusted life year (QALY) is a measure used in health economics to assess the cost effectiveness of an intervention. It is defined as a measure of the state of health of a person or group in which the benefits, in terms of length of life, are adjusted to reflect the quality of life. One QALY is equal to 1 year of life in perfect health.\n\n# Recommended level of physical activity\nThe Chief Medical Officers for England, Wales, Scotland and Northern Ireland Start active, stay active report sets out target levels of physical activity for different groups. For adults, the recommendation is that 'over a week, activity should add up to at least 150 minutes (2½ hours) of moderate-intensity activity, in bouts of 10 minutes or more (one way to approach this is to do 30 minutes on at least 5 days a week)'.\nFor children, the recommendation is that 'all children and young people should engage in moderate- to vigorous-intensity physical activity for at least 60 minutes and up to several hours every day'.\n\n# Virtual cycle races\nThese are competitions where participants log the number of miles they have cycled on their own or as part of a team. The aim is to cycle a predetermined number of miles over a certain time. A target could be, for example, to cycle the number of miles it would take to travel from Lands End to John O'Groats.# References\nBelanger M, Townsend N, Foster C (2011) Age-related differences in physical activity profiles of English adults. Preventive Medicine 52: 247–9\nChief Medical Officers of England, Scotland, Wales and Northern Ireland (2011) Start active, stay active: a report on physical activity from the four home countries' Chief Medical Officers \nCraig R, Shelton N (2008) Health survey for England 2007. Healthy lifestyles: knowledge, attitudes and behaviour. Leeds: The Information Centre for Health and Social Care\nCraig R, Mindell J, Hirani V (2009) Health survey for England 2008. London: The Information Centre for Health and Social Care\nDepartment for Culture, Media and Sport (2011) Taking part 2011/12 quarter 2. London: Department for Culture, Media and Sport\nDepartment for Transport (2007) National travel survey 2006. London: Department for Transport\nDepartment for Transport (2009a) The wider costs of transport in English urban areas in 2009. London: Department for Transport\nDepartment for Transport (2009b) National travel survey 2008. London: Department for Transport\nDepartment for Transport (2010a) Transport trends 2009. London: Department for Transport\nDepartment for Transport (2010b) National travel survey 2009. London: Department for Transport\nDepartment for Transport, Sport England (2012) Local area walking and cycling statistics: England 2010/11. London: Department for Transport\nDepartment of Health (2004) At least five a week. London: Department of Health\nFavez J, Weilenmann M, Stilli J (2009) Cold start extra emissions as a function of engine stop time: evolution over the last 10 years. Atmospheric Environment 43: 996–1007\nFox K, Rickards L (2004) Sport and leisure: results from the sport and leisure module of the 2002 general household survey. London: The Stationery Office\nHouse of Commons Environmental Audit Committee (2010) Air quality: fifth report of session 2009–10. London: The Stationery Office\nMinistry of Transport, Public Works and Water Management (2009) Cycling in the Netherlands. The Netherlands: Ministry of Transport, Public Works and Water Management\nRiddoch CJ, Mattocks C, Deere K et al. (2007) Objective measurement of levels and patterns of physical activity. Archives of Disease in Childhood 92: 963–9\nSinnett D, Williams K, Chatterjee K et al. (2011) Making the case for investment in the walking environment: a review of the evidence. London: Living Streets\nSproston K, Mindell J (Editors) (2006) Health survey for England 2004. The health of ethnic minorities. London: The Information Centre for Health and Social Care'.\nTransport for London (2010) Analysis of cycling potential. London: Transport for London\nTransport for London (2011) Town centre study 2011. London: Transport for London\nVardoulakis S, Heaviside C (Editors) (2012) Health effects of climate change in the UK 2012. Current evidence, recommendations and research gaps. Chilton: Health Protection Agency\nWorld Health Organization (2009) Climate change is affecting our health: Something should be done now. Geneva: World Health Organization# Appendix B Summary of the methods used to develop this guidance\n\n# Introduction\nThe reviews, primary research, expert testimony and economic modelling report include full details of the methods used to select the evidence (including search strategies), assess its quality and summarise it.\nThe minutes of the Programme Development Group (PDG) meetings provide further detail about the Group's interpretation of the evidence and development of the recommendations.\nAll supporting documents are listed in appendix E.\n\n# Key questions\nThe key questions were established as part of the scope. They formed the starting point for the reviews of evidence and were used by the PDG to help develop the recommendations. The overarching questions were:\nWhich local interventions are effective and cost effective at promoting and increasing cycling and walking for recreational and travel purposes?\nWhich local interventions are effective and cost effective at changing population-level norms and behaviour in relation to cycling and walking for recreational and travel purposes?\nWhat factors help or hinder the planning and delivery of walking and cycling-related interventions for recreation or travel purposes?\nWhat factors help or prevent people from walking and cycling for recreation or travel?\nWhat health and other outcomes may be achieved by increasing cycling and walking for travel and recreation?\nThese questions were made more specific for each review (see reviews for further details).\n\n# Reviewing the evidence\n\n## Effectiveness reviews\nOne review of effectiveness was conducted (review 1).\nA number of databases were searched in August 2011 for papers relating to walking and cycling published since 1990. See the review for details of the databases searched.\nIn addition, specific websites were examined and papers from stakeholders and members of the PDG were considered.\nStudies were included in the effectiveness review if they considered the impact of local interventions to raise awareness of, encourage or increase uptake of, walking and cycling for recreational and travel purposes.\nStudies were excluded if they covered:\nnational policy, fiscal or legislative changes\nlocal interventions which solely aimed to change the physical environment.\n\n## Other reviews\nA review of barriers and facilitators (review 2) was conducted.\nA number of databases were searched in August 2011 for papers relating to walking and cycling published since 1990. See the review for details of the databases searched.\nIn addition, specific websites were examined and papers from stakeholders and members of the PDG were considered.\n\n## Selection criteria\nStudies were included if they focused on interventions identified in the scope and addressed barriers and facilitators to walking and cycling.\nStudies were excluded if they focused on:\nNational policy, fiscal and legislative changes.\nLocal interventions which solely aimed to change the physical environment (such as traffic-calming measures, provision of cycle parking facilities or construction of cycle routes).\n\n## Quality appraisal\nIncluded papers were assessed for methodological rigour and quality using the NICE methodology checklist, as set out in the NICE technical manual 'Methods for the development of NICE public health guidance' (see appendix E). Each study was graded (++, +, –) to reflect the risk of potential bias arising from its design and execution.\n++ All or most of the checklist criteria have been fulfilled. Where they have not been fulfilled, the conclusions are very unlikely to alter.\n- Some of the checklist criteria have been fulfilled. Those criteria that have not been fulfilled or not adequately described are unlikely to alter the conclusions.\n– Few or no checklist criteria have been fulfilled. The conclusions of the study are likely or very likely to alter.\nThe evidence was also assessed for its applicability to the areas (populations, settings, interventions) covered by the scope of the guidance. Each evidence statement concludes with a statement of applicability (directly applicable, partially applicable, not applicable).\n\n## Summarising the evidence and making evidence statements\nThe review data was summarised in evidence tables (see full reviews).\nThe findings from the reviews were synthesised and used as the basis for a number of evidence statements relating to each key question. The evidence statements were prepared by the external contractors/public health collaborating centres (see appendix A). The statements reflect their judgement of the strength (quality, quantity and consistency) of evidence and its applicability to the populations and settings in the scope.\n\n# Cost effectiveness\nThere was a review of economic evaluations and an economic modelling exercise.\n\n## Review of economic evaluations\nStudies were identified by searching the NHS Economic Evaluation Database (NHSEED). An additional search was undertaken using an economics study filter.\nThe search focused on health economic studies that dealt with:\ninterventions to increase walking and/or cycling and reported relevant health-related outcomes\ncost–benefit analysis results studies which considered wider outcomes, including travel, congestion and pollution.\nSimplified search strategies were also used to search another economic specific database EconLit.\n\n## Economic modelling\nAn economic model was constructed to incorporate data from the reviews of effectiveness and cost effectiveness. The results are reported in: 'Walking and cycling: local measures to promote walking and cycling as forms of travel or recreation: health economic and modelling report'.\n\n# How the PDG formulated the recommendations\nAt its meetings in November 2011 and January, February and March 2012, the Programme Development Group (PDG) considered the evidence, expert reports and cost effectiveness to determine:\nwhether there was sufficient evidence (in terms of strength and applicability) to form a judgement\nwhere relevant, whether (on balance) the evidence demonstrates that the intervention or programme/activity can be effective or is inconclusive\nwhere relevant, the typical size of effect (where there is one)\nwhether the evidence is applicable to the target groups and context covered by the guidance.\nThe PDG developed draft recommendations through informal consensus, based on the following criteria:\nStrength (type, quality, quantity and consistency) of the evidence.\nThe applicability of the evidence to the populations/settings referred to in the scope.\nEffect size and potential impact on the target population's health.\nImpact on inequalities in health between different groups of the population.\nEquality and diversity legislation.\nEthical issues and social value judgements.\nCost effectiveness (for the NHS and other public sector organisations).\nBalance of harms and benefits.\nEase of implementation and any anticipated changes in practice.\nThe PDG noted that effectiveness can vary according to the context. For instance, geographical factors such as population density in rural or urban areas influence the likelihood of walking or cycling being a viable option for utility travel.\nWhere evidence was lacking, the PDG also considered whether a recommendation should only be implemented as part of a research programme.\nWhere possible, recommendations were linked to evidence statements (see appendix C for details). Where a recommendation was inferred from the evidence, this was indicated by the reference 'IDE' (inference derived from the evidence).# Appendix C The evidence\n\n# Introduction\nThis appendix lists the evidence statements and links them to the relevant recommendations. (See appendix B for the key to quality assessments.) Note: the evidence statements in review 1 (see appendix A for details of the evidence reviews) were amended by NICE and endorsed by the Programme Development Group (PDG). This appendix includes the amended evidence statements from review 1.\nAppendix C also lists six expert reports and their links to the recommendations and sets out a brief summary of findings from the economic analysis.\nThe evidence statements are short summaries of evidence, in a review, report or paper (provided by an expert in the topic area). Each statement has a short code indicating which document the evidence has come from. The letters in the code refer to the type of document the statement is from, and the numbers refer to the document number, and the number of the evidence statement in the document.\nEvidence statement number R1.ES1 indicates that the linked statement is numbered 1 in the document 'Evidence statements on the effectiveness of local interventions to promote cycling and walking for recreational and travel purposes'. Evidence statement numbered R2.ES1 indicates that the linked statement is numbered 1 in the document 'Synthesis of evidence relating to barriers and facilitators to implementing interventions that promote cycling and walking, and to carrying out cycling and walking for recreational and travel purposes'. Evidence statement EM.ES1 indicates that the linked statement is numbered 1 in 'Interventions to promote cycling and walking for recreational and travel purposes: Health economic and modelling report'\nThe reviews, expert reports and economic analysis are available online. Where a recommendation is not directly taken from the evidence statements, but is inferred from the evidence, this is indicated by IDE (inference derived from the evidence).\nWhere the PDG has considered other evidence, it is linked to the appropriate recommendation below. It is also listed in the additional evidence section of this appendix.\nRecommendation 1: IDE; Additional evidence expert papers 2, 4, 6\nRecommendation 2: IDE; Additional evidence expert papers 2, 4, 6\nRecommendation 3: Evidence statements R1.ES5, R1.ES6, R1.ES7; Additional evidence expert papers 2, 4, 6\nRecommendation 4: Evidence statements R1.ES4, EM.ES4\nRecommendation 5: Evidence statements R1.ES3, R1.ES5, R1.ES6, R1.ES7, R1.ES9, R1.ES12, R1.ES19, R2.ES9, R2.ES15, R2.ES18, EM.ES3, EM.ES5; Additional evidence expert papers 2, 3, 4, 5, 6\nRecommendation 6: Evidence statements R1.ES1, R1.ES2, R1.ES7, R1.ES13, R1.ES18, R1.ES21, R1.ES22, R2.ES1, R2.ES2, R2.ES3, R2.ES5, R2.ES6, R2.ES10, R2.ES12, R2.ES13, EM.ES1, EM.ES3; Additional evidence expert papers 1, 5\nRecommendation 7: Evidence statements R1.ES13, R1.ES14, R1.ES18, R1.ES21, R1.ES22, R2.ES3, R2.ES13, EM.ES2; Additional evidence expert paper 5\nRecommendation 8: Evidence statements R1.ES8, R1.ES9, R1.ES10a, R1.ES10b, R1.ES10c, R2.ES15, R2.ES16, EM.ES1; Additional evidence expert paper 1\nRecommendation 9: Evidence statements R1.ES11, R1.ES15, R1.ES16, R1.ES17, R1.ES23, R2.ES2, R2.ES4, R2.ES7, R2.ES9, R2.ES18; Additional evidence expert papers 1, 3\nRecommendation 10: Evidence statements R1.ES20, R2.ES2, R2.ES4\n\n# Evidence statements\nPlease note that the wording of some evidence statements has been altered slightly from those in the evidence review(s) to make them more consistent with each other and NICE's standard house style.\n\n## Evidence statement R1.ES1: Population-level change in mass-media interventions to increase walking\nThere was inconsistent evidence from two studies (both ) on the effectiveness of mass-media interventions (which included paid advertisements , billboards/posters, public relations, educational activities and community participation), delivered in the community in increasing population levels of walking for leisure or travel in adults up to 1 year post intervention. One before-and-after (BA) study showed no effect on walking (the reporting of data in this study was poor) and one cross-sectional (CS) study showed a small, but positive effect on walking.\nOne (+) BA study (UK n=3476, 12 months) – 40-second TV advert supported by a telephone helpline – showed no change in the number of days spent walking for at least 30 minutes: mean of 4.26 days in 1995 and 4.13 days in 1996, no significance statistics given.\nOne (+) CS study (USA n=297, 5 months) – billboard, newspaper, radio, and poster advertisements – showed that those exposed to the campaign were more likely to walk for at least 10 minutes on more days of the week than the control group (5.2 days versus 4.52 days t=2.34, p=0.02).\nPopulation-level evidence on mass-media interventions to increase walking is partially applicable to the UK as one study was conducted in the UK. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES2: Multi-component community-based interventions to promote walking\nThere was inconsistent evidence from six studies concerning the effectiveness of multi-component interventions on increasing population levels of walking for leisure or travel in the long term. Four non-randomised control studies (nRCT) papers (three and one ) showed positive effects on walking and two nRCT papers (one and one ) indicated that the interventions were not effective in increasing walking.\nOne (+) nRCT (Australia n=two wards, 2 years) – park modifications, media campaign, walking maps – showed that those in the intervention ward were more likely than those in the control ward to have walked in the 2 weeks prior to follow up (89.3% versus 81.0% respectively; X2=11.51, p=0.001), and within-ward analysis indicated that walking increased from baseline in the intervention ward (X2=5.85, p=0.016), but not in the control ward (X2=0.07, p=0.794). There was no difference in the number reaching adequate levels of physical activity (health department recommendations).\nOne (++) nRCT (USA n=1233, 12 months) – individually tailored newsletters, interpersonal activities that stressed social support, community-wide events such as walk-a-thons – showed that rates of 7-day walking for any purpose or for exercise declined slightly in the intervention communities compared with the comparison sites (-1.4 min, p=0.91; and -5.6, p=0.37 respectively).\nOne (+) nRCT (USA n=1531, 12 months) as above found that the change in walking was higher in intervention (11.7 minutes) than comparison (6.5 minutes), although not statistically significant. Percentage of respondents who met the recommendation for walking was the same across the intervention and comparison areas: 22.2% and 21.6%, p=0.811.\nOne (+) nRCT (USA n=1472, 8 weeks) – paid advertising, public relations events to generate media coverage, public health educational activities at work sites, churches and local organisations – found a 23% increase in walking observations in the intervention community versus a 6% decrease in the comparison community (OR 1.31, 95% CI 1.14–1.50; p<0.0001).\nOne (++) nRCT (USA n=1472, 12 months) – paid advertisements (TV, radio, cable, newspapers), public relations and community participation – found that the least active group in the intervention population were more likely than control population to have increased daily walking (OR=1.72, 95%CI 1.01–2.95).\nOne (+) nRCT (USA n=4 communities, 8 weeks) – four interventions: Welch Walks (WW): paid media, media relations, community activities; Broome County (BC) walks (BC): WW components + website; Wheeling walks and West Virginia (WV) walks: BC components +12-week participatory planning, policy and environmental changes – found that 32% of insufficiently active persons in Wheeling Walks reported meeting the criteria for regular walking immediately post campaign compared to an 18% increase in the comparator community (OR=2.12, 95%CI 1.41–2.24). An increase in reaching regular walking was observed for the most sedentary group in WV walks (p<0.05). The intervention community in Welch walks demonstrated a twofold (OR=2.0 95%CI 1.01–3.97) gain in weekly walking by at least 30 minutes versus the comparison community. Forty one per cent of the BC walks intervention community increased walking by 30 minutes per week compared to 30% in the control (OR=1.56 95%CI 1.07–2.28).\nThe population-level evidence on multi-component interventions to increase walking is only partially applicable to the UK as studies were conducted in the US and Australia. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES3: Population-level change in mass-media interventions to increase walking and cycling – Australia 'Walk to work day'\nModerate evidence from one BA study reported in two papers (both ) suggests that the mass-media campaign 'Australia walk to work day' (a collaborative annual event in which members of the public are encouraged to walk to work) may be effective in increasing population levels of walking and cycling for travel in adults up to 1 year post intervention. This intervention resulted in positive effects on both walking and cycling.\nOne (+) study (n=1100, at least 1 year) found that overall, total weekly minutes of moderate physical activity increased by 20 minutes per week (t=4.76, p<0.005 with, an decrease in the proportion who were inactive -4.0% p<0.005). Significant population increase in total walk time (+16minutes per week t=2.04, p<0.05) in participants who were employed, and in minutes spent walking increased by 21 minutes per week in 'passive commuters' (t = 2.42, p< 0.05).\nOne (+) study (n=1100, 2 months) found a significant population-level increase in health enhancing active commuting (3.9%, p=0.01).\nThe evidence on mass-media interventions to increase walking and cycling is only partially applicable to the UK as studies were conducted in Australia. The differing environment in Australia must be considered in reference to these studies. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES4: Population-level change in TravelSmart as an intervention to increase walking and cycling\nWeak evidence from a series of evaluation reports (ER) (both ) suggests that TravelSmart is effective in increasing population levels of walking and cycling for travel in adults (who volunteered to participate) at least over 1 year. TravelSmart uses 'Individualised travel marketing' (ITM) which aims to highlight travel choices 'people may not know they have' by providing locally relevant information and support to households. The evidence is moderate as the reports only present percentage change data and limited methodologies. The intervention targets individuals, but data is reported at population level.\nOne (+) evaluation report (Australia n=5 regions, various) found household projects routinely showed decreases in car use of 4–15% and rise in use of walking, cycling and public transport.\nOne (+) evaluation report (UK n=19 regions, various) found cycling for travel increased by between 14% and 69%, travel by walking increased between 9% and 29%, travel by car decreased at each site by between 10 and 14%, overall sustainable travel trips increased at each site (between 9% and 29%).\nThe evidence on this intervention to increase walking and cycling is fully applicable to the UK as most of the data reported is from UK sites. However, the differing environment in Australia must be considered in reference to the data collected there. Individual local contexts as well as the setting will also impact on the applicability of data from individual sites.\n\n## Evidence statement R1.ES5: Population-level change in cycle demonstration towns as interventions to increase cycling\nThere is moderate evidence indicating that cycling demonstration towns (CDT) (multi-component interventions to increase cycling in six towns) are effective in increasing population levels of cycling for active travel in the general population up to 10 years post intervention. One (-) ER, one (+) BA and one (+) interrupted time series (ITS) study showed positive effects on cycling in cycle demonstration towns, although the significance of the effects is not reported. See also R1.ES7 and R1.ES6.\nOne (+) ITS (UK n= six towns, 4 years) found automatic counter data indicated an average increase in cycles counted of 27%. Proportion of pupils cycling to school at least once a week increased from 12% pre-survey to 26% post-survey.\nOne (-) ER (UK n=6 towns, 10 years) found data from automatic cycle counts indicated a 12% increase overall in usage of cycle routes and up to 60% at specific sites (this report also uses data from other interventions).\nOne (+) BA (UK n=1500, 4 years) found the proportion of adult cycling for at least 30 minutes once or more per month increased from 11.8% in 2006 to 15.1% in 2008, an increase of 3.3%-points or 28%.\nThe evidence on cycle demonstration town is directly applicable as it was conducted in the UK.\n\n## Evidence statement R1.ES6: Population-level change in multi-component interventions to increase cycling\nWeak evidence from one (+) nRCT study suggests that multi-component interventions are not effective in increasing population levels of cycling in the general population up to 2 years post intervention, but may result in increased use of bicycle paths and increase in cycling among new/beginner cyclists. See also R1.ES5.\nOne (+) nRCT (n=909, 2 years) – multi-component community-based intervention including: organised bike rides and events, cycling skills courses, distribution of cycling maps of the area, local press coverage – found significantly greater use of the bicycle paths in the intervention area (28.3%) at follow-up compared with the comparison area (16.2%) p<0.001. No self-reported increase in residents who said they cycled in the last year, however, significantly more 'novice'/beginner riders had cycled in the last year in the intervention area (11.5% versus1.4% in the comparison area; p=0.013).\nThe population-level evidence on multi-component interventions to increase cycling is only partially applicable to the UK as the study was conducted in Australia. The differing environment in Australia must be considered in all studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES7: Population-level change in multi-component interventions to increase walking and cycling in adults\nWeak evidence from four (two , two ) of five studies indicates that multi-component interventions delivered in the community are effective in increasing population levels of walking and cycling for travel and/or leisure up to 9 years post-intervention. Evidence from the three BA, and one ITS, showed mostly positive effects of community interventions to encourage cycling and walking for travel and/or leisure. One (+) nRCT indicated that multi-component interventions may reduce a natural decline in walking in women and that among those with a low educational level, cycling may show a small increase. See also R1.ES5 and R1.ES6.\nOne (+) BA (Belgium n=438, 1 year) – physical activity promoted in the entire city of Ghent. Central theme of '10,000 steps/day', with secondary taglines of 'every step counts') and 'every revolution (of bicycle pedals) counts', pedometers given – found that 47.5% increased average step counts by 896 steps/day or more at 1-year follow-up (no statistical analysis; cycling was 'converted' to step counts).\nOne (-) BA (USA n=not reported, 12 months) – multi-component intervention to increase safe physical activity opportunities and encourage walking and biking for short trips – found the number of people seen using active transportation increased from 1028 in 2005 to 1853 in 2006 (63% increase). Walking to school more than doubled at three of four schools engaged for at least 2 years (no other analysis).\nOne (+) BA (UK n=at least 12,000, 4 years) – three 'Sustainable travel towns' which implemented intensive town-wide Smarter Choice Programmes to encourage use of non-car options; bus use, cycling and walking, and less single occupancy cars – found that cycle trips per head grew substantially in all three towns by 26–30%. Comparison towns cycle trips decreased. Walking trips per head grew substantially by 10–13% compared to a national decline in similar towns.\nOne (-) ITS (USA n=not reported, 1 year) – Project U-Turn, active transportation (biking, walking, and transit use) through an integrated approach to active living, ran for 5 years, targeting 36,000. City-wide count of people using active transport, showed an increase of 63% over 1 year, limited study details provided. Also had a major schools component and reported an increase in walking over time, no statistics given.\nOne (+) nRCT (Netherlands n=3114, 5 years) – community-based project with 790 lifestyle interventions, 361 were physical activity focused, example: printed guides of walking and cycling routes – found that there was a smaller decline in walking in women in the intervention compared to control region (-0.3 hours/week versus -2.3 hours/week; p≤0.05); and among those with a low education level there was a significant difference in change in cycling and walking in the intervention versus control region (0.2 hours/week versus -0.3 hours week respectively for cycling and 0.0 hours/week versus -2.2 hours week for walking; both p≤0.05).\nThe population-level evidence on multi-component interventions to increase walking and cycling in adults is only partially applicable to the UK as one studies was conducted in the UK. The differing environment in the USA and Europe must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES8: Population-level change in multi-component interventions to increase walking and cycling in children\nInconsistent evidence from three studies on the effectiveness of school-based multi-component interventions to increase levels of walking and cycling for children. Evidence from two (+) BA studies showed positive effects on school population-level walking in children however evidence from one (++) cluster randomised control study (RCT) showed no effect on cycling and walking for school travel.\nOne (+) BA (UK n=179, 41 months) – school travel plan group developed a walking bus scheme, incentive scheme 'going for gold' included children cycling or scooting to school, also cycle training, pedestrian training, park and walk scheme, curriculum work, school assemblies and newsletters – found walking to school increased from 30% to 58.8%, cycling to school increased from 0– 4%.\nOne (++) cluster RCT (UK n=21 schools, 12 months) – multi-component school travel plans were developed by a school travel coordinator – found the proportion of children walking or cycling to school was not affected by the intervention.\nOne (+) BA (UK n=11 schools, up to approximately 18 months) – 'Safe routes to school'– identified and created safe routes to school, invites community-wide involvement, full-time educator employed to develop curriculum and volunteer team leader in each school – found an increase in number of school trips made by walking (64%) and biking (114%).\nThe population-level evidence on multi-component interventions to increase walking and cycling in children is applicable to the UK as all studies were conducted in the UK. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES9: School-based change in interventions to increase cycling in children\nWeak evidence from one (+) BA study suggests that school-based multi-component interventions may be effective in increasing school population levels of cycling in children. Evidence showed positive effects on walking at the school population level.\nThe study (UK n=52 schools, 1 year) – 'Bike it': school travel plans, cycling champions in schools to demonstrate to parents and pupils that cycling is a popular choice. Percentage of school pupils cycling to school every day increased from 3% to 10%. Number of pupils cycling at least once a week increased from 10% to 27%. Number of pupils who never cycled decreased from 80% to 55%.\nThe evidence on multi-component interventions to increase cycling in children is applicable in the UK as the study was carried out in the UK.\n\n## Evidence statement R1.ES10a: Walking school bus interventions to increase walking\nModerate evidence from three (+) BA studies and one (+) nRCT suggests that walking school bus interventions may be effective in increasing levels of walking at the school population level for children up to 30 months post-intervention.\nOne (+) BA (UK n=309, 14 months) – walking school buses supported by environmental interventions such as street lighting on walking routes – found that participants walking increased from 60% to 68.3%, 25% of that was due to walking buses.\nOne (+) nRCT (USA n=3 primary schools, follow up 6 months after baseline) – Walking School Bus (WSB). The school implemented three routes staffed by parent volunteers, and were compared to two nearby schools without a WSB – found that the number of children who walked to school increased from baseline to follow up by 25% (from 19–26%). Comparison schools showed a decrease in the proportion of children walking to school over the same period (no data given).\nOne (+) BA (UK n=64, 18–30 months) – walking buses at five schools. Information sent home to parents to encourage participation – found that there was an overall average increase of 513 metres walked per day. For children that had previously walked to school the WSB resulted in an average increase of only 19 metres/day, for those that previously travelled to school by a mixture of car and walking: average increase of 309 metres/day and for those that previously regularly travelled by car to get to school: average increase of 1549 metres/day (no statistical analyses reported). Participation in the walking buses declined over time.\nOne (+) nRCT (USA n=643, 12 months) – WSB run by a part-time coordinator and parent volunteers. The intervention included three routes which ranged from 0.3 to 1.5 miles and took 15–40 minutes. The WSB operated once or twice a week – found that higher proportions of students walked to the intervention (25% +/- 2%) versus the control schools (7% +/-1%: p<0.001). Significant increase in walking to school in intervention school from 20% (+/-2%) at baseline.\nThe evidence on school-based walking sessions to increase walking is partially applicable to the UK as two studies were conducted in the UK. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES10b: School-based interventions using pedometers to increase walking\nModerate evidence from one (+) cluster RCT and one (+) ITS suggests that school-based walking interventions which incorporate pedometers may be effective in increasing levels of walking at the school population level for children up to 12 weeks post intervention.\nOne (+) ITS (USA n=169, 6 weeks) – pedometers and a 'Fit bits' programme to implement physical activity breaks in the classroom – mean steps increased from 19,149 (95%CI 18,224–20,073) week 1 to 21,248 (95%CI 19,730-22,765) week 6 (p<0.001) found that overall, walking peaked at week 3; and younger students had a stronger response to the intervention.\nOne (+) cluster RCT (New Zealand n=85, 12 weeks) – physical activity self-monitoring and educative programme – the pedometer (PED) group set daily step targets, and the minutes (MIN) group set daily time based activity goals – found that both intervention groups had significant increase in steps between baseline and week 12 (p<0.001), no significant differences between time points for the control group (p=0.23).\nThe evidence on school-based walking sessions to increase walking is only partially applicable to the UK as studies were undertaken in the USA and New Zealand. The differing environments in these countries must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES10c: School-based walking session interventions to increase walking\nInconsistent evidence from five studies (reported in six papers) on the effectiveness of school-based walking session interventions in increasing levels of walking at the school population level for children up to 48 months post intervention. Evidence from one (+) nRCT and two (+) BA studies (reported in three papers) showed positive effects on school population walking. However one (+) nRCT showed no effect on walking and one (+) cluster RCT had conflicting evidence concerning the intervention effect on walking for school travel.\nOne (+) BA (UK n=585, 48 months) – 'Walk on Tuesday and Thursday' (WOTT) encouraged walking to school, included incentives – found that walking to school increased from 53.3% to 58.7% (percentages only reported). Also reported in a second (+) BA.\nOne (+) nRCT (UK n=60, 10 weeks) – school-based active travel project. Active travel was integrated into the curriculum, and participants used interactive travel planning resources at home – found that mean distance travelled to school by walking increased significantly more in the intervention (389%) than the control (17%: t=-4.679, p<0.001, 95% CI -315 to -795 m).\nOne (+) nRCT (UK n=13 schools, 4 weeks) – interventions linked to national walk to school week – found no difference between intervention and control schools in walking before or after the intervention.\nOne (+) cluster RCT (Australia n=24 schools, 2 months) – health promoting schools policy: classroom activities, pedometer-based walking activities (some schools) development of school travel access guides, parent newsletters, and improving environments with local councils – found that, based on student survey data while both intervention and control groups increased walking by about 4% from baseline, there was no statistically significant difference in mean percentages of change in mode of transport to or from school from baseline to follow-up between the intervention and control groups (no data given).But parent survey data (n=807) indicated a significant increase in walking trips by students in the intervention compared to control schools (28.8% versus 19%, p=0.05).\nOne (+) BA (Australia n=234, 4 weeks) – classroom activities supported by a weekly newsletter to encourage walking to school – found the percentage of walking trips increased by 3.4% and car trips decreased by 3.4%.\nThe evidence on school-based walking sessions to increase walking is partially applicable to the UK as three studies were conducted in the UK. The differing environments in Australia must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES11: Population-level change in workplace-based interventions to increase independent walking and cycling\nWeak evidence from one (+) BA study and one (+) ITS indicates that multi-component interventions delivered in the workplace are effective in increasing population levels of walking and cycling\nOne (+) ITS (UK n=1850 to 2829 in each of four staff surveys, 9 years) – university transport plan: limiting the number of available parking spaces and permits, improving, installing secure cycle storage, subsidised cycle purchase scheme, car share scheme, free bus travel, and discounted season tickets – found that respondents who usually walked to work increased from 19 to 30% (Z=4.24, p<0.001) and regular cyclists increased from 7.0% to 11.8% (not significant).\nOne (+) BA (UK n=2240, 3 years) – Well@Work programmes which consisted of a diverse set of initiatives and actions aimed at promoting and supporting healthy lifestyles – found an increase of 9% in the proportion of employees participating in active travel (walking or cycling), significant increase in employees cycling (4%) or walking (8%) to work.\nThe population-level evidence on multi-component interventions to increase walking and cycling in adults is applicable to the UK as both studies were conducted in the UK. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES12: Individual-level change from participation event to increase cycling\nWeak evidence from one study suggests that a mass participation intervention may be effective in increasing individual-level cycling for leisure in adults. Evidence from one (+) BA study showed a positive effect on cycling 1 month after the intervention.\nOne (+) BA (Australia n=918, 2 months) – mass cycling event – found that participants with low pre-event self-reported cycling ability reported an average of four sessions of cycling in the month before the event and an average of 6.8 sessions in the month after the event (t=5.25, p<0.001).\nThe evidence on mass participation event intervention to increase cycling is only partially applicable to the UK as the study was conducted in Australia. The differing environment in Australia must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES13: Individual-level change in community delivered targeted health information interventions to increase walking\nModerate evidence from six studies suggests that individual, targeted provision of health information (including printed media, telephone support and text messages) delivered in the community are effective in increasing individual levels of walking for leisure or travel in adults up to 1 year post intervention. Five (++) RCTs showed positive effects on walking. One further (++) RCT also showed positive effects on walking, but was designed to test intervention fidelity.\nOne (++) RCT (USA n=117, 3 months) – ten weekly emails containing links to a webpage with an interactive information tailoring tool to promote physical activity – found that walking increased at a faster rate in the intervention group than the control group (β=15.04 , p=.035 ). Intervention group increased walking by 69 minutes/week versus 32 minutes/week in control.\nOne (++) RCT (Australia n=399, 10 weeks) – print only (participants were mailed self-help brochures weekly for 3 weeks) or print plus telephone (participants received the same print programme plus three weekly telephone support calls – found that both intervention groups significantly increased time reported walking for exercise per week (from 130 to 147 minutes: t =-3.50, p<0.001; and from 132 to 150 minutes, t= -2.44, p=0.016).\nOne (++) RCT (USA n=197, 6 months) – counselling weekly telephone calls to assess physical activity levels and problem solve how to fit adequate walking activity into their week – found that women in the intervention group reported more time walked each day than the control women (F =4.10, p<0.05).\nOne (++) RCT (USA n=253, 12 months) – telephone calls with or without counselling, or a control video – found that women in the intervention group showed a linear increase in walking from baseline to 6 months (latent growth analysis to assess the relationship between time and intervention group membership).\nOne (++) RCT (UK n=149, 4 weeks) – two theory-based interventions consisting of forming 'implementation intentions' along with text message reminders to achieve walking-related plans or goals – found a differential change across groups in brisk walking or fast walking (F = 3.12, p=0.048). Two intervention groups which differed in having a plan reminder or goal reminder had a 45% and 42% increase of at least 2 days a week meeting physical activity daily guidelines respectively, with a 22% increase in the control group.\nOne (++) RCT (USA n=50, 12 months) – two interventions consisting of forming 'implementation intentions' along with text message reminders to achieve walking-related plans or goals using social cognitive theory (SCT) – found the greatest increase in walking in interventions that adhered more closely to SCT. High fidelity intervention increased walking by 34.23 minutes a week (+/-81.91) compared to a low fidelity increase of 7.91 minutes a week (+/-47.93, F=3.207 p=0.08).\nThe evidence on community delivered health information interventions is only partially applicable to the UK as most studies were conducted in Australia or the USA with only one UK study included. The differing environment in Australia and the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\nNote: pedometers are a technology which offers an opportunity to present individualised information about walking and so are closely linked to the studies above. Use of pedometers is related to goal setting and monitoring rather than to delivery of information about health benefits or methods to overcome barriers. Studies may use pedometers as one of a number of factors to support increases in walking, in common with other approaches, or may use pedometers solely as a means of measuring change. Pedometer studies are considered below.\n\n## Evidence statement R1.ES14: Individual-level change in community-based pedometer interventions to increase walking\nModerate evidence from 12 studies suggests that pedometer-based interventions delivered in the community are effective in adults (or women only) to increase individual levels of walking for leisure or travel, up to 6 months post intervention. Evidence from five (++) RCTs and 2 BA studies (one and one) showed positive effects on walking for leisure and/or travel in adults. This is supported by data from a (-) CS study. However, one (++) RCT found that short-term improvements in walking 4 weeks post intervention had decreased by 12 months follow-up. Evidence from one (++) RCT and one (+) BA study showed substantial positive effects on walking for leisure and/or travel in women. An additional (++) RCT found that a pedometer-based intervention increased walking in environments with low aesthetics, but not in those with aesthetically pleasing environments.\nOne (++) RCT (UK n=61, 52 weeks) – walking programme with goals set in minutes, or steps or using a pedometer – found that the pedometer group increased walking at 4 weeks (p<0.001), but decreased between 4 weeks and 12 months. No change in minutes or control groups.\nOne (++) RCT (UK n=130, 4 weeks) – motivational component had three stages: participants were shown 10 statements about what would make it easier for them to walk more, asked to complete a scale to show how confident they would be about walking in each situation, and discussed with facilitator and walking plan developed; pedometers were worn – found a significant difference in number of minutes spent walking to week 2 between the control group (M=138.7, SD=93.3) and the intervention group (M=22.5 SD=100.3), from a mean of 19.8 minutes to 32.2 minutes per day (increase of over 60%). Also a significant increase in the number of minutes spent walking per week for intervention group from week 1 to week 4 (mean 287.3, SD=129.4 t=8.12, p<0.001).\nOne (+) BA (USA n=36, 6 weeks) – women who were designated as insufficiently active were given brochures and pedometers and were sent emails. Participants received a pedometer, 6 weeks of step log sheets, self-addressed envelopes, and three commercial brochures describing strategies based on transtheoretical model (TTM) for increasing physical activity and the risks and benefits of physical activity – found that participants significantly increased their total walking minutes from baseline (median 55) to post intervention (median 245: Z=4.03, p=0.001) including walking while at work (Z=2.79, p=0.005, d=0.63), for transport (Z=2.86, p=0.004, d=0.60) and during leisure time (Z=3.54, p=0.001, d=0.81).\nOne (++) RCT (Japan n=68,12 weeks) – feedback based on accelerometer daily physical activity, number of daily steps and time spent performing daily moderate physical activity (MPA) which was provided to each participant every 2 weeks. Participants were recommended to accumulate 9000 steps and 30 minutes of MPA per day – found a significant group interaction for steps (f=10.53, p<0.01). The intervention group increased their steps by 16% (7811 +/-3268 to 9046 +/-2620 steps). There was no significant change in the control group.\nOne (++) RCT (Australia n=314, 3 months) – self-help booklet based on social cognitive theory constructs, plus six weekly diaries printed on reply-paid postcards (WP group), plus a pedometer (WPP group). Three incremental stages, starting with short walks (<15 minutes) 3 days a week, typically by incidental walking, gradually increasing the duration of walks to 3 to 4 days, then (continuously) walking briskly for 30 minutes – found that the mean change in total sessions of all-purpose walking/week increased within all groups from baseline, but increased the most within WPP. The control group had a mean increase of 1.2 sessions/week (95% CI: 0.6-1.8, t=3.97, p<0.001); WP: 1.3 sessions/week (0.5–2.0, t=3.32, p<0.001); WPP: 2.3 sessions/week (1.6–3.1, t=6.30, p<0.001). Leisure time walking sessions/week for the previous 3 months also increased within all groups, with both WP (2.0 sessions/week 1.6–2.4, t=9.49, p<0.001) and WPP (2.1 sessions/week 1.7–2.6, t=9.63, p<0.001) showing a significantly larger increase than the control group (0.9 sessions/week 0.6–1.2, t=5.82, p<0.001). There was a similar pattern for leisure time walking minutes/week for the previous 3 months, but only the WPP group (66 minutes/week 50–82, t=8.05, p<0.001) showed a significant increase compared to the control group (34 minutes/week 21–48, t=5.03, p<0.001). The WPP group was also more likely than controls to meet physical activity recommendations. Unclear if the provision of pedometers provides benefit over and above standardised structure walking programme.\nOne (++) RCT (Australia n=369, 3 months) – participants received a single mail-out of a self-help walking programme (WP) or the same programme plus a pedometer (WPP) – found that only the WPP group were significantly more likely than controls to increase total walking time (Exp = 2.53, p<0.01) and to undertake regular walking (OR=5.85, 95% CI 2.60–12.2) where environment aesthetics (level of greenery and interesting scenery) were perceived to be low; while in aesthetically pleasing environments, the differences in walking measures between intervention and control groups were non-significant.\nOne (+) BA (Japan n=56, 4 months) – subjects were given a pedometer and instructed to walk at least 7,500 steps each day. They were also given additional monthly advice on healthy diet and lifestyle provided in a newsletter – found the mean steps per day increased significantly from 9389 to 11846 (p<0.01).\nOne (++) RCT (USA n=24, 24 weeks) – given pedometer and initially, all (post-menopausal) women were prescribed a distance of 1.4 km/day above their baseline. Distance was then increased by 0.5 km/day until the desired walking distance was met – found that the intervention group increased their daily walking by 4300 steps (2.9 ± 0.2 km/day); significantly different from baseline and from the control group (both p<0.05).\nOne (++) RCT (Australia n=26, 12 weeks) – participants (overweight middle-aged women) in the pedometer group were told to record their pedometer steps on a daily basis for 12 weeks; those in the control group were asked to wear a sealed pedometer for 12 weeks with weekly recording. The pedometer group was also encouraged to reach a daily step goal of 10,000 steps/day – found that the pedometer group daily average number of steps at weeks 6 (8321 ± 884 steps/day) and 12 (9703 ± 921 steps/day) were significantly higher than the baseline daily average (of 6242 ± 541 steps/day: p=0.046 and p=0.035) respectively.\nOne (-) BA (USA n=12, 2 weeks) – participants over 65 years of age; site-specific walking route maps, health counselling session with individualised goal-setting and pedometers – average daily pedometer steps increased between baseline (M=3020, SD=1858) and week 1 (M=4314, SD=2627; t= -2.99, p=0.012) and week 2 (M=4246, SD=2331; t=3.42, p=0.006) found that all participants met their daily step goals in week 1 while 50% met their step goals in week 2.\nOne (-) CS (Canada n=41, 6 months) – lending pedometers to patrons of five public libraries. The pedometers were loaned for maximum of 9 weeks. Education packages were handed out with the pedometer including: information on pedometer use, physical activity/walking recommendations, maps of local trails, and a walking challenge questionnaire – found that 39.5% indicated they walked more since borrowing the pedometer and 60.5% reported walking about the same.\nOne (++) RCT (n=79 12 weeks) – the sessions were based on the Transtheoretical Model of exercise behaviour change. Strategies used included enhancing motivation, overcoming barriers and developing appropriate walking plans. Followed a 12-week pedometer-based walking program – found a significant increase in steps/day for the intervention group between baseline (M=6802, SD=3212) and week 12 (M=9977, SD=4669, t(38)=-6.06, p<0.001, d=0.79, CI 2,115–4236). No significant difference was observed in the control group (t(39)= -0.50, p=0.618, CI -463–770).\nThe evidence on community pedometer interventions to increase walking is only partially applicable to the UK. Three studies were conducted in the UK, with the majority in the USA, Australian, Canada, and Japan. The differing environments must be considered in reference to the studies, particularly for those conducted in Japan. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES15: Individual-level change in workplace pedometer interventions to increase walking\nModerate evidence from 11 studies suggests that pedometer-based interventions delivered in the workplace may be effective in increasing individual levels of walking for leisure or travel, up to 12 months post intervention. Evidence from three (++) RCTs, one (+) nRCT, two (+) BA and two (+) ITS studies showed positive effects on walking for leisure and/or travel in the short term (up to 12 weeks). However, one (+) ITS study which used a competition format, saw the initial increase in walking decline over 12 weeks. One (+) nRCT found significant increases in walking 12 months after the intervention, while another (++) RCT found that initial increase in walking declined by 52 weeks follow-up.\nA (++) RCT (UK n=50, 52 weeks) – walking programme with goals set in steps using an open pedometer for feedback – found that both groups significantly increased step counts from baseline to week 4. Significantly greater number of participants in the intervention (77%) compared with the control (54%) achieved their week 4 goals (X2= 4.752, p=0.03). There was no significant change in step counts from week 4–16 and a significant decrease from week 16–52.\nA (+) ITS (USA n=640 (in 64 teams of 10), 12 weeks) – competition-based employer sponsored physical activity programme using pedometers. Employees formed groups of 10 to undertake the challenge of attaining 10,000 steps per participant per day – found that total weekly steps for all teams combined increased between weeks 1 and 8 (p<0.0001), but declined from weeks 9–12. Increase in total weekly step count between week 1 and 12 not significant. Significant difference in team steps, with post-hoc comparisons indicating significant differences from baseline step counts during weeks 6–8 (F=71.15, p<0.001) but not at the end of the programme.\nA (+) nRCT (Australia n=205, 12 months) – staff defined as inactive received a 3-month self-help walking programme and pedometer plus four maintenance newsletters over 9 months to assist them to maintain their new activity levels. Control received pedometer and programme but no maintenance – found that both intervention groups significantly increased minutes walking (p=0.01). Change in moderate or vigorous physical activity (MVPA) minutes was significantly higher in the standard plus maintenance group compared with the standard group (118 minutes versus 69 minutes, P=0.029). No significant differences between groups were observed for total physical activity (161 minutes versus 117 minutes, P=0.187).\nA (+) ITS (Canada n=106, 12 weeks) – adoption phase: participants met in workplace-based groups with a facilitator for 30–60 minutes each week during a lunch break. Set individual steps per day goals and self-monitored their progress using a pedometer to record daily accumulated steps taken. Then adherence measured for 8 weeks – found that steps per day increased (from 7,029 +/- 3,100 at baseline to a plateau of 10,480 +/- 3,224 steps/day by 3.96 +/- 3.28 weeks of the intervention). Some decreases in activity relative to baseline steps per day, (ranging from -2.4% to -20.6% ).\nA (+) nRCT (Australia n=56, 6 weeks) – the intervention group received a pedometer and step logs. Set a daily step goal based on the previous week's step counts. They received weekly email reminders to wear the pedometer and return that week's log. They also received three commercial brochures. The control group received the intervention but without commercial brochures, intervention emails contained transtheoretical model (TTM)-based strategies – found that daily steps increased significantly (from 6419 ± 2386 during week 1 to 7984 ± 2742 during week 6: p<0.001) for both groups combined. Increases did not differ between groups.\nA (+) ITS (USA n=206, 10 weeks) – each day participants put on pedometers upon arriving at work, prior to getting out of their cars. To increase motivation, participants were encouraged to develop teams, and each team chose a team leader. Weekly motivational emails were sent to participants – found a significant increase in the number of steps per week for weeks 2, 3, 4, 6 and 8 compared to baseline (p=0.001).\nA (++) RCT (UK n=64, 10 weeks) – walking routes which employed prescribed walks around campus with participants asked to complete at least 15 minutes continuous brisk walking every day and 'Walking in task' which encouraged the accumulation of step counts through the working day – found a decrease in steps for the control group (-767 steps/day) and increases in intervention groups for walking routes (+926 steps/day) and walking in tasks (+997 steps/day). (Control versus walking routes p<0.008, control versus walking in tasks p<0.005).\nA (++) RCT (UK, Australia and Spain n=64, 70 and 80 respectively, 10 weeks) – participants in the first intervention group were directed to increase their step count through brisk, sustained, route-based walking during work breaks. The second intervention group was asked to engage in incidental walking and accumulate step counts during working tasks, both groups were instructed to use pedometers to motivate and regulate walking – found that average step count data decreased in the control group (-391 steps/day t=1.76; p <0.08) and significant increases in both the routes (968 steps/day; t=3.9; p<0.001) and the incidental group (699 steps/day; t=2.5; p<0.014).\nA (+) BA (USA n=290, 12 weeks) – participants wore a pedometer at least 5 days per week for 12 weeks and completed questionnaires assessing demographic information. After baseline (week 1) they were given suggested number of steps to meet recommendations, instructions for goal-setting and other behaviour-change strategies to gradually increase number of daily steps – found that the average number of steps increased from week 1 to week 6 (p<0.001) and week 12 (p=0.002).\nA (++) RCT (Canada n=63, 1 week) – intervention group pedometer was worn for 1 week for all waking hours to encourage walking. Control (non-pedometer) participants were informed they could wear a pedometer the following week – found that, compared to the no pedometer group, the pedometer group reported more walking (F=5.22, p=0.03).\nA (+) BA (USA n=188, 10 weeks) – participants were provided with pedometers and given personalised daily and weekly step goals over the 10 week intervention. Local strategies available to the participants included walking groups, marked walking circuits and posted walking maps – found a mean increase of 1503 steps (38% increase over baseline). Mean weekly step counts values for all intervention weeks were significantly higher than baseline (p<0.01).\nThe evidence on workplace pedometer interventions to increase walking is partially applicable to the UK. Three studies were conducted in the UK but most studies were conducted abroad: in USA, Australia, Canada or Spain which may limit the applicability in some cases. The differing environments must be considered in reference to the studies. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES16: Individual-level change in workplace delivered targeted health information interventions to increase walking\nWeak evidence from two studies suggests that individual, targeted provision of health information delivered in the workplace (including flyers, email, telephone calls, website postings, and information booths) may be effective in increasing individual levels of walking for leisure or travel in adults up to 24 weeks post intervention. One (+) RCT study showed a positive effect on walking and one (+) BA study showed a small (borderline significance) positive effect on walking.\nA (+) RCT (USA n=135, 24 weeks) – phone calls once a week versus every 3 weeks, and structured versus non-structured feedback – survival curves indicated that there was a significant effect on walking for treated (the combined four treatment conditions) versus the control condition (LD=17.661 p<0.001) and for frequency of prompting (those prompted once a week against every 3 weeks) (LD=17.719, p<0.0001).\nA (+) BA (USA, n=not reported, 2 weeks) – promotional material distributed via flyers, email, website postings, and at bi-weekly information booths – borderline statistically significant increases in walking counts on a route ('Path to health') from baseline midway through the campaign (p=0.069) and following the campaign: (p=0.075 – p values only reported).\nThe evidence on workplace health information interventions is only partially applicable to the UK as the studies were conducted in the USA. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES17: Individual-level change in workplace delivered targeted health information interventions to increase walking and cycling\nModerate evidence from one (++) RCT study suggests that individual, targeted provision of health information (including a booklet of interactive materials, social marketing and individualised marketing strategies) in the workplace may be effective in increasing individual levels of walking, but not cycling, for travel in adults for up to 6 months post intervention. See also R1.ES4.\nA (++) RCT (UK n=295, 6 months) – interactive materials based on the transtheoretical model of behaviour change: choosing routes, maintaining personal safety, shower and safe cycle storage information, and useful contacts – found a significant increase in time per week spent walking to work (mean 125 minutes/week intervention versus 61 minutes/week control), but no difference in average weekly minutes of cycling between cyclists in the intervention group (n=9) and control group (n=9).\nThe evidence on health information intervention to increase walking and cycling is applicable to the UK as the study was conducted in the UK. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES18: Individual-level change in multi-component interventions to increase walking\nWeak evidence from two (++) BA studies suggests that multi-component interventions have a positive effective on increasing individual levels of walking for leisure or travel up to three months post intervention.\nA (+) BA (USA n=124, 8 weeks) – multi physical activity and dietary program, pedometers – found post intervention that 46.2% (n=43) met the 10,000 steps/day criteria for high activity (no further statistics). This increased from 11.8% at baseline. Average steps increased from 5,969 steps/day to 9,757 steps/day\nA (+) BA (USA n=53, 3 months) – sponsored walking groups, improving walking routes, providing information about walking options, and advocating for pedestrian safety – found self reported walking activity increased from 65 to 109 minutes per day: 44.1% increase (95%CI= 28.0-60.2, p=0.001). The proportion that reported being at least moderately active for at least 150 minutes per week increased from 62% to 81% (19.2 % increase 95% CI= 2.2, 36.3 P=018).\nThe individual level evidence on multi-component interventions to increase walking is only partially applicable to the UK as studies were conducted in the USA. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES19: Individual-level change from cycle training interventions to increase cycling\nWeak evidence from one BA (+) study suggests that cycle training interventions may be effective in increasing individual levels of cycling for active travel amongst those not cycling at baseline, up to 2 months post intervention.\nA (+) BA (Aus n=81, 2 months) – practical skills development and supervised on road or cycle path training. Free courses for beginner and intermediate level cyclists were conducted. Promoted through flyers, posters, media releases, articles and TV and newspaper adverts – found non cyclists at baseline reported significant increase (p<0.001) in minutes cycling.\nThe individual level evidence on multi-component interventions to increase cycling is only partially applicable to the UK as the study was conducted in Australia. The differing environment in Australia must be considered in all studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES20: Individual-level change in healthcare delivered multi-component interventions to increase both walking and cycling in adults\nModerate evidence from 1 (++) RCT study concerning the effect of multi-component interventions on increasing individual levels of both walking and cycling for travel and/or leisure up to 18 months post intervention indicated a positive effect on cycling but no effect on walking.\nA (++) RCT (Sweden n=120, 18 months) – physician meetings, physical activity prescriptions, group counselling, and bicycle provision; control and intervention groups received pedometers – found the intervention group was more likely to achieve recommended level of cycling than controls (38.7% versus. 8.9%, OR=7.8, 95%CI 4.0-15.0, p<0.001) but there was no difference in compliance with the walking recommendation (45.7 versus. 39.3%, OR 1.2, 95%CI 0.7-2.0, p=0.5). Commuting by car and public transport were reduced by 34% (P<0.01) and 37% (P<0.001), respectively in the whole sample, with no differences between groups.\nThe individual level evidence on multi-component interventions to increase walking and cycling in adults is only partially applicable to the UK as the study was conducted in Sweden. The differing environment in Sweden must be considered in reference to this study. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1ES21: Individual-level change in community-based led walking group interventions to increase walking\nInconsistent evidence from 5 studies on the effects of a community-based led walking group interventions on walking. 1 (++) RCT, 1 (++) clustered RCT, 1 (++) nRCT and 1 BA (+) study showed positive effects on walking from community-based walking group interventions; but evidence from a further (++) RCT showed no difference between groups at 12 months.\nA (++) nRCT (UK n=7883, 12 weeks) – 'Get walking, keep walking': Bespoke, led walks and sessions and walking packs aimed at encouraging (predominantly) inactive people, those from deprived communities, black and minority backgrounds, women and younger adults to walk – found 67% of participants increased the amount of exercise they did each week. Walking from 'place to place' increased by 1.1 day/week and walking for leisure by 1 day/week.\nA (++) cluster RCT (USA n=501, 6 months) – leader-led walking group activity or an information-only control group – found significant increase observed in walking activity: p <0.05.\nA (+) BA (Australia n=169, 6 months) – walk leaders received a prescriptive progressive weekly exercise program guided by social cognitive theory, that contained written information on the appropriate length for the walking program; stretching exercises; and ball skills, such as side twist leader ball, participants aged 65-74 – found baseline mean walking time for recreation was one hour (SD =1.65), increasing to 2.69 hours (SD =2.02) per week by the end of the program.\nA (++) RCT (UK n=260, 12 months) – accompanied walks were provided at several different times in the day and evening, during the week and at weekends, and were led by lay volunteers – found at 12 months, although both walking and control groups increased activity (by 35.7% and 22.6% respectively; 95% CI 0.003% to 25.9%) p=0.05), there was no significant difference between them.\nA (++) RCT (USA n=114, 20 weeks) – efficacy based Exercise classes were conducted by trained exercise specialists and employed brisk walking as the aerobic component – found at the end of the 20 week program, subjects in the intervention group walked more miles per week than the control group: p<0.05.Intervention group subjects also walked more often (p<0.01) and accumulated more minutes (p<0.01) than control\nThe evidence on community based walking group sessions to increase walking is only partially applicable to the UK as only two studies were conducted in the UK. The differing environment in the USA and Australia must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES22: Individual-level change in interventions to increase independent community-based walking\nWeak evidence from 2 (+) BA studies and 1 (++) RCT suggests that interventions to increase independent community based walking may be effective in increasing individual walking for leisure, exercise or travel up to 13 weeks post intervention in adults or the whole community.\nA (+) BA (Canada n=39, 8 weeks) – 'mall walking programme', participants provided with pedometers. Participants self-selected the pace, time, and frequency of walking. Encouraged to attend as often as possible between 8am and 10am Monday to Friday – found average daily mall walk steps increased from 5055 (SD 1374) to 5969 (SD 1543): p=0.002, and average daily mall walk time increased from 42.9 (SD 10.6) min to 50.4 (SD 13.5) min: p=0.002.\nA (+) RCT (Aus n=88, 13 weeks) – participants: postnatal women; information, goal setting consultations, activity and self-monitoring daily planner, tailored SMS, nominated social support person – found frequency of walking for exercise (days/week) increased over time in the intervention compared to control group (time×group interaction effect F(2,85)=5.38, p=0.023, medium effect size partial η2=0.06); while change in duration of walking did not show a significant time×group interaction effect (p=0.081; effect size partial η2=0.05), there was a significant group effect with increases in walking duration in the intervention compared to control (p=0.005; medium to large effect size partial η2=0.09).\nA (+) BA (USA n=16, 12 weeks) – walking intervention facilitated by community health workers. Weekly sessions encouraged participants to accumulate at least 30 min of moderate intensity walking on most/all days of the week – found that exposure to the programme resulted in significant increase in walking: 915.8 metabolic equivalent min/week, p=0.002.\nThe evidence on interventions to increase independent community based walking may not be applicable to the UK as studies were conducted in the USA and Canada. The differing environment in the USA must be considered in reference to the studies conducted there. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R1.ES23: Individual-level change in workplace-based interventions to increase independent walking\nInconsistent evidence from 2 (++) RCT studies concerning workplace walking session interventions (conducted in universities) effectiveness in increasing individual levels of walking for staff and/or student participants up to 12 months post intervention. Evidence from 1 RCT showed positive effects on walking while one RCT showed no effect on walking.\nA (++) RCT (USA n=32, 32 weeks) – sedentary adults; walking prescription: 3 brisk walking conditions: 30 continuous minutes, 3 10-minute bouts, or 30 minutes made up of any combination of bouts each at least 5 minutes long; 1 hour information and modelling session followed by weekly meetings with an activity counsellor for 15 weeks. Behavioural methods used to promote adherence: goal setting and mastery, self-management techniques, weekly personal feedback, problem solving, behavioural contracting participants paid $50, refunded on successful completion – found self-reported walking for all intervention groups significantly increased throughout the program: F(6, 186)= 26.16; p<0.001.\nA (++) RCT (USA n=26, 6 weeks) – two 8-week walking for fitness classes – found that neither group increased walking time or number of steps significantly over time.\nThe evidence on workplace (university) based walking sessions to increase walking is only partially applicable to the UK as the studies were conducted in the USA. The differing environments must be considered in reference to the studies conducted in the US. Individual local contexts as well as the setting will also impact on the applicability of individual studies.\n\n## Evidence statement R2.ES1: Providers' and researchers' views of barriers and facilitators to planning and delivering interventions to increase walking\nModerate evidence from four studies suggests that facilitators to planning and delivering interventions included organisational support and sufficient planning time. It may be beneficial to include volunteer leaders at the planning stage.\nHaving previous experience in marketing and a conceptual framework facilitated recruitment efforts. Personal satisfaction, social interaction and a positive rapport with group members were motivational effects of leading walking groups.\nBarriers to planning and delivery included lack of inter-organisational collaboration. This was facilitated by introducing staff in different organisations to each other and being clear about shared goals. Employing an individual to co-ordinate between organisations was a facilitator to implementation.\nDe-motivators to being involved in organising and monitoring groups included researchers' perceived workload, efforts required for effective recruitment, lack of support from and feelings of responsibility for group members.\nA (+) UK evaluation suggested that sufficient planning time is required for successful implementation of a family-based intervention. Involvement of proposed walking leads at the planning stage was suggested as a way of increasing their engagement with the programme.\nA US (+) pilot evaluation reported that walking group policy makers supported the walking group by promoting the intervention and assisting with recruitment. Administrative support was also supplied, and events were organised.\nA (+) study that included interviews from the UK reported that the process of recruiting members to a walking group was draining on time and resources for the organisers, and some volunteers lacked skills in recruitment. Having experience in marketing and a conceptual framework around recruitment was a facilitator to recruiting new members. However, word of mouth was regarded as the most effective recruitment strategy.\nA pilot evaluation reported that running the walking group provided a sense of personal satisfaction for organisers as well as an opportunity for personal development and health promotion. Interaction with club members was a motivator for organisers.\nCollaboration with other organisations was an issue in two studies, due to a focus on their own organisation and lack of communication. In one study this meant that walking routes were not shared and events were less well attended. Club directors could also feel isolated. In the other study, collaboration between a walking association and a family support group was improved through members getting to know each other and being clear that goals were to be shared, and that interventions would run alongside each other rather than new initiatives replacing existing ones. Coordination by one designated officer also facilitated implementation.\nOne study reported that group organisers expressed views about their burden of responsibility for the wellbeing and safety of members, especially if leadership was not shared. Recruitment and maintenance of membership numbers were regarded as a burden, and strategies were developed by the club to limit drop-out. Having to walk at a slow pace with other members was a de-motivator.\nOne UK (+) interview study found that carrying out routine physiological measurements in a pedometer study was regarded as a burden for researchers.\nFindings from these studies have partial applicability to other walking groups. The organisation of walking interventions will differ across countries, regions and groups. Groups may have different goals, and recruit specific populations. There is no reason to believe that the barriers and facilitators described are not applicable to other similar interventions.\n\n## Evidence statement R2.ES2 Participants' views about motivators and barriers to participating in interventions to increase walking\nModerate evidence from five studies suggests that participating in a walking intervention motivated people to walk through the presence of role models, organised routes, and the support of being part of a group.\nFamilies were motivated by the opportunity for children to participate in an activity that was free of charge. For others, the opportunity to improve health and enjoy fresh air and nature were motivational.\nBarriers to motivation include conflicts between walking activities and work / school schedules, and cultural lack of acceptance in regard to work-based activity.\nOne US (+) pilot evaluation reported that having access to a role model and to organised walk routes were motivators to attendance. For women, having the support and security of a group was a motivator (one focus groups, US). For families, the opportunity for children to participate in activities with the family, free of charge, and outside of nursery hours were incentives (one evaluation, UK). For adults, a sense of routine and structure was valued for those who were not in employment (one focus groups, UK).\nParticipants in one (+) UK focus groups study were motivated by the opportunity to improve their health and be out in the fresh air and natural environment.\nHowever, barriers to participation included conflicting schedules with school attendance or workplace responsibilities (one interviews, UK). In a workplace setting, they also reported that increasing walking time required acceptance from colleagues, and this varied depending on the status of the employee within the organisation.\nApplicability: The findings from these studies are applicable to other walking groups. The acceptability of walking interventions will depend upon specific walking group characteristics, settings and aims. There is no reason to believe that the barriers and facilitators reported are not applicable to interventions implemented in the UK.\n\n## Evidence statement R2.ES3 Participants' views about maintaining participation in interventions to increase walking\nModerate evidence from ten studies provided evidence regarding factors associated with maintenance of participation.\nSocial interaction and social support were major factors in maintaining participation. Maintenance was also related to the extent to which activities could be integrated into daily life.\nMonitoring activity, providing people remembered to self-monitor, could increase motivation, though it could also introduce unwanted competition between members.\nOther motivators included variation in walking routes, and incentives such as gifts.\nBarriers to maintenance included the difficulty of integrating walking and attendance at clubs into daily routines. Boredom, dissatisfaction with elements of the club, and incongruent aims were reported factors associated with discontinued membership.\nThe social factor associated with walking in groups was supported by six studies. The social factor was particularly strong for women and older adults. One (+) UK focus group study reported a strong bond and sense of loyalty to the group that facilitated attendance. For men, the social factor was not so important with males tending to prefer walking alone (one focus groups, US).\nSupport was also important; in one intervention, feedback from providers was welcome, though e-mail was the preferred mode.\nA US (+) RCT highlighted the importance of family and friends in supporting the maintenance of walking behaviours. Walking also had a positive effect on interactions with family members.\nA UK (+) interview study reported that walking to deliver messages at work instead of e-mailing created a greater sense of community.\nAn important aspect of walking was the ability to integrate interventions into daily life. The ability to turn up without booking was a positive factor for some, and a sense of routine and structure was valued for those who were not in employment (one focus groups, UK).\nHowever, one study reported that women in particular found difficulty integrating extra walking into daily routines. Life changes, coinciding schedules and other commitments were also a barrier. Wearing female-oriented clothing such as high heels was a barrier to walking while at work. For African–American women, it was difficult to focus on self-based activities.\nMonitoring activities was reported as a motivator. Two studies reported that pedometer use and the process of self-monitoring increased walking behaviours. One reported that step counting gave a sense of achievement.\nHowever, a US observation and interviews (+) study found that in older adults (mainly female), pedometer use and fitness objectives conflicted with the moral economy (shared values regarding social interaction) of the walking group, which was based on sociability rather than competition. In addition, people often forget to complete logs, or to use their pedometer.\nOther incentives included rewards and gifts.\nOne study reported that the atmosphere of the club, mismatch between aims of the club and aims of the participant, as well as the pace required to walk could be barriers to participation in walking interventions. Another also added that boredom could dissuade attendance, and for African–American women, one study reported lack of objectives as potential barriers.\nApplicability: The findings from these studies are applicable to other walking groups. The motivation to maintain walking behaviour within an intervention will depend upon individual circumstances and requirements as well as the characteristics and aims of the club. There is no reason to believe that the barriers and facilitators reported are not applicable in the UK.\n\n## Evidence statement R2.ES4: Participants' views of the benefits of participating in a walking intervention\nModerate evidence from eight studies highlighted the reported benefits of walking as part of a walking intervention.\nPerceived benefits to walking were reported to facilitate motivation and hence walking behaviour (one focus groups, US). Such benefits could be emphasised when encouraging participation in interventions.\nReported benefits included physical and psychological benefits, adding variety to the day and getting out of the house or office. Walking could provide a sense of peace and solitude, and was also fun, providing an opportunity to be out in fresh air and see the sights.\nReported physical benefits were feeling healthy, (one focus groups, US), and fit (one pilot evaluation, US), (one RCT, US), increased energy, (one interview studies, UK), lower blood pressure, weight loss and improved body shape.\nPsychological benefits included enhanced mood, stress reduction, mental and emotional satisfaction, feeling rejuvenated, and having meditative or spiritual feelings. Feeling tired at the end of a walk was associated with a sense of achievement (one focus groups, UK).\nIn a workplace intervention, walking was reported to add variety to the day and improved output at work. For a group of previously sedentary adults, walking became fun, and was a chance to get out of the house. Walking for one group of mid-age women allowed them time to think, time out of the office, time with the family and fresh air.\nBenefits reported from two (+) pedometer-based interventions included seeing the sights (interviews, UK), and socialising with members of the group (observation and interviews, US).\nApplicability: The findings from these studies are applicable to other walking groups. Benefits of walking may differ by setting, though there is no reason to believe that the benefits reported are not applicable in those settings within the UK.\n\n## Evidence statement R2.ES5: Walking intervention participant's views of perceived barriers to walking\nModerate evidence from seven studies highlighted perceived barriers to walking for participants of walking interventions. These included physical and psychological limitations, environmental barriers, and poor weather conditions.\nPhysical barriers to continuing with the walking programme included health problems such as arthritis (one focus groups, US), and physical limitations such as illness and injuries (one RCT,US). Tiredness and depression also prevented some women from continuing attendance.\nPoor weather conditions or hot weather were reported disincentives to walking (one interviews,UK; one pilot evaluation, US;one focus groups, US;one focus groups, UK). One study reported costs of participation as a barrier.\nLack of access to the walking route, and obstacles such as poorly maintained stiles along the walking route were also reported barriers.\nApplicability: The findings from these studies are applicable to other walking groups. The barriers to participation in walking interventions might depend upon individual circumstances, such as age and physical fitness as well as seasonal weather conditions. Weather conditions may be better, or more extreme, in the US, Canada and Australia than in the UK, though there is no reason to believe that the barriers reported are not applicable in the UK.\n\n## Evidence statement R2.ES6: Suggested strategies to overcoming barriers to maintaining walking in a walking intervention\nModerate evidence from two studies highlighted reported strategies to overcome perceived barriers to participating in walking interventions. These included making time, and integrating walking into daily life as well as thinking positively.\nA (+) US RCT reported strategies including scheduling time to walk, problem-solving and using motivators such as positive thinking and focusing on the long-term benefits. Goals were more achievable if walking was made a priority and was fitted into daily life as much as possible. Similarly, a (+) US study (focus groups) reported that for African–American women, weaving walking into family life was a strategy that allowed themselves and the family to participate.\nApplicability: The findings from these studies are applicable to other walking groups. The ability to implement strategies to overcome barriers to participation in walking interventions will depend upon individual circumstances.\n\n## Evidence statement R2. ES7: Providers' views about effective intervention components that motivate walking and cycling\nModerate evidence from one study suggests that workplace efforts to encourage walking and cycling are most successful where they attend to cultural attitude, access, security and available facilities. Incentives and provision of equipment are also motivating.\nThe (+) study (survey and interviews, UK) provides evidence that, across 20 workplace initiatives, walking and cycling are increased where good onsite and offsite access is available, along with provision of showers, drying and changing facilities. Organised walks at lunchtime and cycling groups were an incentive.\nOrganisational attitude was important, with some workplaces marketing the benefits of walking to staff. Motivators such as complementary products or financial incentives were used.\nFor cycling, the ability to borrow equipment or receive discounts on cycling equipment was important, as was having secure parking for cycles.\nApplicability: Findings from this study were taken from a range of workplace initiatives within the UK and so are applicable in UK workplace settings.\n\n## Evidence statement R2.ES9: Participants' views about taking part in interventions to increase cycling\nModerate evidence from one exploratory study and one evaluation showed that facilitators to a led cycling intervention were a feeling of safety and acceptance that was obtained from cycling in a group.\nProvision of acceptable equipment and the need not to wear a helmet was a facilitator for boys.\nIn a workplace-based cycling intervention, facilitators included the provision of storage and changing facilities and raised awareness about benefits.\nThe (++) exploratory study (focus groups, UK) elicited community members' views about use of a cycle trail and a proposed intervention that included led cycling groups.\nThe main facilitator to using the trail for led cycle groups was the protection of riding together in a group. For young women, the image of cycling as 'uncool' was an issue, but this barrier would be lessened if they were cycling with friends.\nImage was also an issue for boys, whose participation would be facilitated by the provision of the 'right' bike, and not having to wear a cycling helmet.\nThe (+) UK evaluation study (found that the main influences on increase in cycling following an intervention were the provision of workplace cycling facilities, a house or job move that made cycling more attractive, and heightened awareness of the importance of physical activity for health. Welcomed and best used measures were secure cycle parking, showering and changing facilities, and cycle purchase loans.\nApplicability: The findings from these UK-based studies are applicable to other potential cycling interventions. The motivation to participate in cycling interventions might depend upon individual circumstances, as well as local geography and usage of the proposed site. Some areas of the UK may be more or less attractive as cycling venues than the one described here. Workplaces will also differ in provision of facilities, and interventions may be affected by factors outside the control of organisers, such as weather conditions.\n\n## Evidence statement R2.ES10: Young people's views about walking for travel or leisure (not related to an intervention)\nModerate evidence from one interview study and one survey study suggests that walking for leisure was facilitated by walking as a social event or as part of a challenge.\nBarriers to walking for travel or leisure for young people are mainly related to lack of time. In addition, having a lot to carry and wearing shoes that were not comfortable were disincentives. Young people report busy lives as a barrier to walking for transport. For men, walking was not sufficiently vigorous to be considered 'exercise'.\nThe (++) UK interview study reported that young people, and especially young men, did not regard walking as vigorous enough to provide exercise. Walking for transport required too much time out of a busy day. Walking for leisure was only acceptable if it included some form of teamwork or challenge. For those that did walk for transport, listening to music was a facilitator as it drowned out noise from traffic and construction sites.\nThe (+) US survey study reported that undergraduates found that lack of time, having a lot to carry, and wearing shoes that were uncomfortable were the most highly rated barriers.\nApplicability: The findings from these studies are applicable to young people in the UK and US. Evidence reflects aspects of daily life that alter with changes through the life course. Participants in this study are constricted by timescales associated with the working day that might not apply to some other populations. There are also specific gender differences in perceptions of walking for fitness.\n\n## Evidence statement R2.ES12: Older people's views about walking for travel or leisure (not related to an intervention)\nModerate evidence from six studies suggests that the main facilitator to walking for travel or leisure in older adults was social interaction.\nBarriers to walking for travel or leisure for older adults are related to limited mobility and fears for safety. These factors were mediated by the external environment, with fears of falling or of swift traffic being commonly voiced.\nWalking indoors was a relatively safe and comfortable alternative if designed appropriately. Walking indoors also incorporated a social aspect to walking.\nOlder adults reported factors that impacted on safety as the main barriers. When walking outside, narrow pavements and obstacles such as parked cars on pavements, and construction sites were barriers to access (one interviews, UK). Traffic was also an issue, with cycle tracks and bus lanes creating hazards. Suggested improvements were wider pavements and better provision for cyclists.\nIn addition, two focus group studies from Canada (one and one ) reported that fear of falling was a barrier to older adults, particularly in icy weather. Uneven pavements and car parks that are not designed for pedestrians were hazards. Older adults often require more time to cross roads, and it was reported that fast roads and poor visibility at crossroads were barriers to outdoor walking.\nSuggestions for improving the walking experience for this group were access to toilets and seating, as well as adequate access to local amenities and pedestrianised shopping areas. Making sure that pavements were smooth and clear of snow and ice was also a factor.\nA (+) UK survey reported that obstructions to mobility included crossings without dropped kerbs, narrow footpaths, and a dropped curb with a steep angle. The authors report that 19% of people aged >80 years could not reach key places if they need to pass through a gap of 1000 mm.\nTwo studies assessed indoor walking for older adults. A (++) observations and interviews study from the UK reported on mall walking that not only contributed to improved physical activity, but also provided a social network and a meaningful work replacement following retirement. Routines were adapted and events were organised in a relatively safe environment compared to outdoors.\nFor older adults in assisted living facilities, a (++) focus group study from the US reported similar facilitators in corridor walking, such as relative safety of being indoors, and the social incentive of meeting people in the corridors. Handrails were valued, as well as appropriate flooring, seating in corridors and adequate toilet arrangements. Public rooms needed to be thoughtfully placed to allow residents optimum access.\nReported barriers to this activity were the lack of varied things to see compared with outside. Facilities with outdoor walking areas provided an opportunity to overcome this barrier providing the walking surfaces were adequate.\nApplicability: The findings from these studies are applicable to older adults in the UK and North America. The evidence reflected safety concerns that alter with changes through the life course such as ageing. Participants in this study were constricted by limited mobility that might not apply to some other populations. Social interaction is important for this population to prevent social exclusion.\n\n## Evidence statement R2.ES13: Views of people from deprived areas about walking for travel or leisure (not related to an intervention)\nModerate evidence from two studies suggests that the main barriers to walking for travel or leisure in people from deprived areas were safety, lack of time and lack of motivation.\nWomen were constricted by perceived dangers from the external environment, family commitments, lack of motivation and lack of walking companions.\nThere was evidence that participants were either out of the habit of walking, or that walking was enforced due to a lack of options.\nFor men, walking was not sufficiently vigorous to be considered 'exercise'.\nTwo studies assessed the views of populations from deprived groups. One (+) UK interview study reported that males did not associate walking with exercise as it is not strenuous enough. Women more often preferred to walk with someone else rather than alone, so walking with a friend, or children was an incentive. Walking with a dog was a motivator for men or women.\nThough health benefits such as weight management and reducing aggression or boredom were recognised by those that did maintain walking activities, there was a habit of not walking that needed to be broken. Lack of motivation, other commitments, lack of time and bad weather were all barriers to continuing walking.\nA (+) UK interview study examined the experiences of women without access to a car and reported feelings of social exclusion due to having to walk in neglected areas and often with very young children, who were tired. Women often had to walk long distances to shops, and feared for their children's safety at busy roads.\nApplicability: The findings from these studies are applicable to people living in deprived areas in the UK. The evidence reflected safety concerns associated with perceived environmental dangers. Participants in this study were constricted by reduced options that might not apply to some other populations. Social interaction is important for this population to increase the feeling of safety, particularly for women. There were also specific gender differences in perceptions of walking for fitness.\n\n## Evidence statement R2.ES15: Views about barriers and facilitators to active travel to school (walking and/or cycling for transport)\nModerate evidence from nine studies suggested that the main facilitators to active travel included the social aspect of walking and spending time with friends, or having quality time with parents.\nBarriers for schoolchildren contemplating active travel to and from school were parental and children's lack of time and dangers from traffic and from intimidation or attack by other people. The missed opportunity by schools to develop children's existing awareness, and displaying conflicting messages was also a barrier. Peer pressure was an important factor for this age group in terms of choices.\nOther reported barriers included distance, carrying heavy bags, and poor weather conditions. Parental habits and commitments as well as fears for their children's safety were also influential on decisions about walking.\nBarriers to cycling for children included a lack of cycle lanes and a lack of facilities to store bicycles.\nThe perceived image of cycling, and a dislike of wearing cycling helmets was also reported to be a barrier.\nThree studies (one focus groups, UK; one focus groups, US; and one survey and interviews, UK) identified recognition in parents and children that walking or cycling would be beneficial to health and could increase a child's confidence and sense of independence around roads. In addition, two studies, (one focus groups, UK) reported that walking with a parent provided valuable time together. Spending time with friends was an important social aspect for older children.\nHowever, barriers to walking or cycling included lack of time; parents often needed to accompany children to different schools and arrive at their place of work in time. Children and parents would need to get out of bed much earlier in the morning in order to fit in walking. Laziness was reported as a reason for not using active travel.\nPeer pressure and the trend toward car ownership was a factor, particularly for cycling, which for some groups was socially unacceptable. Schools may also miss opportunities to develop children's knowledge about sustainable transport choices.\nA US (+) survey and an Australian (+) survey found that among children that did not walk to school, distance was the most commonly reported barrier, followed by traffic danger. Parents restricted their children to playing close to home on their bicycles (one focus groups, UK).\nChildren having to carry heavy bags of books and equipment was a barrier to both walking and cycling, as were bad weather, dark mornings and hilly terrain.\nFor older children who travel without an adult, there were fears for personal safety, of accidents and abductions, of strangers and bullies and of busy traffic. Environmental factors such as poor lighting, secluded areas or woodland on the journey exacerbated these fears.\nA (+) survey from Australia showed that parental perceptions were a factor in decisions to walk. These included parents own physical activity habits, parental working schedules, and parental concerns about safety. Having to attend out-of-school activities was also a factor.\nCycling was associated with particular barriers, such as lack of cycle lanes, and general support for cycling at school such as provision to store bicycles and helmets. Fear of having a bicycle stolen was a disincentive.\nThe image that cycling conveyed was an issue for some. For teenage girls, cycling was perceived as childish. For children that did cycle, the 'coolest' bike was required, and cycling helmets were regarded as 'uncool' (one action research, Australia), lacking in style and fit, with consequences such as negative comments from others. In addition, cycling impacted on personal appearance; for example, cycling helmets dishevelled one's hair.\nApplicability: The findings from these studies are partially applicable as the findings are specific to schoolchildren. While some barriers and facilitators to active travel are applicable to any population, schoolchildren and their parents face particular issues pertaining to safety and practicalities for children. Some barriers differ by age group and gender.\n\n## Evidence statement R2.ES16: Suggestions for strategies to encourage active travel to school (walking and/or cycling for transport)\nModerate evidence from five studies provided suggestions for strategies that might encourage safe active travel in schoolchildren.\nSuggested strategies included environmental improvements to increase safety, changing attitudes to car use, school-based campaigns to assist in cycling skills and awareness, and personal-level encouragement by provision of storage facilities and better design of cycling helmets.\nSuggested strategies that may overcome some of the reported barriers included employing crossing patrols near to schools (one focus groups, US), escort schemes, traffic calming schemes, and pedestrian training (one focus groups, UK).\nA (+) survey from the UK reported that modifying attitudes to car-centredness would be a useful policy; more so than promoting general environmental awareness.\nTo reduce cycling accidents, improved cycle paths and compulsory helmet wearing was suggested in one (+) study (action research, Australia).\nOther suggestions included schools organising walking and cycling groups, providing training in cycling proficiency, and support such as storage for wet clothes and bicycles (one focus groups, UK).\nImproved design of cycling helmets might impact on their use and on cycling behaviour by children.\nApplicability: The findings from these studies are partially applicable as the findings are specific to schoolchildren. While some suggestions to encourage active travel are applicable to any population, schoolchildren and their parents face particular issues pertaining to safety and practicalities for this age group.\n\n## Evidence statement R2.ES18: Adult views about cycling for transport\nModerate evidence from five studies was available regarding barriers and facilitators to adult cycling for transport.\nBenefits of cycling for transport were reported motivators, such as the ability to travel relatively quickly through traffic, the feeling of autonomy and freedom, and benefits for health and the environment. Cycling rather than driving could be encouraged by workplace initiatives.\nBarriers to cycling were reported such as obstacles in the road, pollution and poor weather. Carrying bags and changes of clothing required after getting wet were also reported disincentives.\nCycling for transport requires negotiating space on the road; major barriers were traffic volume, inconsiderate driving and lack of adequate cycling tracks.\nSome cycling behaviours were perceived as inappropriate by some other road users, giving cyclists a poor image and limited relationship with drivers.\nCycling was perceived as male, white and middle class. There was evidence that resistance to this image from female cyclists includes adopting and disseminating ideas for a feminine cycling image.\nReported benefits from commuting by bicycle included swiftness of travel through busy traffic, not having to rely on public transport, and improved fitness (for men) or body shape (for women). An additional factor was reassurance that the environment is being protected (one interviews, UK).\nParents were reported to drive less to work when cycling was encouraged by their workplace (one survey, Australia).\nHowever, cyclists in the city report a number of obstacles that can interrupt the journey, such as poor road surfaces, manhole covers, glass, rough gutters, hilly terrain, parked cars and buses. In addition, pollution and bad weather can be a disincentive (one interviews, UK; one survey and interviews, UK). A (+) survey from Australia reported that women cyclists preferred off-road paths compared to roads with no facilities, and off-road paths compared to on-road lanes.\nCommuting by cycle often involved carrying extra clothes to work and extra time at work to get changed from cycling outfits to work attire, including re-styling hair after wearing a helmet. Lack of available facilities was a barrier to cycling, as were saddle-soreness and tiredness.\nCycling on the road also requires negotiation with other road users. Cyclists reported fears of traffic and of accidents which meant having to be constantly alert for other traffic in order not to collide, and feeling vulnerable when crossing traffic to turn right.\nCyclists reported feeling segregated and invisible on the road. In areas where cycling is traditionally less prominent, there was a 'strangeness' about cycling, which was internalised by cyclists. There was also a perception that cycling is a male (predominantly white) activity, and some women felt the need to construct their own cycling identity, which could mean resisting the 'blokey' image and embracing femininity (for example, wearing heels while cycling; using blogs to reinforce identity).\nApplicability: The findings from these studies are applicable to cyclists who commute in the UK and Australia. Differences in experiences between cycling populations (gender, ethnicity etc.) and between settings in their promotion and support of cycling need to be taken into account.\n\n## Evidence statement R2.ES19: Views about cycling identities\nModerate evidence from one (+) UK focus groups and interviews study that obtained car driver views of adult cycling identities.\nCycling for transport requires negotiating space on the road. Some cycling behaviours were perceived as inappropriate by some other road users, giving cyclists a poor image and limited relationship with drivers.\nCar drivers reported being fearful of collisions, since cars and cycles travel at different speeds, and gave cyclists a wide berth. Some cyclists were reported as behaving poorly on the roads, for example passing through red lights, and this contributed for some, to cyclists having a negative image. Drivers that cycled were more likely to have empathy with cyclists on the road. Cycling proficiency testing, road taxes and compulsory helmet wearing were suggestions for improving the status of cyclists on the road.\nApplicability: Findings from this study are applicable to car drivers in the UK. How cyclists are perceived by other road users and the impact that this may have for cyclists needs to be taken into account.\n\n## Evidence statement EM.ES1: Led walking including 'walking school bus'\nModerate evidence from four studies suggests that led walking interventions (seven different interventions analysed in four studies) could be cost effective.\nA Spanish study: 6-month programme to promote walking-based exercise via a supervised exercise programme with three 50-minute sessions per week. Incremental cost per QALY range of €94– 871 per QALY.\nA US study: community-based social support strategies, including organised walking groups, home visits and phone calls, and newsletters, maps and handouts. Incremental cost per QALY of $27,373 and $39,690 for the two different led walking interventions versus do nothing.\nA UK study: organised community walking groups. The two organised walking group interventions showed a cost per QALY of £301 and £475.\nAnother UK study:walking bus intervention designed to encourage schoolchildren to walk to school. Incremental cost per QALY estimated to be approx. £4007 per QALY gained.\nThe evidence is partially applicable to the UK, with two of the studies UK-based, and the other international studies concerning interventions that could be of UK relevance.\n\n## Evidence statement EM.ES2: Pedometers\nModerate evidence from one Australian study suggests pedometer interventions could be cost effective: pedometer interventions, which used a meta-analysis of eight randomised control trials. Pedometer interventions maintained a net saving even when the intervention effect was modelled to decay completely by the end of the first year. That is, the modelled lifetime cost savings to the health service outweighed the pedometer costs as well as providing health benefits.\nThe evidence is partially applicable to the UK as similar pedometer interventions are of relevance.\n\n## Evidence statement EM.ES3: Media campaigns\nModerate evidence from one UK study suggests media campaigns could be cost-effective: media campaigns circulating maps of walking and cycling routes. The cost-per-QALY of £86 for provision of a healthy living map with walking and cycling routes, and £288 for the promotion of walking and cycling through printed media.\nThe evidence is applicable to the UK.\n\n## Evidence statement EM.ES4: Community health information (TravelSmart)\nModerate evidence from one Australian study suggests TravelSmart interventions could be cost-effective: TravelSmart intervention with individualised information to households on travel choices measuring change in the number of walking and cycling trips made per week. The TravelSmart programme resulted in a cost of $18,000 per disability-adjusted life year (DALY) assuming 50% decay per annum. The TravelSmart programme had net savings with annual decay rates of 0% and 25%, but costs rose to $41,000 per DALY at 75%, and $63,000 per DALY at 100% decay.\nThe evidence is partially applicable to the UK as the TravelSmart style intervention is relevant in the UK.\n\n## Evidence statement EM.ES5: Multi-component (Cycling Demonstration Towns)\nModerate evidence from one UK study suggests that the Cycling Demonstration Towns projects have a good benefit/cost rate.\nThe study: infrastructure measures such as the building of cycle paths, combined with a programme of education and marketing aimed at the general population. Benefits converted to monetary values and compared with the initial investment and running costs to produce a benefit–cost ratio. A range of 2.6–3.5 was given, reflecting the different approaches available for estimating accident and absenteeism benefits. Under all but the most pessimistic of scenarios considered, the benefit–cost ratio remained above one.\nThe evidence on cycle demonstration town is directly applicable as it was conducted in the UK.\n\n# Additional evidence\nExpert paper 1 'Paving the way for everyday walking: 'Living Streets' interventions and public health'\nExpert paper 2 'Making walking and cycling normal: key findings from the understanding walking and cycling research project':\nExpert paper 3 'Programmes to promote cycling – evidence for NICE from CTC':\nExpert paper 4 'Evidence to NICE PDG walking and cycling: experience from Bristol City Council and cycling city (2008–2011)': Ed Plowden, Bristol City Council\nExpert paper 5 'Submission to the NICE programme development group on walking and cycling'\nExpert paper 6 'Effectiveness of interventions to increase cycling'.\n\n# Economic modelling\nOverall, all the interventions modelled were found to be highly cost effective, with each estimated to cost below £10,000 per quality-adjusted life years (QALYs) gained.\nThe economic model was constructed to incorporate, where possible, data from the reviews of effectiveness and cost effectiveness. In addition, it built on the relationship between:\nphysical activity and relative risk of mortality\nlevels of walking and cycling and overall physical activity\nlevels of walking and cycling and motorised travel (especially driving distance, but also driving time and number of trips).\nFour interventions were modelled:\nTwo multi-component interventions (Cycling Demonstration Towns and SustainableTravel Towns).\nPersonalised travel advice (TravelSmart).\nUse of pedometers.\nCommunity-based led walks.\nHealth outcomes were expressed using QALYs gained and incremental net benefit (INB).\nWider impacts (environmental and traffic-related outcomes) were based on a limited selection of environmental outcomes and the value of a statistical life, expressed in terms of environmental benefit-cost ratios. The ratios were calculated based on the framework used by the Department for Transport.\nIt should be noted, that in the Department for Transport framework, most of the calculated benefits derived from health outcomes related to increased physical activity (up to 83%). However, health outcomes were excluded when calculating the environmental benefit-cost ratio, as they had been considered separately in a cost–utility analysis. Thus the results should be interpreted with caution.\nA series of 'what if' analyses was undertaken to determine if the level of cost is justified for interventions producing a particular level of effect. In addition, the trade-off between narrow interventions with large effects per person were compared with wider interventions leading to smaller effects per person.\nA number of assumptions were made which could underestimate or overestimate the cost effectiveness of the interventions. The results of the modeling were non-linear. The key factors influencing outcome were: threshold cost, level of effects, decay in effects and costs related to initial effects.\nThe specific scenarios considered and the full results can be found in 'Interventions to promote cycling and walking for recreational and travel purposes: Health economic and modelling report'.# Appendix D Gaps in the evidence\nThe Programme Development Group (PDG) identified a number of gaps in the evidence related to the programmes under examination based on an assessment of the evidence. These gaps are set out below.\n. There is a lack of UK evidence on whether or not interventions to increase walking or cycling for transport or leisure result in a decrease or increase in participation in other types of physical activity. Evidence is needed for a range of groups within different community settings.\n. There is a lack of evidence on whether people who cycle or walk for recreational purposes, eventually adopt it as a form of transport.\n. There is a lack of evidence on the long-term health, social and environmental impact of short-term interventions to increase walking or cycling. Specifically, there is a lack of evidence on the impact of interventions to encourage walking, cycling or both, for a range of groups within different community settings.\n. There is a lack of evidence on whether it is effective and cost effective to support physically active travel as a segment of a longer journey. Specifically, it is not clear whether such support increases walking or cycling levels and, if it does, how this impacts on the environment.\n. There is a lack of UK evidence on whether differences in urban and rural settings and environments impact on the implementation and effectiveness of interventions to increase walking or cycling. Evidence is needed for a range of groups within different community settings.\n. There is a lack of evidence on the barriers to, and facilitators for, inter-sector and inter-agency collaboration to promote walking and cycling. Evidence is also needed on the interventions that could overcome any identified barriers. Barriers may include the working cultures of different professionals.\n. There is a lack of UK evidence on how effective and cost effective it is to address walking and cycling together or separately. Specifically, there is a lack of evidence on how combining interventions impacts on their effectiveness – and whether multiple interventions have a positive, synergistic effect. Evidence is needed for a range of groups within different community settings.\n. There is a lack of evidence on how people can be helped to make walking or cycling an habitual activity. Evidence is needed for a range of groups within different community settings.\n. There is a lack of UK evidence on the extent to which the provision of a free bus service impacts on walking levels. Evidence is needed for a range of groups within different community settings.\n. There is a lack of UK evidence on the impact that an individual's perception of distance has on their view of how viable cycling or walking is as a mode of transport. There is also a lack of evidence on what interventions can effectively change someone's perception of distance as a barrier to walking and cycling. Evidence is needed for a range of groups within different community settings.\n. There is a lack of UK evidence on the social constructs which act as barriers to, and facilitators for, the uptake of walking or cycling as a mode of transport. Evidence is needed for a range of groups within different communities.\nThe Group made 5 recommendations for research into areas that it believes will be a priority for developing future guidance.# Appendix E Supporting documents\nSupporting documents include the following.\nEvidence reviews:\nReview 1: 'Systematic review and narrative synthesis of the effectiveness of local interventions to promote cycling and walking for recreational and travel purposes', and 'Evidence statements on the effectiveness of local interventions to promote cycling and walking for recreational and travel purposes'\nReview 2: 'Synthesis of evidence relating to barriers and facilitators to implementing interventions that promote cycling and walking, and to carrying out cycling and walking for recreational and travel purposes'.\nEconomic modeling: 'Interventions to promote cycling and walking for recreational and travel purposes: Health economic and modelling report'.\nExpert papers:\nExpert paper 1 'Paving the way for everyday walking: Living Streets interventions and public health'\nExpert paper 2 'Making walking and cycling normal: key findings from the understanding walking and cycling research project'\nExpert paper 3 'Programmes to promote cycling – evidence for NICE from CTC'\nExpert paper 4 'Evidence to NICE PDG walking and cycling: experience from Bristol City Council and cycling city (2008–2011)'\nExpert paper 5 'Submission to the NICE programme development group on walking and cycling'\nExpert paper 6 'Effectiveness of interventions to increase cycling'."}}},{"rowIdx":85,"cells":{"id":{"kind":"string","value":"85a80f631bb21eb38c62adf0ca5d1519f413085d"},"source":{"kind":"string","value":"nice"},"text":{"kind":"string","value":"Tuberculosis\n\nThis guideline covers preventing, identifying and managing latent and active tuberculosis (TB) in children, young people and adults. It aims to improve ways of finding people who have TB in the community and recommends that everyone under 65 with latent TB should be treated. It describes how TB services should be organised, including the role of the TB control board.\n\n# Recommendations\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in making decisions about your care.\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Preventing TB\n\n## Raising and sustaining awareness of TB\nMultidisciplinary TB teams (in collaboration with Public Health England, primary care, the voluntary sector and Health Education England) should identify and support an ongoing TB education programme for local professionals in contact with the general public, and at‑risk groups in particular. This includes, for example, staff in emergency departments, GPs and wider primary care staff, people who work in housing support services, staff who support migrants and those working in walk‑in centres, hostels, substance misuse projects and prisons. \nMultidisciplinary TB teams should ensure the education programme increases other professionals' awareness of the possibility of TB and reduces the stigma associated with it. The programme should include detail on:\ncauses of TB, how it is transmitted, and the signs and symptoms\nlifestyle factors that may mask symptoms\nlocal epidemiology, highlighting under-served groups, other high-risk groups and the fact that TB also occurs in people without risk factors\nprinciples of TB control:\nearly diagnosis and active case-finding\nhow to support treatment (including directly observed therapy)\ndrug resistance\nawareness of drug interactions (including factors such as effect on contraception efficacy)\ncontact investigation after diagnosing an active case\nthe importance of adhering to treatment\ntreatment for TB is free for everyone (irrespective of eligibility for other NHS care)\nsocial and cultural barriers to accessing health services (for example, fear of stigma and staff attitudes)\nlocal referral pathways, including details of who to refer and how\nthe role of allied professionals in awareness‑raising, identifying cases and helping people complete treatment\nmisinformation that causes fear about TB, including concerns about housing people with the condition\nthe best ways to effectively communicate all the above topics with different groups. \nStatutory, community and voluntary organisations and advocates working with the general public, and under‑served and high‑risk groups in particular, should share information on TB education and awareness training with all frontline staff. (They should get information on this from the local multidisciplinary TB team.) \nIf possible, statutory, community and voluntary organisations should ensure peers from under‑served groups and anyone else with experience of TB contribute to, or lead, awareness‑raising activities. (Peers who lead such activities will need training and support.) \nMultidisciplinary TB teams should help professionals working in relevant statutory, community and voluntary organisations to raise awareness of TB among under‑served and other high‑risk groups. These professionals should be able to explain that treatment for TB is free and confidential for everyone (irrespective of eligibility for other NHS care). They should also be able to provide people with details of:\nhow to recognise symptoms in adults and children\nhow people get TB\nthe benefits of diagnosis and treatment (including the fact that TB is treatable and curable)\nlocation and opening hours of testing services\nreferral pathways, including self‑referral\nthe potential interaction of TB medication with other drugs, for example, oral contraceptives and opioids (especially methadone) and HIV treatment\nTB/HIV co‑infection\nhow to address the myths about TB infection and treatment (for example, to counter the belief that TB is hereditary)\nhow to address the stigma associated with TB\nthe risk of migrants from high‑incidence countries developing active TB, even if they have already screened negative for it\ncontact tracing. \nMultidisciplinary TB teams and others working with at‑risk groups should use high quality material to raise awareness of TB (see section 1.1.2). \nMultidisciplinary TB teams and others working with the general public, and with under‑served and other high‑risk groups in particular, should include information on TB with other health‑related messages and existing health promotion programmes tailored to the target group. \nMultidisciplinary TB teams should work in partnership with voluntary organisations and 'community champions' to increase awareness of TB, in particular among under‑served groups at risk of infection but also in the general population. If possible, peers who have experience of TB should contribute to awareness‑raising activities and support people in treatment. \n\n## Providing information for the public about TB\nNational organisations (for example, National Knowledge Service: Tuberculosis, TB Alert, Public Health England, Department of Health and NHS Choices) should work together to develop generic, quality‑assured template materials with consistent up‑to‑date messages. These materials should be made freely available and designed so that they can be adapted to local needs. \nMultidisciplinary TB teams should use these templates for general awareness raising and targeted activities in under‑served and other high‑risk groups. Involve the target group in developing and piloting the materials. \nThe content of any materials should:\nbe up‑to‑date and attractively designed, including pictures and colour if possible\nbe culturally appropriate, taking into account the language, actions, customs, beliefs and values of the group they are aimed at\nbe tailored to the target population's needs\ninclude risks and benefits of treatment, and how to access services, advice and support\ndispel myths\nshow that, by deciding to be tested and treated for TB, a person can be empowered to take responsibility for their own health\nuse language that encourages the person to believe that they can change their behaviour\nbe simple and succinct. \nMake the material available in a range of formats such as written, braille, text messages, electronic, audio (including podcasts), pictorial and video. Make them freely available in a variety of ways, for example, online, as print materials or on memory sticks. \nDisseminate materials in ways likely to reach target groups, for example, via culturally specific radio or TV stations, at shelters, and at community, commercial or religious venues that target groups attend regularly. \n\n## BCG vaccination\nTo improve the uptake of BCG vaccination, identify eligible groups (in line with the Department of Health's Green Book) opportunistically through several routes, for example:\nnew registrations in primary care and with antenatal services, or other points of contact with secondary or tertiary care\npeople entering education, including university\nlinks with statutory and voluntary groups working with new entrants and looked‑after children and young people\nduring contact investigations. \nWhen BCG vaccination is being recommended, discuss the benefits and risks of vaccination or remaining unvaccinated with the person (or, if a child, with the parents), so that they can make an informed decision. Tailor this discussion to the person, use appropriate language, and take into account cultural sensitivities and stigma. \nIf people identified for BCG vaccination through occupational health, contact tracing or new entrant screening are also considered to be at increased risk of being HIV‑positive, offer them HIV testing before BCG vaccination. \nIdentify babies eligible for vaccination (in line with the Green Book) before birth, ideally through antenatal services. \nDiscuss neonatal BCG vaccination for any baby at increased risk of TB with the parents or legal guardian. \nPreferably vaccinate babies at increased risk of TB before discharge from hospital or before handover from midwifery to primary care. Otherwise, vaccinate as soon as possible afterwards, for example, at the 6‑week postnatal check. \nIncorporate computer reminders into maternity service (obstetrics) IT systems for staff, to identify and offer BCG vaccination to babies eligible for vaccination. \nProvide education and training for postnatal ward staff, midwives, health visitors and other clinicians on identifying babies eligible for vaccination, local service information and providing BCG vaccination, including:\ncase definition for at‑risk groups to be offered vaccination\ninformation about the local BCG vaccination policy that can be given verbally, in writing or in any other appropriate format (see sections 1.1.1 and 1.1.2) to parents and carers at the routine examination of the baby before discharge\nlocal service information about BCG vaccination, such as pre‑discharge availability of neonatal vaccination, local BCG clinics and referral for BCG vaccination if this is not available in maternity services\nadministration of BCG vaccination and contraindications. \nPrimary care organisations with a high incidence of TB should consider vaccinating all neonates soon after birth. \nIn areas with a low incidence of TB (see Public Health England's TB rate bands, published in their annual tuberculosis report), primary care organisations should offer BCG vaccination to selected neonates who:\nwere born in an area with a high incidence of TB or\nhave 1 or more parents or grandparents who were born in a high‑incidence country or\nhave a family history of TB in the past 5 years. \nRoutine BCG vaccination is not recommended for children aged 10 to 14 years.\nHealthcare professionals should opportunistically identify unvaccinated children older than 4 weeks and younger than 16 years at increased risk of TB who would have qualified for neonatal BCG (see recommendation 1.1.3.4) and provide Mantoux testing (see the section on diagnosing latent TB in children and young people) and BCG vaccination (if Mantoux‑negative).At the time of publication (January 2016) the BNF states: 'The Mantoux test is recommended for tuberculin skin testing, but no licensed preparation is currently available.' For further guidance, see immunisation against infectious disease (the Green book).\nThis opportunistic vaccination should be in line with the Green Book. \nMantoux testing should not be done routinely before BCG vaccination in children younger than 6 years unless they have a history of residence or prolonged stay (more than 1 month) in a country with a high incidence of TB. \nOffer BCG vaccination to new entrants who are Mantoux‑negative who:\nare from high‑incidence countries and\nare previously unvaccinated (that is, without adequate documentation or a BCG scar) and\nare aged:\nyounger than 16 years or\nto 35 years from sub‑Saharan Africa or a country with a TB incidence of 500 per 100,000 or more. \nDeliver the following interventions in primary care settings to improve uptake of BCG vaccination in people from eligible groups (as outlined in the Green Book):\neducation and support for practice staff, including:\nraising awareness of relevant guidelines and case definition for at‑risk groups\npromoting BCG and TB testing in eligible groups\nincorporating reminders for staff (prompts about eligibility for BCG) on practice computers (for example, embedded in medical records)\nconsider financial incentives for practices for identifying eligible groups for BCG and TB testing\nreminders ('immunisations due') and recall ('immunisations overdue') for people who are eligible for vaccination or for parents of infants and children who are eligible, as outlined in the Green Book. (This could include written reminders, telephone calls from a member of staff or a computerised auto dialler, text messages or a combination of these approaches.) \nUse home visits to give information and advice to people who are disadvantaged on the importance of immunisation. This should be delivered by trained lay health workers, community‑based healthcare staff or nurses. \nOffer BCG vaccination to healthcare workers and other NHS employees as advised in the Green Book. \nOffer BCG vaccination to Mantoux‑negative contacts of people with pulmonary and laryngeal TB (see the section on diagnosing latent TB in all age groups) if they:\nhave not been vaccinated previously (that is, there is no adequate documentation or a BCG scar) and\nare aged 35 years or younger or\nare aged 36 years and older and a healthcare or laboratory worker who has contact with patients or clinical materials. \nOffer BCG vaccination to previously unvaccinated, Mantoux‑negative people aged 35 years or younger in the following groups at increased risk of exposure to TB, in accordance with the Green Book:\nveterinary and other staff such as abattoir workers who handle animal species known to be susceptible to TB, such as simians\nprison staff working directly with prisoners\nstaff of care homes for older people\nstaff of hostels for people who are homeless and facilities accommodating refugees and asylum seekers\npeople going to live or work with local people for more than 3 months in a high‑incidence country. \n\n## Preventing infection in specific settings\nEmployees new to the NHS who will be working with patients or clinical specimens should not start work until they have completed a TB screen or health check, or documentary evidence is provided of such screening having taken place within the preceding 12 months. \nEmployees new to the NHS who will not have contact with patients or clinical specimens should not start work if they have signs or symptoms of TB. \nHealth checks for employees new to the NHS who will have contact with patients or clinical materials should include:\nassessment of personal or family history of TB\nasking about symptoms and signs, possibly by questionnaire\ndocumentary evidence of TB skin (or interferon‑gamma release assay) testing within the past 5 years and/or BCG scar check by an occupational health professional, not relying on the applicant's personal assessment. \nSee the section on healthcare workers for screening new NHS employees for latent TB. \nEmployees who will be working with patients or clinical specimens and who are Mantoux‑ or interferon‑gamma release assay‑negative (see section 1.2.1) should have an individual risk assessment for HIV infection before BCG vaccination is given. \nOffer BCG vaccination to employees of any age who are new to the NHS and are from countries of high TB incidence, or who have had contact with patients in settings with a high TB prevalence, and who are Mantoux‑negative. \nIf a new employee from the UK or other low‑incidence setting, who has not had a BCG vaccination, has a positive Mantoux test and a positive interferon‑gamma release assay, they should have a medical assessment and a chest X‑ray. They should be referred to a TB clinic to determine whether they need TB treatment if the chest X‑ray is abnormal, or to determine whether they need treatment of latent TB infection if the chest X‑ray is normal. \nIf a prospective or current healthcare worker who is Mantoux‑negative (see the section on healthcare workers) declines BCG vaccination, explain the risks and supplement the oral explanation with written advice. If the person still declines BCG vaccination, he or she should not work where there is a risk of exposure to TB. The employer will need to consider each case individually, taking account of employment and health and safety obligations. \nScreen clinical students, agency and locum staff and contract ancillary workers who have contact with patients or clinical materials for TB to the same standard as new employees in healthcare environments, according to the recommendations set out above. Seek documentary evidence of screening to this standard from locum agencies and contractors who carry out their own screening. \nNHS trusts arranging care for NHS patients in non‑NHS settings should ensure that healthcare workers who have contact with patients or clinical materials in these settings have been screened for TB to the same standard as new employees in NHS settings. \nInclude reminders of the symptoms of TB, and the need for prompt reporting of such symptoms, with annual reminders about occupational health for staff who:\nare in regular contact with TB patients or clinical materials or\nhave worked in a high‑risk clinical setting for 4 weeks or longer. Give one‑off reminders after a TB incident on a ward. \nIf no documentary evidence of previous screening is available, screen staff in contact with patients or clinical material who are transferring jobs within the NHS as for new employees (see recommendations 1.2.1.5 to 1.2.1.7 in the section on healthcare workers). \nAssess the risk of TB for a new healthcare worker who knows he or she is HIV‑positive at the time of recruitment as part of the occupational health checks. \nThe employer, through the occupational health department, should be aware of the settings with increased risk of exposure to TB, and that these pose increased risks to HIV‑positive healthcare workers. \nHealthcare workers who are found to be HIV‑positive during employment should have medical and occupational assessments of TB risk, and may need to modify their work to reduce exposure. \n\n# Latent TB\n\n## Diagnosing latent TB in adults\nOffer Mantoux testing to diagnose latent TB in adults aged 18 to 65 who are close contacts of a person with pulmonary or laryngeal TB.\nIf the Mantoux test is inconclusive, refer the person to a TB specialist.\nIf the Mantoux test is positive (an induration of 5 mm or larger, regardless of BCG history) assess for active TB (see the sections on diagnosing active TB in all age groups, diagnosing pulmonary (including laryngeal) TB in all age groups, diagnosing pulmonary (including laryngeal) TB in adults and diagnosing extrapulmonary TB in all age groups).\nIf the Mantoux test is positive but a diagnosis of active TB is excluded, consider an interferon gamma release assay if more evidence of infection is needed to decide on treatment. This could be, for example, if the person needs enhanced case management or if there could be adverse events from treatment.\nIf the Mantoux is positive, and if an IGRA was done and that is also positive, offer them treatment for latent TB infection (see the sections on managing latent TB in all age groups and managing latent TB in adults). At the time of publication (January 2016) the BNF states: 'The Mantoux test is recommended for tuberculin skin testing, but no licensed preparation is currently available.' For further guidance, see immunisation against infectious disease (the Green book).\nIn adults who are anticipated to be or are currently immunocompromised, do a risk assessment to establish whether testing should be offered, taking into account their:\nrisk of progression to active TB based on how severely they are immunocompromised and for how long they have been immunocompromised\nrisk factors for TB infection, such as country of birth or recent contact with an index case with suspected infectious or confirmed pulmonary or laryngeal TB. \nFor adults who are severely immunocompromised, such as those with HIV and CD4 counts of fewer than 200 cells/mm3, or after solid organ or allogeneic stem cell transplant, offer an interferon‑gamma release assay and a concurrent Mantoux test.\nIf either test is positive (for Mantoux, this is an induration of 5 mm or larger, regardless of BCG history), assess for active TB.\nIf this assessment is negative, offer them treatment for latent TB infection. \nFor other adults who are immunocompromised, consider an interferon‑gamma release assay alone or an interferon‑gamma release assay with a concurrent Mantoux test.\nIf either test is positive (for Mantoux, this is an induration of 5 mm or larger, regardless of BCG history), assess for active TB.\nIf this assessment is negative, offer them treatment for latent TB infection. \nOffer a Mantoux test to new NHS employees who will be in contact with patients or clinical materials, if the employees:\nare not new entrants from high‑incidence countries and\nhave not had BCG vaccination (for example, they are without a BCG scar, other documentation or a reliable history). If the Mantoux test is positive, offer an interferon‑gamma release assay. If this is positive, assess for active TB; if this assessment is negative, offer them treatment for latent TB infection. \nOffer a Mantoux test to new NHS employees who are from a high‑incidence country.\nIf the Mantoux test is positive (5 mm or larger, regardless of BCG history), assess for active TB; if this assessment is negative, offer them treatment for latent TB infection.\nIf Mantoux testing is unavailable, offer an interferon‑gamma release assay. \nOffer an interferon‑gamma release assay to new NHS employees who have had contact with patients in settings where TB is highly prevalent:\nIf the interferon‑gamma release assay is positive, assess for active TB and\nif this assessment is negative, offer them treatment for latent TB infection. \nHealthcare workers who are immunocompromised should be screened in the same way as other people who are immunocompromised (see recommendations 1.2.1.2 to 1.2.1.4). \n\n## Diagnosing latent TB in children and young people\nOnly consider using interferon‑gamma release assays alone in children and young people if Mantoux testing is not available or is impractical. This includes for example, situations in which large numbers need to be tested (see the section on incident and outbreak response and recommendation 1.2.3.2). \nRefer children younger than 2 years and in close contact with people with smear‑negative pulmonary or laryngeal TB to a specialist to determine what testing strategy for latent TB should be done. This should be a paediatrician with experience and training in TB, or a general paediatrician with advice from a specialised clinician. \nIf a neonate has been in close contact with people with smear‑positive pulmonary or laryngeal TB who have not had at least 2 weeks of anti‑TB treatment:\nAssess for active TB (see the sections on diagnosing active TB in all age groups, diagnosing pulmonary (including laryngeal) TB in all age groups and diagnosing pulmonary (including laryngeal) TB in children and young people).\nStart isoniazid (with pyridoxine).\nCarry out a Mantoux test after 6 weeks of treatment.\nIf the Mantoux test is inconclusive, refer the child to a TB specialist.\nIf the Mantoux test is positive (5 mm or larger, regardless of BCG history), reassess for active TB; if this assessment is negative, continue isoniazid (with pyridoxine) for a total of 6 months.\nIf the Mantoux test is negative, reassess for active TB and consider an interferon‑gamma release assay:\nif the interferon‑gamma release assay is negative then stop isoniazid (and pyridoxine) and give a BCG vaccination\nif the interferon‑gamma release assay is positive, reassess for active TB; if this assessment for active TB is negative, continue isoniazid (with pyridoxine) for a total of 6 months. \nIf a child aged between 4 weeks and 2 years has been in close contact with people with smear‑positive pulmonary or laryngeal TB who have not had at least 2 weeks of anti‑TB treatment:\nAssess for active TB.\nStart treatment for latent TB (see the sections on managing latent TB in all age groups and managing latent TB in children and young people) and carry out a Mantoux test.\nIf the Mantoux test is inconclusive, refer the child to a TB specialist.\nIf the Mantoux test is positive (5 mm or larger, regardless of BCG history), reassess for active TB; if this assessment is negative, complete treatment for latent TB.\nIf the Mantoux test is negative, continue treatment for latent TB, reassess for active TB after 6 weeks and repeat the Mantoux test:\nif the Mantoux test is negative, consider an interferon‑gamma release assay\nif the interferon‑gamma release assay is negative, treatment for latent TB may be stopped; give a BCG vaccination if the child has not already had one\nif either test is positive, reassess for active TB; if this assessment is negative, complete treatment for latent TB. \nIf a child or young person aged between 2 and 17 years has been in close contact with people with pulmonary or laryngeal TB:\nOffer Mantoux testing.\nIf the Mantoux test is inconclusive, refer the child or young person to a TB specialist.\nIf the Mantoux test is positive (5 mm or larger, regardless of BCG history), assess for active TB; if this assessment is negative, offer them treatment for latent TB infection.\nIf the initial Mantoux test is negative, offer an interferon‑gamma release assay after 6 weeks and repeat the Mantoux test. \nIf latent TB is suspected in children and young people who are anticipated to be or are currently immunocompromised (for example, if they are from a high incidence country or have been in close contact with people with suspected infectious or confirmed pulmonary or laryngeal TB), refer to a TB specialist. \n\n## Diagnosing latent TB in all age groups\nOffer Mantoux testing as the initial diagnostic test for latent TB infection in people who have recently arrived from a high‑incidence country who present to healthcare services. If the Mantoux test is positive (5 mm or larger, regardless of BCG history):\nassess for active TB (see recommendations 1.3.1 to 1.3.5 in the section on active TB) and\nif this assessment is negative, offer them treatment for latent TB infection (see the section on managing latent TB in all age groups to the section on managing latent TB in children and young people).If Mantoux testing is unavailable, offer an interferon‑gamma release assay. \nIn an incident situation when large numbers of people may need to be screened, consider a single interferon‑gamma release assay for people aged 18 to 65 years. For children and young people, follow the recommendations in the sections on diagnosing latent TB in children and young people and immunocompromised children and young people. \nOffer people younger than 65 years from under-served groups a single interferon‑gamma release assay. \nSubstance misuse services with access to an interferon‑gamma release assay should provide testing for people younger than 65 years who misuse substances if they:\nlive in a high incidence area\nare likely to be involved with substance misuse services or other support services on a regular basis (for example, for opioid substitution therapy), when support should be available for directly observed preventive therapy. \nIn high incidence areas (and at prisons that receive prisoners from high incidence areas), prison health services should offer an interferon‑gamma release assay for TB to inmates younger than 65 years who are in regular contact with substance misuse services or other support services. This is provided arrangements have been made for this support to continue after release. \nSubstance misuse services and prison health services should incorporate interferon‑gamma release assay testing with screening for hepatitis B and C, and HIV testing. They should refer prisoners and people who misuse substances with positive interferon‑gamma release assays to local multidisciplinary TB teams for further clinical investigations. For prisoners, these investigations should be done in the prison if practically possible. \nIf the interferon‑gamma release assay is positive, assess for active TB (see the sections on diagnosing active TB in all age groups to diagnosing extrapulmonary TB in all age groups); if this assessment is negative, offer them treatment for latent TB infection (see sections on managing latent TB in all age groups to managing latent TB in children and young people). \n\n## Managing latent TB in all age groups\nBe aware that certain groups of people with latent TB are at increased risk of going on to develop active TB, including people who:\nare HIV‑positive\nare younger than 5 years\nhave excessive alcohol intake\nare injecting drug users\nhave had solid organ transplantation\nhave a haematological malignancy\nare having chemotherapy\nhave had a jejunoileal bypass\nhave diabetes\nhave chronic kidney disease or receive haemodialysis\nhave had a gastrectomy\nare having treatment with anti‑tumour necrosis factor‑alpha or other biologic agents\nhave silicosis. \nFor people, including those with HIV, aged younger than 65 years with evidence of latent TB who have been in close contact with people who have suspected infectious or confirmed active pulmonary or laryngeal drug‑sensitive TB, offer either of the following drug treatments:\nmonths of isoniazid (with pyridoxine) and rifampicin or\nmonths of isoniazid (with pyridoxine). \nBase the choice of regimen on the person's clinical circumstances. Offer:\nmonths of isoniazid (with pyridoxine) and rifampicin to people younger than 35 years if hepatotoxicity is a concern after an assessment of both liver function (including transaminase levels) and risk factors\nmonths of isoniazid (with pyridoxine) if interactions with rifamycins are a concern, for example, in people with HIV or who have had a transplant. \nClearly explain the risks and potential benefits of each treatment regimen. In discussion with the person, select a suitable regimen if they wish to proceed with preventive treatment. \nIf a person also has severe liver disease, for example, Child‑Pugh level B or C, work with a specialist multidisciplinary team with experience of managing TB and liver disease. \nManage treatment with caution, ensuring careful monitoring of liver function, in:\npeople with non‑severe liver disease\npeople with abnormal liver function (including abnormal transaminase levels) before starting treatment for latent TB infection\npeople who misuse alcohol or drugs. \nEnsure people having treatment for latent TB who also have social risk factors, such as misusing alcohol or drugs or being homeless, are linked to support services. They should also have an assessment of social needs and stability, including potential barriers to adherence or treatment completion (see the section on adherence, treatment completion and follow‑up). \nPeople in the groups listed in recommendation 1.2.4.1 who do not have treatment for latent TB, as specified in recommendations 1.2.4.2 to 1.2.4.8, for any reason should be advised of the risks and symptoms of TB (on the basis of an individual risk assessment), usually in a standard letter of the type referred to as 'Inform and advise' information (see section 1.1.2). \n\n## Managing latent TB in adults\nFor adults between the ages of 35 and 65 years, offer drug treatments only if hepatotoxicity is not a concern. \nOffer testing for HIV before starting treatment for latent TB. See the NICE guidelines on increasing the uptake of HIV testing among black Africans in England and increasing the uptake of HIV testing among men who have sex with men. \nOffer adults testing for hepatitis B and C before starting treatment for latent TB. See the NICE guidelines on hepatitis B and C: ways to promote and offer testing to people at increased risk of infection and hepatitis B (chronic): diagnosis and management of chronic hepatitis B in children, young people and adults. \n\n## Managing latent TB in children and young people\nConsider testing children and young people for hepatitis B and C before starting treatment for latent TB. See the NICE guidelines on hepatitis B and C: ways to promote and offer testing to people at increased risk of infection and hepatitis B (chronic): diagnosis and management of chronic hepatitis B in children, young people and adults. \n\n# Active TB\n\n## Diagnosing active TB in all age groups\nIf TB is a possibility, microbiology staff should consider carrying out TB culture on samples (see recommendations 1.3.2.2 and 1.3.2.3), even if it is not requested. \nIf there are clinical signs and symptoms consistent with a diagnosis of TB, start treatment without waiting for culture results. \nConsider completing the standard recommended regimen (see recommendations 1.3.7.2 and 1.3.7.3 in the section on standard treatment), even if subsequent culture results are negative. \n\n## Diagnosing pulmonary (including laryngeal) TB in all age groups\nTake a chest X‑ray; do further diagnostic investigations (as detailed below and summarised in table 1) if chest X‑ray appearances suggest TB. \nSend multiple respiratory samples (3 deep cough sputum samples, preferably including 1 early morning sample) for TB microscopy and culture. \nThis should be before starting treatment if possible or, failing that, within 7 days of starting treatment in people with life‑threatening disease. \nObtain spontaneously‑produced, deep cough sputum samples if possible, otherwise use:\ngastric lavages or 3 inductions of sputum in children and young people (see recommendation 1.5.1.10 in the section on infection control in healthcare settings) or\ninduction of sputum or bronchoscopy and lavage in adults. \nLaboratory practices should be in accordance with the UK's Standards for Microbiology Investigations. \nSend samples for TB culture from autopsy samples if pulmonary or laryngeal TB is a possibility. \n\n## Diagnosing pulmonary (including laryngeal) TB in adults\nRequest rapid diagnostic nucleic acid amplification tests for the M. tuberculosis complex (M. tuberculosis, M. bovis, M. africanum) on primary specimens (listed in table 1) if there is clinical suspicion of TB disease, and:\nthe person has HIV or\nrapid information about mycobacterial species would alter the person's care or\nthe need for a large contact‑tracing initiative is being explored. \n\n## Diagnosing pulmonary (including laryngeal) TB in children and young people\nIn children aged 15 years or younger with suspected pulmonary TB, offer rapid diagnostic nucleic acid amplification tests for the M. tuberculosis complex (M. tuberculosis, M. bovis, M. africanum). Usually only 1 nucleic acid amplification test is needed per specimen type (for example, spontaneous sputum, induced sputum or gastric lavage; see table 1). \nIn young people aged 16 to 18 years use the same criteria as in adults to decide whether to request rapid diagnostic nucleic acid amplification tests (see table 1). \nSuspected site of disease\nPossible imaging techniques\nSpecimen\nRoutine test\nAdditional tests (if it would alter management)\nPulmonary (adult)\nX‑ray (Routine test, see recommendation 1.3.2.1.)\nCT thoraxTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nrespiratory samples:\npreferably spontaneously‑produced, deep cough sputum samples, otherwise induced sputum or bronchoscopy and lavage\npreferably 1 early morning sample\nMicroscopy Culture\nHistology\nNucleic acid amplification test\nPulmonary (young people aged 16 to 17 years)\nX‑ray (Routine test, see recommendation 1.3.2.1.)\nCT thoraxTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nrespiratory samples:\npreferably spontaneously‑produced, deep cough sputum samples, otherwise induced sputum or gastric lavage\npreferably 1 early morning sample\nMicroscopy Culture\nHistology\nNucleic acid amplification test\nPulmonary (children aged 15 years or younger)\nX‑ray (Routine test, see recommendation 1.3.2.1.)\nCT thoraxTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nrespiratory samples:\npreferably spontaneously‑produced, deep cough sputum samples, otherwise induced sputum or gastric lavage\npreferably 1 early morning sample\nMicroscopy\nCulture\nHistology\nNucleic acid amplification tests (1 per specimen type)\nInterferon‑gamma release assay and/or tuberculin skin test (with expert input)\nEither a paediatrician with experience and training in TB or a general paediatrician with advice from a specialised clinician should investigate and manage TB in children and young people. \nAn expert in paediatric TB may request interferon‑gamma release assays and tuberculin skin tests. Interpret these together with other diagnostic tools (such as history taking, clinical examination and imaging). \n\n## Diagnosing extrapulmonary TB in all age groups\nDiscuss the advantages and disadvantages of both biopsy and needle aspiration with the patient, with the aim of obtaining adequate material for diagnosis. \nDo not place part or all of any of the samples in formalin (or other fixative agent) when sending for TB culture. \nThink about a diagnosis of extrapulmonary TB even if rapid diagnostic tests in, for example, cerebrospinal fluid, pleural fluid or ascitic fluid are negative. \nOffer all patients presenting with extrapulmonary TB a chest X‑ray and, if possible, culture of a spontaneously‑produced respiratory sample to exclude or confirm coexisting pulmonary TB (see recommendations 1.3.1 to 1.3.3 in the section on active TB). Also, consider site‑specific tests as described below to exclude or confirm additional sites of TB. \nRefer to an expert for sites not listed here, including TB of the eye and other rare sites of disease. \nUse the site‑specific investigations listed in table 2 to diagnose and assess pleural TB.\nSuspected site of disease\nPossible imaging techniques\nSpecimen\nRoutine test\nAdditional tests on primary specimen (if it would alter management)\nPleural\nX‑ray\nBronchoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nrespiratory samples:\npreferably spontaneously‑produced, deep cough sputum samples, otherwise induced sputum or gastric lavage\npreferably 1 early morning sample\nPleural biopsy\nMicroscopy\nCulture\nHistology\nPleural\nX‑ray\nBronchoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nPleural fluid\nMicroscopy\nCulture\nCytology\nAdenosine deaminase assay\nUse the site‑specific investigations listed in table 3 to diagnose and assess central nervous system TB.\nSuspected site of disease\nPossible imaging techniquesa\nSpecimen\nRoutine test\nAdditional tests on primary specimen (if it would alter management)\nCentral nervous system\nCT (Routine test, see recommendation 1.3.5.8)\nMRI (Routine test, see recommendation 1.3.5.8)Taking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nBiopsy of suspected tuberculoma\nMicroscopy\nCulture\nHistology\nCentral nervous system\nCT (Routine test, see recommendation 1.3.5.8)\nMRI (Routine test, see recommendation 1.3.5.8)Taking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nCerebrospinal fluid\nMicroscopy\nCulture\nCytology\nAdenosine deaminase assay\nMeningeal\nCT (Routine test, see recommendation 1.3.5.8)\nMRI (Routine test, see recommendation 1.3.5.8)Taking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nCerebrospinal fluid\nMicroscopy\nCulture\nCytology\nNucleic acid amplification test\nAdenosine deaminase assay\nOffer a CT or MRI scan to people in whom central nervous system involvement is suspected. \nOffer treatment for TB meningitis if clinical signs and other laboratory findings are consistent with the diagnosis, even if a rapid diagnostic test is negative. \nUse the site‑specific investigations listed in table 4 to diagnose and assess lymph node TB (including intrathoracic mediastinal adenopathy).\nSuspected site of disease\nPossible imaging techniques\nSpecimen\nRoutine test\nAdditional tests on primary specimen (if it would alter management)\nLymph node (including intrathoracic mediastinal adenopathy)\nUltrasound\nCT\nMRITaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nBiopsy\nMicroscopy\nCulture\nHistology\nNucleic acid amplification test\nAspirate\nMicroscopy\nCulture\nCytology\nNucleic acid amplification test\nUse the site‑specific investigations listed in table 5 to diagnose and assess pericardial TB.\nSuspected site of disease\nPossible imaging techniques\nSpecimen\nRoutine test\nAdditional tests on primary specimen (if it would alter management)\nPericardial\nEchocardiogramTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nBiopsy of pericardium\nMicroscopy\nCulture\nHistology\nPericardial\nEchocardiogramTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nPericardial fluid\nMicroscopy\nCulture\nCytology\nNucleic acid amplification test\nAdenosine deaminase assay\nUse the site‑specific investigations listed in table 6 to diagnose and assess gastrointestinal TB.\nSuspected site of disease\nPossible imaging techniques\nSpecimen\nRoutine test\nAdditional tests on primary specimen (if it would alter management)\nGastrointestinal\nUltrasound\nCT\nLaparoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nBiopsy of omentum\nBiopsy of bowel\nBiopsy of liver\nMicroscopy\nCulture\nHistology\nGastrointestinal\nUltrasound\nCT\nLaparoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nAscitic fluid\nMicroscopy\nCulture\nCytology\nAdenosine deaminase assay\nUse the site‑specific investigations listed in table 7 to diagnose and assess genitourinary TB.\nSuspected site of disease\nPossible imaging techniques\nSpecimen\nRoutine test\nAdditional tests on primary specimen (if it would alter management)\nGenitourinary\nUltrasound\nIntravenous urography\nLaparoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nEarly morning urine\nCulture\nGenitourinary\nUltrasound\nIntravenous urography\nLaparoscopyTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nBiopsy from site of disease, such as endometrial curettings or renal biopsy\nMicroscopy\nCulture\nHistology\nUse the site‑specific investigations listed in table 8 to diagnose and assess bone and joint TB.\nSuspected site of disease\nPossible imaging techniques\nSpecimen\nRoutine test\nAdditional test on primary specimen (if it would alter management)\nBone or joint TB\nX‑ray\nCT\nMRITaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment\nBiopsy or aspirate of paraspinal abscess\nBiopsy of joint\nAspiration of joint fluid\nCulture\nUse the site‑specific investigations listed in table 9 to diagnose and assess disseminated TB.\nSuspected site of disease\nPossible imaging techniques\nSpecimen\nRoutine test\nAdditional tests on primary specimen (if it would alter management)\nDisseminated\nCT of the thorax and head\nMRI\nUltrasound of the abdomenTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nBiopsy of site of disease, including lung, liver and bone marrow\nMicroscopy\nCulture\nHistology\nAdditional tests appropriate to site\nDisseminated\nCT of the thorax and head\nMRI\nUltrasound of the abdomenTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nAspirate bone marrow\nBronchial wash\nCerebrospinal fluid\nMicroscopy (if sample available)\nCulture\nCytology\nAdditional tests appropriate to site\nDisseminated\nCT of the thorax and head\nMRI\nUltrasound of the abdomenTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment.\nBlood\nCulture\nAdditional tests appropriate to site\nUse the site‑specific investigations listed in table 10 to diagnose and assess skin TB.\nSuspected site of disease\nPossible imaging techniques\nSpecimen\nRoutine test\nAdditional tests on primary specimen (if it would alter management)\nSkin\nBiopsy\nMicroscopy\nCulture\nHistology\nUse the site‑specific investigations listed in table 11 to diagnose and assess TB in a localised, tuberculous abscess at a site other than a lymph node.\nSuspected site of disease\nPossible imaging techniques\nSpecimen\nRoutine test\nAdditional tests on primary specimen (if it would alter management)\nAbscess outside of the lymph nodes\nUltrasound or other appropriate imagingTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment\nAspirate\nMicroscopy\nCulture\nCytology\nAbscess outside of the lymph nodes\nUltrasound or other appropriate imagingTaking into account, for example, the exact site of suspected disease and the availability of the test at the time of assessment\nBiopsy\nMicroscopy\nCulture\nHistology\n\n## Rapid‑access radiology and other investigation results: referral to multidisciplinary TB team process\nLocal hospitals, clinical commissioning groups and the local multidisciplinary team should consider developing a local pathway for people with imaging highly suggestive of active TB. The pathway should enable them to be referred by the radiology department by the next working day to multidisciplinary TB teams. Consider including the following in the pathway:\nAgreed standardised radiology codes to identify imaging investigations highly suggestive of active TB.\nRegular liaison between multidisciplinary TB teams and the radiology department (for example, weekly) to ensure all patients have been referred to the multidisciplinary team for triage using the agreed local mechanism or pathway. \nReport results of all pathology or other diagnostic results suggesting TB to the multidisciplinary TB team and clinicians who ask for them. \nCommissioners and multidisciplinary teams should consider working with emergency departments to develop direct referral pathways for people with suspected active TB so that:\nthe local multidisciplinary team is informed of all suspected cases of TB using the appropriate process\nreferral is accepted from any appropriate healthcare professional, for example an on‑call radiologist. \nEmergency department clinicians should ensure first‑line diagnostic tests for TB are performed on anyone presenting with suspected TB (see table 1 on diagnostic investigations for pulmonary TB). \nEmergency departments should consider carrying out audits of their direct referrals because of suspected active TB and the outcomes of diagnosis. \nMultidisciplinary TB teams should consider training emergency department staff in:\nusing approaches that do not stigmatise people with TB\ngiving people with TB appropriate advice (see recommendations 1.1.1 and 1.1.2 in the section on raising and sustaining awareness of TB and the section on infection control). \n\n## Managing active TB in all age groups\nOnce a diagnosis of active TB is made:\nthe clinician responsible for care should refer the person with TB to a clinician with training in, and experience of, the specialised care of people with TB\nthe TB service should include specialised nurses and health visitors\nactive TB in children should be managed by a TB specialist (see recommendation 1.3.4.3 in the section on diagnosing pulmonary (including laryngeal) TB in children and young people), and by paediatric trained nursing staff, where possible.If these arrangements are not possible, seek advice from more specialised colleagues throughout the treatment period. \nFor people with active TB without central nervous system involvement, offer:\nisoniazid (with pyridoxine), rifampicin, pyrazinamide and ethambutol for 2 months then\nisoniazid (with pyridoxine) and rifampicin for a further 4 months.Modify the treatment regimen according to drug susceptibility testing. \nFor people with active TB of the central nervous system, offer:\nisoniazid (with pyridoxine), rifampicin, pyrazinamide and ethambutol for 2 months then\nisoniazid (with pyridoxine) and rifampicin for a further 10 months.Modify the treatment regimen according to drug susceptibility testing. \nTest people with active spinal TB who have neurological signs or symptoms for central nervous system involvement (see recommendation 1.3.5.8 in the section on central nervous system TB). Manage direct spinal cord involvement (for example, a spinal cord tuberculoma) as TB of the central nervous system. \nFor people with active spinal TB without central nervous system involvement, do not extend treatment beyond 6 months for residual effects (for example, persistent bending of the spine or vertebral loss). \nTest people with disseminated (including miliary) TB who have neurological signs or symptoms for central nervous system involvement. If there is evidence of central nervous system involvement, treat as for TB of the central nervous system. \nTreat active peripheral lymph node TB in people who have had an affected gland surgically removed with the standard recommended regimen. \nFor people with active TB of the lymph nodes, do not routinely extend treatment beyond 6 months for newly enlarged lymph nodes or sinus formation, or for residual enlargement of the lymph nodes or sinuses. \nUse fixed‑dose combination tablets as part of any TB treatment regimen. \nDo not offer anti‑TB treatment dosing regimens of fewer than 3 times per week. \nOffer a daily dosing schedule to people with active pulmonary TB. \nConsider a daily dosing schedule as first choice in people with active extrapulmonary TB. \nConsider 3 times weekly dosing for people with active TB only if:\na risk assessment identifies a need for directly observed therapy and enhanced case management (see section on adherence, treatment completion and follow‑up) and\ndaily directly observed therapy is not possible. \nIf the person has a comorbidity or coexisting condition such as:\nHIV or\nsevere liver disease, for example, Child‑Pugh level B or C or\nstage 4 or 5 chronic kidney disease (a glomerular filtration rate of <30 ml/minute/1.73m2) or\ndiabetes or\neye disease or impaired vision or\npregnancy or breastfeeding or\na history of alcohol or substance misusework with a specialist multidisciplinary team with experience of managing TB and the comorbidity or coexisting condition. \nFor people with HIV and active TB without central nervous system involvement, do not routinely extend treatment beyond 6 months. \nFor people with HIV and active TB with central nervous system involvement, do not routinely extend treatment beyond 12 months. \nTake into account drug‑to‑drug interactions when co‑prescribing antiretroviral and anti‑TB drugs. \nAt the start of an anti‑TB treatment regimen, offer people with active TB of the central nervous system dexamethasone or prednisolone, initially at a high dose with gradual withdrawal over 4 to 8 weeks. An example of a suitable regimen is listed in table 12.\nDose of dexamethasone by week\nStage 1\nStage 2 or 3\nWeek 1\nmg/kg/day (intravenous)\nmg/kg/day (intravenous)\nWeek 2\nmg/kg/day (intravenous)\nmg/kg/day (intravenous)\nWeek 3\nmg/kg/day (oral)\nmg/kg/day (intravenous)\nWeek 4\nmg/day (oral)\nmg/kg/day (intravenous)\nWeek 5\nmg/day (oral)\nmg/day (oral)\nWeek 6\nmg/day (oral)\nmg/day (oral)\nWeek 7\nmg/day (oral)\nWeek 8\nmg/day (oral)\nAccording to the modified British Medical Research Council criteria for disease severity:\nStage 1: Glasgow coma score of 15 without focal neurological deficits; alert and oriented.\nStage 2: Glasgow coma score of 14 to 11 or 15 with focal neurological deficits.\nStage 3: Glasgow coma score of 10 or less, with or without focal neurological deficits.\nAt the start of an anti‑TB treatment regimen, offer children and young people with active TB of the central nervous system dexamethasone or prednisolone. This should initially be at a high dose with gradual withdrawal over 4 to 8 weeks in line with the British National Formulary for Children. \nAt the start of an anti‑TB treatment regimen, offer adults with active pericardial TB oral prednisolone at a starting dose of 60 mg/day, gradually withdrawing it 2 to 3 weeks after starting treatment. \nAt the start of an anti‑TB treatment regimen, offer children and young people with active pericardial TB oral prednisolone in line with the British National Formulary for Children. Gradually withdraw prednisolone 2 to 3 weeks after starting treatment. \nIf surgery is indicated, the surgeon should fully explain what is involved to the person, either with or after consulting a TB specialist. Discuss the possible benefits and risks with the person and their family members or carers, as appropriate, so that they can make an informed decision. \nConsider referring people with TB of the central nervous system for surgery as a therapeutic intervention only if there is evidence of raised intracranial pressure. \nDo not routinely refer people with spinal TB for surgery to eradicate the disease. \nConsider referring people with spinal TB for surgery if there is spinal instability or evidence of spinal cord compression. \n\n# Drug resistant TB\n\n## Multidrug‑resistant TB\nFor people with clinically suspected TB, a TB specialist should request rapid diagnostic nucleic acid amplification tests for rifampicin resistance on primary specimens if a risk assessment for multidrug resistance identifies any of the following risk factors:\nhistory of previous TB drug treatment, particularly if there was known to be poor adherence to that treatment\ncontact with a known case of multidrug-resistant TB\nbirth or residence in a country in which the World Health Organization reports that a high proportion (5% or more) of new TB cases are multidrug‑resistant.Start infection control measures (see section 1.5). \nIf the rapid diagnostic nucleic acid amplification test for rifampicin resistance is positive:\ncontinue infection control measures until pulmonary or laryngeal disease has been excluded\nmanage treatment along with a multidisciplinary team with experience of managing multidrug‑resistant TB (see the section on service organisation)\n-ffer a treatment regimen involving at least 6 drugs to which the mycobacterium is likely to be sensitive\ntest for resistance to second‑line drugs. \nIf the rapid diagnostic nucleic acid amplification test for the M. tuberculosis complex is positive but rifampicin resistance is not detected, treat as drug‑susceptible TB with the standard regimen (see the section on managing active TB in all age groups). \nIf the rapid diagnostic nucleic acid amplification test for the M. tuberculosis complex is negative in a person at high risk of multidrug‑resistant TB:\n-btain further specimens for nucleic acid amplification testing and culture, if possible\nuse rapid rifampicin resistance detection on cultures that become positive for the M. tuberculosis complex\nconsider waiting for the results of further tests before starting treatment if the person is well\nif urgent treatment is needed, consider managing as multidrug‑resistant TB until sensitivity results are available. \nWhen definitive phenotypic susceptibility results are available, modify treatment as needed (see sections on managing active TB in all age groups and drug‑resistant TB). \nConsider more intensive clinical follow‑up for people with multidrug‑resistant TB. This includes people having directly observed therapy (see the section on adherence, treatment completion and follow‑up) throughout treatment because of the complexity of treatment and risk of adverse events. \nDiscuss the options for organising care for people with multidrug‑resistant TB with clinicians who specialise in this. Seek the person's views and take them into account, and consider shared care (see the section on service organisation). \nConsider surgery as a therapeutic intervention in people with potentially resectable multidrug‑resistant disease if:\n-ptimal medical therapy under direct observation has not worked or\nmedical therapy is likely to fail because of extensively drug-resistant TB. \n\n## Drug‑resistant TB (excluding multidrug‑ and extensively drug‑resistant TB)\nFor people with TB, without central nervous system involvement, that is resistant to just 1 drug consider the treatments in table 13.\nDrug resistance\nFirst 2 months (initial phase)\nContinue with (continuation phase)\nIsoniazid\nRifampicin, pyrazinamide and ethambutol\nRifampicin and ethambutol for 7 months (up to 10 months for extensive disease)\nPyrazinamide\nRifampicin, isoniazid (with pyridoxine) and ethambutol\nRifampicin and isoniazid (with pyridoxine) for 7 months\nEthambutol\nRifampicin, isoniazid (with pyridoxine) and pyrazinamide\nRifampicin and isoniazid (with pyridoxine) for 4 months\nRifampicin\nAs for multidrug‑resistant TB\nAs for multidrug‑resistant TB\nFor people with drug‑resistant TB and central nervous system involvement, involve a TB specialist with experience in managing drug‑resistant TB in decisions about the most appropriate regimen and the duration of treatment. \n\n# Infection control\nNICE has also produced general guidelines on the prevention and control of healthcare-associated infections in primary and community care, and the prevention and control of healthcare-associated infections.\n\n## Healthcare settings\nEnsure healthcare settings can promptly identify people with suspected infectious or confirmed pulmonary or laryngeal TB before or at presentation. Ensure people working in the settings follow the recommendations about testing and treatments (see the sections on latent TB, active TB and drug resistant TB). \nPut people with suspected infectious or confirmed pulmonary or laryngeal TB who will remain in a hospital setting (including emergency, outpatients or inpatient care) in a single room. If this is not possible, keep the person's waiting times to a minimum. This may involve prioritising their care above that of other patients. \nMinimise the number and duration of visits a person with TB makes to an outpatient department while they are still infectious. To minimise the risk of infection, people with infectious TB should be seen at times or in places away from other people. \nIn hospital settings, risk assess people with suspected infectious or confirmed pulmonary TB for multidrug‑resistant TB (see the section on multidrug‑resistant TB). Care for people deemed to be at low risk in a single room, as a minimum. For people deemed to be at high risk:\nprovide care in a negative pressure room and\nhave specimens sent for rapid diagnostic tests, such as nucleic acid amplification tests. \nUnless there is a clear clinical or public health need, such as homelessness, people with suspected infectious or confirmed pulmonary TB should not be admitted to hospital for diagnostic tests or for care. \nDo not admit people with suspected infectious or confirmed pulmonary TB to a ward containing people who are immunocompromised, such as transplant recipients, people with HIV and those on anti‑tumour necrosis factor alpha or other biologics, unless they can be cared for in a negative pressure room on the same ward. \nAssess any visitors to a child with suspected active TB in hospital for symptoms of infectious TB, and keep them separate from other people until they have been excluded as a source of infection (see recommendations 1.2.1 to 1.2.3 in the section on latent TB and the section on contact tracing). \nCare for people with a continuing clinical or public health need for admission with pulmonary TB in a single room (as a minimum) until they have completed 2 weeks of the standard treatment regimen (see the section on managing active TB in all age groups) if they:\nare unlikely to be rifampicin resistant (that is, do not have risk factors for multidrug‑resistant TB) or\nhave negative rifampicin resistance on nucleic acid amplification test or culture. \nConsider de‑escalating isolation after 2 weeks of treatment, taking into account the risks and benefits, if:\nthe person is showing tolerance to the prescribed treatment\nthere is agreement to adhere to treatment\nthere is resolution of cough\nthere is definite clinical improvement on treatment; for example, remaining afebrile for a week\nthere are not immunocompromised people, such as transplant recipients, people with HIV and those on anti‑tumour necrosis factor alpha or other biologics, in the same accommodation\nthe person's initial smear grade was not high; for example, 2 or less\nthere is not extensive pulmonary involvement, including cavitation\nthere is no laryngeal TB. \nIn people who may have TB, only carry out aerosol‑generating procedures such as bronchoscopy, sputum induction or nebuliser treatment in an appropriately engineered and ventilated area (ideally a negative pressure room). \nConsider discharging from hospital people:\nwho do not have a continuing clinical or public health need for admission with pulmonary TB and\nwho are unlikely to be rifampicin resistant (that is, do not have risk factors for multidrug‑resistant TB) or\nwho have negative rifampicin resistance on nucleic acid amplification test or culture.If discharged, the person should avoid congregate settings for the first 2 weeks of their treatment. \nExplain to inpatients with suspected infectious or confirmed pulmonary or laryngeal TB that they will need to wear a surgical mask in the hospital whenever they leave their room. Ask them to continue wearing it until they have had at least 2 weeks of treatment. \nOffer people advice on simple respiratory hygiene measures. \n\n## Non‑healthcare settings\nIn non‑healthcare settings catering for large numbers of people and populations at high risk of TB (such as detention settings, residential hostels and day centres):\npromote simple respiratory hygiene\nensure awareness of symptoms of potentially infectious TB to enable prompt healthcare referral\nwork with the local public health team and the local authority to ensure accommodation for people with TB\nensure adequate ventilation. \nIn prisons or immigration removal centres, everyone with X‑ray changes indicative of active TB, as well as those with symptoms who are awaiting X‑ray, should be isolated in an adequately ventilated individual room or cell. Prisoners and detainees should be retained on medical hold until they have:\nproven smear‑negative and had an X‑ray that does not suggest active TB or\nhad a negative risk assessment for multidrug‑resistant TB and completed 2 weeks of the standard treatment regimen. \n\n## Multidrug‑resistant TB\nIf people with suspected or known infectious multidrug‑resistant TB are admitted to hospital, admit them to a negative pressure room. If none is available locally, transfer them to a hospital that has these facilities and a clinician experienced in managing complex drug‑resistant cases. Carry out care in a negative pressure room for people with:\nsuspected multidrug‑resistant TB, until non‑resistance is confirmed\nconfirmed multidrug‑resistant TB, until they have 3 negative smears at weekly intervals and ideally have a negative culture. \nAs soon as possible, explore options to reduce the psychosocial impact of prolonged isolation. For example, through providing free access to internet, telephone and television, and accompanied walks in the open air. \nConsider earlier discharge for people with confirmed multidrug‑resistant TB, if there are suitable facilities for home isolation and the person will adhere to the care plan. \nFor people with confirmed multidrug‑resistant TB whose symptoms have improved and who are unable to produce sputum, discharge decisions should be taken by the multidisciplinary team and the health protection team. \nStaff and visitors should wear filtering face piece (FFP3) masks during contact with a person with suspected or known multidrug‑resistant TB while the person is thought to be infectious. \nBefore deciding to discharge a person with suspected or known multidrug‑resistant TB from hospital, agree with the person and their carers secure arrangements for supervising and administering all anti‑TB therapy. \nDiscuss the decision to discharge a person with suspected or known multidrug‑resistant TB with:\nthe infection control team and\nthe local microbiologist and\nthe local TB service and\nthe health protection team. \nEnsure negative pressure rooms used for infection control in multidrug‑resistant TB meet the standards of the Interdepartmental Working Group on Tuberculosis, and are clearly identified for staff, for example by a standard sign. Keep such signs up to date. \n\n# Case finding\n\n## Contact tracing\nOnce a person has been diagnosed with active TB, the diagnosing physician should inform relevant colleagues so that the need for contact tracing can be assessed without delay. Contact tracing should not be delayed until notification. \nOffer screening to the close contacts of any person with pulmonary or laryngeal TB. \nAssess symptomatic close contacts for active TB (see recommendations 1.3.1 to 1.3.4 in the section on active TB). \nIn asymptomatic close contacts younger than 65 years, consider standard testing for latent TB (see recommendations 1.2.1 to 1.2.3 in the section on latent TB), followed by consideration of BCG vaccination in line with the section on BCG vaccination or treatment for latent TB infection (see recommendations 1.2.4 to 1.2.6 in the section on latent TB) once active TB has been ruled out for people who:\nare previously unvaccinated and\nare contacts of a person with smear‑positive pulmonary or laryngeal TB and\nare Mantoux‑negative.At the time of publication (January 2016) the BNF states: 'The Mantoux test is recommended for tuberculin skin testing, but no licensed preparation is currently available.' For further guidance, see immunisation against infectious disease (the Green book). \nIn asymptomatic close contacts older than 65 years, consider a chest X‑ray (if there are no contraindications), possibly leading to further investigation for active TB. \nDo not routinely assess social contacts of people with TB, who will include most workplace contacts. \nAssess the need for tracing social contacts of people with pulmonary or laryngeal TB if:\nthe index case is judged to be particularly infectious (for example, evidenced by transmission to close contacts) or\nany social contacts are known to possess features that put them at high risk of going on to develop active TB. \nOffer 'inform and advise' information to close and social contacts of people with smear‑positive TB (see section on providing information for the public about TB). \nAfter diagnosis of TB in an aircraft traveller, do not routinely carry out contact tracing of fellow passengers. \nThe notifying clinician should inform the relevant consultant in communicable disease control or health protection if:\nless than 3 months has elapsed since the flight and the flight was longer than 8 hours and\nthe index case is smear‑positive and either\nthe index case has multidrug‑resistant TB or\nthe index case coughed frequently during the flight. \nThe consultant in communicable disease control or health protection should provide the airline with 'inform and advise' information to send to passengers seated in the same part of the aircraft as the index case. \nIf the TB index case is an aircraft crew member, contact tracing of passengers should not routinely take place. \nIf the TB index case is an aircraft crew member, contact tracing of other members of staff is appropriate, in accordance with the usual principles for screening workplace colleagues. \nAfter diagnosis of TB in a school pupil or member of staff, the consultant in communicable disease control or health protection should be prepared to explain the prevention and control procedures to staff, parents and the press. Advice on managing these incidents and their public relations is available from the Public Health England health protection team and the local authority. \nIf a school pupil is diagnosed with smear‑positive TB, carry out a risk assessment of the need to test the rest of his or her class (if there is a single class group), or the rest of the year group who share classes, as part of contact tracing. \nIf a teacher has smear‑positive TB, assess the pupils in his or her classes during the preceding 3 months as part of contact tracing. \nConsider extending contact tracing in schools to include children and teachers involved in extracurricular activities, and non‑teaching staff, on the basis of:\nthe degree of infectivity of the index case\nthe length of time the index case was in contact with others\nwhether contacts are unusually susceptible to infection\nthe proximity of contact. \nTreat secondary cases of smear‑positive TB as index cases for contact tracing. \nIf the index case of a school pupil's TB infection is not found, and the child is not in a high‑risk group for TB, contact tracing and screening (by either symptom enquiry or chest X‑ray) should be considered for all relevant members of staff at the school. \nWhen an adult who works in childcare (including people who provide childcare informally) is diagnosed with smear‑positive TB, follow recommendations 1.6.1.1 to 1.6.1.8. \nIf TB is diagnosed in a hospital inpatient, do a risk assessment. This should take into account:\nthe degree of infectivity of the index case\nthe length of time before the infectious patient was isolated\nwhether other patients are unusually susceptible to infection\nthe proximity of contact. \nCarry out contact tracing and testing only for patients for whom the risk is regarded as significant. \nRegard patients as at risk of infection if they spent more than 8 hours in the same bay as an inpatient with smear‑positive TB who had a cough. Document the risk in the contact's clinical notes, for the attention of the contact's consultant. Give the contact 'inform and advise' information, and inform their GP. \nIf patients were exposed to a patient with smear‑positive TB for long enough to be equivalent to close contacts (as determined by the risk assessment), or an exposed patient is known to be particularly susceptible to infection, manage their TB risk in the same way as close contacts. \nIf an inpatient with smear‑positive TB is found to have multidrug‑resistant TB, or if exposed patients are HIV positive, trace contacts following the Interdepartmental Working Group on Tuberculosis guidelines. \nIn cases of doubt when planning contact tracing after diagnosing smear‑positive TB in an inpatient, seek further advice from the local or national Public Health England or Wales unit or people experienced in the field. \n\n## Opportunistic case finding\nAssess and manage TB in new entrants from high incidence countries who present to healthcare services as follows:\nassess risk of HIV, including HIV prevalence rates in the country of origin, and take this into account when deciding whether to give a BCG vaccination\n-ffer testing for latent TB (see recommendations 1.2.1 to 1.2.3 in the section on latent TB)\nassess for active TB if the test for latent TB is positive (see recommendations 1.3.1 to 1.3.5 in the section on active TB)\n-ffer treatment to people aged 65 years or younger in whom active TB has been excluded but who have a positive Mantoux test or a positive interferon‑gamma release assay for latent TB infection (see recommendations 1.2.4 to 1.2.6 in the section on latent TB)\nconsider offering BCG for unvaccinated people who are Mantoux‑ or interferon‑gamma release assay‑negative (see the section on BCG vaccination)\ngive 'inform and advise' information to people who do not have active TB and are not being offered BCG or treatment for latent TB infection (see the section on providing information for the public about TB). \nPrimary care services should support local, community‑based and voluntary organisations that work with vulnerable migrants to ensure they:\nregister with a primary care provider\nknow how to use NHS services (emergency or primary care). \nHealthcare professionals, including primary care staff, responsible for testing new entrants should test all vulnerable migrants who have not previously been checked. This is regardless of when they arrived in England. People born in countries with an incidence of more than 150 per 100,000 per year should be made a priority for latent TB testing when they arrive here. \nIn areas of identified need (see the section on local needs assessment), including major urban centres with a high incidence of TB, commissioners should:\nensure there is a programme of active case‑finding using mobile X‑ray in places where homeless people and people who misuse substances congregate (this includes: homeless day centres, rolling shelters, hostels and temporary shelters established as part of cold weather initiatives and venues housing needle and syringe programmes)\nbase the frequency of screening at any 1 location on population turnover\nwhere local demand does not warrant a mobile X‑ray team, consider commissioning mobile X‑ray capacity from another area. \nMultidisciplinary TB teams should consider using simple incentives, such as providing hot drinks and snacks, to encourage people to attend for testing. \nCommissioners of TB prevention and control programmes should consider offering people who are homeless and people who misuse substances other health interventions when they are screened for TB at a mobile X‑ray unit. (Examples may include blood‑borne virus screening, dentistry and podiatry services.) \nMultidisciplinary TB teams should work closely with mobile X‑ray teams and frontline staff in hostels and day centres to promote TB screening and to ensure appropriate onward referrals and follow‑up. \nMultidisciplinary TB teams should consider using peer educators to promote the uptake of TB screening in hostels and day centres. \nMultidisciplinary TB teams should provide routine data to TB control boards on: screening uptake, referrals and the number of active TB cases identified. \nHealthcare professionals in prisons and immigration removal centres should ensure prisoners and detainees are screened for TB within 48 hours of arrival. \nPrisons with Department of Health‑funded static digital X‑ray facilities for TB screening should X‑ray all new prisoners and detainees (including those being transferred from other establishments) if they have not had a chest X‑ray in the past 6 months. This should take place within 48 hours of arrival. \nPrison and immigration removal centre health staff should report all suspected and confirmed TB cases to the local multidisciplinary TB team within 1 working day. \nMultidisciplinary TB staff should visit every confirmed TB case in a prison or immigration removal centre in their locality within 5 working days. \nIf a case of active TB is identified, the local Public Health England unit, in conjunction with the multidisciplinary TB team, should plan a contact investigations exercise. They should also consider using mobile X‑ray to check for further cases. \n\n## Active case finding in under‑served groups\nMultidisciplinary TB teams should follow NICE recommendations on contact tracing (see the section on contact tracing).They should coordinate contact investigations at places where the person with TB spends significant amounts of time. Examples could include pubs, crack houses, parks and community centres. The aim is to help identify people who have been living with them and people they frequently socialise with. \nMultidisciplinary TB teams dealing with someone from an under-served group should work alongside health and social care professionals known to them to help trace relevant contacts. They should also work in partnership with voluntary, community and statutory organisations to conduct outreach contact investigations. \nMultidisciplinary TB teams should, if available and appropriate, encourage peer educators or TB programme support workers to help with contact investigations involving under‑served people who have complex social networks. \nMultidisciplinary TB teams in discussion with local Public Health England health protection teams should consider using digital mobile X‑ray for active case‑finding in settings identified by looking at social networks as places where under‑served people at risk congregate. They should also provide the necessary support so that multidisciplinary TB teams can use strain‑typing and social network analysis to ascertain where transmission is occurring in the community. (Examples of transmission sites may include pubs, crack houses, hostels and day centres.) They should focus on active case‑finding in the settings identified. \n\n## Incident and outbreak response\nMultidisciplinary TB teams should coordinate incident or outbreak contact investigations at places where the person with active TB spends significant amounts of time. Examples include workplaces, schools, colleges, universities, childcare settings. Identify people that the person with TB frequently spends substantial time with, as outlined in the section on contact tracing. \nMultidisciplinary TB teams should refer any incident in a congregate setting to the local Public Health England health protection team for risk assessment within 5 working days of suspicion of a potential incident. \nTB control boards working with local health protection teams should, through local arrangements, mobilise existing staff or have access to an incident team that will:\nundertake an incident risk assessment and provide advice\nsupport or undertake contact investigations\nprovide information and communication support to the multidisciplinary TB team, the local director of public health, the setting in which the incident has occurred and the people affected including:\nwritten advice, printed or by email\nquestion and answer sessions\ntelephone advice\nmedia engagement\ngather and collate data, and report on outcomes to measure the effectiveness of the investigation (for example, offering testing to all people identified at risk and monitoring uptake)\nreport back to TB control boards at appropriate times. This includes when outcomes of initial investigation of people classified as close contacts are available. It also includes when a decision is made to broaden the investigation to the next stage using the concentric circle method for risk assessment. \nWhen incidents have been identified, multidisciplinary TB teams in discussion with local Public Health England health protection teams should consider providing support for strain‑typing and other analysis to ascertain where transmission is occurring. (Examples of transmission sites may include workplaces, schools, colleges, universities, childcare settings.) \nIn all types of contact investigation scenarios (active case finding, incident or outbreak investigations) multidisciplinary TB teams should investigate all people who have been in contact with children who have pulmonary or extrapulmonary TB to identify the primary source of infection. If necessary, they should look beyond immediate close contacts to find the source. \n\n# Adherence, treatment completion and follow‑up\n\n## Improving adherence: case management including directly observed therapy\nAllocate a named TB case manager to everyone with active TB as soon as possible after diagnosis (and within 5 days). The clinical team should tell each person who their named TB case manager is and provide contact details. \nThe TB case managers should work with the person diagnosed with TB to develop a health and social care plan, and support them to complete therapy successfully. The TB case manager should:\n-ffer a risk assessment to every person with TB, to identify their needs and whether they should have enhanced case management including directly observed therapy\neducate the person about TB and the treatment\ndevelop an individual care plan after discussion with the person\ngain the person's consent to the plan and agree a review date (for example, when moving from initiation to maintenance, or at each contact to ensure the person's needs are being met)\ncoordinate discharge planning, especially for people on directly observed therapy\ninvolve representatives from other allied professions and key workers from all organisations who work with the person, if appropriate\nexplore appropriate ways that peers and voluntary organisations can provide support. \nOffer directly observed therapy as part of enhanced case management in people who:\ndo not adhere to treatment (or have not in the past)\nhave been treated previously for TB\nhave a history of homelessness, drug or alcohol misuse\nare currently in prison, or have been in the past 5 years\nhave a major psychiatric, memory or cognitive disorder\nare in denial of the TB diagnosis\nhave multidrug‑resistant TB\nrequest directly observed therapy after discussion with the clinical team\nare too ill to administer the treatment themselves. \nIn children whose parents are members of any of the above groups, offer directly observed therapy as part of enhanced case management and include advice and support for parents to assist with treatment completion. \nRe‑evaluate the need for directly observed therapy throughout the course of TB treatment whenever the person's (or in the case of children, parents') circumstances change. \nTB case managers should ensure the health and social care plan (particularly if directly observed therapy is needed) identifies why a person may not attend for diagnostic testing or follow a treatment plan, and how they can be encouraged to do so. It should also include ways to address issues such as fear of stigmatisation, support needs and/or cultural beliefs, and may include information on:\ndemographics (for example, age, nationality, place of birth, length of time in UK)\nall current prescribing regimens\nhousing needs and living situation, including looked‑after children\nsubstance misuse (drugs or alcohol)\nany contact with the criminal justice system\nthe need for hepatitis B and C or HIV testing (see recommendations 1.2.5.2 and 1.2.5.3 in the section on managing latent TB in adults and recommendation 1.2.6.1 in the section on managing latent TB in children and young people)\nHIV status\n-ther health conditions (physical or mental)\ncommunication factors (for example, language and literacy levels)\nability to access treatment (mobility and transport needs)\nemployment or entitlement to benefits\nlegal or immigration status (including risk of removal or relocation within the UK)\nany enablers or incentives to overcome anything that is stopping diagnosis or treatment. \nThe health and social care plan should:\nstate who will be observing treatment and where (if the person is having directly observed therapy this should be provided at a location that is convenient and accessible to them, for example, at a methadone clinic) \ninclude actions to take if contact with the person is lost (for example, keeping details of people who might be able to help re‑establish contact) \nrefer to, and be coordinated with, any other care plan already established for the person \ndefine the support needed to address any unmet health and social care needs (for example, support to gain housing or other benefits, or to help them access other health or social care services) \ninclude a commitment from the person to complete their TB treatment \nbe supported by frequent contact with any key workers who work with the person. \nMultidisciplinary TB teams should aim to find people with active TB who are lost to follow-up, or who stop using services before completing diagnostic investigations. They should report all those lost to follow‑up to local Public Health England teams, GPs, the referring organisation and specialist outreach teams. \n\n## Other strategies to encourage people to follow their treatment plan\nTo encourage people to follow their treatment plan, involve people in treatment decisions for active or latent TB from the start. Emphasise the importance of following the treatment plan when agreeing the regimen. \nMultidisciplinary TB teams should implement strategies for active and latent TB to encourage people to follow the treatment plan and prevent people stopping treatment early. These could include:\nreminder letters, printed information, telephone calls, texts and apps using an appropriate language \nhealth education counselling and patient‑centred interviews \ntailored health education booklets from quality sources (see section on providing information for the public about TB) \nhome visits \nrandom urine tests and other monitoring (for example, pill counts) \naccess to free TB treatment for everyone (irrespective of eligibility for other NHS care) and information about help with paying for prescriptions \nsocial and psychological support (including cultural case management and broader social support) \nadvice and support for parents and carers \nincentives and enablers to help people follow their treatment regimen. \nTB control boards should ensure services take into account the barriers facing vulnerable migrants who may need treatment, and in particular the stigma they may face. Other issues include the location of services (both geographically and in terms of opening times) and people's language and cultural needs, in terms of the format of advice and the type of information given. \n\n## Strategies in prisons or immigration removal centres\nOn arrival at a prison or immigration removal centre, healthcare professionals should ask all prisoners and detainees (including those being transferred from other establishments) if they are taking TB medication, to ensure continuity of treatment. \nAll prisoners and immigration removal centre detainees having treatment for active TB should have a named TB case manager. The case manager should be responsible for contingency planning for discharge from prison or detention. \nPrisons and immigration removal centres should ensure multidisciplinary TB staff have access to prisoners and detainees who need treatment (for example, by being given security clearance). \nAll prisoners having treatment for active TB should have directly observed therapy. \nPrison health services should have contingency, liaison and handover arrangements to ensure continuity of care before any prisoner on TB treatment is transferred between prisons or released. In addition, other agencies working with prisoners or detainees should also be involved in this planning. \nPrison and immigration removal centre healthcare services should liaise with the named TB case manager (from the multidisciplinary TB team) to ensure contingency plans for continuation of treatment are drawn up for prisoners and immigration removal centre detainees with TB. \nMultidisciplinary TB teams should ensure accommodation is available for the duration of TB treatment after the prisoner or detainee's release (see section on Identifying and managing active TB in prisons, custody suites or immigration removal centres: organisational factors). \nMultidisciplinary TB teams should ensure directly observed therapy is arranged for prisoners or detainees being treated for TB after their release. This should be available close to where they will live in the community. \n\n## Re‑establishing treatment for active or latent TB after interruptions because of adverse events\nIn people who have experienced a treatment interruption because of drug‑induced hepatotoxicity:\ninvestigate other causes of acute liver reactions and\nwait until aspartate or alanine transaminase levels fall below twice the upper limit of normal, bilirubin levels return to the normal range and hepatotoxic symptoms have resolved then\nsequentially reintroduce each of the anti‑TB drugs at full dose over a period of no more than 10 days, starting with ethambutol and either isoniazid (with pyridoxine) or rifampicin. \nIn people with severe or highly infectious TB who need to interrupt standard therapy because of a reaction, consider continuing treatment:\nfor hepatotoxicity, a combination of at least 2 anti‑TB drugs of low hepatotoxicity (such as ethambutol and streptomycin, with or without a fluoroquinolone antibiotic, such as levofloxacin or moxifloxacin) and monitor with a liver specialist for further reactions See MHRA advice for restrictions and precautions for using fluoroquinolone antibiotics due to very rare reports of disabling and potentially long-lasting or irreversible side effects affecting musculoskeletal and nervous systems. Warnings include: stopping treatment at first signs of a serious adverse reaction (such as tendonitis), prescribing with special caution in people over 60 years and avoiding coadministration with a corticosteroid (March 2019).Not licensed for tuberculosis, so use would be off label. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information.\nfor a cutaneous reaction, a combination of at least 2 anti‑TB drugs with a low risk of cutaneous reactions (such as ethambutol and streptomycin) and monitor with a dermatologist for further reactions. \nIf another reaction of a similar or greater severity occurs because of reintroducing a particular drug, do not give that drug in future regimens and consider extending the total regimen accordingly. \n\n## Follow‑up after treatment completion\nFollow‑up clinic visits should not be conducted routinely after treatment completion. \nTell patients to watch for symptoms of relapse and how to contact the TB service rapidly through primary care or a TB clinic. Key workers should ensure that patients at increased risk of relapse are particularly well informed about symptoms. \nPatients who have had drug‑resistant TB should be considered for follow‑up for 12 months after completing treatment. Patients who have had multidrug‑resistant TB should be considered for prolonged follow‑up. \n\n# Service organisation\nWhen using the recommendations in this section with under served groups, also check sections 1.1.1 on raising and sustaining awareness, 1.1.2 on providing information for the public, 1.6.2 on opportunistic case finding, 1.6.3 on active case finding in under served groups and 1.7 on adherence, treatment completion and follow up. See also, recommendations on under served groups in section 1.2.3 on diagnosing latent TB in all age groups.\n\n## Strategic oversight and commissioning of TB prevention and control activities\nPublic Health England, in partnership with NHS England, should take responsibility for national oversight of TB prevention and control activities. This includes setting up TB control boards (see section 1.8.2). \nPublic Health England and NHS England should consider working together to establish control boards in agreed geographical areas and employ appropriate staff (see recommendation 1.8.2.3). \nClinical commissioning groups and local authority public health teams working in partnership with Public Health England and NHS England should consider collaborative commissioning arrangements through TB control boards. This could, for example, include working with 1 or more clinical commissioning groups to cover a major metropolitan district, region or TB control board area taking into account:\nlocal TB incidence\nlocal at‑risk populations and their movements across different geographical areas\nexisting service configurations for organisations involved in TB prevention and control\nthe need to share services, such as mobile X‑ray facilities, and outreach incident teams across different geographical areas. \nTB control boards should develop TB prevention and control programmes working with commissioners, Public Health England and NHS England. The board could include clinical, commissioning (from clinical commissioning groups, local government and the voluntary sector) and public health leaders and people with TB or groups who advocate on their behalf from across the control board area. This may include identifying a lead clinical commissioning group, which could be led by an executive director of that commissioning group working with the board. Feedback mechanisms between local commissioning groups and the TB control board should be developed. \nAn executive director of local commissioning groups, working with the local director of public health or another nominated public health consultant, should lead implementation of the programme in their locality. The lead should ensure a comprehensive prevention and control programme is commissioned to support the level of need (see section on local needs assessment) and that they work with the control board regularly. \nWorking together through TB control boards and local networks, commissioners, local government and Public Health England should ensure TB prevention and control programmes set up multidisciplinary TB teams to provide all TB services (see section on commissioning multidisciplinary TB support). They should ensure that local strategy and service commissioning focuses on an end-to-end pathway. \nWorking together through TB control boards, commissioners and Public Health England should ensure the TB prevention and control programme is informed by relevant NICE guidance and developed in collaboration with clinical services. It should also be informed by the standard minimum data set collected through local needs assessment and service audit. \nWorking together through TB control boards, commissioners and Public Health England should ensure the TB prevention and control programme targets all ages, including children, and covers all aspects of TB prevention and control (see recommendations 1.8.2.1 and 1.8.2.2), including but not limited to:\nactive case finding (contact investigations and identifying latent TB in high‑risk groups)\nawareness‑raising activities\nstandard and enhanced case management (including providing directly observed therapy and free treatment)\nfinding people lost to follow‑up and encouraging them back into treatment\nincident and outbreak control\nmonitoring, evaluating and gathering surveillance and outcome data. \nWorking together through TB control boards, commissioners, Public Health England and the voluntary sector should ensure TB prevention and control programmes take account of the need to work with other programmes targeting specific high‑risk groups, such as those who are under-served. Examples include programmes focused on the health of asylum seekers and refugees, under-served children, homelessness and housing, offenders and people who misuse substances. \nTB control boards should consider integrating TB and HIV services, joint clinics and training opportunities. \nCommissioners should consider commissioning support and advice to all groups diagnosed with TB irrespective of whether they are under‑served. \n\n## Developing the TB prevention and control programme\nTB control boards should be responsible for developing a TB prevention and control programme based on the national strategy and evidence‑based models. \nTB control boards should plan, oversee, support and monitor local TB control, including clinical and public health services and workforce planning. \nTB control boards should assess services in their area, identify gaps in provision and develop plans to meet these, including:\nundertaking a workforce review to support local or regional commissioning of TB services to meet the needs of their population (see sections on local needs assessment and cohort review)\nsupporting development of appropriate services and pathways to improve access and early diagnosis (see the sections on rapid‑access radiology and other investigation results: referral to multidisciplinary TB team process, non‑clinical roles including TB support workers and rapid‑access TB services)\nnegotiating arrangements to cover the cost of additional services to address specific gaps in current TB control arrangements. \nTB control boards should ensure cohort review is undertaken at least quarterly, and the results are fed back to local clinical and TB networks. These should be agreed by accountable bodies such as clinical commissioning groups, trust management, regional Public Health England and centre directors and local authority directors of public health as agreed, all of whom should make sure appropriate action is taken. \nTB control boards should enable full and consistent use of national guidelines including:\nensuring the needs of all people with TB, particularly under‑served populations, are addressed\nensuring contact tracing arrangements are appropriate to the needs of the population (see the section on case finding)\nassuring themselves that TB control in low‑incidence areas is established and delivered appropriately (see the section on rural services: organisational and support factors)\nassuring themselves that multidrug‑resistant TB is managed appropriately (see the section on multidrug‑resistant TB) and mechanisms are in place to ensure:\nthere is sufficient clinical expertise available to manage cases\nregional multidrug‑resistant TB networks take account of expert advice (see section 1.8.3). \nTB control boards should develop links and partnerships and establish agreed relationships and lines of accountability between TB control boards and local clinical and TB networks. This includes engaging with other key stakeholders to ensure universal coverage of TB control efforts. \nTB control boards should collaborate with their local and regional partners. They should agree and establish regular monitoring, surveillance and reporting arrangements with all partners to support needs assessment (see the section on local needs assessment) and regular audit and evaluation. \nTB control board staff should have clearly defined roles and responsibilities. Their roles and responsibilities could include:\nEstablishing the links, partnerships and relationships between all aspects of the control board area within their remit (if necessary across usual geographical commissioning boundaries).\nDeveloping and supporting adoption and implementation of evidence‑based model service specifications for the clinical and public health actions needed to control TB including:\nimproving access and early diagnosis (see the sections on raising and sustaining awareness of TB, providing information for the public about TB, rapid‑access radiology and other investigation results: referral to multidisciplinary TB team process and non‑clinical roles including TB support workers)\ndiagnostics, treatment and care services (see the sections on latent TB and active TB)\ncontact investigations and tracing (see the sections on diagnosing latent TB in adults and case finding)\ncohort review\nvaccination (see the section on BCG vaccination)\ndrug resistance (see the section on multidrug‑resistant TB)\ntackling TB in under‑served populations\nsurveillance, monitoring and quality assurance\nworkforce development and commissioning (see the sections on commissioning multidisciplinary TB support and non‑clinical roles including TB support workers). \nTB control boards should ensure there is sufficient capacity available to them to manage a sudden increase in demand such as:\nTB contact investigations, (such as incidents in congregate settings)\nlarge scale active case‑finding initiatives in under‑served groups in the community\n-utbreaks in a variety of settings or sites where transmission risk may be high, including but not limited to schools, workplaces, hostels and prisons. \nTo set up, monitor and evaluate a TB control programme, TB control boards should:\nagree plans within their partnerships to assess local services against the service specifications\ndevelop plans and quality standards to secure improvements\nestablish quality assurance mechanisms and regular audits including, but not limited to, cohort review for all aspects of the TB control board partnership plans. \nTB control boards should (in collaboration with commissioners) consider the need for a TB network local coordinator, particularly if working across multiple clinical commissioning group areas (see recommendation 1.8.1.3). \nThe coordinator should work in close collaboration with clinicians and all relevant multidisciplinary TB teams to develop the network and be responsible for:\nsetting up the network and developing it based on needs, reporting back to the TB control board regularly\nestablishing the links, partnerships and relationships across their local network (if necessary across usual geographical commissioning boundaries). \n\n## Regional multidrug‑resistant TB network\nTB control boards should consider setting up a regional multidisciplinary TB network to oversee management of multidrug‑resistant TB. This could:\nIdentify and designate regional expert centres.\nEnsure all healthcare professionals who suspect or treat a case of multidrug‑resistant TB are informed about and have access to specialist advisory services for multidrug‑resistant TB. This includes the designated expert centre in their regional network and may also include the national advisory service for multidrug-resistant TB (currently provided by the British Thoracic Society).\nEnsure all cases of multidrug‑resistant TB are discussed at the regional multidisciplinary TB team meeting in the local clinical network.\nFormally consider and record the advice from the specialist advisory services for multidrug‑resistant TB provided by the designated regional expert centre or the national advisory service for multidrug‑resistant TB. \n\n## Rural services: organisational and support factors\nCommissioners in rural areas (working with the TB control board) should consider collaborative approaches to deliver and manage TB services. They could, for example, set up a network including areas with high and low incidence of TB. \n\n## Local needs assessment\nDirectors of public health, in discussion with local health protection teams, should ensure that TB is part of the joint strategic needs assessment. \nDirectors of public health should provide commissioners of TB prevention and control programmes and TB control boards with local needs assessment information annually using data provided by Public Health England. \nCommissioners of TB prevention and control programmes should ensure services reflect the needs of their area, identified by needs assessment. Health and wellbeing boards should ensure that local TB services have been commissioned based on local needs identified through needs assessment. \nDirectors of public health and TB control boards should use cohort review (see section 1.8.6) and other methods to collect data on the following, to inform local needs assessment:\nNumber of annual notified TB cases (see Public Health England's enhanced TB surveillance data and annual 'suite of indicators').\nSize, composition (for example, age and ethnicity) and distribution of local at‑risk groups.\nIndices of social deprivation.\nLocal statutory and non‑statutory services working with these groups.\nOrganisation of local TB services, including the composition and capacity of the local multidisciplinary TB team(see the results of local audit) and location of services. This may also include data to support evaluating the need for integrated TB/HIV services including joint clinics.\nNumbers needing enhanced case management (see the section on adherence, treatment completion and follow‑up).\nNumbers receiving directly observed therapy from the start of, or at any point during, treatment (see Public Health England's enhanced TB surveillance data).\nEvidence of recent transmission (for example, using DNA fingerprinting or surrogate markers such as number of cases in children under 5 years (see UK TB national strain-typing database and local incident and outbreak reports).\nCompleteness and yield of contact investigations. This includes: proportion of smear‑positive cases with 0, 5 or more contacts identified; proportion of identified contacts clinically assessed; and proportion of contacts with latent TB infection who successfully complete treatment.\nActive case‑finding initiatives, incident contact investigations and identification of latent TB infection in high‑risk groups.\nTreatment outcomes for everyone grouped according to social risk factors and by the use of directly observed therapy (including rates of loss to follow‑up and treatment interruptions, see Public Health England's enhanced TB surveillance data).\nLocal education and awareness‑raising programmes for under‑served groups, professionals and practitioners working with them.\nViews and experiences of people with TB, carers and the services working with them. \nLocal needs assessments should also be equity proofed to assess the potential effect of planning, commissioning and policy decisions on health inequalities (see planning and commissioning services in NICE's local government briefing on health inequalities and population health). \n\n## Cohort review\nTB control boards and prevention and control programme leads should initiate, audit and evaluate cohort reviews in their commissioning area. Quarterly cohort review meetings should take place in the area covered by the programme. Combine these meetings with others if possible, or use technology to make it easier for clinicians and case managers to attend. \nTB case managers should present standardised information on each case, including: demographic information, HIV test results, pre‑treatment and ongoing status (clinical, laboratory, radiology), adherence to treatment and the results of contact investigations. \nTB case managers and key allied professionals from the TB prevention and control programme should attend cohort review meetings. This could include the lead clinician (who may or may not be the case manager). Either a paediatrician with experience and training in the treatment of TB or a general paediatrician with advice from a specialised clinician should be present when cases of children with TB are presented. \nThe chair of the cohort review should not work for any of the TB services included in the review. Examples of possible chairs include a public health consultant, a specialist physician or a senior TB nurse, preferably from a different geographical area. Alternatively the chair could be a representative from the local Public Health England health protection team or the TB control board. \nMultidisciplinary TB teams, in conjunction with Public Health England units, should collate and present cohort review data on TB treatment and the outcome of contact investigations at the review meetings. In addition, progress towards national, regional and local service targets should be presented. \nTB control boards, directors of public health and local public health consultants should ensure outputs from the cohort review feed into the needs assessment for TB services. TB control board directors should attend the cohort review at least once a year. \nTB case managers should feed back promptly to multidisciplinary TB teams on issues identified as a result of cohort review. The results of the cohort review should be collated locally and agreed by the chair before being fed back to TB control boards, commissioners and health and wellbeing boards regularly and via needs assessment. \nPeople participating in a cohort review should review the results and evaluate local services (for example, auditing adverse outcomes, rates of culture confirmation, treatment completion rates or time to diagnosis). \n\n## Commissioning multidisciplinary TB support\nCommissioners should ensure multidisciplinary TB teams:\nHave the skills and resources to manage the care of people with active TB who are not from under‑served groups. \nInclude at least 1 TB case manager with responsibility for planning and coordinating the care of under‑served people and those with active TB who receive enhanced case management. \nHave the resources to manage latent TB care in under‑served groups and the wider population. \nInclude a range of clinical specialties in the multidisciplinary TB team, including paediatrics, infection control and respiratory medicine. \nHave regular attendance at these multidisciplinary team and cohort review meetings for all team members included as a programmed activity as part of their work planning. \nHave the skills and resources necessary to manage the care of people with complex social and clinical needs (either directly or via an established route). This includes the ability to provide prompt access (or if necessary, referral) to skilled outreach and advocacy workers who can draw on the services of allied practitioners. The aim is to address people's housing, asylum, immigration, welfare, substance dependency and other health and social care needs. (The allied practitioner support should include both a specified housing officer and a social worker.) \nCan provide rapid access TB clinics for all cases, including under‑served groups. \nConsider providing administration support for TB nurses and case managers so they have capacity for clinical and case management work. This could include giving TB nurses access to computer hardware and software. \nHave the resources to provide a continuous service throughout the year, ensuring the TB service accounts for the following to manage continuity of care:\nplanned absence (for example, professional development, mandatory training, annual, maternity or paternity leave)\nunplanned absence (such as sickness absence). \nCan provide prompt access to a professional who has training and experience in assessing and protecting children and vulnerable adults at risk of abuse or neglect. \nHave access to funds through local government and clinical commissioning groups that can be used flexibly to improve adherence to treatment among under‑served groups. For example, funds could be used to provide transport to clinics, to provide support or enablers for treatment, or for paying outreach workers or community services to support directly observed therapy. Funds may also be used to provide accommodation during treatment. \nHave the resources to provide ongoing TB awareness‑raising activities for professional, community and voluntary (including advocacy) groups that work with populations at high risk of TB (see the section on raising and sustaining awareness of TB). These resources could be financed by local government or clinical commissioning groups. \nCommissioners should ensure NHS England's safe staffing principles are applied when commissioning TB services. The staffing ratios used in Public Health England and NHS England's collaborative tuberculosis strategy for England (published in 2015) came from NICE's guideline on tuberculosis: identification and management in under-served groups (published in 2012) which has been replaced by this guideline.NICE's 2012 guideline on tuberculosis: identification and management in under-served groups recommended 1 WTE case manager per 40 incident cases needing standard management and 1 WTE case manager per 20 incident cases needing enhanced case management. \n\n## Non‑clinical roles including TB support workers\nTB control boards and local TB services should consider employing trained, non‑clinically qualified professionals to work alongside clinical teams to agreed protocols, and to contribute to a variety of activities. Examples of this may include awareness raising and supporting people to attend appointments (including other health and social care appointments). They could also help with collecting samples, contact tracing, case management including directly observed therapy and cohort review, or any other aspect of the service if:\nthey are trained to deliver the intervention or processes effectively\nthey are supported, mentored and supervised by a named case manager, such as a TB nurse\nthey have the skills to monitor, evaluate and report on their work practices and outcomes to maintain a process of ongoing evaluation and service improvement in relation to cohort review (see the section on cohort review). \nTB control boards should ensure that people working in the TB service have the right knowledge, engagement, advocacy and communication skills to meet the needs (for example, language, cultural or other requirements) of all the groups they may work with. \nCommissioners should consider taking into account different needs across traditional geographical and organisational boundaries. Put agreements in place so that staff can work across these boundaries, covering the whole service or TB control board area if appropriate. \nCommissioners and TB control boards should ensure they put in place appropriate governance (including clear lines of accountability and extension of scope of practice) and data sharing practices and agreements. This includes ensuring they are part of service level agreements between NHS and non‑NHS services, for example, the third sector or local government, and appropriate training has been completed. \n\n## Rapid‑access TB services\nMultidisciplinary TB teams should establish relationships with statutory, community and voluntary organisations that work with people at risk of TB to develop appropriate TB referral pathways. They should ensure these organisations know how to refer people to local TB services. \nMultidisciplinary TB teams should accept referrals from healthcare providers and allied organisations working in the community with under‑served groups. This includes voluntary and statutory organisations (for example, mobile X‑ray teams or community organisations or outreach workers working with vulnerable migrants). \nMultidisciplinary TB teams should accept self‑referrals to TB clinics by people who suspect they have TB or have recently been in contact with someone with TB. \nMultidisciplinary TB teams should consider accepting direct referrals from emergency departments (see the section on rapid‑access radiology and other investigation results: referral to multidisciplinary TB team process). \nHealthcare professionals should consider urgent referral to TB clinics for people with suspected active TB. They should also ensure the results from first‑line diagnostic tests (including a sputum smear and chest X‑ray) are available before the person sees a specialist. (Note: this should not delay the referral.) \nMultidisciplinary TB teams should have pathways to triage referrals, start investigations and collect clinical information before the person is seen by a physician. \nWhile triaging, multidisciplinary TB teams should ensure everyone is given information about TB as part of the process (see the section on providing information for the public about TB). This should include who the person should contact if they have any questions and how to access advice or information from support groups, national charities such as TB Alert and other sources such as local government (for example, public health or social care teams). \nMultidisciplinary TB teams should ensure people who have a smear‑positive result or imaging features highly suggestive of smear‑positive TB (for example, evidence of cavitation on chest X‑ray) are assessed the next working day. This is so that case management and infection control procedures start promptly. \nThe multidisciplinary TB team should assess people who are not smear‑positive but have imaging that suggests pulmonary or laryngeal TB as soon as possible. This should be no later than 5 working days after a referral. \nMultidisciplinary TB teams should, where necessary, be able to provide or arrange outreach services to ensure sputum samples or other assessments such as contact investigations can be arranged in the community. \n\n## Identifying and managing active TB in prisons, custody suites or immigration removal centres: organisational factors\nMultidisciplinary TB teams, prisons, custody suites and immigration removal centre healthcare services should have named TB liaison leads to ensure they can communicate effectively with each other. \nPrison, custody suites and immigration removal centre healthcare services should develop a TB policy by working with the TB control board and multidisciplinary TB team and the local Public Health England health protection team. \nMultidisciplinary TB teams, in conjunction with prisons, custody suites and immigration removal centre healthcare services, should agree a care pathway for TB. This is to ensure that any suspected or confirmed cases are reported to, and managed by, the multidisciplinary TB team. \nMultidisciplinary TB teams, in liaison with prisons, custody suites or immigration removal centre healthcare providers, should manage all cases of active TB. Investigations and follow‑up should be undertaken within the prison or immigration removal centre if possible. \n\n## Accommodation during treatment\nMultidisciplinary TB teams should assess the living circumstances of people with TB. Where there is a housing need they should work with allied agencies to ensure that all those who are entitled to state‑funded accommodation receive it as early as possible during their treatment, for example, as a result of a statutory homelessness review and identified need. \nMultidisciplinary TB teams, commissioners, local authority housing lead officers and other social landlords, providers of hostel accommodation, hospital discharge teams, Public Health England and the Local Government Association should work together to agree a process for identifying and providing accommodation for homeless people diagnosed with active pulmonary TB who are otherwise ineligible for state‑funded accommodation. This includes people who are not sleeping rough but do not have access to housing or recourse to public funds. The process should detail the person's eligibility and ensure they are given accommodation for the duration of their TB treatment. \nLocal government and clinical commissioning groups should fund accommodation for homeless people diagnosed with active TB who are otherwise ineligible for state‑funded accommodation. Use health and public health resources, in line with the Care Act 2014. \nMultidisciplinary TB teams should make people who would not otherwise be entitled to state‑funded accommodation aware that they may lose this accommodation if they do not comply with treatment. They should ensure plans are made to continue housing people once their TB treatment is completed. \nPublic Health England, working with the Local Government Association and their special interest groups, should consider working with national housing organisations such as the Chartered Institute of Housing, Homeless Link, Sitra and the National Housing Federation to raise the profile of TB. This is to ensure people with TB are considered a priority for housing. \nConsider training housing commissioners and frontline staff on TB and the need for housing support, so that they understand that a stable home life is a prerequisite to successful TB treatment. \n\n# Terms used in this guideline\n\n## Active case‑finding\nSystematically identifying people with active or latent TB using tests, examinations or other procedures.\n\n## Adherence\nThe term adherence refers to the person's ability or willingness to keep to a treatment regimen as directed.\n\n## Adults\nPeople aged 18 or older.\n\n## Case management\nCase management involves follow‑up of a person suspected or confirmed to have TB. It needs a collaborative, multidisciplinary approach and should start as soon as possible after a suspected case is discovered.\n\n## Case manager\nStandard and enhanced case management is overseen by a case manager who will usually be a specialist TB nurse or (in low‑incidence areas) a nurse with responsibilities that include TB. Depending on the person's circumstances and needs, case management can also be provided by appropriately trained and supported non‑clinical members of the TB multidisciplinary team.\n\n## Children\nPeople aged 15 or younger.\n\n## Children and young people\nPeople aged 17 or younger.\n\n## Close contacts\n'Close contacts' are people who have had prolonged, frequent or intense contact with a person with infectious TB. For example, these could include 'household contacts', those who share a bedroom, kitchen, bathroom or sitting room with the index case. Close contacts may also include boyfriends or girlfriends and frequent visitors to the home of the index case. Depending in the circumstances, occasionally coworkers are classed as 'close contacts although they are more usually classed as 'social contacts'.\n\n## Cohort review\nCohort review is a systematic quarterly audit of the management and treatment of all TB patients and their contacts. The 'cohort' is a group of cases counted over a specific time, usually 3 months. Brief details of the management and outcomes of each case are reviewed in a group setting. The case manager presents the cases they are responsible for, giving the opportunity to discuss problems and difficulties in case management, service strengths and weaknesses, and staff training needs.\n\n## Congregate setting\nA place where people congregate or an institutional setting such as a workplace, prison, hostel, or childcare or educational setting, where social contacts might have had significant exposure to TB.\n\n## Contact\nA person who has spent time with someone with infectious TB. See also 'close contact' and 'social contact'.\n\n## Contact investigation\nClinical investigations (diagnostic testing) of people identified as having had significant exposure to a case of TB, including tests to diagnose latent or active TB. The aims of contact investigations are to:\ndetect active TB earlier to offer treatment and prevent further transmission\ndetect latent TB that may benefit from drug treatment\ndetect people not infected but for whom BCG vaccination might be appropriate.\n\n## Contact tracing\nIdentifying people who may have come into contact with a person with infectious TB and assessing them for risk of significant exposure to TB. The aim is to find associated cases, to detect people with latent TB and to identify those not infected but for whom BCG vaccination might be appropriate.\n\n## Disseminated TB\nBlood‑borne spread of TB that may or may not be accompanied by chest X‑ray or high resolution CT changes.\n\n## Enablers\nMethods of helping someone to overcome barriers to completing diagnostic investigations and TB treatment. Examples of barriers include: transport, housing, nutrition and immigration status.\n\n## Enhanced case management\nManagement of TB for someone with clinically or socially complex needs. It starts as soon as TB is suspected. As part of enhanced case management, the need for directly observed treatment is considered, along with a package of supportive care tailored to the person's needs.\n\n## Equity proofed\nTools such as health equity audit and health impact assessment have been used systematically to assess the potential effect of all policies, programmes and activities (including those without an explicit health focus) on health inequalities. Equity proofing helps ensure all policies and programmes address the social determinants of health and health inequalities. Including a health equity audit as part of the joint strategic needs assessment can help local authorities and their partners to:\ndevelop strategy and plans according to need\nidentify and work with community and health partners\ncommission activities based on the best available evidence\nimplement interventions to tackle inequity.\n\n## End‑to‑end pathway\nThe pathway from awareness raising and primary prevention, through diagnosis to treatment completion, incorporating all aspects such as contact tracing and other infection control mechanisms, for example, access to isolation facilities. This includes governance and commissioning considerations so that a comprehensive clinical and public health service is developed and delivered across any agreed geographical footprint.\n\n## Extrapulmonary TB\nActive TB disease in any site other than the lungs or tracheobronchial tree.\n\n## Extensively drug‑resistant TB\nResistance to at least isoniazid and rifampicin, 1 injectable agent (capreomycin, kanamycin or amikacin) and 1 fluoroquinolone.\n\n## High incidence\nA high‑incidence country or area has more than 40 cases of TB per 100,000 people per year. Public Health England lists high‑incidence countries and areas of the UK on its website.\n\n## High‑risk groups\nThe term 'high‑risk groups' is used in this guideline to mean adults, young people and children from any ethnic background, regardless of migration status, who are at increased risk of having or contracting TB. This includes people classified as under‑served, people identified as contacts according to the case finding recommendations, new entrants from high‑incidence countries and people who are immunocompromised.\n\n## Homelessness\nFor the purposes of TB control, a broad and inclusive definition of homelessness has been adopted that incorporates overcrowded and substandard accommodation. It includes people:\nwho share an enclosed air space with people at high risk of undetected active pulmonary TB (that is, people with a history of rough sleeping, hostel residence or substance misuse)\nwithout the means to securely store prescribed medication\nwithout private space in which to self‑administer TB treatment\nwithout secure accommodation in which to rest and recuperate in safety and dignity for the full duration of planned treatment.\n\n## Immigration removal centres\nImmigration removal centres are private or prison‑run holding centres for migrants waiting to be accepted by, or deported from, the UK. Immigration removal centres are also known as immigration detention centres and pre‑departure accommodation.\n\n## Immunocompromised\nIn this guideline, immunocompromised refers to a person who has a significantly impaired immune system. For instance, this may be because of prolonged corticosteroid use, tumour necrosis factor‑alpha antagonists, antirejection therapy, immunosuppression‑causing medication or comorbid states that affect the immune system, for example, HIV, chronic renal disease, many haematological and solid cancers, and diabetes.\n\n## Incident risk assessment\nAssessment of risk of exposure to TB in a congregate setting to decide on the need for and extent of contact investigation. The risk assessment would take into consideration factors such as infectiousness of the index case, vulnerability of contacts to TB infection, length of contact with or exposure to an infectious case and the built environment (for example, size of the rooms, ventilation and overcrowding).\n\n## Index case\nThe initial person found to have TB, whose contacts are screened. The source of their infection may be found to be 1 of the contacts, but the person who presents first is regarded as the index case.\n\n## Induration\nThe firm skin reaction occurring after a tuberculin skin test to diagnose latent TB infection. It is measured, and the result used to determine whether the test result is classified as positive or negative. This guideline recommends a threshold of 5 mm for tuberculin skin test positivity.\n\n## Infectious TB\nActive smear‑positive pulmonary TB, that is with acid fast bacilli visible on microscopy. Active TB affecting other parts of the respiratory tract or oral cavity, though rare, is also considered infectious.\n\n## Isolation\nAn infection control measure in which people with infectious TB are kept away from others who may be at risk of infection. This guideline deals with 3 levels of isolation for infection control in hospital settings:\nnegative pressure rooms, which have air pressure continuously or automatically measured, as defined by NHS Property Services\nsingle rooms that are not negative pressure but are vented to the outside of the building\nbeds on a ward, for which no particular engineering standards are needed.\n\n## Lost to follow‑up\nPeople are defined as 'lost to follow‑up' if they cannot be contacted within 10 working days of:\ntheir first missed outpatient appointment (if they are on self‑administered treatment)\ntheir first missed directly observed therapy appointment (if they are on directly observed therapy).\n\n## Multidisciplinary TB teams\nA team of professionals with a mix of skills to meet the needs of someone with TB who also has complex physical and psychosocial issues (that is, someone who is under‑served). Team members will include a social worker, voluntary sector and local housing representatives, TB lead physician and nurse, a case manager, a pharmacist, an infectious disease doctor or consultant in communicable disease control or health protection, a peer supporter or advocate and a psychiatrist.\n\n## Multidrug‑resistant TB\nTB resistant to isoniazid and rifampicin, with or without any other resistance.\n\n## Negative pressure room\nUsed to isolate some patients known or suspected to have infectious TB. A negative pressure room is one where the air from the room is sucked out into dedicated ducting through a filter and into the outside air, at a distance from all other air intakes. The pressure should be 10 pascals below the ambient air pressure.\n\n## Neonates\nChildren aged 4 weeks or younger.\n\n## New entrant\nAnyone coming to work or settle in the UK. This includes immigrants, refugees, asylum seekers, students and people on work permits. It also includes UK‑born people, or UK citizens, re‑entering the country after a prolonged stay in a high‑incidence country.\n\n## Opportunistic case‑finding\nOpportunistic identification of people with active or latent TB using tests, examinations or other procedures in the course of existing appointments or interactions, rather than identification through formal screening programmes.\n\n## Outbreak\nThere is no robust, widely accepted threshold for an outbreak of a disease, but in practical terms an outbreak is the occurrence of an unusually high number of cases in associated people, in a small geographical area, or in a relatively short period of time.\n\n## Peers\nPeers are people who may have experienced TB. They are often in a good position to help convey, with empathy, the need for testing or treatment. They may be recruited from specific populations. With support they can communicate health messages, assist with contact investigations or testing and offer people support while they are being tested or treated.\n\n## Prisons\nAny state prison establishments, including young offender institutions.\n\n## Rapid access\nIn the context of TB services, rapid access refers to timely support from a specialist team.\n\n## Smear grade\nThe number of bacilli found in a sputum sample, believed to relate to the degree of infectivity of the person. There are several systems but in general recording goes from no mycobacteria in 100 fields (0 or negative) to more than 10 acid‑fast bacilli per field in at least 20 fields (grade 3).\n\n## Social contacts\nSomeone who has had contact with a person with infectious TB but has not been in prolonged, frequent or intense contact.\n\n## Substance misuse\nSubstance misuse is defined as intoxication by, or regular excessive consumption of or dependence on, psychoactive substances, leading to social, psychological, physical or legal problems. It includes problematic use of both legal and illegal drugs.\n\n## TB control board\nA partnership of mixed professionals and lay people who have experience of leading, commissioning, managing or supporting people with TB. Board members are likely to include the voluntary sector, housing representatives, TB specialists and other clinicians, consultants in communicable disease control or health protection, peer supporter and advocate groups, clinical commissioning groups, executive officers, local government commissioners and an independent chair. This list is not intended to be exhaustive; membership should be determined based on an area's needs, agreements and commissioning arrangements.\n\n## Treatment interruption\nA break in the prescribed anti‑TB regimen for 2 weeks or more in the initial phase, or more than 20% of prescribed doses missed intermittently.\n\n## Under‑served groups\nThis term is used in this guideline to mean groups of adults, young people and children from any ethnic background, regardless of migration status. They are 'under‑served' if their social circumstances, language, culture or lifestyle (or those of their parents or carers) make it difficult to:\nrecognise the clinical onset of TB\naccess diagnostic and treatment services\nself‑administer treatment (or, in the case of children and young people, have treatment administered by a parent or carer)\nattend regular appointments for clinical follow‑up.\nThe groups classified as under‑served in this guideline are:\npeople who are homeless\npeople who misuse substances\nprisoners\nvulnerable migrants.\n\n## Under‑served children\nGroups of children identified as potentially under served include:\nunaccompanied minors\nchildren whose parents are under served, including vulnerable migrants\nchildren whose parents are in prison or who abuse substances\nchildren from Gypsy and Traveller communities\nlooked‑after children.\n\n## Vulnerable migrants\nVulnerable migrants may include undocumented migrants and those with no recourse to public funds. Some refugees, asylum seekers and new entrants to the country may also fall into this category.\n\n## Young people\nPeople aged 16 or 17.# Context\nTuberculosis (TB) is a curable infectious disease caused by a type of bacterium called Mycobacterium tuberculosis ('M. tuberculosis' or 'M.Tb'), or other bacterium in the M. tuberculosis complex (that is, M. bovis or M. africanum). It is spread by droplets containing the bacteria being coughed out by someone with infectious TB, and then being inhaled by other people.\nThe initial infection clears in over 80% of people but, in a few cases, a defensive barrier is built round the infection and the TB bacteria lie dormant. This is called latent TB; the person is not ill and is not infectious. If the immune system fails to build the defensive barrier, or the barrier fails later, latent TB can spread in the lung (pulmonary TB) or develop in the other parts of the body it has spread to (extrapulmonary TB). Only a small proportion of people with latent TB will develop symptoms ('active TB').\nMany cases of TB can be prevented by public health measures and, when clinical disease does occur, most people can be cured if treated properly. Taking medication in the wrong dose or combination, irregularly or for too short a time can lead to drug resistance. Drug‑resistant strains of TB are much harder to treat and significantly increase a person's risk of long‑term complications or death. If left untreated, 1 person with active pulmonary TB may infect as many as 10 to 15 people every year.\nTB incidence in the UK has increased since the early 1990s, but has remained relatively stable since 2005. Despite this, it remains high compared with many other western European countries. Cases tend to cluster in urban areas where populations of at‑risk groups are high. These include areas with many people born in countries with a high incidence of TB, areas with a high level of homelessness, poor housing or poverty, and areas with high rates of problem drug use.\nThe NHS and Public Health England, as well as a local authority public health teams and many third sector organisations, have been working to reduce the harm caused by TB to many individuals and communities. TB is a notifiable disease, meaning that clinicians have a statutory duty to notify local authorities or a local Public Health England centre of suspected cases, and efforts have been made to strengthen services and ensure clear lines of accountability and responsibility. However, a stronger approach to TB control is now needed to build on this work. Indicators of TB incidence and TB treatment outcomes have been included in the Public Health Outcomes Framework. In addition, Public Health England and NHS England have designed a collaborative tuberculosis strategy for England that brings together best practice in clinical care, social support and public health. Agencies at all levels, including national and local government, clinical commissioning groups and third sector partners, are committed to working in partnership to decrease the incidence of TB, fight the spread of drug‑resistant forms of the disease, reduce current health inequality and, ultimately, eliminate TB as a public health problem in England.# Recommendations for research\nThe guideline committee has made the following recommendations for research. The guideline committee's full set of research recommendations is detailed in the full guideline.\n\n# Universal compared with risk‑based approach to using rapid diagnostic tests\nIn people with suspected TB, what is the relative clinical and cost effectiveness of universal and risk‑based use of rapid nucleic acid amplification tests?\n\n## Why this is important\nThe guideline committee noted that there were 2 possible approaches to using rapid nucleic acid amplification tests for suspected TB. The current approach is to use them only if TB is strongly suspected and rapid information about mycobacterial species would alter the person's care. Another approach is to use them in anyone with a possible diagnosis of TB. There is a trade‑off between ensuring that all people with active TB are diagnosed and avoiding a large number of false positives, which leads to unnecessary treatment. This trade‑off may lead to differences in the cost effectiveness of each approach. NICE's systematic review of the diagnosis of active TB did not identify any robust evidence on this, nor did the health technology assessment on using nucleic acid amplification tests to detect drug resistance. Cost‑effectiveness studies are needed to improve understanding in this area.\n\n# Diagnosis in children\nApart from culture, what other diagnostic tests or combinations of tests are effective in establishing an accurate diagnosis of active respiratory TB in children and young people with suspected active TB?\n\n## Why this is important\nThe guideline committee noted the lack of evidence on the diagnosis of active TB in children. The disease manifests differently in children than in adults, and more evidence would have been useful to the committee. Cross‑sectional studies are needed to examine the relative accuracy of different tests, and the most appropriate specimen type for these tests, compared with tests currently in use. In particular, the poor accuracy of many tests in children means that diagnostic strategies that is, combinations of tests, should be investigated, including both tests with high sensitivity and tests based on host response.\n\n# Treating isoniazid‑resistant TB\nFor isoniazid‑resistant TB, what is the most effective regimen for reducing mortality and morbidity?\n\n## Why this is important\nThere is little evidence for the treatment of isoniazid resistant TB. This is the most common form of drug resistance in the UK, occurring in 7.5% of TB cases. Currently, treatment is not always successful, even when the recommended drugs are given for the recommended time and there are no adherence issues. It is particularly difficult to treat if there are treatment interruptions or if the central nervous system is involved. Randomised controlled trials are needed to compare different anti‑TB regimens for isoniazid‑resistant TB, assessing mortality, treatment success or treatment failure, rates of relapse and adverse events.\n\n# Impact of infection control measures on quality of life\nWhat effects does isolation have on the quality of life of people being treated for TB?\n\n## Why this is important\nIsolation is known to significantly affect a person's quality of life. Despite this, the guideline committee identified no reliable data on the impact of isolation on quality of life. This information is essential in producing economic models that reflect the real costs of isolation. Data on the impact of isolation on quality of life need to be collected and reported.\n\n# Treatment interruptions caused by adverse events (specifically hepatotoxicity)\nFor people with active, drug susceptible TB who experience treatment interruptions because of adverse events, particularly hepatotoxicity, what approach to re‑establishing treatment is most effective in reducing mortality and morbidity?\n\n## Why this is important\nThere is little evidence on re‑establishing treatment after interruptions because of adverse events. This is key to ensuring treatment success without relapse or the emergence of drug resistance, but avoiding further adverse events is also important. Randomised controlled trials are needed to compare approaches to re‑establishing treatment for active, drug susceptible TB after it is interrupted because of adverse events, particularly hepatotoxicity. These trials should assess mortality, treatment success or failure, rates of relapse, the recurrence of adverse events and the emergence of drug resistance. Approaches evaluated could compare, for example, restarting regimens with lengthening their duration, as well as sequential reintroduction. Approaches should vary depending on the proportion of doses missed and the stage of treatment (initial or continuation phase) in which the interruption occurred. Prospective observational cohort studies with multivariable analyses may also be useful."}}},{"rowIdx":86,"cells":{"id":{"kind":"string","value":"65a0ea6ad84ab7b2c5b58c63d2a46a1f98af1d80"},"source":{"kind":"string","value":"cdc"},"text":{"kind":"string","value":"On May 14, 1796, Edward Jenner, an English physician, inoculated James Phipps, age 8, with material from a cowpox lesion on the hand of a milkmaid. Jenner subsequently demonstrated that the child was protected against smallpox. This procedure became known as vaccination, which resulted in the global eradication of smallpox 181 years later.# Introduction\nThis report provides technical guidance regarding common immunization concerns for health-care providers who administer vaccines to children, adolescents, and adults. Vaccine recommendations are based on characteristics of the immunobiologic product, scientific knowledge regarding the principles of active and passive immunization, the epidemiology and burden of diseases (i.e., morbidity, mortality, costs of treatment, and loss of productivity), the safety of vaccines, and the cost analysis of preventive measures as judged by public health officials and specialists in clinical and preventive medicine.\nBenefits and risks are associated with using all immunobiologics. No vaccine is completely safe or 100% effective. Benefits of vaccination include partial or complete protection against the consequences of infection for the vaccinated person, as well as overall benefits to society as a whole. Benefits include protection from symptomatic illness, im-proved quality of life and productivity, and prevention of death. Societal benefits include creation and maintenance of herd immunity against communicable diseases, prevention of disease outbreaks, and reduction in health-care-related costs. Vaccination risks range from common, minor, and local adverse effects to rare, severe, and life-threatening conditions. Thus, recommendations for immunization practices balance scientific evidence of benefits for each person and to society against the potential costs and risks of vaccination programs.\nStandards for child and adolescent immunization practices and standards for adult immunization practices (1,2) have been published to assist with implementing vaccination programs and maximizing their benefits. Any person or institution that provides vaccination services should adopt these standards to improve immunization delivery and protect children, adolescents, and adults from vaccine-preventable diseases.\nTo maximize the benefits of vaccination, this report provides general information regarding immunobiologics and provides practical guidelines concerning vaccine administration and technique. To minimize risk from vaccine administration, this report delineates situations that warrant precautions or contraindications to using a vaccine. These recommendations are intended for use in the United States be-\n\n# General Recommendations on Immunization\n\n# Recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP)\nMMWR February 8,\ncause vaccine availability and use, as well as epidemiologic circumstances, differ in other countries. Individual circumstances might warrant deviations from these recommendations. The relative balance of benefits and risks can change as diseases are controlled or eradicated. For example, because wild poliovirus transmission has been interrupted in the United States since 1979, the only indigenous cases of paralytic poliomyelitis reported since that time have been caused by live oral poliovirus vaccine (OPV). In 1997, to reduce the risk for vaccine-associated paralytic polio (VAPP), increased use of inactivated poliovirus vaccine (IPV) was recommended in the United States (3). In 1999, to eliminate the risk for VAPP, exclusive use of IPV was recommended for routine vaccination in the United States (4), and OPV subsequently became unavailable for routine use. However, because of superior ability to induce intestinal immunity and to prevent spread among close contacts, OPV remains the vaccine of choice for areas where wild poliovirus is still present. Until worldwide eradication of poliovirus is accomplished, continued vaccination of the U.S. population against poliovirus will be necessary.\n\n# Timing and Spacing of Immunobiologics General Principles for Vaccine Scheduling\nOptimal response to a vaccine depends on multiple factors, including the nature of the vaccine and the age and immune status of the recipient. Recommendations for the age at which vaccines are administered are influenced by age-specific risks for disease, age-specific risks for complications, ability of persons of a certain age to respond to the vaccine, and potential interference with the immune response by passively transferred maternal antibody. Vaccines are recommended for members of the youngest age group at risk for experiencing the disease for whom efficacy and safety have been demonstrated.\nCertain products, including inactivated vaccines, toxoids, recombinant subunit and polysaccharide conjugate vaccines, require administering >2 doses for development of an adequate and persisting antibody response. Tetanus and diphtheria toxoids require periodic reinforcement or booster doses to maintain protective antibody concentrations. Unconjugated polysaccharide vaccines do not induce T-cell memory, and booster doses are not expected to produce substantially increased protection. Conjugation with a protein carrier improves the effectiveness of polysaccharide vaccines by inducing T-celldependent immunologic function. Vaccines that stimulate both cell-mediated immunity and neutralizing antibodies (e.g., live attenuated virus vaccines) usually can induce prolonged, often lifelong immunity, even if antibody titers decline as time progresses (5). Subsequent exposure to infection usually does not lead to viremia but to a rapid anamnestic antibody response.\nApproximately 90%-95% of recipients of a single dose of a parenterally administered live vaccine at the recommended age (i.e., measles, mumps, rubella , varicella, and yellow fever), develop protective antibody within 2 weeks of the dose. However, because a limited proportion of recipients (13 years fail to respond to the first dose of varicella vaccine; 99% of recipients seroconvert after two doses (8).\nThe recommended childhood vaccination schedule is revised annually and is published each January. Recommendations for vaccination of adolescents and adults are revised less frequently, except for influenza vaccine recommendations, which are published annually. Physicians and other health-care providers should always ensure that they are following the most up-to-date schedules, which are available from CDC's National Immunization Program website at (accessed October 11, 2001).\n\n# Spacing of Multiple Doses of the Same Antigen\nVaccination providers are encouraged to adhere as closely as possible to the recommended childhood immunization schedule. Clinical studies have reported that recommended ages and intervals between doses of multidose antigens provide optimal protection or have the best evidence of efficacy. Recommended vaccines and recommended intervals between doses are provided in this report (Table 1).\nIn certain circumstances, administering doses of a multidose vaccine at shorter than the recommended intervals might be necessary. This can occur when a person is behind schedule and needs to be brought up-to-date as quickly as possible or when international travel is impending. In these situations, an accelerated schedule can be used that uses intervals between doses shorter than those recommended for routine vaccination. Although the effectiveness of all accelerated schedules has not been evaluated in clinical trials, the Advisory Committee on Immunization Practices (ACIP) believes that the immune response when accelerated intervals are used is acceptable and will lead to adequate protection. The accelerated, or minimum, inter-\n\n# PPV2\n-7 yrs § § § --- Combination vaccines are available. Using licensed combination vaccines is preferred over separate injections of their equivalent component vaccines (Source: CDC. Combination vaccines for childhood immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP). MMWR 1999;48:5). When administering combination vaccines, the minimum age for administration is the oldest age for any of the individual components; the minimum interval between doses is equal to the greatest interval of any of the individual antigens. † A combination hepatitis B-Hib vaccine is available (Comvax ® , manufactured by Merck Vaccine Division). This vaccine should not be administered to infants aged 8 weeks after Hepatitis B2 and 16 weeks after Hepatitis B1, and it should not be administered before age 6 months. ¶ Calendar months. The minimum interval between DTaP3 and DTaP4 is recommended to be >6 months. However, DTaP4 does not need to be repeated if administered >4 months after DTaP3. † † For Hib and PCV, children receiving the first dose of vaccine at age >7 months require fewer doses to complete the series ( . § § For a regimen of only polyribosylribitol phosphate-meningococcal outer membrane protein (PRP-OMP, PedvaxHib ® , manufactured by Merck), a dose administered at age 6 months is not required. ¶ ¶ During a measles outbreak, if cases are occurring among infants aged 6 months can be undertaken as an outbreak control measure. However, doses administered at age 5 days earlier than the minimum interval or age should not be counted as valid doses and should be repeated as age-appropriate. The repeat dose should be spaced after the invalid dose by the recommended minimum interval as provided in this report (Table 1). For example, if Haemophilus influenzae type b (Hib) doses one and two were administered only 2 weeks apart, dose two is invalid and should be repeated. The repeat dose should be administered >4 weeks after the invalid (second) dose. The repeat dose would be counted as the second valid dose. Doses administered >5 days before the minimum age should be repeated on or after the child reaches the minimum age and >4 weeks after the invalid dose. For example, if varicella vaccine were administered at age 10 months, the repeat dose would be administered no earlier than the child's first birthday.\nCertain vaccines produce increased rates of local or systemic reactions in certain recipients when administered too frequently (e.g., adult tetanus-diphtheria toxoid , pediatric diphtheria-tetanus toxoid , and tetanus toxoid) (10,11). Such reactions are thought to result from the formation of antigen-antibody complexes. Optimal record keeping, maintaining patient histories, and adhering to recommended sched-ules can decrease the incidence of such reactions without adversely affecting immunity.\n\n# Simultaneous Administration\nExperimental evidence and extensive clinical experience have strengthened the scientific basis for administering vaccines simultaneously (i.e., during the same office visit, not combined in the same syringe). Simultaneously administering all vaccines for which a person is eligible is critical, including for childhood vaccination programs, because simultaneous administration increases the probability that a child will be fully immunized at the appropriate age. A study conducted during a measles outbreak demonstrated that approximately one third of measles cases among unvaccinated but vaccine-eligible preschool children could have been prevented if MMR had been administered at the same visit when another vaccine was administered (12). Simultaneous administration also is critical when preparing for foreign travel and if uncertainty exists that a person will return for further doses of vaccine.\nSimultaneously administering the most widely used live and inactivated vaccines have produced seroconversion rates and rates of adverse reactions similar to those observed when the vaccines are administered separately (13)(14)(15)(16). Routinely administering all vaccines simultaneously is recommended for children who are the appropriate age to receive them and for whom no specific contraindications exist at the time of the visit. Administering combined MMR vaccine yields results similar to administering individual measles, mumps, and rubella vaccines at different sites. Therefore, no medical basis exists for administering these vaccines separately for routine vaccination instead of the preferred MMR combined vaccine (6). Administering separate antigens would result in a delay in protection for the deferred components. Response to MMR and varicella vaccines administered on the same day is identical to vaccines administered a month apart (17). No evidence exists that OPV interferes with parenterally administered live vaccines. OPV can be administered simultaneously or at any interval before or after parenteral live vaccines. No data exist regarding the immunogenicity of oral Ty21a typhoid vaccine when administered concurrently or within 30 days of live virus vaccines. In the absence of such data, if typhoid vaccination is warranted, it should not be delayed because of administration of virus vaccines (18).\nSimultaneously administering pneumococcal polysaccharide vaccine and inactivated influenza vaccine elicits a satisfactory antibody response without increasing the incidence or severity of adverse reactions (19). Simultaneously administering pneumococcal polysaccharide vaccine and inactivated influenza vaccine is strongly recommended for all persons for whom both vaccines are indicated. Hepatitis B vaccine administered with yellow fever vaccine is as safe and immunogenic as when these vaccines are administered separately (20). Measles and yellow fever vaccines have been administered safely at the same visit and without reduction of immunogenicity of each of the components (21,22).\nDepending on vaccines administered in the first year of life, children aged 12-15 months can receive <7 injections during a single visit (MMR, varicella, Hib, pneumococcal conjugate, diphtheria and tetanus toxoids and acellular pertussis , IPV, and hepatitis B vaccines). To help reduce the number of injections at the 12-15-month visit, the IPV primary series can be completed before the child's first birthday. MMR and varicella vaccines should be administered at the same visit that occurs as soon as possible on or after the first birthday. The majority of children aged 1 year who have received two (polyribosylribitol phosphate-meningococcal outer membrane protein ) or three (PRP-tetanus , diphtheria CRM 197 protein conjugate ) prior doses of Hib vaccine, and three prior doses of DTaP and pneumococcal conjugate vaccine have developed protection (23,24). The third (PRP-OMP) or fourth (PRP-T, HbOC) dose of the Hib series, and the fourth doses of DTaP and pneumococcal conjugate vaccines are critical in boosting antibody titer and ensuring continued protection (24)(25)(26). However, the booster dose of the Hib or pneumococcal conjugate series can be deferred until ages 15-18 months for children who are likely to return for future visits. The fourth dose of DTaP is recommended to be administered at ages 15-18 months, but can be administered as early as age 12 months under certain circumstances (25). For infants at low risk for infection with hepatitis B virus (i.e., the mother tested negative for hepatitis B surface antigen at the time of delivery and the child is not of Asian or Pacific Islander descent), the hepatitis B vaccine series can be completed at any time during ages 6-18 months. Recommended spacing of doses should be maintained (Table 1).\nUse of combination vaccines can reduce the number of injections required at an office visit. Licensed combination vaccines can be used whenever any components of the combination are indicated and its other components are not contraindicated. Use of licensed combination vaccines is preferred over separate injection of their equivalent component vaccines (27). Only combination vaccines approved by the Food and Drug Administration (FDA) should be used. Individual vaccines must never be mixed in the same syringe unless they are specifically approved for mixing by FDA. Only one vaccine (DTaP and PRP-T Hib vaccine, marketed as TriHIBit ® ) is FDA-approved for mixing in the same syringe. This vaccine should not be used for primary vaccination in infants aged 2, 4, and 6 months, but it can be used as a booster after any Hib vaccine.\n\n# Nonsimultaneous Administration\nInactivated vaccines do not interfere with the immune response to other inactivated vaccines or to live vaccines. An inactivated vaccine can be administered either simultaneously or at any time before or after a different inactivated vaccine or live vaccine (Table 2).\nThe immune response to one live-virus vaccine might be impaired if administered within 30 days of another livevirus vaccine (28,29). Data are limited concerning interference between live vaccines. In a study conducted in two U.S. health maintenance organizations, persons who received varicella vaccine 30 days after MMR (30). In contrast, a 1999 study determined that the response to yellow fever vaccine is not affected by monovalent measles vaccine administered 1-27 days earlier (21). The effect of nonsimultaneously administering rubella, mumps, varicella, and yellow fever vaccines is unknown.\nTo minimize the potential risk for interference, parenterally administered live vaccines not administered on the same day should be administered >4 weeks apart whenever possible (Table 2). If parenterally administered live vaccines are separated by 4 weeks after the last, invalid dose. Yellow fever vaccine can be administered at any time after single-antigen measles vaccine. Ty21a typhoid vaccine and parenteral live vaccines (i.e.,\n\n# Spacing of Antibody-Containing Products and Vaccines Live Vaccines\nTy21a typhoid and yellow fever vaccines can be administered at any time before, concurrent with, or after administering any immune globulin or hyperimmune globulin (e.g., hepatitis B immune globulin and rabies immune globulin). Blood (e.g., whole blood, packed red blood cells, and plasma) and other antibody-containing blood products (e.g., immune globulin, hyperimmune globulin, and intravenous immune globulin ) can inhibit the immune response to measles and rubella vaccines for >3 months (31,32). The effect of blood and immune globulin preparations on the response to mumps and varicella vaccines is unknown, but commercial immune globulin preparations contain antibodies to these viruses. Blood products available in the United States are unlikely to contain a substantial amount of antibody to yellow fever vaccine virus. The length of time that interference with parenteral live vaccination (except yellow fever vaccine) can persist after the antibody-containing product is a function of the amount of antigen-specific antibody contained in the product (31)(32)(33). Therefore, after an antibody-containing product is received, parenteral live vaccines (except yellow fever vaccine) should be delayed until the passive antibody has degraded (Table 3). Recommended intervals between receipt of various blood products and measles-containing vaccine and varicella vaccine are listed in this report (Table 4). If a dose of parenteral live-virus vaccine (except yellow fever vaccine) is administered after an antibody-containing product but at an interval shorter than recommended in this report, the vaccine dose should be repeated unless serologic testing indicates a response to the vaccine. The repeat dose or serologic testing should be performed after the interval indicated for the antibody-containing product (Table 4).\nAlthough passively acquired antibodies can interfere with the response to rubella vaccine, the low dose of anti-Rho(D) globulin administered to postpartum women has not been demonstrated to reduce the response to the RA27/3 strain rubella vaccine (34). Because of the importance of rubella immunity among childbearing-age women (6,35), the postpartum vaccination of rubella-susceptible women with rubella or MMR vaccine should not be delayed because of receipt of anti-Rho(D) globulin or any other blood product during the last trimester of pregnancy or at delivery. These women should be vaccinated immediately after delivery and, if possible, tested >3 months later to ensure immunity to rubella and, if necessary, to measles (6).\nInterference can occur if administering an antibodycontaining product becomes necessary after administering MMR, its individual components, or varicella vaccine. Usually, vaccine virus replication and stimulation of immunity will occur 1-2 weeks after vaccination. Thus, if the interval be- Antibody-containing products 2 weeks - Blood products containing substantial amounts of immunoglobulin, including intramuscular and intravenous immune globulin, specific hyperimmune globulin (e.g, hepatitis B immune globulin, tetanus immune globulin, varicella zoster immune globulin, and rabies immune globulin), whole blood, packed red cells, plasma, and platelet products. † Yellow fever and oral Ty21a typhoid vaccines are exceptions to these recommendations. These live attenuated vaccines can be administered at any time before, after, or simultaneously with an antibody-containing product without substantially decreasing the antibody response. § The duration of interference of antibody-containing products with the immune response to the measles component of measles-containing vaccine, and possibly varicella vaccine, is dose-related (see Table 4).\ntween administering any of these vaccines and subsequent administration of an antibody-containing product is <14 days, vaccination should be repeated after the recommended interval (Tables 3,4), unless serologic testing indicates that antibodies were produced.\nA humanized mouse monoclonal antibody product (palivizumab) is available for prevention of respiratory syncytial virus infection among infants and young children. This product contains only antibody to respiratory syncytial virus; hence, it will not interfere with immune response to live or inactivated vaccines.\n\n# Inactivated Vaccines\nAntibody-containing products interact less with inactivated vaccines, toxoids, recombinant subunit, and polysaccharide vaccines than with live vaccines (36). Therefore, administering inactivated vaccines and toxoids either simultaneously with or at any interval before or after receipt of an antibody-containing product should not substantially impair development of a protective antibody response (Table 3). The vaccine or toxoid and antibody preparation should be administered at different sites by using the standard rec-\n\n# Interchangeability of Vaccines from Different Manufacturers\nNumerous vaccines are available from different manufacturers, and these vaccines usually are not identical in antigen content or amount or method of formulation. Manufacturers use different production processes, and their products might contain different concentrations of antigen per dose or different stabilizers or preservatives.\nAvailable data indicate that infants who receive sequential doses of different Hib conjugate, hepatitis B, and hepatitis A vaccines produce a satisfactory antibody response after a complete primary series (37)(38)(39)(40). All brands of Hib conjugate, hepatitis B, § and hepatitis A vaccines are interchangeable within their respective series. If different brands of Hib conjugate vaccine are administered, a total of three doses is considered adequate for the primary series among infants. After completing the primary series, any Hib conjugate vaccine can be used for the booster dose at ages 12-18 months.\nData are limited regarding the safety, immunogenicity, and efficacy of using acellular pertussis (as DTaP) vaccines from different manufacturers for successive doses of the pertussis series. Available data from one study indicate that, for the first three doses of the DTaP series, one or two doses of Tripedia ® (manufactured by Aventis Pasteur) followed by Infanrix ® (manufactured by GlaxoSmithKline) for the remaining doses(s) is comparable to three doses of Tripedia with regard to immunogenicity, as measured by antibodies to diphtheria, tetanus, and pertussis toxoid, and filamentous hemagglutinin (41). However, in the absence of a clear serologic correlate of protection for pertussis, the relevance of these immunogenicity data for protection against pertussis is unknown. Whenever feasible, the same brand of DTaP vaccine should be used for all doses of the vaccination series; however, vaccination providers might not know or have available the type of DTaP vaccine previously administered to a child. In this situation, any DTaP vaccine should be used to continue or complete the series. Vaccination should not be deferred because the brand used for previous doses is not available or is unknown (25,42).\n\n# Lapsed Vaccination Schedule\nVaccination providers are encouraged to administer vaccines as close to the recommended intervals as possible.\nHowever, longer-than-recommended intervals between doses do not reduce final antibody concentrations, although protection might not be attained until the recommended number of doses has been administered. An interruption in the vaccination schedule does not require restarting the entire series of a vaccine or toxoid or the addition of extra doses.\n\n# Unknown or Uncertain Vaccination Status\nVaccination providers frequently encounter persons who do not have adequate documentation of vaccinations. Providers should only accept written, dated records as evidence of vaccination. With the exception of pneumococcal polysaccharide vaccine (43), self-reported doses of vaccine without written documentation should not be accepted. Although vaccinations should not be postponed if records cannot be found, an attempt to locate missing records should be made by contacting previous health-care providers and searching for a personally held record. If records cannot be located, these persons should be considered susceptible and should be started on the age-appropriate vaccination schedule. Serologic testing for immunity is an alternative to vaccination for certain antigens (e.g., measles, mumps, rubella, varicella, tetanus, diphtheria, hepatitis A, hepatitis B, and poliovirus) (see Vaccination of Internationally Adopted Children).\n\n# Contraindications and Precautions\nContraindications and precautions to vaccination dictate circumstances when vaccines will not be administered. The majority of contraindications and precautions are temporary, and the vaccination can be administered later. A contraindication is a condition in a recipient that increases the risk for a serious adverse reaction. A vaccine will not be administered when a contraindication is present. For example, administering influenza vaccine to a person with an anaphylactic allergy to egg protein could cause serious illness in or death of the recipient.\nNational standards for pediatric immunization practices have been established and include true contraindications and precautions to vaccination (Table 5) (1). The only true contraindication applicable to all vaccines is a history of a severe allergic reaction after a prior dose of vaccine or to a vaccine constituent (unless the recipient has been desensitized). Severely immunocompromised persons should not receive live vaccines. Children who experience an encephalopathy <7 days after administration of a previous dose of diphtheria and tetanus toxoids and whole-cell pertussis vac- § The exception is the two-dose hepatitis B vaccination series for adolescents aged 11-15 years. Only Recombivax HB ® (Merck Vaccine Division) should be used in this schedule. Engerix-B ® is not approved by FDA for this schedule. A precaution is a condition in a recipient that might increase the risk for a serious adverse reaction or that might compromise the ability of the vaccine to produce immunity (e.g., administering measles vaccine to a person with passive immunity to measles from a blood transfusion). Injury could result, or a person might experience a more se-\n\n# Contraindication\nSevere allergic reaction after a previous dose or to a vaccine component\n\n# Precautions\nInfant weighing 28 days. Substantially immunosuppressive steroid dose is considered to be >2 weeks of daily receipt of 20 mg or 2 mg/kg body weight of prednisone or equivalent. † † Measles vaccination can suppress tuberculin reactivity temporarily. Measles-containing vaccine can be administered on the same day as tuberculin skin testing. If testing cannot be performed until after the day of MMR vaccination, the test should be postponed for >4 weeks after the vaccination. If an urgent need exists to skin test, do so with the understanding that reactivity might be reduced by the vaccine. § § See text for details. ¶ ¶ If a vaccinee experiences a presumed vaccine-related rash 7-25 days after vaccination, avoid direct contact with immunocompromised persons for the duration of the rash. vere reaction to the vaccine than would have otherwise been expected; however, the risk for this happening is less than expected with a contraindication. Under normal circumstances, vaccinations should be deferred when a precaution is present. However, a vaccination might be indicated in the presence of a precaution because the benefit of protection from the vaccine outweighs the risk for an adverse reaction. For example, caution should be exercised in vaccinating a child with DTaP who, within 48 hours of receipt of a prior dose of DTP or DTaP, experienced fever >40.5C (105F); had persistent, inconsolable crying for >3 hours; collapsed or experienced a shock-like state; or had a seizure <3 days after receiving the previous dose of DTP or DTaP. However, administering a pertussis-containing vaccine should be considered if the risk for pertussis is increased (e.g., during a pertussis outbreak) (25). The presence of a moderate or severe acute illness with or without a fever is a precaution to administration of all vaccines. Other precautions are listed in this report (Table 5).\nPhysicians and other health-care providers might inappropriately consider certain conditions or circumstances to be true contraindications or precautions to vaccination. This misconception results in missed opportunities to administer recommended vaccines (44). Likewise, physicians and other health-care providers might fail to understand what constitutes a true contraindication or precaution and might administer a vaccine when it should be withheld. This practice can result in an increased risk for an adverse reaction to the vaccine. Conditions often inappropriately regarded as contraindications to vaccination are listed in this report (Table 5). Among the most common are diarrhea and minor upperrespiratory tract illnesses (including otitis media) with or without fever, mild to moderate local reactions to a previous dose of vaccine, current antimicrobial therapy, and the convalescent phase of an acute illness.\nThe decision to administer or delay vaccination because of a current or recent acute illness depends on the severity of symptoms and the etiology of the disease. All vaccines can be administered to persons with minor acute illness (e.g., diarrhea or mild upper-respiratory tract infection with or without fever). Studies indicate that failure to vaccinate children with minor illnesses can seriously impede vaccination efforts (45)(46)(47). Among persons whose compliance with medical care cannot be ensured, use of every opportunity to provide appropriate vaccinations is critical.\nThe majority of studies support the safety and efficacy of vaccinating persons who have mild illness (48)(49)(50). For example, in the United States, >97% of children with mild illnesses produced measles antibody after vaccination (51). Only one limited study has reported a lower rate of seroconversion (79%) to the measles component of MMR vaccine among children with minor, afebrile upper-respiratory tract infections (52). Therefore, vaccination should not be delayed because of the presence of mild respiratory tract illness or other acute illness with or without fever.\nPersons with moderate or severe acute illness should be vaccinated as soon as they have recovered from the acute phase of the illness. This precaution avoids superimposing adverse effects of the vaccine on the underlying illness or mistakenly attributing a manifestation of the underlying illness to the vaccine.\nRoutine physical examinations and measuring temperatures are not prerequisites for vaccinating infants and children who appear to be healthy. Asking the parent or guardian if the child is ill and then postponing vaccination for those with moderate to severe illness, or proceeding with vaccination if no contraindications exist, are appropriate procedures in childhood immunization programs.\nA family history of seizures or other central nervous system disorders is not a contraindication to administration of pertussis or other vaccines. However, delaying pertussis vaccination for infants and children with a history of previous seizures until the child's neurologic status has been assessed is prudent. Pertussis vaccine should not be administered to infants with evolving neurologic conditions until a treatment regimen has been established and the condition has stabilized (25).\n\n# Vaccine Administration Infection Control and Sterile Technique\nPersons administering vaccines should follow necessary precautions to minimize risk for spreading disease. Hands should be washed with soap and water or cleansed with an alcoholbased waterless antiseptic hand rub between each patient contact. Gloves are not required when administering vaccinations, unless persons administering vaccinations are likely to come into contact with potentially infectious body fluids or have open lesions on their hands. Syringes and needles used for injections must be sterile and disposable to minimize the risk of contamination. A separate needle and syringe should be used for each injection. Changing needles between drawing vaccine from a vial and injecting it into a recipient is unnecessary. Different vaccines should never be mixed in the same syringe unless specifically licensed for such use.\nDisposable needles and syringes should be discarded in labeled, puncture-proof containers to prevent inadvertent needle-stick injury or reuse. Safety needles or needle-free injection devices also can reduce the risk for injury and February 8, 2002 should be used whenever available (see Occupational Safety Regulations).\n\n# Recommended Routes of Injection and Needle Length\nRoutes of administration are recommended by the manufacturer for each immunobiologic. Deviation from the recommended route of administration might reduce vaccine efficacy (53,54) or increase local adverse reactions (55)(56)(57). Injectable immunobiologics should be administered where the likelihood of local, neural, vascular, or tissue injury is limited. Vaccines containing adjuvants should be injected into the muscle mass; when administered subcutaneously or intradermally, they can cause local irritation, induration, skin discoloration, inflammation, and granuloma formation.\n\n# Subcutaneous Injections\nSubcutaneous injections usually are administered at a 45degree angle into the thigh of infants aged 12 months. Subcutaneous injections can be administered into the upper-outer triceps area of an infant, if necessary. A 5/8-inch, 23-25-gauge needle should be inserted into the subcutaneous tissue.\n\n# Intramuscular Injections\nIntramuscular injections are administered at a 90-degree angle into the anterolateral aspect of the thigh or the deltoid muscle of the upper arm. The buttock should not be used for administration of vaccines or toxoids because of the potential risk of injury to the sciatic nerve (58). In addition, injection into the buttock has been associated with decreased immunogenicity of hepatitis B and rabies vaccines in adults, presumably because of inadvertent subcutaneous injection or injection into deep fat tissue (53,59).\nFor all intramuscular injections, the needle should be long enough to reach the muscle mass and prevent vaccine from seeping into subcutaneous tissue, but not so long as to involve underlying nerves and blood vessels or bone (54,(60)(61)(62). Vaccinators should be familiar with the anatomy of the area into which they are injecting vaccine. An individual decision on needle size and site of injection must be made for each person on the basis of age, the volume of the material to be administered, the size of the muscle, and the depth below the muscle surface into which the material is to be injected.\nAlthough certain vaccination specialists advocate aspiration (i.e., the syringe plunger pulled back before injection), no data exist to document the necessity for this procedure.\nIf aspiration results in blood in the needle hub, the needle should be withdrawn and a new site should be selected.\nInfants (persons aged <12 months). Among the majority of infants, the anterolateral aspect of the thigh provides the largest muscle mass and is therefore the recommended site for injection. For the majority of infants, a 7/8-1-inch, 22-25-gauge needle is sufficient to penetrate muscle in the infant's thigh.\n\n# Toddlers and Older Children (persons aged >12 months-18 years).\nThe deltoid muscle can be used if the muscle mass is adequate. The needle size can range from 22 to 25 gauge and from 7/8 to 1¼ inches, on the basis of the size of the muscle. For toddlers, the anterolateral thigh can be used, but the needle should be longer, usually 1 inch.\n\n# Adults (persons aged >18 years).\nFor adults, the deltoid muscle is recommended for routine intramuscular vaccinations. The anterolateral thigh can be used. The suggested needle size is 1-1½ inches and 22-25 gauge.\n\n# Intradermal Injections\nIntradermal injections are usually administered on the volar surface of the forearm. With the bevel facing upwards, a 3/8-3/4-inch, 25-27-gauge needle can be inserted into the epidermis at an angle parallel to the long axis of the forearm. The needle should be inserted so that the entire bevel penetrates the skin and the injected solution raises a small bleb. Because of the small amounts of antigen used in intradermal vaccinations, care must be taken not to inject the vaccine subcutaneously because it can result in a suboptimal immunologic response.\n\n# Multiple Vaccinations\nIf >2 vaccine preparations are administered or if vaccine and an immune globulin preparation are administered simultaneously, each preparation should be administered at a different anatomic site. If >2 injections must be administered in a single limb, the thigh is usually the preferred site because of the greater muscle mass; the injections should be sufficiently separated (i.e., >1 inch) so that any local reactions can be differentiated (55,63). For older children and adults, the deltoid muscle can be used for multiple intramuscular injections, if necessary. The location of each injection should documented in the person's medical record.\n\n# Jet Injection\nJet injectors (JIs) are needle-free devices that drive liquid medication through a nozzle orifice, creating a narrow stream under high pressure that penetrates skin to deliver a drug or vaccine into intradermal, subcutaneous, or intramuscular tis-sues (64,65). Increasing attention to JI technology as an alternative to conventional needle injection has resulted from recent efforts to reduce the frequency of needle-stick injuries to health-care workers (66) and to overcome the improper reuse and other drawbacks of needles and syringes in economically developing countries (67)(68)(69). JIs have been reported safe and effective in administering different live and inactivated vaccines for viral and bacterial diseases (69). The immune responses generated are usually equivalent to, and occasionally greater than, those induced by needle injection. However, local reactions or injury (e.g., redness, induration, pain, blood, and ecchymosis at the injection site) can be more frequent for vaccines delivered by JIs compared with needle injection (65,69).\nCertain JIs were developed for situations in which substantial numbers of persons must be vaccinated rapidly, but personnel or supplies are insufficient to do so with conventional needle injection. Such high-workload devices vaccinate consecutive patients from the same nozzle orifice, fluid pathway, and dose chamber, which is refilled automatically from attached vials containing <50 doses each. Since the 1950s, these devices have been used extensively among military recruits and for mass vaccination campaigns for disease control and eradication (64). An outbreak of hepatitis B among patients receiving injections from a multiple-use-nozzle JI was documented (70,71), and subsequent laboratory, field, and animal studies demonstrated that such devices could become contaminated with blood (69,72,73).\nNo U.S.-licensed, high-workload vaccination devices of unquestioned safety are available to vaccination programs. Efforts are under way for the research and development of new high-workload JIs using disposable-cartridge technology that avoids reuse of any unsterilized components having contact with the medication fluid pathway or patient's blood. Until such devices become licensed and available, the use of existing multiple-use-nozzle JIs should be limited. Use can be considered when the theoretical risk for bloodborne disease transmission is outweighed by the benefits of rapid vaccination with limited personnel in responding to serious disease threats (e.g., pandemic influenza or bioterrorism event), and by any competing risks of iatrogenic or occupational infections resulting from conventional needles and syringes. Before such emergency use of multiple-use-nozzle JIs, health-care workers should consult with local, state, national, or international health agencies or organizations that have experience in their use.\nIn the 1990s, a new generation of low-workload JIs were introduced with disposable cartridges serving as dose chambers and nozzle (69). With the provision of a new sterile cartridge for each patient and other correct use, these devices avoid the safety concerns described previously for multiple-use-nozzle devices. They can be used in accordance with their labeling for intradermal, subcutaneous, or intramuscular administration.\n\n# Methods for Alleviating Discomfort and Pain Associated with Vaccination\nComfort measures and distraction techniques (e.g., playing music or pretending to blow away the pain) might help children cope with the discomfort associated with vaccination. Pretreatment (30-60 minutes before injection) with 5% topical lidocaine-prilocaine emulsion (EMLA ® cream or disk ) can decrease the pain of vaccination among infants by causing superficial anesthesia (74,75). Preliminary evidence indicates that this cream does not interfere with the immune response to MMR (76). Topical lidocaine-prilocaine emulsion should not be used on infants aged <12 months who are receiving treatment with methemoglobin-inducing agents because of the possible development of methemoglobinemia (77). Acetaminophen has been used among children to reduce the discomfort and fever associated with vaccination (78). However, acetaminophen can cause formation of methemoglobin and, thus, might interact with lidocaine-prilocaine cream, if used concurrently (77). Ibuprofen or other nonaspirin analgesic can be used, if necessary. Use of a topical refrigerant (vapocoolant) spray can reduce the shortterm pain associated with injections and can be as effective as lidocaine-prilocaine cream (79). Administering sweettasting fluid orally immediately before injection can result in a calming or analgesic effect among certain infants.\n\n# Nonstandard Vaccination Practices\nRecommendations regarding route, site, and dosage of immunobiologics are derived from data from clinical trials, from practical experience, and from theoretical considerations. ACIP strongly discourages variations from the recommended route, site, volume, or number of doses of any vaccine.\nVariation from the recommended route and site can result in inadequate protection. The immunogenicity of hepatitis B vaccine and rabies vaccine is substantially lower when the gluteal rather than the deltoid site is used for administration (53,59). Hepatitis B vaccine administered intradermally can result in a lower seroconversion rate and final titer of hepatitis B surface antibody than when administered by the deltoid intramuscular route (80,81). Doses of rabies vaccine administered in the gluteal site should not be counted as valid doses and should be repeated. Hepatitis B vaccine administered by any route or site other than intramuscularly in the anterolateral thigh or deltoid muscle should not be counted as valid and should be repeated, unless serologic testing indicates that an adequate response has been achieved.\nLive attenuated parenteral vaccines (e.g., MMR, varicella, or yellow fever) and certain inactivated vaccines (e.g., IPV, pneumococcal polysaccharide, and anthrax) are recommended by the manufacturers to be administered by subcutaneous injection. Pneumococcal polysaccharide and IPV are approved for either intramuscular or subcutaneous administration. Response to these vaccines probably will not be affected if the vaccines are administered by the intramuscular rather then subcutaneous route. Repeating doses of vaccine administered by the intramuscular route rather than by the subcutaneous route is unnecessary.\nAdministering volumes smaller than those recommended (e.g., split doses) can result in inadequate protection. Using larger than the recommended dose can be hazardous because of excessive local or systemic concentrations of antigens or other vaccine constituents. Using multiple reduced doses that together equal a full immunizing dose or using smaller divided doses is not endorsed or recommended. Any vaccination using less than the standard dose should not be counted, and the person should be revaccinated according to age, unless serologic testing indicates that an adequate response has been achieved.\n\n# Preventing Adverse Reactions\nVaccines are intended to produce active immunity to specific antigens. An adverse reaction is an untoward effect that occurs after a vaccination that is extraneous to the vaccine's primary purpose of producing immunity. Adverse reactions also are called vaccine side effects.\nAll vaccines might cause adverse reactions (82). Vaccine adverse reactions are classified by three general categories: local, systemic, and allergic. Local reactions are usually the least severe and most frequent. Systemic reactions (e.g., fever) occur less frequently than local reactions. Serious allergic reactions (e.g., anaphylaxis) are the most severe and least frequent. Severe adverse reactions are rare.\nThe key to preventing the majority of serious adverse reactions is screening. Every person who administers vaccines should screen patients for contraindications and precautions to the vaccine before it is administered (Table 5). Standardized screening questionnaires have been developed and are available from certain state immunization programs and other sources (e.g., the Immunization Action Coalition at ).\nSevere allergic reactions after vaccination are rare. However, all physicians and other health-care providers who administer vaccines should have procedures in place for the emergency management of a person who experiences an anaphylactic reaction. All vaccine providers should be familiar with the office emergency plan and be certified in cardiopulmonary resuscitation.\nSyncope (vasovagal or vasodepressor reaction) can occur after vaccination, most commonly among adolescents and young adults. During 1990-August 2001, a total of 2,269 reports to the Vaccine Adverse Event Reporting system were coded as syncope. Forty percent of these episodes were reported among persons aged 10-18 years (CDC, unpublished data, 2001). Approximately 12% of reported syncopal episodes resulted in hospitalization because of injury or medical evaluation. Serious injury, including skull fractures and cerebral bleeding, have been reported to result from syncopal episodes after vaccination. A published review of syncope after vaccination reported that 63% of syncopal episodes occurred <5 minutes after vaccination, and 89% occurred within 15 minutes after vaccination (83). Although syncopal episodes are uncommon and serious allergic reactions are rare, certain vaccination specialists recommend that persons be observed for 15-20 minutes after being vaccinated, if possible (84). If syncope develops, patients should be observed until the symptoms resolve.\n\n# Managing Acute Vaccine Reactions\nAlthough rare after vaccination, the immediate onset and life-threatening nature of an anaphylactic reaction require that personnel and facilities providing vaccinations be capable of providing initial care for suspected anaphylaxis. Epinephrine and equipment for maintaining an airway should be available for immediate use.\nAnaphylaxis usually begins within minutes of vaccine administration. Rapidly recognizing and initiating treatment are required to prevent possible progression to cardiovascular collapse. If flushing, facial edema, urticaria, itching, swelling of the mouth or throat, wheezing, difficulty breathing, or other signs of anaphylaxis occur, the patient should be placed in a recumbent position with the legs elevated. Aqueous epinephrine (1:1000) should be administered and can be repeated within 10-20 minutes (84). A dose of diphenhydramine hydrochloride might shorten the reaction, but it will have little immediate effect. Maintenance of an airway and oxygen administration might be necessary. Arrangements should be made for immediate transfer to an emergency facility for further evaluation and treatment.\n\n# Occupational Safety Regulations\nBloodborne diseases (e.g., hepatitis B and C and human immunodeficiency virus ) are occupational hazards for health-care workers. In November 2000, to reduce the incidence of needle-stick injuries among health-care workers and the consequent risk for bloodborne diseases acquired from patients, the Needlestick Safety and Prevention Act was signed into law. The act directed the Occupational Safety and Health Administration (OSHA) to strengthen its existing bloodborne pathogen standards. Those standards were revised and became effective in April 2001 (66). These federal regulations require that safer injection devices (e.g., needle-shielding syringes or needle-free injectors) be used for parenteral vaccination in all clinical settings when such devices are appropriate, commercially available, and capable of achieving the intended clinical purpose. The rules also require that records be kept documenting the incidence of injuries caused by medical sharps (except in workplaces with <10 employees) and that nonmanagerial employees be involved in the evaluation and selection of safer devices to be procured.\nNeedle-shielding or needle-free devices that might satisfy the occupational safety regulations for administering parenteral injections are available in the United States and are listed at multiple websites (69,85-87). ¶ Additional information regarding implementation and enforcement of these regulations is available at the OSHA website at / needlesticks (accessed October 31, 2001).\n\n# Storage and Handling of Immunobiologics\nFailure to adhere to recommended specifications for storage and handling of immunobiologics can reduce potency, resulting in an inadequate immune response in the recipient. Recommendations included in a product's package insert, including reconstitution of the vaccine, should be followed carefully. Vaccine quality is the shared responsibility of all parties from the time the vaccine is manufactured until administration. All vaccines should be inspected upon delivery and monitored during storage to ensure that the cold chain has been maintained. Vaccines should continue to be stored at recommended temperatures immediately upon receipt. Certain vaccines (e.g., MMR, varicella, and yellow fever) are sensitive to increased temperature. All other vaccines are sensitive to freezing. Mishandled vaccine usually is not distinguishable from potent vaccine. When in doubt regarding the appropriate handling of a vaccine, vaccination providers should contact the manufacturer. Vaccines that have been mishandled (e.g., inactivated vaccines and toxoids that have been exposed to freezing temperatures) or that are beyond their expiration date should not be administered. If mishandled or expired vaccines are administered inadvertently, they should not be counted as valid doses and should be repeated, unless serologic testing indicates a response to the vaccine.\nLive attenuated virus vaccines should be administered promptly after reconstitution. Varicella vaccine must be administered <30 minutes after reconstitution. Yellow fever vaccine must be used <1 hour after reconstitution. MMR vaccine must be administered <8 hours after reconstitution. If not administered within these prescribed time periods after reconstitution, the vaccine must be discarded.\nThe majority of vaccines have a similar appearance after being drawn into a syringe. Instances in which the wrong vaccine inadvertently was administered are attributable to the practice of prefilling syringes or drawing doses of a vaccine into multiple syringes before their immediate need. ACIP discourages the routine practice of prefilling syringes because of the potential for such administration errors. To prevent errors, vaccine doses should not be drawn into a syringe until immediately before administration. In certain circumstances where a single vaccine type is being used (e.g., in advance of a community influenza vaccination campaign), filling multiple syringes before their immediate use can be considered. Care should be taken to ensure that the cold chain is maintained until the vaccine is administered. When the syringes are filled, the type of vaccine, lot number, and date of filling must be carefully labeled on each syringe, and the doses should be administered as soon as possible after filling.\nCertain vaccines are distributed in multidose vials. When opened, the remaining doses from partially used multidose vials can be administered until the expiration date printed on the vial or vaccine packaging, provided that the vial has been stored correctly and that the vaccine is not visibly contaminated. ¶ Internet sites with device listings are identified for information purposes only. CDC, the U.S. Public Health Service, and the Department of Health and Human Services do not endorse any specific device or imply that the devices listed would all satisfy the needle-stick prevention regulations.\n\n# MMWR February 8, 2002\n\n# Special Situations\n\n# Concurrently Administering Antimicrobial Agents and Vaccines\nWith limited exceptions, using an antibiotic is not a contraindication to vaccination. Antimicrobial agents have no effect on the response to live attenuated vaccines, except live oral Ty21a typhoid vaccine, and have no effect on inactivated, recombinant subunit, or polysaccharide vaccines or toxoids. Ty21a typhoid vaccine should not be administered to persons receiving antimicrobial agents until >24 hours after any antibiotic dose (18).\nAntiviral drugs used for treatment or prophylaxis of influenza virus infections have no effect on the response to inactivated influenza vaccine (88). Antiviral drugs active against herpesviruses (e.g., acyclovir or valacyclovir) might reduce the efficacy of live attenuated varicella vaccine. These drugs should be discontinued >24 hours before administration of varicella vaccine, if possible.\nThe antimalarial drug mefloquine (Lariam ® ) could affect the immune response to oral Ty21a typhoid vaccine if both are taken simultaneously (89,90). To minimize this effect, administering Ty21a typhoid vaccine >24 hours before or after a dose of mefloquine is prudent.\n\n# Tuberculosis Screening and Skin Test Reactivity\nMeasles illness, severe acute or chronic infections, HIV infection, and malnutrition can create an anergic state during which the tuberculin skin test (usually known as purified protein derivative skin test) might give a false negative reaction (91)(92)(93). Although any live attenuated measles vaccine can theoretically suppress PPD reactivity, the degree of suppression is probably less than that occurring from acute infection from wild measles virus. Although routine PPD screening of all children is no longer recommended, PPD screening is sometimes needed at the same time as administering a measles-containing vaccine (e.g., for well-child care, school entrance, or for employee health reasons), and the following options should be considered:\n- PPD and measles-containing vaccine can be administered at the same visit (preferred option). Simultaneously administering PPD and measles-containing vaccine does not interfere with reading the PPD result at 48-72 hours and ensures that the person has received measles vaccine. - If the measles-containing vaccine has been administered recently, PPD screening should be delayed >4 weeks after vaccination. A delay in performing PPD will re-move the concern of any theoretical but transient suppression of PPD reactivity from the vaccine. - PPD screening can be performed and read before administering the measles-containing vaccine. This option is the least favored because it will delay receipt of the measles-containing vaccine. No data exist for the potential degree of PPD suppression that might be associated with other parenteral live attenuated virus vaccines (e.g., varicella or yellow fever). Nevertheless, in the absence of data, following guidelines for measlescontaining vaccine when scheduling PPD screening and administering other parenteral live attenuated virus vaccines is prudent. If a risk exists that the opportunity to vaccinate might be missed, vaccination should not be delayed only because of these theoretical considerations.\nMucosally administered live attenuated virus vaccines (e.g., OPV and intranasally administered influenza vaccine) are unlikely to affect the response to PPD. No evidence has been reported that inactivated vaccines, polysaccharide vaccines, recombinant, or subunit vaccines, or toxoids interfere with response to PPD.\nPPD reactivity in the absence of tuberculosis disease is not a contraindication to administration of any vaccine, including parenteral live attenuated virus vaccines. Tuberculosis disease is not a contraindication to vaccination, unless the person is moderately or severely ill. Although no studies have reported the effect of MMR vaccine on persons with untreated tuberculosis, a theoretical basis exists for concern that measles vaccine might exacerbate tuberculosis (6). Consequently, before administering MMR to persons with untreated active tuberculosis, initiating antituberculosis therapy is advisable (6). Ruling out concurrent immunosuppression (e.g., immunosuppression caused by HIV infection) before administering live attenuated vaccines is also prudent.\n\n# Severe Allergy to Vaccine Components\nVaccine components can cause allergic reactions among certain recipients. These reactions can be local or systemic and can include mild to severe anaphylaxis or anaphylactic-like responses (e.g., generalized urticaria or hives, wheezing, swelling of the mouth and throat, difficulty breathing, hypotension, and shock). Allergic reactions might be caused by the vaccine antigen, residual animal protein, antimicrobial agents, preservatives, stabilizers, or other vaccine components (94). An extensive listing of vaccine components, their use, and the vaccines that contain each component has been published (95) and is also available from CDC's National Immunization Program website at (accessed October 31,2001).\nThe most common animal protein allergen is egg protein, which is found in vaccines prepared by using embryonated chicken eggs (influenza and yellow fever vaccines). Ordinarily, persons who are able to eat eggs or egg products safely can receive these vaccines; persons with histories of anaphylactic or anaphylactic-like allergy to eggs or egg proteins should not be administered these vaccines. Asking persons if they can eat eggs without adverse effects is a reasonable way to determine who might be at risk for allergic reactions from receiving yellow fever and influenza vaccines. A regimen for administering influenza vaccine to children with egg hypersensitivity and severe asthma has been developed (96).\nMeasles and mumps vaccine viruses are grown in chick embryo fibroblast tissue culture. Persons with a serious egg allergy can receive measles-or mumps-containing vaccines without skin testing or desensitization to egg protein (6). Rubella and varicella vaccines are grown in human diploid cell cultures and can safely be administered to persons with histories of severe allergy to eggs or egg proteins. The rare serious allergic reaction after measles or mumps vaccination or MMR are not believed to be caused by egg antigens, but to other components of the vaccine (e.g., gelatin) (97-100). MMR, its component vaccines, and other vaccines contain hydrolyzed gelatin as a stabilizer. Extreme caution should be exercised when administering vaccines that contain gelatin to persons who have a history of an anaphylactic reaction to gelatin or gelatincontaining products. Before administering gelatincontaining vaccines to such persons, skin testing for sensitivity to gelatin can be considered. However, no specific protocols for this approach have been published.\nCertain vaccines contain trace amounts of antibiotics or other preservatives (e.g., neomycin or thimerosal) to which patients might be severely allergic. The information provided in the vaccine package insert should be reviewed carefully before deciding if the rare patient with such allergies should receive the vaccine. No licensed vaccine contains penicillin or penicillin derivatives.\nCertain vaccines contain trace amounts of neomycin. Persons who have experienced anaphylactic reactions to neomycin should not receive these vaccines. Most often, neomycin allergy is a contact dermatitis, a manifestation of a delayed type (cell-mediated) immune response, rather than anaphylaxis (101,102). A history of delayed type reactions to neomycin is not a contraindication for administration of these vaccines.\nThimerosal is an organic mercurial compound in use since the 1930s and added to certain immunobiologic products as a preservative. A joint statement issued by the U.S. Public Health Service and the American Academy of Pediatrics (AAP) in 1999 (103) and agreed to by the American Academy of Family Physicians (AAFP) later in 1999, established the goal of removing thimerosal as soon as possible from vaccines routinely recommended for infants. Although no evidence exists of any harm caused by low levels of thimerosal in vaccines and the risk was only theoretical (104), this goal was established as a precautionary measure.\nThe public is concerned about the health effects of mercury exposure of any type, and the elimination of mercury from vaccines was judged a feasible means of reducing an infant's total exposure to mercury in a world where other environmental sources of exposure are more difficult or impossible to eliminate (e.g., certain foods). Since mid-2001, vaccines routinely recommended for children have been manufactured without thimerosal as a preservative and contain either no thimerosal or only trace amounts. Thimerosal as a preservative is present in certain other vaccines (e.g., Td, DT, one of two adult hepatitis B vaccines, and influenza vaccine). A trace thimerosal formulation of one brand of influenza vaccine was licensed by FDA in September 2001.\nReceiving thimerosal-containing vaccines has been believed to lead to induction of allergy. However, limited scientific basis exists for this assertion (94). Hypersensitivity to thimerosal usually consists of local delayed type hypersensitivity reactions (105)(106)(107). Thimerosal elicits positive delayed type hypersensitivity patch tests in 1%-18% of persons tested, but these tests have limited or no clinical relevance (108,109). The majority of patients do not experience reactions to thimerosal administered as a component of vaccines even when patch or intradermal tests for thimerosal indicate hypersensitivity (109). A localized or delayed type hypersensitivity reaction to thimerosal is not a contraindication to receipt of a vaccine that contains thimerosal.\n\n# Latex Allergy\nLatex is liquid sap from the commercial rubber tree. Latex contains naturally occurring impurities (e.g., plant proteins and peptides), which are believed to be responsible for allergic reactions. Latex is processed to form natural rubber latex and dry natural rubber. Dry natural rubber and natural rubber latex might contain the same plant impurities as latex but in lesser amounts. Natural rubber latex is used to produce medical gloves, catheters, and other products. Dry natural rubber is used in syringe plungers, vial stoppers, and injection ports on intravascular tubing. Synthetic rubber and synthetic latex also are used in medical gloves, syringe plungers, and vial stoppers. Synthetic rubber and synthetic latex do not contain natural rubber or natural latex, and therefore, do not contain the impurities linked to allergic reactions. The most common type of latex sensitivity is contacttype (type 4) allergy, usually as a result of prolonged contact with latex-containing gloves (110). However, injectionprocedure-associated latex allergies among patients with diabetes have been described (111)(112)(113). Allergic reactions (including anaphylaxis) after vaccination procedures are rare. Only one report of an allergic reaction after administering hepatitis B vaccine in a patient with known severe allergy (anaphylaxis) to latex has been published (114).\nIf a person reports a severe (anaphylactic) allergy to latex, vaccines supplied in vials or syringes that contain natural rubber should not be administered, unless the benefit of vaccination outweighs the risk of an allergic reaction to the vaccine. For latex allergies other than anaphylactic allergies (e.g., a history of contact allergy to latex gloves), vaccines supplied in vials or syringes that contain dry natural rubber or natural rubber latex can be administered.\n\n# Vaccination of Premature Infants\nIn the majority of cases, infants born prematurely, regardless of birth weight, should be vaccinated at the same chronological age and according to the same schedule and precautions as full-term infants and children. Birth weight and size are not factors in deciding whether to postpone routine vaccination of a clinically stable premature infant (115)(116)(117), except for hepatitis B vaccine. The full recommended dose of each vaccine should be used. Divided or reduced doses are not recommended (118).\nStudies demonstrate that decreased seroconversion rates might occur among certain premature infants with low birth weights (i.e., <2,000 grams) after administration of hepatitis B vaccine at birth (119). However, by chronological age 1 month, all premature infants, regardless of initial birth weight or gestational age are as likely to respond as adequately as older and larger infants (120)(121)(122). A premature infant born to HBsAg-positive mothers and mothers with unknown HBsAg status must receive immunoprophylaxis with hepatitis B vaccine and hepatitis B immunoglobulin (HBIG) <12 hours after birth. If these infants weigh <2,000 grams at birth, the initial vaccine dose should not be counted towards completion of the hepatitis B vaccine series, and three additional doses of hepatitis B vaccine should be administered, beginning when the infant is age 1 month. The optimal timing of the first dose of hepatitis B vaccine for premature infants of HBsAg-negative mothers with a birth weight of <2,000 grams has not been determined. However, these infants can receive the first dose of the hepatitis B vaccine series at chronological age 1 month. Premature infants discharged from the hospital before chronological age 1 month can also be administered hepatitis B vaccine at discharge, if they are medically stable and have gained weight consistently.\n\n# Breast-Feeding and Vaccination\nNeither inactivated nor live vaccines administered to a lactating woman affect the safety of breast-feeding for mothers or infants. Breast-feeding does not adversely affect immunization and is not a contraindication for any vaccine. Limited data indicate that breast-feeding can enhance the response to certain vaccine antigens (123). Breast-fed infants should be vaccinated according to routine recommended schedules (124)(125)(126).\nAlthough live vaccines multiply within the mother's body, the majority have not been demonstrated to be excreted in human milk. Although rubella vaccine virus might be excreted in human milk, the virus usually does not infect the infant. If infection does occur, it is well-tolerated because the viruses are attenuated (127). Inactivated, recombinant, subunit, polysaccharide, conjugate vaccines and toxoids pose no risk for mothers who are breast-feeding or for their infants.\n\n# Vaccination During Pregnancy\nRisk to a developing fetus from vaccination of the mother during pregnancy is primarily theoretical. No evidence exists of risk from vaccinating pregnant women with inactivated virus or bacterial vaccines or toxoids (128,129). Benefits of vaccinating pregnant women usually outweigh potential risks when the likelihood of disease exposure is high, when infection would pose a risk to the mother or fetus, and when the vaccine is unlikely to cause harm.\nTd toxoid is indicated routinely for pregnant women. Previously vaccinated pregnant women who have not received a Td vaccination within the last 10 years should receive a booster dose. Pregnant women who are not immunized or only partially immunized against tetanus should complete the primary series (130). Depending on when a woman seeks prenatal care and the required interval between doses, one or two doses of Td can be administered before delivery. Women for whom the vaccine is indicated, but who have not completed the recommended three-dose series during pregnancy, should receive follow-up after delivery to ensure the series is completed.\nWomen in the second and third trimesters of pregnancy have been demonstrated to be at increased risk for hospitalization from influenza (131). Therefore, routine influenza vaccina-tion is recommended for healthy women who will be beyond the first trimester of pregnancy (i.e., >14 weeks of gestation) during influenza season (usually December-March in the United States) (88). Women who have medical conditions that increase their risk for complications of influenza should be vaccinated before the influenza season, regardless of the stage of pregnancy.\nIPV can be administered to pregnant women who are at risk for exposure to wild-type poliovirus infection (4). Hepatitis B vaccine is recommended for pregnant women at risk for hepatitis B virus infection (132). Hepatitis A, pneumococcal polysaccharide, and meningococcal polysaccharide vaccines should be considered for women at increased risk for those infections (43,133,134).\nPregnant women who must travel to areas where the risk for yellow fever is high should receive yellow fever vaccine, because the limited theoretical risk from vaccination is substantially outweighed by the risk for yellow fever infection (22,135). Pregnancy is a contraindication for measles, mumps, rubella, and varicella vaccines. Although of theoretical concern, no cases of congenital rubella or varicella syndrome or abnormalities attributable to fetal infection have been observed among infants born to susceptible women who received rubella or varicella vaccines during pregnancy (6,136). Because of the importance of protecting women of childbearing age against rubella, reasonable practices in any immunization program include asking women if they are pregnant or intend to become pregnant in the next 4 weeks, not vaccinating women who state that they are pregnant, explaining the potential risk for the fetus to women who state that they are not pregnant, and counseling women who are vaccinated not to become pregnant during the 4 weeks after MMR vaccination (6,35,137). Routine pregnancy testing of women of childbearing age before administering a live-virus vaccine is not recommended (6). If a pregnant woman is inadvertently vaccinated or if she becomes pregnant within 4 weeks after MMR or varicella vaccination, she should be counseled regarding the theoretical basis of concern for the fetus; however, MMR or varicella vaccination during pregnancy should not ordinarily be a reason to terminate pregnancy (6,8).\nPersons who receive MMR vaccine do not transmit the vaccine viruses to contacts (6). Transmission of varicella vaccine virus to contacts is rare (138). MMR and varicella vaccines should be administered when indicated to the children and other household contacts of pregnant women (6,8).\nAll pregnant women should be evaluated for immunity to rubella and be tested for the presence of HBsAg (6,35,132). Women susceptible to rubella should be vaccinated immedi-ately after delivery. A woman known to be HBsAg-positive should be followed carefully to ensure that the infant receives HBIG and begins the hepatitis B vaccine series <12 hours after birth and that the infant completes the recommended hepatitis B vaccine series (132). No known risk exists for the fetus from passive immunization of pregnant women with immune globulin preparations.\n\n# Vaccination of Internationally Adopted Children\nThe ability of a clinician to determine that a person is protected on the basis of their country of origin and their records alone is limited. Internationally adopted children should receive vaccines according to recommended schedules for children in the United States. Only written documentation should be accepted as evidence of prior vaccination. Written records are more likely to predict protection if the vaccines, dates of administration, intervals between doses, and the child's age at the time of immunization are comparable to the current U.S. recommendations. Although vaccines with inadequate potency have been produced in other countries (139,140), the majority of vaccines used worldwide are produced with adequate quality control standards and are potent.\nThe number of American families adopting children from outside the United States has increased substantially in recent years (141). Adopted children's birth countries often have immunization schedules that differ from the recommended childhood immunization schedule in the United States. Differences in the U.S. immunization schedule and those used in other countries include the vaccines administered, the recommended ages of administration, and the number and timing of doses.\nData are inconclusive regarding the extent to which an internationally adopted child's immunization record reflects the child's protection. A child's record might indicate administration of MMR vaccine when only single-antigen measles vaccine was administered. A study of children adopted from the People's Republic of China, Russia, and Eastern Europe determined that only 39% (range: 17%-88% by country) of children with documentation of >3 doses of DTP before adoption had protective levels of diphtheria and tetanus antitoxin (142). However, antibody testing was performed by using a hemagglutination assay, which tends to underestimate protection and cannot directly be compared with antibody concentration (143). Another study measured antibody to diphtheria and tetanus toxins among 51 children who had records of having received >2 doses of DTP. The majority of the children were from Russia, Eastern Europe, and Asian countries, and 78% had re-ceived all their vaccine doses in an orphanage. Overall, 94% had evidence of protection against diphtheria (EIA > 0.1 IU/mL). A total of 84% had protection against tetanus (enzyme-linked immunosorbent assay > 0.5 IU/mL). Among children without protective tetanus antitoxin concentration, all except one had records of >3 doses of vaccine, and the majority of nonprotective concentrations were categorized as indeterminate (ELISA = 0.05-0.49 IU/mL) (144). Reasons for the discrepant findings in these two studies probably relate to different laboratory methodologies; the study using a hemagglutination assay might have underestimated the number of children who were protected. Additional studies using standardized methodologies are needed. Data are likely to remain limited for countries other than the People's Republic of China, Russia, and Eastern Europe because of the limited number of adoptees from other countries.\nPhysicians and other health-care providers can follow one of multiple approaches if a question exists regarding whether vaccines administered to an international adoptee were im-munogenic. Repeating the vaccinations is an acceptable option. Doing so is usually safe and avoids the need to obtain and interpret serologic tests. If avoiding unnecessary injections is desired, judicious use of serologic testing might be helpful in determining which immunizations are needed. This report provides guidance on possible approaches to evaluation and revaccination for each vaccine recommended universally for children in the United States (see Table 6 and the following sections).\n\n# MMR Vaccine\nThe simplest approach to resolving concerns regarding MMR immunization among internationally adopted children is to revaccinate with one or two doses of MMR vaccine, depending on the child's age. Serious adverse events after MMR vaccinations are rare (6). No evidence indicates that administering MMR vaccine increases the risk for adverse reactions among persons who are already immune to measles, mumps, or rubella as a result of previous vaccination or natural disease. Doses of measles-containing vaccine Serologic testing for neutralizing antibody to poliovirus types 1, 2, and 3 (limited availability), or administer single dose of IPV, followed by serologic testing for neutralizing antibody to poliovirus types 1, 2, and 3\nChildren whose records indicate receipt of >3 doses: serologic testing for specific IgG antibody to diphtheria and tetanus toxins before administering additional doses (see text), or administer a single booster dose of DTaP, followed by serological testing after 1 month for specific IgG antibody to diphtheria and tetanus toxins with revaccination as appropriate (see text) --\n\n# TABLE 6. Approaches to the evaluation and vaccination of internationally adopted children\n\n# Vaccine\nRecommended approach Alternative approach administered before the first birthday should not be counted as part of the series (6). Alternatively, serologic testing for immunoglobulin G (IgG) antibody to vaccine viruses indicated on the vaccination record can be considered. Serologic testing is widely available for measles and rubella IgG antibody. A child whose record indicates receipt of monovalent measles or measles-rubella vaccine at age >1 year and who has protective antibody against measles and rubella should receive a single dose of MMR as age-appropriate to ensure protection against mumps (and rubella if measles vaccine alone had been used). If a child whose record indicates receipt of MMR at age >12 months has a protective concentration of antibody to measles, no additional vaccination is needed unless required for school entry.\n\n# Hib Vaccine\nSerologic correlates of protection for children vaccinated >2 months previously might be difficult to interpret. Because the number of vaccinations needed for protection decreases with age and adverse events are rare (24), ageappropriate vaccination should be provided. Hib vaccination is not recommended routinely for children aged >5 years.\n\n# Hepatitis B Vaccine\nSerologic testing for HBsAg is recommended for international adoptees, and children determined to be HBsAgpositive should be monitored for the development of liver disease. Household members of HBsAg-positive children should be vaccinated. A child whose records indicate receipt of >3 doses of vaccine can be considered protected, and additional doses are not needed if >1 doses were administered at age >6 months. Children who received their last hepatitis B vaccine dose at age 6 months. Those who have received <3 doses should complete the series at the recommended intervals and ages (Table 1).\n\n# Poliovirus Vaccine\nThe simplest approach is to revaccinate internationally adopted children with IPV according to the U.S. schedule. Adverse events after IPV are rare (4). Children appropriately vaccinated with three doses of OPV in economically developing countries might have suboptimal seroconversion, including to type 3 poliovirus (125). Serologic testing for neutralizing antibody to poliovirus types 1, 2, and 3 can be obtained commercially and at certain state health department laboratories. Children with protective titers against all three types do not need revaccination and should complete the schedule as age-appropriate. Alternately, because the booster response after a single dose of IPV is excellent among children who previously received OPV (3), a single dose of IPV can be administered initially with serologic testing performed 1 month later.\n\n# DTaP Vaccine\nVaccination providers can revaccinate a child with DTaP vaccine without regard to recorded doses; however, one concern regarding this approach is that data indicate increased rates of local adverse reactions after the fourth and fifth doses of DTP or DTaP (42). If a revaccination approach is adopted and a severe local reaction occurs, serologic testing for specific IgG antibody to tetanus and diphtheria toxins can be measured before administering additional doses. Protective concentration indicates that further doses are unnecessary and subsequent vaccination should occur as ageappropriate. No established serologic correlates exist for protection against pertussis.\nFor a child whose record indicates receipt of >3 doses of DTP or DTaP, serologic testing for specific IgG antibody to both diphtheria and tetanus toxin before additional doses is a reasonable approach. If a protective concentration is present, recorded doses can be considered valid, and the vaccination series should be completed as age-appropriate. Indeterminate antibody concentration might indicate immunologic memory but antibody waning; serology can be repeated after a booster dose if the vaccination provider wishes to avoid revaccination with a complete series.\nAlternately, for a child whose records indicate receipt of >3 doses, a single booster dose can be administered, followed by serologic testing after 1 month for specific IgG antibody to both diphtheria and tetanus toxins. If a protective concentration is obtained, the recorded doses can be considered valid and the vaccination series completed as age-appropriate. Children with indeterminate concentration after a booster dose should be revaccinated with a complete series.\n\n# Varicella Vaccine\nVaricella vaccine is not administered in the majority of countries. A child who lacks a reliable medical history regarding prior varicella disease should be vaccinated as ageappropriate (8).\n\n# Pneumococcal Vaccines\nPneumococcal conjugate and pneumococcal polysaccharide vaccines are not administered in the majority of coun- tries and should be administered as age-appropriate or as indicated by the presence of underlying medical conditions (26,43).\n\n# Altered Immunocompetence\nACIP's statement regarding vaccinating immunocompromised persons summarizes recommendations regarding the efficacy, safety, and use of specific vaccines and immune globulin preparations for immunocompromised persons (145). ACIP statements regarding individual vaccines or immune globulins contain additional information regarding those concerns.\nSevere immunosuppression can be the result of congenital immunodeficiency, HIV infection, leukemia, lymphoma, generalized malignancy or therapy with alkylating agents, antimetabolites, radiation, or a high dose, prolonged course of corticosteroids. The degree to which a person is immunocompromised should be determined by a physician. Severe complications have followed vaccination with live-virus vaccines and live bacterial vaccines among immunocompromised patients (146)(147)(148)(149)(150)(151)(152)(153). These patients should not receive live vaccines except in certain circumstances that are noted in the following paragraphs. MMR vaccine viruses are not transmitted to contacts, and transmission of varicella vaccine virus is rare (6,138). MMR and varicella vaccines should be administered to susceptible household and other close contacts of immunocompromised patients when indicated.\nPersons with HIV infection are at increased risk for severe complications if infected with measles. No severe or unusual adverse events have been reported after measles vaccination among HIV-infected persons who did not have evidence of severe immunosuppression (154)(155)(156)(157). As a result, MMR vaccination is recommended for all HIVinfected persons who do not have evidence of severe immunosuppression † † and for whom measles vaccination would otherwise be indicated.\nChildren with HIV infection are at increased risk for complications of primary varicella and for herpes zoster, compared with immunocompetent children (138,158). Limited data among asymptomatic or mildly symptomatic HIVinfected children (CDC class N1 or A1, age-specific CD4 + lymphocyte percentages of >25%) indicate that varicella vaccine is immunogenic, effective, and safe (138,159). Varicella vaccine should be considered for asymptomatic or mildly symptomatic HIV-infected children in CDC class N1 or A1 with age-specific CD4 + T lymphocyte percentages of >25%. Eligible children should receive two doses of varicella vaccine with a 3-month interval between doses (138).\nHIV-infected persons who are receiving regular doses of IGIV might not respond to varicella vaccine or MMR or its individual component vaccines because of the continued presence of passively acquired antibody. However, because of the potential benefit, measles vaccination should be considered approximately 2 weeks before the next scheduled dose of IGIV (if not otherwise contraindicated), although an optimal immune response is unlikely to occur. Unless serologic testing indicates that specific antibodies have been produced, vaccination should be repeated (if not otherwise contraindicated) after the recommended interval (Table 4). An additional dose of IGIV should be considered for persons on maintenance IGIV therapy who are exposed to measles >3 weeks after administering a standard dose (100-400 mg/kg body weight) of IGIV.\nPersons with cellular immunodeficiency should not receive varicella vaccine. However, ACIP recommends that persons with impaired humoral immunity (e.g., hypogammaglobulinemia or dysgammaglobulinemia) should be vaccinated (138,160).\nInactivated, recombinant, subunit, polysaccharide, and conjugate vaccines and toxoids can be administered to all immunocompromised patients, although response to such vaccines might be suboptimal. If indicated, all inactivated vaccines are recommended for immunocompromised persons in usual doses and schedules. In addition, pneumococcal, meningococcal, and Hib vaccines are recommended specifically for certain groups of immunocompromised patients, including those with functional or anatomic asplenia (145,161).\nExcept for influenza vaccine, which should be administered annually (88), vaccination during chemotherapy or radiation therapy should be avoided because antibody response is suboptimal. Patients vaccinated while receiving immunosuppressive therapy or in the 2 weeks before starting therapy should be considered unimmunized and should be revaccinated >3 months after therapy is discontinued. Patients with leukemia in remission whose chemotherapy has been terminated for >3 months can receive live-virus vaccines. † † As defined by a low age-specific total CD4 + T lymphocyte count or a low CD4 + T lymphocyte count as a percentage of total lymphocytes. ACIP recommendations for using MMR vaccine contain additional details regarding the criteria for severe immunosuppression in persons with HIV infection (Source: CDC. Measles, mumps, and rubella -vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the Advisory Committee on Immunization Practices . MMWR 1998;47:1-57).\n\n# Corticosteroids\nThe exact amount of systemically absorbed corticosteroids and the duration of administration needed to suppress the immune system of an otherwise immunocompetent person are not well-defined. The majority of experts agree that corticosteroid therapy usually is not a contraindication to administering live-virus vaccine when it is shortterm (i.e., 2 mg/kg of body weight or a total of 20 mg/day of prednisone or equivalent for children who weigh >10 kg, when administered for >2 weeks as sufficiently immunosuppressive to raise concern regarding the safety of vaccination with live-virus vaccines (84,145). Corticosteroids used in greater than physiologic doses also can reduce the immune response to vaccines. Vaccination providers should wait >1 month after discontinuation of therapy before administering a live-virus vaccine to patients who have received high systemically absorbed doses of corticosteroids for >2 weeks.\n\n# Vaccination of Hematopoietic Stem Cell Transplant Recipients\nHematopoietic stem cell transplant (HSCT) is the infusion of hematopoietic stem cells from a donor into a patient who has received chemotherapy and often radiation, both of which are usually bone marrow ablative. HSCT is used to treat a variety of neoplastic diseases, hematologic disorders, immunodeficiency syndromes, congenital enzyme deficiencies, and autoimmune disorders. HSCT recipients can receive either their own cells (i.e., autologous HSCT) or cells from a donor other than the transplant recipient (i.e., allogeneic HSCT). The source of the transplanted stem cells can be from either a donor's bone marrow or peripheral blood or harvested from the umbilical cord of a newborn infant (162).\nAntibody titers to vaccine-preventable diseases (e.g., tetanus, poliovirus, measles, mumps, rubella, and encapsulated bacteria) decline during the 1-4 years after allogeneic or autologous HSCT if the recipient is not revaccinated (163)(164)(165)(166)(167).\nHSCT recipients are at increased risk for certain vaccine-pre-ventable diseases, including those caused by encapsulated bacteria (i.e., pneumococcal and Hib infections). As a result, HSCT recipients should be routinely revaccinated after HSCT, regardless of the source of the transplanted stem cells. Revaccination with inactivated, recombinant, subunit, polysaccharide, and Hib vaccines should begin 12 months after HSCT (162). An exception to this recommendation is for influenza vaccine, which should be administered at >6 months after HSCT and annually for the life of the recipient thereafter. MMR vaccine should be administered 24 months after transplantation if the HSCT recipient is presumed to be immunocompetent. Varicella, meningococcal, and pneumococcal conjugate vaccines are not recommended for HSCT recipients because of insufficient experience using these vaccines among HSCT recipients (162). The household and other close contacts of HSCT recipients and health-care workers who care for HSCT recipients, should be appropriately vaccinated, including against influenza, measles, and varicella. Additional details of vaccination of HSCT recipients and their contacts can be found in a specific CDC report on this topic (162).\n\n# Vaccinating Persons with Bleeding Disorders and Persons Receiving Anticoagulant Therapy\nPersons with bleeding disorders (e.g., hemophilia) and persons receiving anticoagulant therapy have an increased risk for acquiring hepatitis B and at least the same risk as the general population of acquiring other vaccinepreventable diseases. However, because of the risk for hematoma formation after injections, intramuscular injections are often avoided among persons with bleeding disorders by using the subcutaneous or intradermal routes for vaccines that are administered normally by the intramuscular route. Hepatitis B vaccine administered intramuscularly to 153 persons with hemophilia by using a 23-gauge needle, followed by steady pressure to the site for 1-2 minutes, resulted in a 4% bruising rate with no patients requiring factor supplementation (168). Whether antigens that produce more local reactions (e.g., pertussis) would produce an equally low rate of bruising is unknown.\nWhen hepatitis B or any other intramuscular vaccine is indicated for a patient with a bleeding disorder or a person receiving anticoagulant therapy, the vaccine should be administered intramuscularly if, in the opinion of a physician familiar with the patient's bleeding risk, the vaccine can be administered with reasonable safety by this route. If the patient receives antihemophilia or similar therapy, intramuscular vaccinations can be scheduled shortly after such\n\n# Vaccination Records\n\n# Consent to Vaccinate\nThe National Childhood Vaccine Injury Act of 1986 (42 U.S.C. § 300aa-26) requires that all health-care providers in the United States who administer any vaccine covered by the act § § must provide a copy of the relevant, current edition of the vaccine information materials that have been produced by CDC before administering each dose of the vaccine. The vaccine information material must be provided to the parent or legal representative of any child or to any adult to whom the physician or other health-care provider intends to administer the vaccine. The Act does not require that a signature be obtained, but documentation of consent is recommended or required by certain state or local authorities.\n\n# Provider Records\nDocumentation of patient vaccinations helps ensure that persons in need of a vaccine receive it and that adequately vaccinated patients are not overimmunized, possibly increasing the risk for local adverse events (e.g., tetanus toxoid). Serologic test results for vaccine-preventable diseases (e.g., those for rubella screening) as well as documented episodes of adverse events also should be recorded in the permanent medical record of the vaccine recipient.\nHealth-care providers who administer vaccines covered by the National Childhood Vaccine Injury Act are required to ensure that the permanent medical record of the recipient (or a permanent office log or file) indicates the date the vaccine was administered, the vaccine manufacturer, the vaccine lot number, and the name, address, and title of the person administering the vaccine. Additionally, the provider is required to record the edition date of the vaccine information materials distributed and the date those materials were provided. Regarding this Act, the term health-care provider is defined as any licensed health-care professional, organization, or institution, whether private or public (including federal, state, and local departments and agencies), under whose authority a specified vaccine is adminis-tered. ACIP recommends that this same information be kept for all vaccines, not just for those required by the National Childhood Vaccine Injury Act.\n\n# Patients' Personal Records\nOfficial immunization cards have been adopted by every state, territory, and the District of Columbia to encourage uniformity of records and to facilitate assessment of immunization status by schools and child care centers. The records also are key tools in immunization education programs aimed at increasing parental and patient awareness of the need for vaccines. A permanent immunization record card should be established for each newborn infant and maintained by the parent or guardian. In certain states, these cards are distributed to new mothers before discharge from the hospital. Using immunization record cards for adolescents and adults also is encouraged.\n\n# Registries\nImmunization registries are confidential, populationbased, computerized information systems that collect vaccination data for as many children as possible within a geographic area. Registries are a critical tool that can increase and sustain increased vaccination coverage by consolidating vaccination records of children from multiple providers, generating reminder and recall vaccination notices for each child, and providing official vaccination forms and vaccination coverage assessments (169). A fully operational immunization registry also can prevent duplicate vaccinations, limit missed appointments, reduce vaccine waste, and reduce staff time required to produce or locate immunization records or certificates. The National Vaccine Advisory Committee strongly encourages development of community-or state-based immunization registry systems and recommends that vaccination providers participate in these registries whenever possible (170,171). A 95% participation of children aged <6 years in fully operational population-based immunization registries is a national health objective for 2010 (172).\n\n# Reporting Adverse Events After Vaccination\nModern vaccines are safe and effective; however, adverse events have been reported after administration of all vaccines (82). These events range from frequent, minor, local reactions to extremely rare, severe, systemic illness (e.g., encephalopathy). Establishing evidence for cause-and-effect relationships on the basis of case reports and case series alone is impos- § § As of January 2002, vaccines covered by the act include diphtheria, tetanus, pertussis, measles, mumps, rubella, poliovirus, hepatitis B, Hib, varicella, and pneumococcal conjugate. sible because temporal association alone does not necessarily indicate causation. Unless the syndrome that occurs after vaccination is clinically or pathologically distinctive, more detailed epidemiologic studies to compare the incidence of the event among vaccinees with the incidence among unvaccinated persons are often necessary. Reporting adverse events to public health authorities, including serious events, is a key stimulus to developing studies to confirm or refute a causal association with vaccination. More complete information regarding adverse reactions to a specific vaccine can be found in the ACIP recommendations for that vaccine and in a specific statement on vaccine adverse reactions (82).\nThe National Childhood Vaccine Injury Act requires health-care providers to report selected events occurring after vaccination to the Vaccine Adverse Event Reporting System (VAERS). Events for which reporting is required appear in the Vaccine Injury Table . ¶ ¶ Persons other than healthcare workers also can report adverse events to VAERS. Adverse events other than those that must be reported or that occur after administration of vaccines not covered by the act, including events that are serious or unusual, also should be reported to VAERS, even if the physician or other healthcare provider is uncertain they are related causally. VAERS forms and instructions are available in the FDA Drug Bulletin, by calling the 24-hour VAERS Hotline at 800-822-7967, or from the VAERS website at (accessed November 7, 2001).\n\n# Vaccine Injury Compensation Program\nThe National Vaccine Injury Compensation Program, established by the National Childhood Vaccine Injury Act, is a no-fault system in which persons thought to have suffered an injury or death as a result of administration of a covered vaccine can seek compensation. The program, which became operational on October 1, 1988, is intended as an alternative to civil litigation under the traditional tort system in that negligence need not be proven. Claims arising from covered vaccines must first be adjudicated through the program before civil litigation can be pursued.\nThe program relies on a Vaccine Injury\n\n# Benefit and Risk Communication\nParents, guardians, legal representatives, and adolescent and adult patients should be informed regarding the benefits and risks of vaccines in understandable language. Opportunity for questions should be provided before each vaccination. Discussion of the benefits and risks of vaccination is sound medical practice and is required by law.\nThe National Childhood Vaccine Injury Act requires that vaccine information materials be developed for each vaccine covered by the Act. These materials, known as Vaccine Information Statements, must be provided by all public and private vaccination providers each time a vaccine is administered. a dialogue regarding the risks and benefits of certain vaccines. Having a basic understanding of how patients view vaccine risk and developing effective approaches in dealing with vaccine safety concerns when they arise is imperative for vaccination providers. Each person understands and reacts to vaccine information on the basis of different factors, including prior experience, education, personal values, method of data presentation, perceptions of the risk for disease, perceived ability to control those risks, and their risk preference. Increasingly, through the media and nonauthoritative Internet sites, decisions regarding risk are based on inaccurate information. Only through direct dialogue with parents and by using available resources, health-care professionals can prevent acceptance of media reports and information from nonauthoritative Internet sites as scientific fact.\nWhen a parent or patient initiates discussion regarding a vaccine controversy, the health-care professional should discuss the specific concerns and provide factual information, using language that is appropriate. Effective, empathetic vaccine risk communication is essential in responding to misinformation and concerns, although recognizing that for certain persons, risk assessment and decision-making is difficult and confusing. Certain vaccines might be acceptable to the resistant parent. Their concerns should then be addressed in the context of this information, using the Vaccine Information Statements and offering other resource materials (e.g., information available on the National Immunization Program website).\nAlthough a limited number of providers might choose to exclude from their practice those patients who question or refuse vaccination, the more effective public health strategy is to identify common ground and discuss measures that need to be followed if the patient's decision is to defer vaccination. Health-care providers can reinforce key points regarding each vaccine, including safety, and emphasize risks encountered by unimmunized children. Parents should be advised of state laws pertaining to school or child care entry, which might require that unimmunized children stay home from school during outbreaks. Documentation of these discussions in the patient's record, including the refusal to receive certain vaccines (i.e., informed refusal), might reduce any potential liability if a vaccine-preventable disease occurs in the unimmunized patient.\n\n# Vaccination Programs\nThe best way to reduce vaccine-preventable diseases is to have a highly immune population. Universal vaccination is a critical part of quality health care and should be accomplished through routine and intensive vaccination programs implemented in physicians' offices and in public health clinics. Programs should be established and maintained in all communities to ensure vaccination of all children at the recommended age. In addition, appropriate vaccinations should be available for all adolescents and adults.\nPhysicians and other pediatric vaccination providers should adhere to the standards for child and adolescent immunization practices (1). These standards define appropriate vaccination practices for both the public and private sectors. The standards provide guidance on practices that will result in eliminating barriers to vaccination. These include practices aimed at eliminating unnecessary prerequisites for receiving vaccinations, eliminating missed opportunities to vaccinate, improving procedures to assess vaccination needs, enhancing knowledge regarding vaccinations among parents and providers, and improving the management and reporting of adverse events. Additionally, the standards address the importance of recall and reminder systems and using assessments to monitor clinic or office vaccination coverage levels among patients.\nStandards of practice also have been published to increase vaccination coverage among adults (2). Persons aged >65 years and all adults with medical conditions that place them at risk for pneumococcal disease should receive >1 doses of pneumococcal polysaccharide vaccine. All persons aged >50 years and those with medical conditions that increase the risk for complications from influenza should receive annual influenza vaccination. All adults should complete a primary series of tetanus and diphtheria toxoids and receive a booster dose every 10 years. Adult vaccination programs also should provide MMR and varicella vaccines whenever possible to anyone susceptible to measles, mumps, rubella, or varicella. Persons born after 1956 who are attending college (or other posthigh school educational institutions), who are employed in environments that place them at increased risk for measles transmission (e.g., health-care facilities), or who are traveling to areas with endemic measles, should have documentation of having received two doses of MMR on or after their first birthday or other evidence of immunity (6,173). All other adults born after 1956 should have documentation of >1 doses of MMR vaccine on or after their first birthday or have other evidence of immunity. No evidence indicates that administering MMR vaccine increases the risk for adverse reactions among persons who are already immune to measles, mumps, or rubella as a result of previous vaccination or disease. Widespread use of hepatitis B vaccine is encouraged for all persons who might be at in-creased risk (e.g., adolescents and adults who are either in a group at high risk or reside in areas with increased rates of injection-drug use, teenage pregnancy, or sexually transmitted disease).\nEvery visit to a physician or other health-care provider can be an opportunity to update a patient's immunization status with needed vaccinations. Official health agencies should take necessary steps, including developing and enforcing school immunization requirements, to ensure that students at all grade levels (including college) and those in child care centers are protected against vaccine-preventable diseases. Agencies also should encourage institutions (e.g., hospitals and long-term care facilities) to adopt policies regarding the appropriate vaccination of patients, residents, and employees (173).\nDates of vaccination (day, month, and year) should be recorded on institutional immunization records (e.g., those kept in schools and child care centers). This record will facilitate assessments that a primary vaccination series has been completed according to an appropriate schedule and that needed booster doses have been administered at the appropriate time.\nThe independent, nonfederal Task Force on Community Preventive Services (the Task Force) gives public health decision-makers recommendations on population-based in-terventions to promote health and prevent disease, injury, disability, and premature death. The recommendations are based on systematic reviews of the scientific literature regarding effectiveness and cost-effectiveness of these interventions. In addition, the Task Force identifies critical information regarding the other effects of these interventions, as well as the applicability to specific populations and settings and the potential barriers to implementation. This information is available through the Internet at (accessed November 7, 2001).\nBeginning in 1996, the Task Force systematically reviewed published evidence on the effectiveness and cost-effectiveness of population-based interventions to increase coverage of vaccines recommended for routine use among children, adolescents, and adults. A total of 197 articles were identified that evaluated a relevant intervention, met inclusion criteria, and were published during 1980-1997. Reviews of 17 specific interventions were published in 1999 (174)(175)(176).\nUsing the results of their review, the Task Force made recommendations regarding the use of these interventions (177). A number of interventions were identified and recommended on the basis of published evidence. The interventions and the recommendations are summarized in this report (Table 7). able for intravenous use. Intravenous immune globulin is used primarily for replacement therapy in primary antibody-deficiency disorders, for treatment of Kawasaki disease, immune thrombocytopenic purpura, hypogammaglobulinemia in chronic lymphocytic leukemia, and certain cases of human immunodeficiency virus infection (Table 2). Hyperimmune globulin (specific). Special preparations obtained from blood plasma from donor pools preselected for a high antibody content against a specific antigen (e.g., hepatitis B immune globulin, varicella-zoster immune globulin, rabies immune globulin, tetanus immune globulin, vaccinia immune globulin, cytomegalovirus immune globulin, respiratory syncytial virus immune globulin, botulism immune globulin).\nMonoclonal antibody. An antibody product prepared from a single lymphocyte clone, which contains only antibody against a single microorganism.\nAntitoxin. A solution of antibodies against a toxin. Antitoxin can be derived from either human (e.g., tetanus antitoxin) or animal (usually equine) sources (e.g., diphtheria and botulism antitoxin). Antitoxins are used to confer passive immunity and for treatment.\nVaccination and Immunization. The terms vaccine and vaccination are derived from vacca, the Latin term for cow. Vaccine was the term used by Edward Jenner to describe material used (i.e., cowpox virus) to produce immunity to smallpox. The term vaccination was used by Louis Pasteur in the 19 th century to include the physical act of administering any vaccine or toxoid. Immunization is a more inclusive term, denoting the process of inducing or providing immunity by administering an immunobiologic. Immunization can be active or passive. Active immunization is the production of antibody or other immune responses through administration of a vaccine or toxoid. Passive immunization means the provision of temporary immunity by the administration of preformed antibodies. Four types of immunobiologics are administered for passive immunization: 1) pooled human immune globulin or intravenous immune globulin, 2) hyperimmune globulin (specific) preparations, 3) monoclonal antibody preparations, and 4) antitoxins from nonhuman sources. Although persons often use the terms vaccination and immunization interchangeably in reference to active immunization, the terms are not synonymous because the administration of an immunobiologic cannot be equated automatically with development of adequate immunity.\n\n# Vaccine Information Sources\nIn addition to these general recommendations, other sources are available that contain specific and updated vaccine information.\n\n# National Immunization Information Hotline\nThe National Immunization Information Hotline is supported by CDC's National Immunization Program and provides vaccination information for health-care providers and the public, 8:00 am-11:00 pm, Monday-Friday:\nTelephone (English): 800-232-2522 Telephone (Spanish): 800-232-0233 Telephone (TTY): 800-243-7889 Internet: (accessed November 7, 2001)\n\n# CDC's National Immunization Program\nCDC's National Immunization Program website provides direct access to immunization recommendations of the Advisory Committee on Immunization Practices (ACIP), vaccination schedules, vaccine safety information, publications, provider education and training, and links to other immunization-related websites. It is located at http:// www.cdc.gov/nip (accessed November 7, 2001).\n\n# Morbidity and Mortality Weekly Report\nACIP recommendations regarding vaccine use, statements of vaccine policy as they are developed, and reports of specific disease activity are published by CDC in the Morbidity and Mortality Weekly Report (MMWR) series. Electronic subscriptions are free and available at / subscribe.html (accessed November 7, 2001\n\n# American Academy of Family Physicians (AAFP)\nInformation from the professional organization of family physicians is available at (accessed November 7, 2001).\n\n# Immunization Action Coalition\nThis source provides extensive free provider and patient information, including translations of Vaccine Information Statements into multiple languages. The Internet address is (accessed November 7, 2001).\n\n# National Network for Immunization Information\nThis information source is provided by the Infectious Diseases Society of America, Pediatric Infectious Diseases Society, AAP, American Nurses Association, and other professional organizations. It provides objective, science-based information regarding vaccines for the public and providers. The Internet site is (accessed November 7, 2001).\n\n# Vaccine Education Center\nLocated at the Children's Hospital of Philadelphia, this source provides patient and provider information. The Internet address is (accessed November 7, 2001).\n\n# Institute for Vaccine Safety\n\n# Located at Johns Hopkins University School of Public\nHealth, this source provides information regarding vaccine safety concerns and objective and timely information to healthcare providers and parents. It is available at http:// www.vaccinesafety.edu (accessed November 7, 2001).\n\n# National Partnership for Immunization\nThis national organization encourages greater acceptance and use of vaccinations for all ages through partnerships with public and private organizations. Their Internet address is http:// www.partnersforimmunization.org (accessed November 7, 2001).\n\n# State and Local Health Departments\nState and local health departments provide technical advice through hotlines, electronic mail, and Internet sites, including printed information regarding vaccines and immunization schedules, posters, and other educational materials. nical errors in vaccine preparation, handling, or administration; 4) coincidental: associated temporally with vaccination by chance or caused by underlying illness. Special studies are needed to determine if an adverse event is a reaction or the result of another cause (Sources: Chen RT. Special methodological issues in pharmacoepidemiology studies of vaccine safety. In: Strom BL, ed. Pharmacoepidemiology. Adverse reaction. An undesirable medical condition that has been demonstrated to be caused by a vaccine. Evidence for the causal relationship is usually obtained through randomized clinical trials, controlled epidemiologic studies, isolation of the vaccine strain from the pathogenic site, or recurrence of the condition with repeated vaccination (i.e., rechallenge); synonyms include side effect and adverse effect).\nImmunobiologic. Antigenic substances (e.g., vaccines and toxoids) or antibody-containing preparations (e.g., globulins and antitoxins) from human or animal donors. These products are used for active or passive immunization or therapy. The following are examples of immunobiologics:\nVaccine. A suspension of live (usually attenuated) or inactivated microorganisms (e.g., bacteria or viruses) or fractions thereof administered to induce immunity and prevent infectious disease or its sequelae. Some vaccines contain highly defined antigens (e.g., the polysaccharide of Haemophilus influenzae type b or the surface antigen of hepatitis B); others have antigens that are complex or incompletely defined (e.g., killed Bordetella pertussis or live attenuated viruses).\nToxoid. A modified bacterial toxin that has been made nontoxic, but retains the ability to stimulate the formation of antibodies to the toxin.\nImmune globulin. A sterile solution containing antibodies, which are usually obtained from human blood. It is obtained by cold ethanol fractionation of large pools of blood plasma and contains 15%-18% protein. Intended for intramuscular administration, immune globulin is primarily indicated for routine maintenance of immunity among certain immunodeficient persons and for passive protection against measles and hepatitis A.\nIntravenous immune globulin. A product derived from blood plasma from a donor pool similar to the immune globulin pool, but prepared so that it is suit-\n\n# Abbreviations Used in This Publication\n\n# Definitions Used in This Report\nAdverse event. An untoward event that occurs after a vaccination that might be caused by the vaccine product or vaccination process. It includes events that are 1) vaccineinduced: caused by the intrinsic characteristic of the vaccine preparation and the individual response of the vaccinee; these events would not have occurred without vaccination (e.g., vaccine-associated paralytic poliomyelitis); 2) vaccinepotentiated: would have occurred anyway, but were precipitated by the vaccination (e.g., first febrile seizure in a predisposed child); 3) programmatic error: caused by tech-\n\n# What action is recommended if varicella vaccine is inadvertently administered 10 days after a dose of measles-mumps-rubella (MMR) vaccine?\nA. Repeat both vaccines >4 weeks after the varicella vaccine was administered. B. Repeat only the MMR vaccine >4 weeks after the varicella. C. Repeat only the varicella vaccine >4 weeks after the inadvertently administered dose of varicella vaccine. D. Repeat only the varicella vaccine >6 months after the inadvertently administered dose of varicella vaccine. E. No action is recommended; both doses are counted as valid.\n\n# Goal and Objectives\nThis MMWR provides general guidelines on immunizations. These recommendations were developed by CDC staff, the Advisory Committee on Immunization Practices (ACIP), and the American Academy of Family Physicians (AAFP). The goal of this report is to improve vaccination practices in the United States. Upon completion of this activity, the reader should be able to a) identify valid contraindications and precautions for commonly used vaccines; b) locate the minimum age and minimum spacing between doses for vaccines routinely used in the United States; c) describe recommended methods for administration of vaccines; and d) list requirements for vaccination providers as specified by the National Childhood Vaccine Injury Act of 1986. To receive continuing education credit, please answer all of the following questions.\n\n# What action is recommended if the interval between doses of hepatitis B vaccine is longer than the recommended interval?\nA. Add one additional dose. B. Add two additional doses. C. Restart the series from the beginning. D. Perform a serologic test to determine if a response to the vaccine has been obtained. E. Continue the series, ignoring the prolonged interval."}}},{"rowIdx":87,"cells":{"id":{"kind":"string","value":"1003f78bb49085934bf4795be1683424e01a6e82"},"source":{"kind":"string","value":"who"},"text":{"kind":"string","value":"HIV refers to the human immunodeficiency virus. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of HIV infections globally.The following definitions for adults, adolescents, children and infants are used to ensure consistency within these guidelines. Other agencies may use different definitions. - An adult is a person older than 19 years. - An adolescent is a person 10-19 years old inclusive. - A child is a person younger than 10 years old. - An infant is a child younger than one year of age. Serodiscordant couples are couples in which one partner is living with HIV and the other is HIV-negative. A couple refers to two people in an ongoing sexual relationship; each of these people is referred to as a partner in the relationship. How individuals define their relationships will vary according to their cultural and social context. Key populations are groups that have a disproportionate burden of HIV in many settings. They frequently face legal and social challenges that increase their vulnerability to HIV, including barriers to accessing HIV prevention and treatment. Key populations include (1) men who have sex with men, (2) people who inject drugs, (3) people in prisons and closed settings, (4) sex workers and (5) transgender people. Vulnerable populations are populations that are vulnerable to HIV in certain situations or contexts, such as adolescents (particularly adolescent girls in sub-Saharan Africa), orphans, people with disabilities and migrant and mobile workers. They may also face social and legal barriers to accessing HIV prevention and treatment. These populations are not affected by HIV uniformly in all countries and epidemics. Each country should define the specific populations that are vulnerable and key to their epidemic and response, based on the epidemiological and social context.ARV (antiretroviral) drugs refer to the medicines used to treat HIV. ART (antiretroviral therapy) refers to the use of a combination of three or more ARV drugs for treating HIV infection. ART involves lifelong treatment. Use of ARV drugs for HIV prevention refers to the HIV prevention benefits of ARV drugs and includes ARV drugs given to the mother or infant for preventing the mother-to-child transmission of HIV (PMTCT), ARV drugs to reduce the transmission of HIV among serodiscordant couples and ARV drugs to prevent people from acquiring HIV when they are exposed (postexposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP). Viral suppression refers to a viral load below the detection threshold using viral assays.Definition of key terms Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV Viral failure refers to the inability to achieve or maintain viral suppression below a certain threshold. Treatment failure: the current WHO virological criterion for treatment failure is 1000 copies per ml or more. Universal access to ART is defined broadly as a high level of access (80% or more of the eligible population) that is accessible and affordable. It does not necessarily mean 100% coverage. Preventing the mother-to-child transmission of HIV: Previous WHO guidelines have used the terms \"options A, B and B+\" to refer to different approaches to preventing the motherto-child transmission of HIV. The 2013 WHO guidelines recommended a choice between two approaches: (1) providing ART during pregnancy and breastfeeding to women who are otherwise not eligible for ART (option B) and (2) providing lifelong ART to all pregnant and breastfeeding women living with HIV regardless of CD4 count or clinical stage (option B+).Continuum of HIV services refers to a comprehensive package of HIV prevention, diagnostic, treatment, care and support services provided for people at risk of or living with HIV and their families. Examples of these services include combination HIV prevention including pre-exposure prophylaxis; HIV testing and linkage to care; management of opportunistic infections and other comorbid conditions; initiating, maintaining and monitoring ART; switching to second-line and third-line ART; and palliative care. Continuum of HIV care refers to a comprehensive package of HIV services for people living with HIV.#\nThe recommendations in this guideline will form part of the updated WHO consolidated ARV guidelines to be published in 2016. The complete guidelines will provide expanded operational and service delivery guidance to support implementation at the country level. They will provide guidance on effectively integrating HIV and other services and strategies to optimize quality along the continuum of HIV services, including adherence to treatment and retention in care.\n\n# Target audience\nThis guideline is primarily intended for use by national HIV programme managers. It will also be of interest to the following audiences:\n- national HIV treatment and prevention advisory boards;\n- national TB programme managers;\n- national hepatitis programme managers;\n- managers of maternal, newborn and child health and reproductive health programmes;\n- clinicians and other health service providers;\n- managers of national laboratory services;\n- people living with HIV and community-based organizations; and\n- international and bilateral agencies and organizations that provide financial and technical support to HIV programmes in resource-limited settings.\n\n# Guiding principles\nThe following principles have informed the development of this guideline and should guide the implementation of its recommendations.\n- The guideline should contribute to and expedite the achievement of important global HIV and other health goals for 2016-2021.\n- The guideline is based on a public health approach to scaling up the use of ARV drugs along the continuum of HIV prevention, treatment and care.\n- In addition to strengthening the continuum of HIV services, the recommendations in the guideline should be implemented with a view to strengthening broader health systems, especially primary and chronic care.\n- Implementation of the guideline needs to be accompanied by efforts to promote and protect the human rights of people in need of HIV services, including by ensuring informed consent, preventing stigma and discrimination in the provision of services and promoting gender equity.\n- Implementation of the recommendations in this guideline should be informed by local context, including HIV epidemiology, availability of resources, the organization and capacity of the health system and anticipated cost-effectiveness.\n\n# Methods for developing the guidelines 1.5.1 Competing interests\nAll external contributors to the development of this guideline, including members of the Core Group, Clinical Guideline Development Group and External Review Group, completed a WHO Declaration of Interests form. In accordance with the WHO Declaration of Interests policy for experts, a brief biography of each Clinical Guideline Development Group member was published on the WHO HIV website for a period of 14 days with a description of the objective of the meeting. No public comments or objections were received concerning the group membership.\nThe responsible technical officer reviewed all the Declaration of Interests forms completed by the Clinical Guideline Development Group members. A management plan for each declared conflict was agreed and recorded (Annex 1 includes the note for the record of the Declaration of Interests forms and management decisions). All declared interests and management strategies were discussed with the chairs and methodologist. Conflicts of interest were shared at the start of the Clinical Guideline Development Group meeting and participation closely monitored by the WHO Guideline Steering Group and GRADE methodologist. The majority of the Clinical Guideline Development Group did not declare significant conflicts of interest for this meeting.\nEvery effort was made to ensure that the representation of the Clinical Guideline Development Group minimized conflicts of interests. The Guideline Steering Group acknowledges that limiting the participation of key experts is challenging given the significant contribution of pharmaceutical companies in the field of HIV research and ARV drug trials and the participation of several experts as investigators in relevant trials.\nThe Guideline Steering Group assessed all completed Declaration of Interests forms for other external contributors to the guidelines. Individual participation was reviewed in respect of the interests declared. All Declaration of Interests forms are on electronic file at the WHO Department of HIV/AIDS and will be maintained for at least 10 years.\n\n# Guideline contributors\nThree external review teams conducted systematic reviews to support this guideline. Annex 2 provides full details of the team leader and team members. Nandi Siegfried was the GRADE methodologist for this guideline.\nAn internal Guideline Steering Group of WHO staff and consultants coordinated the overall guideline development process. Meg Doherty and Rachel Beanland of the Department of HIV/AIDS led the Guideline Steering Group.\nA Core Group of external experts provided strategic guidance to the guideline development process. Members of the Core Group also provided external review of the guideline.\nAn external Clinical Guideline Development Group convened by WHO reviewed evidence and developed the recommendations. The composition of the Clinical Guideline Development Group was in accordance with WHO procedures for developing guidelines (10) and included HIV experts, researchers, programme managers, epidemiologists, human rights experts, United Nations agencies and representatives of civil society organizations and networks of people living with HIV. Representatives from civil society were selected from a call for nominations; three participants were selected from more than 90 applications. The WHO HIV Civil Society Reference Group contributed to the selection process. Appropriate representation by region and sex was considered. The Co-Chairs of the Clinical Guideline Development Group also participated in the Core Group to ensure consistency.\nWHO also recruited an External Review Group of experts in the field to review and provide comments on the guideline.\n- 5 Methods\n\n# Methods for evidence synthesis\n\n# Key information sources\nThe WHO Guideline Steering Group formulated PICO questions (population, intervention, comparator and outcome) to guide the systematic reviews to support the development of the guideline. Scoping meetings on the treatment of HIV among adolescents (11) and on the use of pre-exposure prophylaxis for preventing people from acquiring HIV contributed to this process.\nThe following three PICO questions of relevance to this guideline were identified.\n- In adults, adolescents and children with HIV, is ART initiated at a threshold above CD4 500 cells/mm 3 compared with less than 500 cells/mm 3 more harmful?\n- Should pregnant and breastfeeding women with HIV started on triple ARV drugs continue on lifelong ART regardless of eligibility criteria?\n- Should oral PrEP containing TDF be offered as an additional prevention choice for people at substantial risk of HIV infection as part of combination prevention approaches?\nNo changes have been made to the scope of the guideline since approval of the planning proposal.\nA list of potential outcomes of interest for each question was circulated to all members of the Clinical Guideline Development Group, and each member scored the importance on a scale of 1 (not important) to 9 (critical) from the perspective of individuals living with HIV. The average of the scores and variability for each outcome was used to inform the decision-making.\nSystematic review teams developed protocols and conducted reviews in accordance with PRISMA reporting guidelines for systematic reviews and meta-analyses (12). Annex 2 includes search strategies, quality assessment and synthesis of findings.\nQualitative literature reviews were conducted to support all three questions. To further explore acceptability, community consultations were conducted on when to start ART (Annex 2). Seven networks of people living with HIV, supported by a global research organization, conducted 24 workshops to assess the acceptability of earlier initiation of ART for people living with HIV, caregivers and service providers in eight countries (India, Indonesia, Kenya, Peru, Portugal, Ukraine, Zambia and Zimbabwe).\nAn additional global consultation on adolescent treatment and care and a facility-based situational analysis also contributed to the evidence base on the acceptability of earlier initiation of ART for adolescents.\n\n# Quality of evidence and strength of the recommendations\nThe GRADE method was used to rate the quality of the evidence (13)(14)(15)(16)(17)(18)(19)(20)(21) and determine the strength of the recommendations (Table 1) (22).\nThe quality of evidence is defined as the confidence that the reported estimates of effect are adequate to support a specific recommendation. The GRADE system classifies the quality of evidence as high, moderate, low and very low. Randomized controlled trials are initially rated as high-quality evidence but may be downgraded for several reasons, including risk of bias, inconsistency of results, indirectness of evidence, imprecision and publication bias. Observational studies are initially rated as low-quality evidence but may be upgraded if the magnitude of the treatment effect is very large, if evidence indicates a dose-response relationship or if all plausible biases would underestimate the effect.\n\n# Quality of evidence Rationale High\nWe are very confident that the true effect lies close to that of the estimate of the effect\nWe are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different\nOur confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect\n\n# Very low\nWe have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of the effect\n\n# Table 1 GRADE quality of evidence\nThe strength of a recommendation reflects the degree of confidence of the Clinical Guideline Development Group that the desirable effects of the recommendation outweigh the undesirable effects based on the quality of the evidence. Desirable effects (potential benefits) may include beneficial health outcomes (such as reduced incidence of HIV and reduced morbidity and mortality); reduction of burden on the individual and/or health services; and potential cost savings for the individual, communities, programme and/or health system. Undesirable effects (potential harm) include those affecting individuals, families, communities or health services.\nHarm may include the resource use and cost implications of implementing the recommendations; adverse clinical outcomes (such as drug resistance or drug toxicity); and legal ramifications, in which certain practices are criminalized.\nThe strength of a recommendation can be either strong or conditional.\nA strong recommendation is one for which there is confidence that the desirable effects of adherence to the recommendation clearly outweigh the undesirable effects.\nA conditional recommendation is one for which the quality of evidence may be low or may apply only to specific groups or settings, or the panel concludes that the desirable effects of adherence to the recommendation probably outweigh the undesirable effects or are closely balanced, but the panel is not confident about these trade-offs in all situations. At implementation, monitoring and rigorous evaluation is needed to address these uncertainties, which are likely to provide new evidence that may change the calculation of the balance of tradeoffs and suggest how to overcome any implementation challenges.\n\n# Clinical Guideline Development Group meeting\nThe Clinical Guideline Development Group met for five days in Geneva, Switzerland in June 2015.\nThe systematic reviews and evidence to decision-making tables prepared in accordance with the GRADE process (Table 2) were presented, and the methodologist facilitated discussions. Annex 2 provides all evidence to decision-making tables, which include GRADE evidence profile tables.\n\n# Domain Rationale\n\n# Quality of the evidence\nThis is an assessment of the degree of confidence in the estimate of the effect: that is, the likelihood that the effect will differ substantially from what the research found. \"Differ substantially\" means a large enough difference that it might affect a decision.\n\n# Benefits and risks\nWhen a new recommendation is developed, desirable effects (benefits) need to be weighed against undesirable effects (risks), considering any previous recommendation or another alternative. The larger the gap or gradient in favour of the benefits over the risks, the more likely that a strong recommendation will be made.\nValues of outcomes This is a judgement of how much the people affected by an intervention or option value each of the outcomes. How much people value outcomes in relation to each other needs to be considered when weighing up the desirable effects of a treatment against the undesirable effects.\n\n# Costs and resource implications\nHow large the requirements are in resource use of the intervention and the alternative. Costs: the value of the resources that are consumed (such as staff time, drugs and use of equipment) as the consequences of an intervention or option. Cost-effectiveness: the cost of a treatment in relation to its effects.\nLower cost (monetary, infrastructure, equipment or human resources) or greater cost-effectiveness is more likely to support a strong recommendation.\nThe absence of avoidable or remediable health differences among groups of people that may be defined socially, economically, demographically or geographically.\nHow much a treatment or recommendation is accepted by the people who are affected by it or who are implementing it. If the recommendation is likely to be widely accepted or valued highly, it is likely that a strong recommendation will be made. If there is a great deal of variability or strong reasons that the recommended course of action is unlikely to be accepted, it is more likely that a conditional recommendation will be made.\nIs it feasible to implement an intervention and to sustain it? If an intervention is achievable in a setting where the greatest impact is expected, a strong recommendation is appropriate.\n\n# Table 2 Criteria for consideration in evidence to decision-making tables\nThe Clinical Guideline Development Group made decisions by consensus. Voting was conducted as a decision-making aid for the question of when to initiate ART for adults in relation to the strength of the recommendation (with a majority vote of 70%).\n\n# Peer review\nA draft of the guideline was circulated for review to members of the Clinical Guideline Development Group, the Core Group and the External Review Group. The WHO Guideline Steering Group reviewed the comments and incorporated them into the final document following discussion with the technical leads.\n\n# Oral pre-exposure prophylaxis for preventing the acquisition of HIV infection 2.3 Programmatic note on the recommendations\nGuideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV\n\n# Format of the recommendations\nThe recommendations are presented in the following format to reflect the review of the evidence and other considerations by the Clinical Guideline Development Group.\nRecommendation. The recommendation and the strength and quality of evidence assessed using the GRADE method are stated. Background. Previous WHO guidance in this area and key developments since recommendations were last published are described. When the recommendation relates to a specific population, key issues for that population may be briefly summarized.\nRationale and supporting evidence. New evidence on which the recommendation is based and other key operational and programmatic considerations that informed the development of the recommendation are summarized.\nThis includes assessments of: (2). This strong recommendation was based on moderate-quality evidence from three randomized controlled trials (3-5) and 21 observational studies showing that initiating ART at or below a CD4 threshold of 500 cells/mm 3 compared with later initiation reduced the risk of progression to AIDS and/or death, TB and developing a non-AIDS-defining illness and increased the likelihood of immune recovery. In addition, high-quality evidence from one randomized controlled trial indicated that earlier ART can markedly reduce the risk of sexual transmission to HIV-negative sexual partners among heterosexual couples (4).\nMathematical models and ecological studies also suggested that initiating ART earlier could affect HIV incidence at the population level if there is high uptake of sustained testing, ART coverage and retention (28)(29)(30)(31)(32). For people with certain clinical conditions such as TB, hepatitis B (HBV) coinfection requiring HBV treatment, pregnancy, breastfeeding and HIV serodiscordant couples, the 2013 guidelines recommended initiating ART regardless of WHO clinical stage or at any CD4 cell count.\nGlobal ART coverage for all individuals living with HIV had reached approximately 41% -or 15 million people -by March 2015 (33). According to the WHO Country Intelligence Database, by June 2014, more than half (60%) of the 58 WHO HIV focus countries had adopted the CD4 threshold of 500 cells/ mm 3 or less for initiating ART, and 7% (n=4) had already moved the CD4 threshold to above 500 cells/ mm 3 (Fig. 1) (34). Although the median CD4 count at the time of ART initiation is increasing, it remains significantly lower than 350 cells/mm 3 in almost all settings, including high-income countries (35,36), and late presentation for treatment is associated with high early mortality rates, higher direct healthcare costs and poor retention in care (37)(38)(39). Increasing knowledge of HIV status, strengthening links between testing and care, modifying health systems to manage patient volumes and ensuring optimal long-term retention and adherence remain significant challenges in many settings (40).\n\n# Fig. 1. Uptake of WHO policy on the threshold for initiating ART among adults and adolescents living with HIV in low-and middle-income countries, 2014\n\n# Rationale and supporting evidence\nInitiating ART among all adults living with HIV regardless of WHO clinical stage or at any CD4 cell count Since 2013, evidence and programmatic experience have continued to favour earlier initiation of ART because of reduced mortality, morbidity and HIV transmission outcomes. Increasing evidence from systematic reviews and cohort analyses also indicates that untreated HIV infection may be associated with the development of several non-AIDS-defining conditions (including cardiovascular disease, kidney disease, liver disease, several types of cancer and neurocognitive disorders) (41)(42)(43)(44) and that initiating ART earlier reduces such events and improves survival.\nRecent evidence from a large randomized clinical trial also shows that, as demonstrated for heterosexual serodiscordant couples, ART substantially reduces sexual transmission to HIVnegative sexual partners among homosexual couples (45).\nThe recommendation to initiate ART at any CD4 cell count was based on a systematic review with GRADE evidence profiles that assessed the quality and strength of the evidence from one randomized controlled trial ( 46) and 17 observational studies (11,12,(15)(16)(17)(18)(19)23,27,30,(47)(48)(49)(50)(51)(52) reporting clinical, immunological and virological outcomes and HIV transmission.\nIn the analysis of data from the single randomized controlled trial (TEMPRANO), moderatequality evidence (downgraded from high quality because of imprecision) showed that initiating ART at a CD4 count >500 cells/mm 3 in the absence of other treatment indications, leads to less severe HIV morbidity (combined outcome of death, AIDS and severe non-AIDS diseases such as malignancies and bacterial diseases) compared with treatment initiation at a CD4 count at or below 500 cells/mm 3 (hazard ratio = 0.56, 95% confidence interval (CI) 0.33-0.94) (46).\nLimited data from another randomized clinical trial (START study) unpublished at the time of the Clinical Guideline Development Group meeting were available but not incorporated into the systematic review or GRADE table (53). The Data and Safety Monitoring Board advised immediate dissemination of the findings from the START study because of predefined stopping rules. The START trial was not part of the systematic review because the comparison groups did not match the review PICO and was therefore not considered in relation to the quality of the evidence. Box 1 summarizes the key findings from the START study that were presented to the Clinical Guideline Development Group and are supportive of the new recommendation.\nAnalysis of the observational studies found a significantly lower risk of HIV disease progression (50), and the TEMPRANO randomized controlled trial data demonstrated from modelling the potential lower rates of HIV transmission to uninfected partners ( 46), but the evidence was rated as very low quality in both cases. However, interim data from the HPTN 052 clinical trial indicated that early ART is highly effective at prevention of sexual transmission of HIV (54). Similar to the START trial, relevant data from the HPTN 052 were unpublished at the time of the guidelines review meeting and were not incorporated into the systematic review due to a different comparator to that of the review. Box 2 summarizes these data.\n\n# When to start: adults\n- 1.1 When to start: adults\n\n# Box 1. The START study\nThe Strategic Timing of Antiretroviral Treatment (START) trial enrolled 4685 people at 215 sites in 35 countries. Twenty-seven percent of the participants were women, and approximately half were gay men. The study examined the rates of AIDS and serious AIDS-defining illness or death among people who were randomized to receive immediate ART versus deferring ART until their CD4 count dropped below 350 cells/mm 3. The median baseline CD4 count was 651 cells/mm 3 in the intervention group. In the deferred group, the median CD4 count at ART initiation was 408 cells/mm 3. Follow-up lasted for a mean of three years. A total of 86 events (death, AIDS and serious non-AIDS events) occurred among those with later treatment initiation, whereas 41 events occurred among those starting ART immediately, representing a 57% reduction in negative outcomes among those treated early. In both groups, most events occurred when CD4 counts were higher than 500 cells/mm 3. The study also showed that immediate ART reduced both AIDS-related and non-AIDS-related events, but the benefit was greater for AIDS-related events. Tuberculosis (TB), Kaposi sarcoma and lymphoma -the most common AIDS-related events -all occurred less frequently in the immediate ART group. Cancer rates (combining AIDS and non-AIDS malignancies) were lower in the immediate ART group, but cardiovascular disease rates were similar between groups. These effects were consistent in countries of different income levels and across geographical regions.\n\n# Box 2. New data from HPTN 052\nThe HIV Prevention Trials Network (HPTN) 052 study showed that starting ART early reduced the overall risk of HIV sexual transmission to uninfected partners by 93% (54).\nIn this Phase 3 randomized controlled trial, 1763 HIV serodiscordant couples from 13 sites in 9 countries (97% of whom were heterosexual couples) were enrolled and followed for approximately four years. The participating couples were randomly assigned to one of two treatment groups. In the first group, the participants living with HIV began ART immediately. In the second group, the participants living with HIV delayed treatment until their CD4 counts fell below 250 cells/mm 3 or they were diagnosed with an AIDS-related illness. All participants in both groups received counselling on safe sex practices, free condoms, treatment for sexually transmitted infections, frequent HIV testing and evaluation and treatment for any complications related to HIV. The median CD4 count at study entry was 436 cells/mm 3. The HIV-uninfected partners tested negative for the virus within 14 days of entering the study. In the overall analysis, from April 2005 through to May 2015, the investigators found that 78 initially negative partners became infected with HIV, and 46 of 70 cases where linkage status was confirmed (66%) of these partners acquiring HIV could be linked to the positive partner using phylogenetic analysis.\nThree of the 46 linked infections occurred in the early ART arm and 43 in the delayed ART arm, leading to a 93% risk reduction for linked transmission. In the final analysis, all linked partner infections that were diagnosed after ART began are likely to have occurred when the virus was not suppressed by the treatment regimen (4 of 8 cases). The investigators did not observe any linked partner infections when the HIV-infected participant's virus was stably suppressed by ART. The results indicate that ART is highly effective at preventing the heterosexual transmission of HIV if viral suppression is achieved and maintained.\nModerate-quality evidence from the TEMPRANO trial showed that initiating ART at a CD4 count above 500 cells/mm 3 was not associated with increased risk of grade 3 or 4 adverse events 2 (46). Low-quality evidence from observational data showed an increased risk of any severe laboratory adverse event and hepatic adverse events in individuals initiating ART at CD4 count above 500 cells/mm 3 although this was not associated with treatment discontinuation (48).\nProgrammatic data from several countries that are offering earlier ART either to all people living with HIV or to specific populations have shown significant increases in ART uptake and linkage to care, reduction in the time between HIV diagnosis and ART initiation regardless of baseline CD4 cell count and an increase in the median CD4 value at ART initiation. Retention in care has not differed between individuals who start at CD4 counts above 500 cells/mm 3 compared with those who started based on the standard of care (55)(56)(57).\nInitiating ART among adults with severe or advanced HIV disease or with CD4 count at or below 350 cells/mm 3 as a priority\nThe benefits of initiating ART are greatest among individuals with symptomatic HIV disease or those with lower CD4 counts. The strength and quality of evidence for this recommendation established in the 2010 ART guidelines (58) remains unchanged. Moderate-quality evidence from two randomized controlled trials and several observational studies show that initiating ART at CD4 counts at or below 350 cells/mm 3 significantly reduces mortality, disease progression and the incidence of opportunistic diseases, especially TB and non-AIDS-defining conditions (59). Further, several studies and programmatic data suggest that late diagnosis (often defined as CD4 count at or below 350 cells/mm 3 and late treatment initiation are very common, even in high-income settings (60,61).\n\n# Comparing benefits and harm\nThe benefits of earlier ART initiation include fewer events of severe HIV morbidity and disease progression, improved uptake and initial linkage to care, better immune recovery and decreased HIV transmission. However, not all observational studies have consistently demonstrated the beneficial effect of initiating ART at CD4 cell count at or above 500 cells/mm 3 on mortality, the incidence of inflammation-related non-AIDS events and ongoing viral replication compared with initiation at CD4 at or below 500 cells/mm 3. Follow-up will be needed to evaluate the potential harm and benefits of ART over a lifetime.\nIt is increasingly recognized that, in settings with a high burden of HIV and TB infections, increasing ART coverage is associated with decreasing TB case notifications, and this is likely to improve when ART is started earlier.\nA modelling exercise based on national cohort data from four countries in sub-Saharan Africa concluded that programmatic gains and mortality reduction were accrued by eliminating the pre-ART period, suggesting that making treatment available to everyone will strengthen the continuum of care (62).\n\n# Cost and cost-effectiveness\nThe same modelling exercise indicates that expanding ART eligibility criteria to above 500 cells/ mm 3 or regardless of CD4 cell count and linking to HIV care could result in 6-14% fewer people dying from HIV-related causes during the next decade (62). In this exercise, the vast majority of the impact is caused by programmatic simplification leading to more people initiating ART in a timely manner and therefore avoiding adverse outcomes during the per-ART period rather any 2.1.1 When to start: adults 2.1.1 When to start: adults direct therapeutic benefits. The increased cost of earlier ART would be partly offset by subsequent reduced costs (such as decreased hospitalization and increased productivity) and preventing people from acquiring HIV infection. The modelling results suggest that such a change is likely to be cost-effective in many settings if people initiating ART adhere to treatment and retention in care is maintained. Costs will increase significantly but far less than if the additional outreach interventions required to maintain individuals in pre-ART care are also included.\nAccording to UNAIDS estimates, expanding ART to all people living with HIV is projected to avert 21 million AIDS-related deaths and 28 million new infections by 2030 (63). However, these benefits require high testing uptake, high treatment coverage, sustained adherence and high rates of retention in care. The cost implications at the regional and country levels can also vary and should be further explored, since countries have different levels of current treatment coverage and local cost considerations depending on their context and resources.\n\n# Equity and acceptability\nConcerns have been expressed that, given limited resources, very early treatment could result in some people who urgently need treatment being displaced by people for whom treatment would be beneficial but is less urgently needed. For this reason, initiating ART among adults with severe or advanced HIV disease or with a CD4 count at or below 350 cells/mm 3 is recommended as a priority in this guideline. Additional concerns that mandatory or coercive approaches will be used among high-risk marginalized populations highlight the importance of adequate patient information, informed consent, appropriate health worker training and rights-based legal frameworks to facilitate access.\nThe community-led global consultation examining the acceptability of earlier initiation of ART at a higher CD4 count for people living with HIV, caregivers and service providers found that earlier initiation was considered acceptable. Participants in the consultation emphasized the need for collaborative decision-making with service providers to ensure that the ultimate decision to initiate ART rests with the person living with HIV. Motivation to start and adhere to treatment may be more difficult for people who feel well and have higher CD4 counts than for people who are or have been ill. Stigma and discrimination continue to act as barriers to treatment access and adherence. Critical factors in promoting ongoing engagement in care and adherence include ensuring access to a stable supply of free or affordable ARV drugs, facilities that are easily accessible and that ensure confidentiality, sympathetic providers and community adherence support.\nA qualitative literature review showed that acceptability for earlier treatment is greater when people know that treatment reduces mortality risk. Service providers recognize the preventive benefits of earlier ART and the need for earlier ART initiation for asymptomatic people. Among people living with HIV, acceptance increases when they also have comorbidities or conditions associated with a higher risk of HIV transmission. Issues cited in the literature supported those identified in community consultations.\nAccording to cohort and national programme data, the number of people needing treatment could increase by up to 35% if ART is initiated at any CD4 count rather than at or below 500 cells/mm 3 (63). Modelling estimates predict that this increase would be lower, in the range of 7% to 21% over five years, because not all people living with HIV are diagnosed and present for care immediately. Country experience has also shown that moving to a higher CD4 threshold for ART initiation may not necessarily lead to a significant immediate increase in the numbers of people who actually access treatment in the absence of increased uptake of HIV testing, stronger linkage to care, adequate treatment monitoring and sustained adherence support. Late presentation for treatment is still quite common, with the median CD4 count at ART initiation below 350 cells/mm 3 in the majority of settings, including high-income countries (59,60).\nGuideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV\n\n# Implementation considerations\nRegardless of the epidemic profile and disease burden, priority should be given to people with symptomatic HIV disease or with CD4 count at or below 350 cells/mm 3 who are at high risk of mortality and most likely to benefit from ART in the short term.\nInitiating ART at CD4 counts above 500 cells/mm 3 may involve additional human, infrastructure and financial resources. Countries vary in health system capacity and are at different stages in ART coverage and quality of care. A phased approach to implementation may be needed, especially in settings with a high burden of HIV infection, lower ART coverage, less developed health systems, lower rates of testing, poor pre-ART care, weaker human resources, limited laboratory capacity, budget constraints and/or competing health priorities. In such settings, equity considerations and giving priority to those who most need treatment should guide implementation. The updated consolidated guidelines will provide further guidance in this area.\nThe increased need for ART associated with early initiation may place demands on the health system in some settings that could increase the risk of drug resistance, such as drug stockouts, insufficient patient preparation and suboptimal adherence. To maximize the long-term effectiveness of first-line ART regimens and ensure that people are taking the most effective regimen, the scaling up of HIV treatment should be accompanied by measures to monitor and improve service quality at the site and programme levels.\nIn all settings, continued monitoring of the long-term safety profile of ARV drugs and the implications of earlier initiation for drug resistance, toxicity and adherence will be needed. It also remains essential to address structural and social barriers to accessing treatment faced by key populations, such as criminalization, discrimination and stigma (64)(65)(66).\n\n# Research gaps\nSeveral ongoing implementation trials are evaluating the feasibility, acceptability, cost-effectiveness and impact of immediate treatment for all people living with HIV regardless of CD4 cell count at the population level (SEARCH and MaxART studies). Primary outcome results are not expected before 2017 or 2018 (67,68). Three large randomized trials are examining the population effect of early ART initiation on HIV incidence and mortality (Botswana Combination Prevention Trial, HPTN-071 (PopART) study and 12249 ANRS TasP trial), with results expected in 2018 or 2019 (69)(70)(71).\nOther research priorities include assessing the incidence of short-and long-term severe adverse events as a result of increased exposure to ART, barriers to and enablers of adherence and longterm retention in care and the impact on the cascade of care and the magnitude of the prevention benefit of early initiation of ART, especially among key populations and adolescents.\n\n# When to start ART among pregnant and breastfeeding women Recommendation\nART should be initiated in all pregnant and breastfeeding women living with HIV regardless of WHO clinical stage and at any CD4 cell count and continued lifelong (strong recommendation, moderate-quality evidence).\n\n# When to start: pregnant and breastfeeding women\n- 1.2 When to start: pregnant and breastfeeding women\nProgrammes to prevent mother-to-child transmission were some of the earliest public health interventions that used ARV drugs to reduce the risk of HIV transmission. Initially, the regimen recommended by WHO was a single dose of nevirapine given to the mother during labour and to the infant in the first few days of life. With the launch of the \"3 by 5\" initiative and the rolling out of national HIV care and treatment programmes, the guidelines made an important shift, recommending that pregnant women should be tested for HIV and then assessed for treatment eligibility. Those considered eligible for treatment should be offered combination lifelong antiretroviral therapy for their own health, while those who were not eligible should receive short courses of antiretroviral prophylaxis for PMTCT. Although eligibility criteria have changed and the preferred regimens for ART and for PMTCT prophylaxis have evolved, this distinction between treatment and prophylaxis became a fixture of PMTCT programmes.\nIn 2013, the consolidated ARV guidelines recommended that all pregnant and breastfeeding women be initiated on ART regardless of clinical eligibility. This recommendation was driven by practical experience from programmes showing that PMTCT prophylaxis (using different drugs at different times in the course of pregnancy, labour and delivery as well as long duration of infant prophylaxis while breastfeeding) was more challenging to implement in the field than giving ART to all pregnant women (especially if the ART regimen was a once-daily fixed-dose combination tablet). However, the guidelines still offered programmes the option to either continue ART lifelong in all women (option B+) or to stop ART after the period of mother-to-child transmission risk in women who did not otherwise meet eligibility criteria (option B). Option B+ was felt to be of the greatest benefit in settings with high HIV prevalence and high fertility in which initiating ART among all pregnant and breastfeeding women would reduce HIV incidence and prevent HIV transmission in both current and future pregnancies.\nFollowing the release of the 2013 guidelines, many countries moved to adopt option B+ as the preferred approach for PMTCT programmes. The most recent Global AIDS Response Progress Reporting data show that the majority of countries, including almost all the 22 high-priority countries listed in the Global Plan towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive (72), are now either piloting or implementing lifelong ART for all pregnant and breastfeeding women living with HIV at a national scale (Fig. 2).\n\n# Fig. 2. Adoption of policy on preventing the mother-to-child transmission of HIV in low-and middle-income countries, 2014\nIncreasing evidence to support earlier ART initiation among all adults as described in the previous section, as well as widespread uptake of option B+ and emerging programme data on the success of option B+ in practice, all support a revised recommendation in 2015 that all pregnant and breastfeeding women living with HIV should initiate ART and remain on lifelong treatment regardless of clinical or CD4 stage of disease. As a result, option B is no longer relevant.\nProviding ART to all pregnant and breastfeeding women living with HIV serves three synergistic purposes: (1) improving individual health outcomes, (2) preventing mother-to-child transmission of HIV and (3) preventing the horizontal transmission of HIV from the mother to an uninfected sexual partner.\n\n# Rationale and supporting evidence\nThe evidence on options B and B+ and the clinical and immunological impact of stopping ART among postpartum women were reviewed in the context of increasing data showing the benefit of ART at all stages of HIV disease and the strong, new recommendation to initiate ART among all adults with HIV at any CD4 count.\nA systematic review was conducted to compare option B and option B+ in terms of maternal health outcomes. The review did not identify any randomized controlled trials or observational studies that directly compared options B and B+; however, 18 studies reported on option B outcomes -comprising four randomized controlled trials (73-76), three single-arm trials (77-79) and 11 cohort studies (80-90) -and 10 cohort studies reported on outcomes associated with option B+ (91)(92)(93)(94)(95)(96)(97)(98)(99)(100). All the studies evaluating option B+ suggested that women experienced health benefits in terms of immunological and clinical parameters. None of the studies included in the review reported on how option B+ affected HIV transmission rates to partners, although this is an important likely benefit for women who remain on lifelong ART.\nSince the key difference between option B and option B+ is not when ART is started but whether it is stopped, literature on the clinical and immunological impact of stopping ART among women during the postpartum period was also reviewed. Five cohort studies and one randomized controlled trial were identified that examined changes in clinical and immunological parameters following discontinuation of ARV drugs. Most of these studies used the historical threshold for ART initiation of CD4 count below 350 cells/mm 3 and in several cases mothers were receiving ARV prophylaxis rather than ART, but all showed a gradual decline in immune function after ARV drugs were stopped. Using the time frame of six months after discontinuation, 6-20% of women with a baseline CD4 count below 500 cells/mm 3 had become eligible, whereas only 1.5% of women became eligible if the baseline CD4 was above 500 cells/mm 3 (101,102). A lower baseline CD4 count was also associated with a 2.5-fold higher risk of WHO stage 2 or 3 clinical events (103).\nApart from the impact on clinical and immunological outcome, there are also programmatic consequences of stopping ARV drugs among postpartum women. In one study from Malawi, loss to follow-up post-delivery was much higher in women with baseline CD4 above 350 cells/ mm 3 (who were not eligible for treatment) than those with CD4 below 350 cells/mm 3 (who were eligible and started on ART) (104). The findings were similar in a South African cohort where the women who were considered ineligible for ART were twice as likely to be lost to follow-up at six months postpartum as the women who had started treatment (105).\nThe body of evidence demonstrates the advantages of lifelong ART for pregnant and breastfeeding women and adds to the compelling data from recent randomized clinical trials suggesting that all adults with HIV benefit from ART at any CD4 and regardless of their clinical stage of disease.\n\n# Comparing benefits and harm\nMost countries are moving to adopt universal ART for all pregnant and breastfeeding women. The benefits include improved health outcomes, lower mortality and the potential for reduction of horizontal transmission of HIV. Women may be less likely to drop out of care after the end of the transmission risk period and may avoid some of the clinical and operational complexity of repeated cycles of stopping and starting ART in subsequent pregnancies.\nThe risks to offering lifelong ART to all pregnant and breastfeeding women living with HIV as opposed to ART only during the period of mother-to-child transmission risk include the potential for cumulative drug toxicity and the possibility of poor adherence with long-term use, potentially leading to the development of drug resistance. In general, these risks for pregnant and breastfeeding women are similar to those for non-pregnant adults. A further potential risk to the fetus may arise from exposure to ARV drugs, especially when given early in the gestational period. Early gestation exposure is more likely with the change in guidelines for adults, as a greater number of women of childbearing age will initiate ART across all CD4 counts. To date, no evidence suggests a significant increased risk of congenital anomalies associated with the currently recommended first-line ARV drug regimens (106). How the recommendations are implemented may also affect outcomes.\nThe costs associated with implementing option B+ will probably require increased resources, especially in the short term. Nevertheless, overall, the benefits of option B+ are considered to outweigh the potential harm.\n\n# Cost and cost-effectiveness\nIn a cost-modelling exercise, the total cost (including drugs, diagnostics and service delivery) of keeping a woman on option B+ was an estimated US$ 2069 over five years (107). However, since maintaining a woman off ART also incurs costs for monitoring and follow-up, the incremental cost of moving from option B to option B+ was relatively low and varied between US$ 92 and US$ 605 depending on baseline CD4 and breastfeeding status. Several model-based analyses have supported the cost-effectiveness of strategies for preventing the mother-to-child transmission of HIV, with many finding option B and B+ to be cost-saving or highly cost-effective compared with option A. When outcomes beyond the mother-to-child transmission of HIV are considered, such as maternal health, preventing the mother-to-child transmission of HIV in future pregnancies and preventing horizontal transmission, option B+ has been found to be highly cost-effective compared with option B (108,109).\n\n# Equity and acceptability\nA qualitative literature review on the acceptability of option B+ indicated high acceptability of lifelong ART among pregnant and breastfeeding women as well as among service providers. Women have raised some concerns about fear of drug toxicity for themselves and their children, but women generally value the health benefits and the ability to protect their children and their partners from HIV (110,111). The review also highlighted some of the challenges of lifelong treatment, including disclosure to partners and employers, stigma, lack of support and costs and time off work associated with clinic visits and drug pick-ups.\nEarly programme experience from South Africa suggests that pregnant women find same-day initiation of ART (starting ART on the day of HIV diagnosis) acceptable, especially because in this setting, many women are already aware of their status, have high levels of treatment literacy and can access support services (112). By contrast, same-day ART initiation in Malawi has been associated with a high rate of early loss to follow-up, with many women failing to return for a second visit (113).\nThe recommendation to initiate ART for all adults with HIV at any CD4 count will likely add to the acceptability of ART for pregnant and breastfeeding women, since it normalizes what may previously have been considered stigmatizing. A simplified and harmonized approach to ART among pregnant and non-pregnant adults will also promote health equity.\n\n# Implementation considerations\nMany of the concerns raised about the recommendation to give all pregnant and breastfeeding women lifelong ART relate to how this policy should be implemented. Programme managers must address the issues of ensuring the quality of HIV testing, determining when to initiate ART in a newly diagnosed woman and maintaining the continuity of ART services in the postpartum period when implementing this recommendation.\nART for pregnant and breastfeeding women should ideally be delivered within maternal, newborn and child health clinics by integrating HIV and antenatal care. Integrated services benefit mothers, and this is likely to be feasible in settings with a high burden of HIV infection. However, achieving integration will depend on the context and the resources available in terms of staff time and physical space. In one retrospective cohort study from Malawi, 45% of the women interviewed reported that, although they started ART in an antenatal care clinic, they were referred to separate ART services soon after delivery (114). There is no established model for when to transition mothers on ART out of maternal, newborn and child health services, but a recent report from South Africa highlighted the importance of this potential additional loss point in the PMTCT cascade. In a retrospective review of women referred to ART clinics in the postpartum period, up to 25% did not remain in care five months after referral (115).\nBeyond issues related to clinical service delivery, a key consideration for national programmes is the need for strengthened data systems to track women on ART across multiple delivery sites, along with the need for targeted interventions to improve adherence and retention, such as community support and the use of peer counsellors.\n\n# Research gaps\nSignificant knowledge gaps remain about where and how best to implement option B+ to improve retention and follow-up of the mother and infant pair. For example, the integration of ARV drug delivery in antenatal care and maternal, neonatal and childcare services as opposed to referral to ART clinics requires further implementation and assessment.\nAdolescents and young women living with HIV face unique challenges in preventing the transmission of HIV to their children and attending to their own health needs, including poor access to reproductive health services, poor uptake of testing and poor retention in care (116). Operational research is urgently needed to identify the drivers of poor outcomes among adolescents, to define how to provide adolescent-friendly maternal and newborn health services and to develop specific strategies to improve retention in care.\nAlthough ART in pregnancy and during breastfeeding provides clear public health benefit in terms of maternal health and PMTCT, the potential long-term harm from fetal and infant exposure to maternal drugs is poorly understood. The risk of congenital birth defects is likely to be low for the currently recommended first-line ARV drugs, but little is known about newer drugs and the possible effects on growth, development and organ maturation resulting from exposure to ART absorbed across the placenta and through breast-milk.\n\n# When to start: adolescents\n\n# When to start: adolescents\nThe review of evidence, programmatic data, operational considerations and values and preferences expressed by young people living with HIV led to the development of a separate recommendation for adolescents. This highlights the important considerations of initiating ART and providing treatment and care for adolescents living with HIV.\nAn estimated 2.1 million adolescents (10-19 years old) globally were living with HIV in 2013. HIV-related deaths among adolescents are estimated to have tripled since 2000, making HIV the second leading cause of death among adolescents worldwide (117).\nAdolescence is marked by rapid physical, neurodevelopmental, emotional and social changes (118). Although data are lacking on HIV mortality in the age group 5-14 years old, adolescents appear to be underserved by current HIV services, have significantly worse access to and coverage of ART than adults, have high risk of loss to follow-up (119)(120)(121) and have suboptimal adherence and special requirements for comprehensive care, including psychosocial support and sexual and reproductive health care (122)(123)(124). Adolescents also face significant barriers to accessing the essential health and support services they need, especially because of policy and legal barriers related to the age of consent (125).\nThe 2013 WHO consolidated ARV guidelines aligned the clinical and immunological criteria for ART eligibility among adolescents with those for adults (treatment initiation for WHO clinical stage 3 or 4 disease or at a CD4 count at or below 500 cells/mm 3 with the aim of enhancing programmatic simplicity and avoiding delays in treatment initiation while assessing eligibility.\n\n# Rationale and supporting evidence\nThe recommendation is also based on the strong operational and programmatic advantages of alignment with the criteria for initiating ART among adults and children and the clinical benefits demonstrated by evidence from adult studies (126).\nA systematic review of the evidence did not identify any study investigating treatment initiation strategies specific to adolescents. This subgroup was also not captured by adult studies that assessed the clinical outcomes of immediate versus CD4-driven ART initiation (127,128).\nPerinatally infected adolescents are more likely to experience chronic diseases and neurodevelopmental, growth and pubertal delays in comparison to their age-matched peers. Older adolescents who acquire HIV behaviourally do not present the same clinical features but face potentially greater challenges in dealing with stigma and lack of family and community support to access care.\n\n# When to start ART among adolescents (10-19 years of age) Recommendation\n- ART should be initiated among all adolescents living with HIV regardless of WHO clinical stage and at any CD4 cell count (conditional recommendation, low-quality evidence).\n- As a priority, ART should be initiated among all adolescents with severe or advanced HIV clinical disease (WHO clinical stage 3 or 4) and adolescents with CD4 count ≤350 cells/mm 3 (strong recommendation, moderate-quality evidence).\nThere are some limitations in extrapolating from the evidence for adults and some uncertainty around the potential benefits that immediate initiation of ART may have on adolescent health outcomes given the unique challenges that may arise in achieving long-term adherence and retention among adolescents. For this reason, the quality of the evidence reviewed for adults was downgraded for indirectness, and the overall quality of the evidence for treating all adolescents living with HIV was rated as low.\n\n# Comparing benefits and harm\nTo assess the potential benefits of starting ART earlier, a causal modelling study of data from southern and western Africa and Europe was updated using prospective data. This examined 4553 ART-naive perinatally infected adolescents 10-15 years old (median age 12.4 years), of whom 14% presented with CD4 counts above the existing eligibility thresholds of 500 cells/mm 3. In the analysis, median follow-up time was 656 days. Mortality appeared higher when ART was started very late. However, after four years of follow-up, the difference between immediate ART versus initiating ART at or below 500 cells/mm 3 was insignificant. These differences were similar for the adolescents who presented with a CD4 count above 500 cells/mm 3. Overall, the study did not show any clear survival or growth benefit from early treatment in this population (129).\nIndirect evidence showed that perinatally infected adolescents for whom treatment initiation is delayed to 10 years of age are unlikely to normalize CD4 count (130) and, after onset of chronic lung disease, do not fully recover lung functioning (131), suggesting that adolescents who have survived through childhood untreated may have limited gains from initiating ART earlier compared with younger children.\nThe high risk of loss to follow-up in this age group, particularly among adolescents aged 15-19 years (132)(133)(134)(135)(136), is an important factor in assessing the trade-off between risks and benefits of earlier ART initiation. Adolescents are also known to be less adherent than adults and younger children (137). Two systematic reviews on adherence and viral suppression showed varying rates for adolescents (138,139), and treatment failure was observed among 10% of 1007 perinatally infected children in the COHERE cohort, with the risk being higher with a longer time on ART and when treatment was started in adolescence (140).\nDespite the limited clinical evidence in support of earlier treatment initiation for both perinatally and behaviourally infected adolescents and potential concerns attached to the risk of drug resistance because of poor adherence, experience to date suggests that aligning with the initiation criteria for adults will contribute to simplifying programming and further expanding ART coverage (141) and present crucial opportunities to engage adolescents living with HIV in care.\n\n# Equity and acceptability\nIn community consultations, adolescents, service providers, parents and caregivers emphasized the importance of ensuring that priority be given to adolescents most in need of treatment as well as the challenge of adherence (142)(143)(144)(145). The key challenges identified included forgetting to take medicines, having unstable lives not conducive to daily medication and relative lack of power in treatment decision-making. Effective interventions and services to support adherence among adolescents -including community interventions and the use of peer educators -are required.\n\n# Feasibility and resource use\nEarlier initiation of ART among adolescents is likely to be feasible within existing health systems. Because of late diagnosis (146), many adolescents are already likely to be eligible based on 2013 initiation criteria, and the increase in the overall number of adolescents starting treatment would therefore be relatively small (141). Increased patient enrolments would nevertheless increase demands on supply chains and provider workload. The experience of some national programmes has shown that, although all adolescents 10-15 years old can be treated, challenges include ensuring that commodities are available, strengthening laboratory systems and conducting provider training (141).\nIncreased demand for commodities, human resources and infrastructure is expected to require additional funding. A costing analysis shows that ARV drugs are likely to be the most significant cost driver (147). Laboratory commodities are likely to be the second largest contributor to total cost, followed by human resources and co-trimoxazole.\n\n# Implementation considerations\nEnsuring that adolescents are diagnosed and receive ART in a timely manner will require developing adolescent-friendly health services and providers and strongly emphasizing support for adherence and retention in care. The full update of the consolidated guidelines will contain further guidance on operational and service delivery approaches to support the implementation of adolescent-friendly health services.\n\n# Research gaps\nHow earlier ART affects retention, adherence and HIV drug resistance among adolescents with less advanced disease requires further investigation. Improved age disaggregation of existing cohort and surveillance data is needed to improve understanding of adolescent-specific issues and needs.\n\n# When to start: adolescents\nA review of evidence, together with programmatic data and operational considerations, has led to revised recommendations in 2015 to initiate ART in all children with HIV, aligning the recommendation for children with the new recommendations for adults and adolescents.\nInfants and young children living with HIV have an exceptionally high risk of poor outcomes, with up to 52% of children born living with HIV dying before the age of two years in the absence of any intervention (148). By five years of age, the risk of mortality and disease progression in the absence of treatment falls to rates similar to those of young adults (149,150). Improved access to early infant diagnosis has increased the identification of infants living with HIV, but rates of ART initiation among infants living with HIV -all of whom should initiate treatment -remain suboptimal. Overall, most children who are eligible for ART are still not being treated, and ART coverage among children lags significantly behind that among adults: 32% versus 40% globally in 2014 (151).\nDiagnosing and retaining children exposed to and living with HIV in care present unique challenges because of their dependence on a caregiver. Loss to follow-up has been particularly high (152), with retention especially challenging for children who are in HIV care but not receiving ART (153).\nThe 2013 WHO ARV guidelines aligned clinical and immunological criteria for ART eligibility for children older than five years with those for adults: that is, treatment was recommended for WHO clinical stage 3 or 4 disease or CD4 counts at or below 500 cells/mm 3. ART was also recommended for all children living with HIV younger than five years of age regardless of clinical or immunological status. For children between one and five years of age, it was recommended that those younger than two years of age with WHO stage 3 or 4 clinical disease or CD4 percentage below 25% or CD4 count below 750 cells/mm 3 be given priority. For infants younger than one year of age, a strong recommendation to treat regardless of clinical and immunological conditions was maintained. The 2013 guidelines recognized the challenges of treating infants in their first two weeks of life because of lack of treatment options for which safe and effective dosing has been established and the lack of experience globally, further complicated by the high rates of prematurity and low birth weight in low-and middle-income countries.\nCountries with a high burden of HIV among children have rapidly adopted the 2013 treatment criteria (154), and some countries have decided to expand ART to all children and adolescents younger than 15 years to simplify ART delivery (155).\n\n# When to start ART among children (younger than 10 years of age) Recommendation\nART should be initiated among all children living with HIV, regardless of WHO clinical stage or at any CD4 cell count.\n- Infants diagnosed in the first year of life (strong recommendation, moderate-quality evidence).\n- Children living with HIV one year old to less than 10 years old (conditional recommendation, low-quality evidence).\nAs a priority, ART should be initiated among all children ≤2 years old or with WHO stage 3 or 4 or CD4 count ≤750 cells/mm³ or CD percentage <25% among children younger than 5 years and CD4 count ≤350 cells/mm³ among children 5 years and older.\n\n# Rationale and supporting evidence\nA systematic review (127) conducted in 2013 and updated in 2015 identified only one randomized clinical trial, PREDICT, that assessed the clinical benefit of early ART initiation among children (156).\nThe trial enrolled 300 children (1-12 years old, median age 6.4 years) with CD4 percentage above 15% and without United States Centers for Disease Control and Prevention stage C disease, randomizing them to either early treatment or deferred treatment until the CD4 percentage fell below 15%. There was no difference in AIDS-free survival or neurodevelopmental outcomes between the two arms, but height gain was better among those initiating ART earlier (157).\nA causal modelling study (158), also updated in 2015 using prospective data, assessed outcomes for 7358 ART-naive children 5-10 years old (median age 7.2 years), of whom 26% (1903) presented with CD4 counts exceeding the existing eligibility threshold of 500 cells/mm 3. In this analysis, after five years of follow-up, early ART differed slightly but significantly in mortality from waiting for the CD4 count to fall below 500 cells/mm 3. The causal modelling analysis also showed significantly better growth response among those starting ART immediately (159).\nIn addition, other evidence suggests that initiating ART earlier could mitigate the negative effects of HIV infection on growth and pubertal and nervous system development (160)(161)(162)(163)(164)(165)(166).\nEarlier ART may also promote immune recovery. In a study of the long-term effects of ART on CD4 cell evolution in children receiving ART, children with a greater degree of immunosuppression at baseline did not recover to normal values (CD4% >25%) even after five years of ART, whereas the CD4 percentage among children starting ART at higher CD4 levels normalized within a year of receiving ART (167). As shown by the normalization of inflammatory markers, earlier ART initiation is also likely to reduce HIV-induced chronic immune activation, thus potentially limiting the onset of chronic lung disease and increased risk of cardiovascular disease for which clinical correlates are still missing among children (168).\n\n# Fig. 3. Adoption of ART initiation for infants and children in low-and middle-income countries from the Global AIDS Response Progress Reporting, 2014\nGuideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV\nThe recommendation to start ART immediately is conditional for children living with HIV from 1 to less than 10 years old because of the paucity of evidence supporting ART initiation regardless of the clinical and immunological conditions in this population (160,161). However, this approach is expected to provide significant programmatic advantages, especially in settings with limited access to immunological testing, a high burden of HIV disease and low ART coverage among children.\n\n# Comparing benefits and harm\nIn addition to clinical considerations, earlier ART is likely to expand coverage in this age group. A rapid assessment conducted in May 2015 to assess the implementation of a policy to treat all children younger than 15 years in Uganda found a 74% increase in the number of children newly initiating ART and an increase in ART coverage among children from 22% to 32% between 2013 and 2014 (141). The proportion of children receiving ART at lower-level health facilities increased from 42% to 46%, suggesting that simplifying the criteria for initiating treatment could also be instrumental in effectively decentralizing ART services. In addition, the time from eligibility to ART initiation significantly decreased, suggesting that simpler initiation criteria allowed more rapid treatment initiation. Programmatic experience suggests that children receiving ART have better retention than those in care but not receiving ART ( 155). The retention rates in Uganda appeared to be comparable among children starting ART when eligible or with CD4 above 500 cells/mm 3 but there was a reduction in retention at six months, highlighting the need to ensure that children and caregivers receive appropriate counselling and support to stay in care.\nThe potential harm of earlier ART initiation includes short-term side effects that may predispose children to suboptimal ART adherence and subsequently treatment failure (169,170), along with the emergence of drug resistance and the need for second-and third-line regimens, for which options suitable for children are still limited. Treatment failure was observed in 10% of cases in the COHERE cohort, with the risk being higher the longer children are on ART and the older they are when initiating ART (171).\nIncreasing demands on the health system, drug stock-outs and consequent treatment discontinuation may also contribute to treatment failure and HIV drug resistance. Long-term side effects and chronic disease may result in increased morbidity and affect quality of life in adulthood. On balance, the likely clinical and programmatic benefits of earlier ART are likely to outweigh these potential types of harm.\n\n# Equity and acceptability\nExpanding ART to every child living with HIV is expected to increase equity and be well accepted.\nIn community consultations, the acceptability of earlier treatment of children living with HIV from the perspectives of parents, caregivers and health-care providers was based on the perceived health benefits for the child. However, psychosocial support for parents and caregivers, especially for disclosure, was highlighted as critical to facilitating initiation and improving adherence (172).\n\n# Feasibility and resource use\nImplementing this recommendation is likely to be feasible, since it represents a relatively small increased burden on current health systems (141). Late diagnosis is still common (173), and an estimated 80% or more of children identified as living with HIV would already be eligible for ART based on 2013 recommendations. However, increased numbers of children receiving ART may also lead to higher demand on supply chain systems and increased provider workload. Laboratory monitoring will need to be strengthened to monitor treatment efficacy and identify treatment 2.1.4 When to start: children 2.1.4 When to start: children failures among children. The experience of some national programmes has demonstrated that treating all children with HIV is feasible but also highlights the importance of secure commodity supplies, adequate health worker training and the need to ensure sustainability of resources (141).\nIncreased demand for HIV commodities, human resources and infrastructure may require increased funding. A costing analysis in Zambia has shown that ARV drugs are likely to be the most significant cost driver, accounting for 81% of total costs among children 0-14 years old. Laboratory commodities were the second largest contributor to total cost, followed by human resources and co-trimoxazole (141).\n\n# Implementation considerations\nAs ART is expanded to all children regardless of clinical and immune status, children younger than two years or children with WHO stage 3 or 4 disease or CD4 percentage below 25% or CD4 count at or below 750 cells/mm³ (if younger than five years) and CD4 counts at or below 350 cells/mm 3 (if older than five years) should be given priority for treatment because of their higher risk of death and rapid disease progression.\nImplementation approaches should include using opportunities to deliver ART for children in maternal, newborn and child health settings (175).\nExpanding ART services for children will require strategies to improve retention in care and to support adherence. Careful clinical monitoring remains essential to assess the risk of treatment failure, but lack of laboratory monitoring should not be a barrier to initiating ART (176).\n\n# Research gaps\nHow earlier ART affects retention, adherence and potential HIV drug resistance among children with less advanced disease needs to be investigated further. Optimal service delivery models to ensure rapid identification and ART initiation among infants and children also need to be investigated. Strategies are needed to provide an integrated package of care to reduce overall child mortality.\nOral PrEP is the use of ARV drugs by HIV-uninfected people to block the acquisition of HIV before exposure to HIV.\nTwelve trials of the effectiveness of oral PrEP have been conducted among serodiscordant couples, heterosexual men, women, men who have sex with men, people who inject drugs and transgender women (177)(178)(179)(180)(181)(182)(183)(184)(185)(186)(187)(188). Where adherence has been high, significant levels of efficacy have been achieved, showing the value of this intervention as part of combination prevention approaches.\nIn 2012, WHO recommended PrEP for use among serodiscordant couples, men who have sex with men and transgender people on the basis that demonstration projects were needed to ascertain optimal delivery approaches (189). In 2014, WHO developed consolidated HIV guidelines for key populations, including men who have sex with men, people who inject drugs, sex workers, transgender people and people in prisons and other closed settings (190). In those guidelines, PrEP was strongly recommended for men who have sex with men.\nThis new recommendation replaces the previous WHO recommendations on PrEP and enables the offer of PrEP to be considered for people at substantial risk of acquiring HIV rather than limiting the recommendation to specific populations. Box 3 discusses the definition of \"substantial risk\".\nThe new recommendation will enable a wider range of populations to benefit from this additional prevention option. It also allows the offer of PrEP to be based on individual assessment, rather than risk group, and is intended to foster implementation that is informed by local epidemiological evidence regarding risk factors for acquiring HIV.\n\n# Box 3. Defining \"substantial risk\"\nSubstantial risk of HIV infection is provisionally defined as HIV incidence greater than 3 per 100 person-years in the absence of PrEP. HIV incidence greater than 3 per 100 person-years has been identified among some groups of men who have sex with men, transgender women in many settings and heterosexual men and women who have sexual partners with undiagnosed or untreated HIV infection. Individual risk varies within groups at substantial risk depending on individual behaviour and the characteristics of sexual partners. Most of the PrEP trials reviewed for this recommendation identified and recruited groups at substantial risk of acquiring HIV infection, as demonstrated by the HIV incidence rate among participants in control arms that ranged between 3 to 9 per 100 person-years in most studies. Indeed, the HIV incidence in control arms of PrEP trials was often higher than anticipated, suggesting that PrEP attracts people at particularly high risk (187). In locations where the overall incidence of HIV infection is low, there may be individuals at substantial risk who would be attracted to PrEP services.\nHIV incidence greater than 2 per 100 person-years was considered sufficient to warrant offering oral PrEP in the recommendations issued by the International Antiviral Society -USA expert panel in 2014 (191). Thresholds for offering PrEP may vary depending on a variety of considerations, including available resources and the relative costs, feasibility and demand for PrEP and other opportunities.\n\n# Oral pre-exposure prophylaxis for preventing the acquisition of HIV infection Recommendation\nOral PrEP containing TDF should be offered as an additional prevention choice for people at substantial risk of HIV infection as part of combination HIV prevention approaches (strong recommendation, high-quality evidence).\n\n# Oral PrEP\n\n# Oral PrEP\n\n# Rationale and supporting evidence\nA systematic review and meta-analysis of PrEP trials containing TDF demonstrated that PrEP is effective in reducing the risk of acquiring HIV infection (192). The level of protection did not differ by age, gender, regimen (TDF versus FTC + TDF) and mode of acquiring HIV (rectal, penile or vaginal). The level of protection was strongly correlated with adherence.\n\n# HIV infection\nHIV infection was measured in 11 randomized controlled trials comparing PrEP to placebo, three randomized controlled trials comparing PrEP to no PrEP (such as delayed PrEP or \"no pill\") and three observational studies. Across data from 10 trials comparing PrEP with placebo, the results from a meta-analysis demonstrated a 51% reduction in risk of HIV infection for PrEP versus placebo (192).\n\n# Mode of acquisition\nWhen studies were stratified by mode of acquisition (rectal, vaginal or penile exposure), PrEP showed similar effectiveness across groups. The relative risk of HIV infection for PrEP versus placebo for rectal exposure is 0.34 (95% CI: 0.15-0.80, P = 0.01). For penile or vaginal exposure, the relative risk of HIV infection for PrEP versus placebo is 0.54 (95% CI: 0.32-0.90, P = 0.02) (192). Parenteral exposure to HIV was not analysed separately because only one study explicitly included people who inject drugs, and their exposure to HIV arose from sexual practices and incomplete access to sterile injection equipment.\n\n# Sex and gender\nOf the 10 randomized PrEP trials reporting HIV outcomes, women were included in six studies and men in seven studies. PrEP was effective for both men and women. The relative risk of HIV infection for PrEP versus placebo was 0.57 (95% CI 0.34-0.94; P = 0.03) among women and 0.38 (95% 0.20-0.60; P = 0.0001) among men. Two placebo-controlled trials that targeted women exclusively showed very low uptake of PrEP (less than one third) in the active arm and no effectiveness on an intent-to-treat basis (183,186). PrEP effectiveness among women in four trials that included both women and men was higher. For example, among women younger than 30 years in a trial that included both men and women, the effectiveness was 72% (95% CI: 29-92%, P = 0.01) for TDF and 77% (95% CI: 25-90%, P = 0.01) for FTC + TDF PrEP (180). The results from a recent study (HPTN 067) among young, predominately single South African women receiving open-label FTC + TDF as PrEP showed that young women can maintain adherence, with 80% having substantial concentrations of drug detected at week 4 and 65% at week 24 in the daily PrEP arm (193). More information about PrEP in transgender populations is needed.\nWhen all studies were analysed together, the results produced significant heterogeneity. The results from meta-regression conducted to evaluate whether certain variables moderated the effect of PrEP on reducing the risk of acquiring HIV infection demonstrated that adherence is a significant moderator.\nWhen studies were stratified according to adherence levels (high, moderate and low), heterogeneity was greatly reduced within adherence subgroups, demonstrating that most heterogeneity between studies can be explained by differing adherence levels. Within adherence subgroups, PrEP is the most efficacious among the high-adherence group (defined as >70% drug detection, but all studies in this group had adherence at or above 80%) and significantly reduces the risk of acquiring HIV infection in studies with moderate levels of adherence (41-70% drug detection). Among studies with low adherence (40% or lower drug detection), PrEP shows no effect in reducing HIV infection (192).\nTen randomized controlled trials comparing PrEP with placebo presented data on any adverse event. The risk of experiencing at least one adverse event during follow-up was common in participants in all trials. Across studies, the rates of any adverse event did not differ for PrEP versus placebo. Similarly, there were no differences across subgroups, including mode of acquisition, adherence, sex, drug regimen, drug dosing or age.\nEleven randomized controlled trials comparing PrEP with placebo presented the results for any grade 3 or 4 adverse event. Across studies, there was no statistical difference in rates of any grade 3 or 4 adverse event for PrEP versus placebo and there were no statistical differences across subgroup analyses, including adherence, sex, drug regimen, drug dosing or age (192).\nSeveral studies noted subclinical declines in renal functioning and bone mineral density among PrEP users (194)(195)(196). These subclinical changes did not result in clinical events and were not progressive over time.\n\n# Drug resistance\nThe risk of drug resistance to FTC was overall low (11 people with FTC-or TDF-resistant HIV infection among 9222 PrEP users, or 0.1%), and this occurred mainly among people who were acutely infected with HIV when initiating PrEP: 7 people with FTC-or TDF-resistant HIV infection among 9222 PrEP users. The proportion of people with drug-resistant HIV infection did not differ in the PrEP and placebo groups among everyone at risk, although the number of events was low (n = 6 people infected). Multiple HIV infections were averted for every case of FTC resistance associated with starting PrEP in the presence of acute HIV infection (192). Modelling the HIV drug resistance resulting from ART is predicted to far exceed that resulting from PrEP (197). Although mathematical models inform the risk of resistance, their results rely on data from clinical trials and make assumptions about risk of drug resistance selection during PrEP. How implementing PrEP on a large scale affects resistance overall is unknown, and active surveillance during PrEP scale-up may therefore be warranted.\n\n# Sexual and reproductive health outcomes\nNo evidence indicated that PrEP led to risk compensation in sexual practices, such as decreased condom use or more sexual partners (198,199).\nPrEP does not appear to affect the effectiveness of hormonal contraception, although two studies found trends towards higher rates of pregnancy among oral contraceptive users who also took PrEP. When multivariate analysis accounted for confounders, this relationship became nonsignificant. Oral PrEP was not associated with increased adverse pregnancy-related events among women taking PrEP during early pregnancy (180,186). More information is needed about interactions between PrEP and the hormone therapy used by transgender populations.\nThe review sought to evaluate the effectiveness of PrEP in preventing HIV infection in the context of access to a combination of standard approaches to HIV prevention (192). Across all trials, PrEP was provided in the context of a package of HIV prevention interventions, including regular HIV testing and counselling, provision of condoms, screening and treatment for sexually transmitted infections, adherence counselling and other options relevant to the study population, such as access to contraception for women and methadone maintenance for people who inject opioids.\n\n# Oral PrEP\n\n# Oral PrEP\nCost and cost-effectiveness\nThe HIV incidence threshold for cost-saving implementation of PrEP will vary depending on the relative costs of PrEP versus treatment for HIV infection and the anticipated effectiveness of PrEP.\nIn some situations, PrEP may be cost saving, but other interventions may be more cost saving and scalable. Monetary costs should not be the only consideration, since staying free of HIV and having control over HIV risk is of intangible value to people and communities.\nOffering PrEP in situations where the incidence of HIV is greater than 3 per 100 person-years is expected to be cost saving in many situations. Offering PrEP at lower incidence thresholds may still be cost-effective.\nA review of cost-effectiveness studies for PrEP found that, in generalized epidemics, giving priority for the use of PrEP to people at substantial risk of acquiring HIV infection increases impact (200). Some of these studies found PrEP to be cost-effective within the context of ART expansion; others found no benefit. Among concentrated epidemics (such as men who have sex with men in the United States), PrEP could significantly impact the epidemic. Studies have found PrEP to be cost-effective depending on the cost of the drug and delivery systems when PrEP uptake is higher among people at substantial risk. Higher PrEP uptake and adherence have been observed among men who have sex with men in demonstration projects (178,193). The results vary widely depending on epidemic type, location and model parameters, including efficacy, cost, HIV incidence and target population (201).\n\n# Equity and acceptability\nPreventing HIV infection among PrEP users will contribute to equitable health outcomes by sustaining their health and the health of their sexual partners. Access to PrEP also provides opportunities for accessing sexual health services, and people at substantial HIV risk are often currently medically underserved and have few other effective HIV prevention options. Extending PrEP recommendations beyond narrowly defined groups (such as men who have sex with men and serodiscordant couples) allows for more equitable access and will reduce future treatment costs overall by preventing HIV infection in populations with a high incidence.\nPrEP acceptability has been reported in multiple populations: women, serodiscordant couples, female sex workers, young women, people who inject drugs, transgender people, service providers and men who have sex with men. A qualitative literature review (Annex 2) (131 peerreviewed articles and 46 abstracts) showed that individuals have substantial interest in accessing PrEP as an additional choice for HIV prevention. Population support for provision of PrEP was based on the knowledge of safety and effectiveness and the compatibility of PrEP with other prevention strategies.\nOral PrEP for diverse populations has proven feasible in multiple trial settings and demonstration projects. Two placebo-controlled trials among women (183,186) found significant barriers to uptake and adherence. However, programme settings differ from trials. PrEP adherence among women has been high when open-label PrEP is provided (HPTN 067 ADAPT Study and the TDF2 Open Label Extension) (202,203).\nThe iPrEx OLE project and the Partners Demonstration project both show that PrEP implementation is feasible for different populations, including men and women (177,178).\nThe PROUD study, conducted in the United Kingdom and designed to mimic real-life settings, demonstrated that PrEP is feasible and effective and is not associated with significant changes in behavioural risk (187). Other PrEP demonstration projects in Botswana, South Africa, Thailand and the United States of America confirm that protective levels of adherence are feasible for most PrEP users (202)(203)(204)(205)(206)(207), although challenges remain to achieve high levels of adherence among young people (207).\n\n# Implementation considerations\nThere are significant concerns about implementing PrEP, especially in legal environments in which the rights of people at substantial risk of HIV are violated. PrEP should not displace or threaten the implementation of effective and well established HIV prevention interventions, such as condom programming and harm reduction. Stigma is a driver of HIV and could be decreased or increased depending on the how PrEP is implemented. PrEP should be promoted as a positive choice among people for whom it is suitable and their communities, in conjunction with other appropriate prevention interventions.\nWHO will publish comprehensive implementation guidance for PrEP in 2016. The implementation guidance will include practical suggestions for human resource utilization, laboratory monitoring, pharmacy services, drug procurement, counselling, communication, community engagement, coordination of services (including testing, treatment, PrEP, post-exposure prophylaxis and other sexual and reproductive health services) and programme management. The implementation guidance is briefly summarized here. Health-care providers should be trained and supported so that they can explore sexual and injecting risk behaviour with people and help them consider their risk of acquiring HIV infection and the range of prevention options, including PrEP. This requires providing respectful and inclusive services, a familiarity with techniques for discussing sensitive behaviour and a strong patient-provider relationship that enables discussions of facilitators and barriers to engagement in health-care services, adherence and self-care. Service providers should be aware of the emotional and physical trauma that people at substantial risk of acquiring HIV infection may have experienced (208). The capacity for respectful work with people who have experienced trauma involves communication and skills development. Developing services that are suited to young people, especially young women and key populations, is essential for the success of all HIV treatment and prevention programmes, including PrEP.\nMeeting the needs of populations at substantial risk of HIV infection requires the full participation of communities in developing and implementing programmes. The following are good participatory practices.\n- Recognize the leadership and resilience of key populations in addressing the HIV epidemic at both the local and global levels and sustain their response through adequate funding and support of community-based organizations.\n- Ensure access to accurate knowledge and information about PrEP and early treatment by strengthening the capacity of the community-based organizations in educating and training their communities on issues pertaining to their use.\n- Promote and expand community-based services, especially services led by key populations.\n- Ensure that PrEP is offered as a choice, free of coercion, and with access to other prevention strategies that may be preferred by the individuals at substantial risk.\n- Increase political commitment to rights, including the rights of key populations, by decriminalizing consensual sexual activity and gender expression.\nPeople at substantial risk of acquiring HIV are often medically underserved, have few other effective HIV prevention options and may face social and legal challenges. Providing PrEP may\ngive opportunities for increased access to a range of other health services and social support, including vaccinations for hepatitis B, reproductive health services, sexual health services (including managing sexually transmitted infections), mental health services and primary health care.\nHIV testing is required before PrEP is offered and regularly while PrEP is taken. Using qualityassured HIV testing is important, and using more sensitive tests has multiple advantages, including earlier HIV diagnosis and treatment, better counselling for people with acute HIV infection and minimizing the risk of drug resistance during pre-and post-exposure prophylaxis.\n\n# Research gaps\nOperational research is needed in diverse settings to generate demand for prevention services (including PEP and PrEP) and to identify and engage people at substantial risk for HIV. Additional research is needed on how to support adherence, especially for adolescents, young women and transgender men and women. Such research should generate practical knowledge and skills through implementation.\nSevere long-term toxicity of TDF for HIV treatment is rare. Surveillance of large-scale use of PrEP could identify rare but important clinical adverse events. For outcomes with few events (drug resistance and reproductive health outcomes), active surveillance during PrEP scale-up is warranted. WHO provides a range of guidance on toxicity monitoring (212).\nThe impact of PrEP on sexual practices may vary according to social and cultural contexts. The implementation of PrEP in diverse situations will provide opportunities for understanding how PrEP influences sexual practices, which may include improved sexual health and emotional wellbeing, a decrease of stigma and discrimination towards people living with HIV or increased use of other HIV prevention methods. Adverse behavioural and social outcomes are also possible, although they have not been observed so far. The role of gender norms may also influence the uptake of prevention and treatment services, including PrEP, and could be useful focus for qualitative implementation research.\nThe Ipergay trial showed high-level efficacy of PrEP dosing before and after sex among men who have sex with men who reported frequent sexual activity (204). The HPTN 067 trial randomly compared recommendations for daily and non-daily PrEP regimens and found that the daily recommendation was associated with the highest concentrations of drug, the highest adherence and high coverage of sex events with pre-and post-exposure dosing among men who have sex with men in Bangkok and New York and women in Cape Town (202,204,205). Medication requirements and use were also higher for those randomized to a recommendation for daily use. Daily dosing was the preferred recommendation, or a preferred recommendation, for the majority of users. How best to adapt PrEP recommendations to diverse and changing sexual practices is an important focus for implementation research.\nPrEP costs are substantial, and include costs for clinic staff, medications, laboratory testing, pharmacy services, community education, provider education and monitoring and evaluation. Implementation research should include evaluation of strategies for minimizing costs that do not compromise safety, effectiveness or the quality of information provided to prospective PrEP users. Ways to negotiate lower prices for medications and laboratory tests could be developed using volume purchasing. PrEP is amendable to algorithmic care, which would enable task sharing with less costly and more available staff. Research is needed to determine whether HIV status and renal function can be less frequently monitored without increasing the risk of adverse clinical outcomes. Optimal recommendations for starting and stopping PrEP to maximize use during periods of substantial risk would decrease medication requirements and increase the impact on HIV transmission.\nAdditional research on how best to integrate PrEP services with other services is needed. PrEP is compatible with HIV testing, HIV treatment services, sexual health services, condom provision, behavioural counselling, harm reduction, empowerment programmes, contraceptive services, reproductive health services and primary health care. PEP started after recent exposure to HIV can be transitioned to PrEP after 28 days if there is continuing substantial risk. How best to integrate PrEP into these existing services is not known and may vary in different locations.\n\n# Programmatic note\n\n# Programmatic note\nGuideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV\n\n# Programmatic note on the recommendations\n\n# Guidance on service delivery\nA wide range of operational considerations needs to be addressed as countries begin dialogue and planning to implement the recommendations in this guideline. The complete update to the consolidated WHO ARV guidelines to be published in 2016 will include programmatic and operational guidance based on evidence reviews for key PICO questions on operational issues, including the following topics related to the care of individuals living with HIV:\n- frequency of clinic visits and medication pick-ups for stable patients;\n- interventions to facilitate linkage to care, retention in care and adherence to medication; and\n- strengthening services, including task shifting and integration of care.\nImplementation guidance for PrEP will also be published in 2016. In addition, the recently published consolidated guidelines on HIV testing services (213) and strategic information (214) will be of value to countries to identify people living with HIV and to ensure that countries effectively monitor their programmes.\n\n# CD4 count and viral load monitoring\nDuring the past decade, WHO guidelines for ART in low-and middle-income countries have evolved towards recommending that countries phase in viral load for monitoring treatment and, since 2013, WHO has recommended viral load monitoring as the preferred approach to monitor patient response to ART. Most countries have adopted this recommendation and are in the process of scaling up viral load monitoring capacity.\nPreviously, the main way to monitor response to ART was through either clinical or immunological (CD4 cell count) monitoring, and in settings where both immunological and virological monitoring is available, both are generally done.\nGiven the recommendations in this guideline to initiate ART at any CD4 count, it may be reasonable to reduce or stop CD4 cell count for monitoring in settings where viral load monitoring can be assured. Nevertheless, CD4 count testing still has an important role to play in assessing baseline risk of disease progression, for starting and stopping prophylaxis and in making prioritysetting decisions regarding ART initiation in settings where universal treatment is not possible. CD4 cell count measurement may also be important for individuals for whom ART is failing.\nThe complete update of the consolidated ARV guidelines will include updated recommendations and operational guidance on clinical monitoring, including use of CD4 count and viral load testing.\nAdherence to ART is a primary determinant of viral suppression and risk of transmission, disease progression and death. Suboptimal adherence is a major challenge in all regions, at all stages of HIV disease, and is associated with a diversity of patient-and programme-related challenges. Individual factors may include forgetting doses; being away from home; changes in daily routines; depression or other illness; limited understanding of treatment benefits; a lack of interest or desire to take the medicines; and substance or alcohol use. Adherence to ART may also be challenging in the absence of supportive environments for people living with HIV and because\n\n# Fig. 4. WHO generic framework for setting priorities\n-f HIV-related stigma and discrimination. Medication-related factors may include adverse events; the complexity of dosing regimens; the pill burden; and dietary restrictions. Health system factors include distance to health services; long waiting times to receive care and obtain refills; and the burden of the direct and indirect costs of care.\nSpecific population groups facing additional adherence challenges may include pregnant and postpartum women, adolescents, infants and children, key populations and people with mental health and substance use disorders.\nLong-term adherence to treatment is critical for the success of ART and presents new challenges as PrEP programmes are brought to scale. The updated consolidated ARV guidelines to be published in 2016 will provide guidance on adherence support based on updated evidence and lessons from recent programmatic experience.\n\n# Setting priorities\nThe impact of these guidelines will be determined by the extent to which they are implemented in the specific country contexts. Although global and national HIV goals are becoming more ambitious and aim to ultimately end AIDS by 2030, many low-and middle-income countries may have limited available resources and implementation capacity. It is therefore important that informed choices be made on implementing these guidelines.\nWHO has developed a draft priority-setting framework for HIV and other similar communicable disease programmes (Fig. 4). The purpose of the framework is to provide a structured approach by which national stakeholders can address issues of priority-setting in the face of competing programme needs and limited available resources. The framework outlines issues to be considered in setting priorities but does not make specific recommendations on what should be given priority, as these decisions are highly context and country specific. The details of this framework will be made available in the complete update to the consolidated ARV guidelines to be published in 2016.\n\n# Management plans\n- Conditional participation: continued involvement in the meeting and publicly disclose the expert's interest at the start of the meeting and in the report of the meeting and relevant publications or work products. - Partial exclusion: limited involvement: (a) exclude expert from that portion of the meeting or work where conflict of interest has been identified and/or exclude the expert from participating in the decision-making process. Reported interest to be publicly disclosed to other meeting participants and in the report of the meeting and relevant publications or work products. Partial exclusion was carefully monitored in the meeting. - Total exclusion: expert was excluded from the meeting altogether.\n\n# PICO questions\nA1.1 In adults, adolescents and children with HIV, is ART initiated at a threshold above CD4 500 cells/mm 3 compared with less than 500 cells/mm 3 more harmful? A1.3 Should pregnant and breastfeeding women with HIV started on triple ARV drugs continue on lifelong ART regardless of eligibility criteria? E1.1 Should oral PrEP containing TDF be offered as an additional prevention choice for people at substantial risk of HIV infection as part of combination prevention approaches?"}}},{"rowIdx":88,"cells":{"id":{"kind":"string","value":"4c242a21b896c6a43a4b3ea7829b80f33a8ae2f3"},"source":{"kind":"string","value":"cdc"},"text":{"kind":"string","value":"Through the Act, Congress charged NIOSH with recommending occupational safety and health standards and describing exposure levels that are safe for various periods of employment, including but not limited to the exposures at which no worker will suffer diminished health, functional capacity, or life expectancy because of his or her work experience. Criteria documents contain a critical review of the scientific and technical information about the prevalence of hazards, the existence of safety and health risks, and the adequacy of control m eth ods. By means of criteria documents, NIOSH communicates these recommended standards to regulatory agencies, including the Occupational Safety and Health Administration (OSHA), health professionals in academic institutions, industry, organized labor, public interest groups, and others in the occupational safety and health community. This criteria document is derived from the NIOSH evaluation of critical health effects studies of occupational exposure to hexavalent chromium (Cr) compounds. It provides recommenda tions for controlling workplace exposures including a revised recommended exposure limit (REL) derived using current quantitative risk assessment methodology on human health effects data. This document supersedes the 1975 Criteria for a Recommended Standard: Occupational Exposure to Chromium(VI) and NIOSH Testimony to OSHA on the Proposed Rule on Occupational Exposure to Hexavalent Chromium [NIOSH 1975a[NIOSH , 2005a. Cr(VI) compounds include a large group of chemicals with varying chemical properties, uses, and workplace exposures. Their properties include corrosion-resistance, durability, and hardness. So dium dichromate is the most common chromium chemical from which other Cr(VI) compounds may be produced. Materials containing Cr(VI) include various paint and prim er pigments, graphic art supplies, fungicides, corrosion inhibitors, and wood preservatives. Some of the industries in which the largest numbers of workers are exposed to high concentrations of Cr(VI) compounds include electroplating, welding, and painting. An estimated 558,000 U.S. workers are exposed to airborne Cr(VI) compounds in the workplace. Cr(VI) is a well-established occupational carcinogen associated with lung cancer and nasal and sinus cancer. NIOSH considers all Cr(VI) compounds to be occupational carcinogens. NIOSH rec ommends that airborne exposure to all Cr(VI) compounds be limited to a concentration of 0.2 Cr(VI)/m3 for an 8-hr time-weighted average (TWA) exposure, during a 40-hr workweek. The REL is intended to reduce workers' risk of lung cancer associated with occupational exposure to Cr(VI) compounds over a 45-year working lifetime. It is expected that reducing airborne workplace expo sures to Cr(VI) will also reduce the nonmalignant respiratory effects of Cr(VI) compounds, includ ing irritated, ulcerated, or perforated nasal septa and other potential adverse health effects. Becauseof the residual risk of lung cancer at the REL, NIOSH further recommends that continued efforts be made to reduce Cr(VI) exposures to below the REL. A hierarchy of controls, including elimina tion, substitution, engineering controls, administrative controls, and the use of personal protective equipment, should be followed to control workplace exposures.# Executive Summary\nIn this criteria document, the National Institute for Occupational Safety and Health (NIOSH) re views the critical health effects studies of hexavalent chromium (Cr ) compounds in order to update its assessment of the potential health effects of occupational exposure to Cr(VI) compounds and its recommendations to prevent and control these workplace exposures. NIOSH reviews the following aspects of workplace exposure to Cr(VI) compounds: the potential for exposures (Chap ter 2), analytical methods and considerations (Chapter 3), human health effects (Chapter 4), ex perimental studies (Chapter 5), and quantitative risk assessments (Chapter 6). Based on evalua tion of this information, NIOSH provides recommendations for a revised recommended exposure limit (REL) for Cr(VI) compounds (Chapter 7) and other recommendations for risk management (Chapter 8).\nThis criteria document supersedes previous NIOSH Cr(VI) policy statements, including the 1975 NIOSH Criteria for a Recommended Standard: Occupational Exposure to Chromium(VI) and NIOSH Testimony to OSHA on the Proposed Rule on Occupational Exposure to Hexavalent Chromium .\nCr(VI) compounds include a large group of chemicals with varying chemical properties, uses, and workplace exposures. Their properties include corrosion-resistance, durability, and hardness. Workers may be exposed to airborne Cr(VI) when these compounds are manufactured from oth er forms of Cr (e.g., the production of chromates from chromite ore); when products containing Cr(VI) are used to manufacture other products (e.g., chromate-containing paints, electroplating); or when products containing other forms of Cr are used in processes that result in the formation of Cr(VI) as a by-product (e.g., welding). In the marketplace, the most prevalent materials that con tain chromium are chromite ore, chromium chemicals, ferroalloys, and metal. Sodium dichromate is the most common chromium chemical from which other Cr(VI) compounds may be produced. Cr(VI) compounds commonly manufactured include sodium dichromate, sodium chromate, p o tassium dichromate, potassium chromate, ammonium dichromate, and Cr(VI) oxide. Other m an ufactured materials containing Cr(VI) include various paint and prim er pigments, graphic arts supplies, fungicides, and corrosion inhibitors.\nAn estimated 558,000 U.S. workers are exposed to airborne Cr(VI) compounds in the workplace. Some of the industries in which the largest numbers of workers are exposed to high concentra tions of airborne Cr(VI) compounds include electroplating, welding, and painting. An estimated 1,045,500 U.S. workers have dermal exposure to Cr(VI) in cement, primarily in the construction industry.\nCr(VI) is a well-established occupational carcinogen associated with lung cancer and nasal and sinus cancer. NIOSH considers all Cr(VI) compounds to be occupational carcinogens compounds as encountered in the chromate production, chromate pigment production and chromium plating industries\" (i.e., IARC category \"Group 1\" carcinogen) . Cr(VI) compounds were reaf firmed as an IARC Group 1 carcinogen (lung) in 2009 . The National Toxicology Program (NTP) identified Cr(VI) compounds as carcinogens in its first annual report on carcinogens in 1980 . Nonmalignant respiratory effects of Cr(VI) compounds in clude irritated, ulcerated, or perforated nasal septa. Other adverse health effects, including repro ductive and developmental effects, have been reviewed by other government agencies . Studies of the Baltimore and Painesville cohorts of chromate production workers provide the best information for predicting Cr(VI) cancer risks because of the quality of the exposure estimation, large amount of worker data available for analysis, extent of ex posure, and years of follow-up . NIOSH selected the Baltimore cohort for analysis because it has a greater num ber of lung cancer deaths, better smoking histories, and a more comprehensive retrospective exposure archive. The NIOSH risk assessment estimates an excess lifetime risk of lung cancer death of 6 per 1,000 workers at 1 |ig Cr(V I)/m 3 (the previ ous REL) and approximately 1 per 1,000 workers at 0.2 ^g Cr(VI)/m3 (the revised REL) . The basis for the previous REL for carcinogenic Cr(VI) compounds was the quantitative limitation of the analytical m ethod available in 1975.\nBased on the results of the NIOSH quantitative risk assessment , NIOSH recom mends that airborne exposure to all Cr(VI) compounds be limited to a concentration of 0.2 Cr(VI)/m3 for an 8-hr TWA exposure, during a 40-hr workweek. The REL is intended to reduce workers' risk of lung cancer associated with occupational exposure to Cr(VI) compounds over a 45-year working lifetime. It is expected that reducing airborne workplace exposures to Cr(VI) will also reduce the nonmalignant respiratory effects of Cr(VI) compounds, including irritated, ulcer ated, or perforated nasal septa and other potential adverse health effects. Because of the residual risk of lung cancer at the REL, NIOSH recommends that continued efforts be made to reduce ex posures to Cr(VI) compounds below the REL.\nThe available scientific evidence supports the inclusion of all Cr(VI) compounds into this recom mendation. Cr(VI) compounds studied have demonstrated their carcinogenic potential in animal, in vitro, or human studies . Molecular toxicology studies provide additional support for classifying Cr(VI) compounds as occupational carcinogens.\nThe NIOSH REL is a health-based recommendation derived from the results of the NIOSH quan titative risk assessment conducted on hum an health effects data. Additional considerations include analytical feasibility and the achievability of engineering controls. NIOSH M ethod 7605, OSHA M ethod ID-215, and international consensus standard analytical methods can quantitatively assess worker exposure to Cr(VI) at the REL. Based on a qualitative assessment of workplace exposure data, NIOSH acknowledges that Cr(VI) exposures below the REL can be achieved in some work places using existing technologies but are more difficult to control in others . Some operations, including hard chromium electroplating, chromate-paint spray application, atomized-alloy spray-coating, and welding may have difficulty in consistently achieving exposures at or below the REL by means of engineering controls and work practices . The extensive analysis of workplace exposures conducted for the OSHA rule-making process supports the NIOSH assessment that the REL is achievable in some workplaces but difficult to achieve in others .\nA hierarchy of controls, including elimination, substitution, engineering controls, administrative controls, and the use of personal protective equipment, should be followed to control workplace exposures. The REL is intended to promote the proper use of existing control technologies and to encourage the research and development of new control technologies where needed, in order to control workplace Cr(VI) exposures.\nAt this time, there are insufficient data to conduct a quantitative risk assessment for workers ex posed to Cr(VI), other than chromate production workers or specific Cr(VI) compounds other than sodium dichromate. However, epidemiologic studies demonstrate that the health effects of airborne exposure to Cr(VI) are similar across workplaces and industries (see Chapter 4). There fore, the results of the NIOSH quantitative risk assessment conducted on chromate production workers are used as the basis of the REL for all workplace exposures to Cr(VI) compounds.\nThe prim ary focus of this document is preventing workplace airborne exposure to Cr(VI) com pounds to reduce workers' risk of lung cancer. However, NIOSH also recommends that dermal exposure to Cr(VI) compounds be prevented in the workplace to reduce adverse dermal effects including skin irritation, skin ulcers, skin sensitization, and allergic contact dermatitis.\nNIOSH recommends that employers implement measures to protect the health of workers exposed to Cr(VI) compounds under a comprehensive safety and health program, including hazard com munication, respiratory protection programs, smoking cessation, and medical monitoring. These elements, in combination with efforts to maintain airborne Cr(VI) concentrations below the REL and prevent dermal contact with Cr(VI) compounds, will further protect the health of workers.\n\n# Contents\n\n# Introduction 1.1 Purpose and Scope\nThis criteria document describes the most recent NIOSH scientific evaluation of occupational ex posure to hexavalent chromium (Cr ) com pounds, including the justification for a revised recommended exposure limit (REL) derived us ing current quantitative risk assessment m eth odology on human health effects data. This cri teria document focuses on the relevant critical literature published since the 1975 Criteria for a Recommended Standard: Occupational Exposure to Chromium(VI) . The policies and recommendations in this document pro vide updates to the NIOSH Testimony on the OSHA Proposed Rule on Occupational Exposure to Hexavalent Chromium and the correspond ing NIOSH Post-Hearing Comments . This final document incorporates the NIOSH response to peer, stakeholder, and pub lic review comments received during the exter nal review process.\n\n# History of NIOSH Cr(VI) Policy\nIn the 1973 Criteria for a Recommended Stan dard: Occupational Exposure to Chromic Acid, NIOSH recommended that the federal standard for chromic acid, 0.1 mg chromium trioxide/ m3, as a 15-minute ceiling concentration, be retained because of reports of nasal ulceration occurring at concentrations only slightly above this concentration . In addition, NIOSH recom m ended 0.05 mg chrom ium trioxide/m 3 time-weighted average (TWA) for an 8-hour workday, 40-hour work week, to protect against possible chronic effects, includ ing lung cancer and liver damage.\nIn the 1975 Criteria for a Recommended Stan dard: Occupational Exposure to Chromium(VI), NIOSH supported two distinct recommended standards for Cr(VI) compounds . Some Cr(VI) compounds were consid ered noncarcinogenic at that time, including the chromates and bichromates of hydrogen, lithium, sodium, potassium, rubidium, cesi um, and ammonium, and chromic acid anhy dride. These Cr(VI) compounds are relatively soluble in water. It was recommended that a 10-hr TWA limit of 25 |ig Cr(VI)/m 3 and a 15-minute ceiling limit of 50 |ig Cr(VI)/m 3 be applied to these Cr(VI) compounds.\nAll other Cr(VI) compounds were considered carcinogenic . These Cr(VI) compounds are relatively insoluble in water. At that time, NIOSH subscribed to a carcino gen policy that called for \"no detectable expo sure levels for proven carcinogenic substances\" . The basis for the REL for car cinogenic Cr(VI) compounds, 1 |ig Cr(VI)/m3 TWA, was the quantitative limitation of the an alytical m ethod available at that time for mea suring workplace exposures to Cr(VI).\nNIOSH revised its policy on Cr(VI) com pounds in the NIOSH Testimony on the OSHA Proposed Rule on Air Contaminants . NIOSH testified that although insol uble Cr(VI) compounds had previously been demonstrated to be carcinogenic, there was now sufficient evidence that soluble Cr(VI) com pounds were also carcinogenic. NIOSH recom mended that all Cr(VI) compounds, whether soluble or insoluble in water, be classified as po tential occupational carcinogens based on the OSHA carcinogen policy. NIOSH also recom mended the adoption of the most protective of the available standards, the NIOSH RELs. Con sequently the REL of 1 |ig Cr(VI)/m3 TWA was adopted by NIOSH for all Cr(VI) compounds.\nNIOSH reaffirmed its policy that all Cr(VI) compounds be classified as occupational car cinogens in the NIOSH Comments on the OSHA Request for Information on Occupation al Exposure to Hexavalent Chromium and the NIOSH Testimony on the OSHA Proposed Rule on Occupational Exposure to Hexavalent Chro mium [NIOSH 2002[NIOSH , 2005a. Other NIOSH Cr(VI) policies were reaffirmed or updated at that time [NIOSH 2002[NIOSH , 2005a. This criteria document updates the NIOSH Cr(VI) policies, including the revised REL, based on its most recent scientific evaluation.\n\n# The REL for Cr(VI) Compounds\nNIOSH recommends that airborne exposure to all Cr(VI) compounds be limited to a con centration of 0.2 ^g C r(V I)/m 3 for an 8-hr TWA exposure during a 40-hr workweek. The use of NIOSH M ethod 7605 (or validated equivalents) is recommended for Cr(VI) de term ination. The REL represents the upper limit of exposure for each worker during each work shift. Because of the residual risk of lung cancer at the REL, NIOSH further recom mends that all reasonable efforts be made to reduce exposures to Cr(VI) compounds below the REL. The available scientific evidence sup ports the inclusion of all Cr(VI) compounds into this recommendation. The REL is intended to reduce workers' risk of lung cancer associ ated with occupational exposure to Cr(VI) compounds over a 45-year working lifetime.\nAlthough the quantitative analysis is based on lung cancer mortality data, it is expected that reducing airborne workplace exposures will also reduce the nonmalignant respiratory ef fects of Cr(VI) compounds, which include ir ritated, ulcerated, or perforated nasal septa.\nWorkers are exposed to various Cr(VI) com pounds in many different industries and work places. Currently there are inadequate exposure assessment and health effects data to quantita tively assess the occupational risk of exposure to each Cr(VI) compound in every workplace. NIOSH used the quantitative risk assessment of chromate production workers conducted by Park et al. as the basis for the deriva tion of the revised REL for Cr(VI) compounds. This assessment analyzes the data of Gibb et al. , the most extensive database of work place Cr(VI) exposure measurements available, including smoking data on most workers. These chromate production workers were exposed pri marily to sodium dichromate, a soluble Cr(VI) compound. Although the risk of worker expo sure to insoluble Cr(VI) compounds cannot be quantified, the results of animal studies indi cate that this risk is likely as great, if not greater than, exposure to soluble Cr(VI) compounds . The carcinogenicity of in soluble Cr(VI) compounds has been dem on strated in animal and human studies . Animal studies have demonstrated the carcinogenic potential of soluble and insolu ble Cr(VI) compounds . Recent molecular toxi cology studies provide further support for clas sifying Cr(VI) compounds as occupational car cinogens without providing sufficient data to quantify different RELs for specific compounds . Based on its evaluation of the data currently available, NIOSH recommends that the REL apply to all Cr(VI) compounds.\nThere are inadequate data to exclude any single Cr(VI) compound from this recommendation.\nIn addition to limiting airborne concentrations of Cr(VI) compounds, NIOSH recommends that dermal exposure to Cr(VI) be prevented in the workplace to reduce the risk of adverse dermal health effects, including irritation, ul cers, skin sensitization, and allergic contact dermatitis.\nProperties, Production, and Potential for Exposure\n\n# Physical and Chemical Properties\nChromium (Cr) is a metallic element that oc curs in several valence states, including Cr-4 and Cr-2 through Cr+6. In nature, chromium ex ists almost exclusively in the trivalent (Cr) and hexavalent (Cr) oxidation states. In industry, the oxidation states most commonly found are Cr(0) (metallic or elemental chro mium), Cr(III), and Cr(VI).\nChemical and physical properties of select Cr(VI) compounds are listed in Table 2-1. The chemical and physical properties of Cr(VI) compounds relevant to workplace sampling and analysis are discussed further in Chapter 3, \"Measurement of Exposure.\"\n\n# Production and Use in the United States\nIn the marketplace, the most prevalent mate rials that contain chromium are chromite ore, chromium chemicals, ferroalloys, and metal. In 2010, the United States consumed about 2% of world chromite ore production in im port ed materials such as chromite ore, chromium chemicals, chromium ferroalloys, chromium metal, and stainless steel . One U.S. company mined chromite ore and one U.S. chemical firm used imported chromite to produce chromium chemicals. Stainless-and heat-resisting-steel producers were the lead ing consumers of ferrochromium. The United\nStates is a major world producer of chromium metal, chromium chemicals, and stainless steel . Table 2-2 lists select statistics of chromium use in the United States .\nSodium dichromate is the prim ary chemical from which other Cr(VI) compounds are p ro duced. Currently the United States has only one sodium dichromate production facility.\nAlthough production processes may vary, the following is a general description of Cr(VI) com pound production. The process begins by roasting chromite ore with soda ash and varying amounts of lime at very high tem per atures to form sodium chromate. Impurities are removed through a series of pH adjust ments and filtrations. The sodium chromate is acidified with sulfuric acid to form sodium dichromate. Chromic acid can be produced by reacting concentrated sodium dichromate liquor with sulfuric acid. O ther Cr(VI) com pounds can be produced from sodium dichromate by adjusting the pH and adding other compounds. Solutions of Cr(VI) compounds thus formed can then be crystallized, p u ri fied, packaged, and sold. Cr(VI) compounds commonly m anufactured include sodium dichromate, sodium chromate, potassium dichromate, potassium chromate, am monium dichromate, and Cr(VI) oxide. O ther m ate rials containing Cr(VI) commonly m anufac tured include various paint and prim er pig ments, graphic art supplies, fungicides, and corrosion inhibitors.\n\n# Potential Sources of Occupational Exposure 2.3.1 Airborne Exposure\nWorkers are potentially exposed to airborne Cr(VI) compounds in three different workplace scenarios: (1) when Cr(VI) com pounds are manufactured from other forms of Cr such as in the production of chromates from chromite ore; (2) when products or substances contain ing Cr(VI) are used to manufacture other prod ucts such as chromate-containing paints; or (3) when products containing other forms of Cr are used in processes and operations that result in the formation of Cr(VI) as a by-product, such as in welding.\nMany of the processes and operations with worker exposure to Cr(VI) are those in which products or substances that contain Cr(VI) are used to manufacture other products. Cr(VI) compounds impart critical chemical and phys ical properties such as hardness and corrosion resistance to manufactured products. Chro mate compounds used in the manufacture of paints result in products with superior corro sion resistance. Chromic acid used in electro plating operations results in the deposition of a durable layer of chromium metal onto a basemetal part. Anti-corrosion pigments, paints, and coatings provide durability to materials and products exposed to the weather and other extreme conditions.\nOperations and processes in which Cr(VI) is formed as a by-product include those utilizing metals containing metallic chromium, includ ing welding and the therm al cutting of metals; steel mills; and iron and steel foundries. Fer rous metal alloys contain chromium metal in varying compositions, lower concentrations in m ild steel and carbon steel, and higher concentrations in stainless steels and other high-chrom ium alloys. The extremely high temperatures used in these operations and processes result in the oxidation of the metal lic forms of chromium to Cr(VI). In welding operations both the base metal of the parts be ing joined and the consumable metal (weld ing rod or wire) added to create the joint have varying compositions of chromium. During the welding process, both are heated to the melting point, and a fraction of the melted metal vapor izes. Any vaporized m etal that escapes the welding-arc area quickly condenses and oxidizes into welding fume, and an appreciable fraction of the chromium in this fume is in the form of Cr(VI) . The Cr(VI) content of the fume and the resultant potential for Cr(VI) exposures are de pendent on several process factors, most impor tantly the welding process and shield-gas type, and the Cr content of both the consumable mate rial and the base metal .\nThe bioaccessibility of inhaled Cr(VI) from welding fume may vary depending on the fume-generation source. Characterizations of bioaccessibility and biological indices of Cr(VI) exposure have been reported .\n\n# Dermal Exposure\nDermal exposure to Cr(VI) may occur with any task or process in which there is the p o tential for splashing, spilling, or other skin contact with material that contains Cr(VI\n\n# Dermal Exposure\nThe construction industry has the greatest number of workers at risk of dermal exposure to Cr(VI) due to working with Portland cement. Exposures can occur from contact with a vari ety of construction materials containing Port land cement, including cement, mortar, stucco, and terrazzo. Examples of construction workers with potential exposure to wet cement include bricklayers, cement masons, concrete finishers, construction craft laborers, hod carriers, plas terers, terrazzo workers, and tile setters .\nWorkers in many other industries are at risk of dermal exposure if there is any splashing, spill ing, or other skin contact with material con taining Cr(VI). Other industries with reported dermal exposure include chromate production ; electroplating ; and grinding of stain less and acid-proof steel .\n\n# Number of U.S. Workers Potentially Exposed\nThe National Occupational Hazard Survey, conducted by NIOSH from 1972 through 1974, estimated that 2.5 million workers were poten tially exposed to chromium and its compounds . It was estimated that 175,000 and the manufacture of refractory brick, col ored glass, prefabricated concrete products, and treated wood products. The field surveys represent a series of case studies rather than a statistically representative characterization of U.S. occupational exposures to Cr(VI). A limi tation of this study is that for some operations only one or two samples were collected.\nThe industrial processes and operations were classified into four categories, using the expo sure and exposure-control information collect ed at each site. Each category was determined based on a qualitative assessment of the relative difficulty of controlling Cr(VI) exposures to the existing REL of 1 ^g/m3. The measured ex posures were compared with the existing REL.\nFor exposures exceeding the existing REL, the extent to which the REL was exceeded was considered, and a qualitative assessment of the effectiveness of the existing controls was made.\nAn assessment based on professional judgment determined the relative difficulty of improving control effectiveness to achieve the REL. The four categories into which the processes or op erations were categorized are as follows:\n1. Those with minimal worker exposures to Cr(VI) in air (Table 2-4).\n2. Those with workers' exposures to Cr(VI) in air easier to control to existing NIOSH REL than categories ( 3) and ( 4) (Table 2-5).\n3. Those with workers' exposures to Cr(VI) in air moderately difficult to control to the ex isting NIOSH REL (Table 2-6).\n4. Those with workers' exposures to Cr(VI) in air most difficult to control to the existing NIOSH REL (Table 2- 7).\nThe results of the field surveys are summarized in Tables 2-4 through 2-7. The results char acterize the potential exposures as affected by engineering controls and other environmental factors, but not by the use or disuse of PPE. The PBZ air samples were collected outside any re spiratory protection or other PPE (such as welding helmets) worn by the workers. A wide variety of processes and operations were clas sified as those with minimal worker exposures to Cr(VI) in air (Table 2- 4) or where workers' Cr(VI) exposures were determined to be easier to control to the existing REL (Table 2 -5). Most of the processes and operations where control ling workers' Cr(VI) exposures to the existing REL were determined to be moderately dif ficult to control involved joining and cutting metals, when the chromium content of the m a terials involved was relatively high (Table 2-6).\nIn the category where it was determined to be most difficult to control workers' airborne Cr(VI) exposures to the existing REL, all of the processes and operations involved the ap plication of coatings and finishes (Table 2- Source: Blade et al. . 'Abbreviations: GSD = geometric standard deviation; n = num ber of samples; LEV = local exhaust ventilation; mfg=manufacturing; MIG = metal inert gas; n = num ber of samples; ND = not detected; PBZ = personal breathing zone; SIC = Standard Industrial Classification; TIG = tungsten inert gas.\nf Concentration value preceded by a \"less-than\" symbol (<) indicates that the Cr(VI) level in the sampled air was less than the m inim um detectable concentration (i.e., the mass of Cr collected in the sample was less than the analytical limit of detection ). A concentration value preceded by an \"approximately\" symbol (~) indicates that Cr(VI) was detectable in the sampled air, but at a level less than the m inim um quantifiable concentration (i.e., the mass of Cr collected in the sample was between the analytical LOD and limit of quantification ). These concentration values are less precise than fully quantifiable values. *SIC codes were in use when these surveys were conducted. See the SIC M anual at www.osha.gov/pls/imis/sic_manual.html. Properties, Production, and Potential for Exposure Source: Blade et al. . - Abbreviations: FCAW = flux cored arc welding; GM = geometric mean; GSD = geometric standard deviation; n = num ber of samples; LEV = local exhaust ventilation; mfg = m an ufacturing; MIG = m etal inert gas; n = num ber of samples; ND = not detected; PBZ = personal breathing zone; SIC = Standard Industrial Classification; SMAW = shield-m etal arc welding; TIG = tungsten inert gas. C oncentration value preceded by a \"less-than\" symbol (<) indicates that the Cr(VI) level in the sam pled air was less than the m inim um detectable concentration (i.e., the mass of Cr collected in the sample was less than the analytical limit of detection ). *SIC codes were in use when these surveys were conducted. See the SIC M anual at www.osha.gov/pls/imis/sic_manual.html. Source: Blade et al. . - Abbreviations: GM = geometric mean; GSD = geometric standard deviation; n = num ber of samples; LEV = local exhaust ventilation; mfg = m anufacturing; MIG = metal inert gas; n = num ber of samples; ND = not detected; PBZ = personal breathing zone; SIC = Standard Industrial Classification; TIG = tungsten inert gas.\nf Concentration value preceded by a \"less-than\" symbol (<) indicates that the Cr(VI) level in the sampled air was less than the m inim um detectable concentration (i.e., the mass of Cr collected in the sample was less than the analytical limit of detection ). For some other samples in these sets, Cr(VI) was detectable in the sampled air but at a level less than the m inim um quantifiable concentration (i.e., the mass o f Cr collected in the sample was between the analytical LOD and limit of quantification ). These concentration values are less precise than fully quantifiable values. *SIC codes were in use when these surveys were conducted. See the SIC M anual at www.osha.gov/pls/imis/sic_manual.html. Source: Blade et al. . - Abbreviations: GM = geometric mean; GSD = geometric standard deviation; n = num ber of samples; LEV = local exhaust ventilation; mfg = m anufacturing; n = num ber of samples; ND = not detected; PBZ = personal breathing zone; SIC = Standard Industrial Classification.\nf Concentration value preceded by a \"less-than\" symbol () indicates that the reported value is an estimate, and the \"true\" concentration likely is greater, because of air-sampling pum p failure before the end of the intended sampling period. *SIC codes were in use when these surveys were conducted. See the SIC M anual at www.osha.gov/pls/imis/sic_manual.html.\n Properties, Production, and Potential for Exposure\n\n# Welding and Thermal Cutting of Metals\nWelders are the largest group of workers poten tially exposed to Cr(VI) compounds. Cr(VI)\nexposures to welders are dependent on several process factors, most importantly the welding process and shield-gas type, and the Cr content of both the consumable material and the base metal [Keane et al. 2009;Heung et al. 2007;EPRI 2009;Meeker et al. 2010\n\n# Occupational Exposure Limits\nThe NIOSH REL for all Cr(VI) compounds is 0.\n\n# IDLH Value\nAn immediately dangerous to life or health (IDLH) condition is one that poses a threat of exposure to airborne contaminants when that exposure is likely to cause death or immediate or delayed perm anent adverse health effects or prevent escape from such an environment . The purpose of establishing an IDLH value is (1) to ensure that the worker can escape from a given contaminated environ ment in the event of failure of the respiratory protection equipment and ( 2) is considered a maximum level above which only a highly reli able breathing apparatus providing maximum worker protection is perm itted .\nThe IDLH for chromic acid and chromates is 15 mg Cr(VI)/m 3 .\n\n# Future Trends\nIndustry sectors with the greatest number of workers exposed to Cr(VI) compounds, and the largest number of workers exposed to Cr(VI) compounds above the revised REL, include welding, painting, electroplating, steel mills, and iron and steel foundries . Re cent national and international regulations on workplace and environmental Cr(VI) exposures have stimulated the research and development of substitutes for Cr(VI). Some defense-related industries are eliminating or limiting Cr(VI) use where proven substitutes are available . However, it is ex pected that worker exposure to Cr(VI) com pounds will continue in many operations u n til acceptable substitutes have been developed and adopted. It is expected that some existing exposures, such as Cr(VI) exposure during the removal of lead chromate paints, will continue to be a risk of Cr(VI) exposure to workers for many years .\nSome industries, such as woodworking, print ing ink manufacturing, and printing have de creased their use of Cr(VI) compounds . However, many of these workplaces have only a small num ber of employees or low exposure levels.\n\n# Measurement of Exposure\n\n# Air-Sampling Methods\n\n# Air Sample Collection\nThere are several m ethods developed by NIOSH and others to quantify Cr(VI) levels in workplace air. Specific air-sampling proce dures such as sampling airflow rates and rec ommended sample-air volumes are specified in each of the methods, but they share similar sample-collection principles. All are suitable for the collection of long-term, time-integrated samples to characterize time-weighted aver age (TWA), personal breathing zone (PBZ) exposures across full work shifts.\nEach PBZ sample is collected using a batterypowered air-sampling pum p to draw air at a m easured rate through a plastic cassette containing a filter selected in accordance with the specific sampling m ethod and the consid erations described above. The airflow rate of each air-sampling pump should be calibrated before and after each work shift it is used, and the flow rate adjusted as needed according to the nominal rate specified in the method. Usu ally when measuring a PBZ exposure, the air inlet of the filter cassette is held in the worker's breathing zone by clipping the cassette to the worker's shirt collar, and the pump is clipped to the worker's belt, with flexible plastic tubing connecting the filter cassette and pump. The air inlet should be located so that the exposure is measured outside a respirator or any other personal protective equipment (PPE) being worn by the worker.\nW hen sampling for welding fumes, the filter cassette should be placed inside the welding helmet to obtain an accurate measurement of the worker's exposure . The practice of placing the sampling device inside PPE applies only to PPE that is not intended to provide respiratory protection, such as welding helmets or face shields. If the PPE has supplied air, such as a welding hood or an abrasive blasting hood, then the sample is taken outside the PPE .\nFor the collection of an area air sample, an en tire sampling apparatus (pump, tubing, filter cassette) can be placed in a stationary loca tion. This m ethod can also be used to collect short-term task samples (e.g., 15 m inutes), if high enough concentrations are expected, so that the much smaller air volume collected during the short sample duration contains enough Cr(VI) to exceed the detection limits.\nThe procedures specified in each m ethod for handling the samples and preparing them for on-site analysis or shipment to an analytical labo ratory should be carefully followed, including providing the proper numbers of field-blank and media-blank samples specified in the method.\n\n# Air Sampling Considerations\nImportant sampling considerations when deter mining Cr(VI) levels in workplace air have been reviewed .\nIt is important to select a filter material that does not react with Cr(VI\n\n# Biological Markers\n\n# Biological Markers of Exposure\n\n# Measurement of chromium in urine\nUrinary chromium levels are a measure of to tal chromium exposure as Cr(VI) is reduced within the body to Cr(III). ACGIH has recommended Biological Exposure Index es (BEIs) for the increase in urinary chromium concentration of 10 ^g/g creatinine during a work shift and 30 ^g/g creatinine at the end of shift at the end of the workweek. These BEIs are applicable to manual metal arc (MMA) stainless steel welding and apply only to work ers with a history of chronic Cr(VI) exposure. Gylseth et al. Chen et al. reported an association of skin disease and/or smoking habit with elevat ed urinary Cr levels in cement workers. Smok ing increased urinary Cr levels an average of 25 ^g/L; hand eczema increased urinary Cr levels more than 30 ^g/L. Workers with skin disease who were also smokers had higher u ri nary Cr levels than those with only skin disease or smoking habits. Workers who did not regu larly wear PPE had higher average urinary Cr levels, with the difference between glove users and non-users being the greatest (P < 0.001).\nIndividual differences in the ability to reduce Cr(VI) have been demonstrated . Individuals with a weaker ca pacity to reduce Cr(VI) have lower urine Cr levels compared with individuals who have a stronger capacity to reduce Cr(VI). Therefore, analyzing only urinary Cr levels may not pro vide an accurate analysis of occupational expo sure and health hazard. Angerer et al. measured Cr concentra tions in the erythrocytes, plasma, and urine of 103 MM A and/or MIG welders. Personal air monitoring was also conducted. Airborne chromium trioxide concentrations for MMA welders ranged from < 1 to 50 ^g/m3, with 50% < 4 ^g/m 3. Airborne chromium trioxide con centrations for MIG welders ranged from < 1 to 80 ^g/m3 with a median of 10 ^g/m 3. More than half (54%) of measured erythrocyte Cr levels were below the limit of detection (LOD) of 0.6 (J.g/l. Erythrocyte Cr concentration was recommended for its specificity but limited by its low sensitivity. Chromium was detected in the plasma of all welders, ranging from 2.2 to 68.5 (J.g/l; approximately 2 to 50 times higher than the level in non-exposed people. Plasma Cr concentration was recommended as a sen sitive parameter, limited by its lack of specific ity. Erythrocyte, plasma, and urine chromium levels were highly correlated with each other (P < 0.0001).\n\n# Measurement of chromium in blood, plasma, and blood cells\n\n# Biological Markers of Effect\n\n# Renal biomarkers\nThe concentration levels of certain proteins and enzymes in the urine of workers may indicate early effects of Cr(VI) exposure. Liu et al. measured urinary N-acetyl-fi-glucosaminidase (NAG), fi2-microglobulin (fi2M), total protein, and microalbumin levels in 34 hard-chrome plat ing workers, 98 nickel-chrome electroplating workers, and 46 aluminum anode-oxidation workers who had no metal exposure and served as the reference group. Hard-chrome platers were exposed to the highest airborne chromi um concentrations (geometric mean 4.20 |ig C r/m 3 TWA) and had the highest urinary NAG concentrations (geometric mean of 4.9 IU/g creatinine). NAG levels were significantly higher among hard-chrome plating workers, while the other biological markers measured were not. NAG levels were significantly associ ated with age (P < 0.05) and gender (P < 0.01) and not associated with employment duration.\n\n# Genotoxic biomarkers\nGenotoxic biomarkers may indicate exposure to mutagenic carcinogens. More information about the genotoxic effects of Cr(VI) com pounds is presented in Chapter 5, Section 5.2. Gao et al. detected DNA strand breaks in human lymphocytes in vitro 3 hours after so dium dichromate incubation, and in male Wistar rat lymphocytes 24 hours after intratracheal instillation. The DNA damage resulting from Cr(VI) exposure is dependent on the reactive intermediates generated . Gao et al. investigated DNA damage in the lymphocytes of workers exposed to Cr(VI). No significant increases in DNA strand breaks or 8-OHdG levels were found in the lympho cytes of exposed workers in comparison with the lyphocytes of controls. The exposure level for the exposed group was reported to be ap proximately 0.01 mg Cr(VI)/m3. Gambelunghe et al. evaluated DNA strand breaks and apoptosis in the peripheral lymphocytes of chrome-plating workers. Pre vious air monitoring at this plant indicated total chromium levels from 0.4 to 4.5 |ig/m3. Workers exposed to Cr(VI) had higher levels of chromium in their urine, erythrocytes, and lymphocytes than unexposed controls. The comet assay demonstrated an increase in DNA strand breaks in workers exposed to Cr(VI). The percentage of apoptotic nuclei did not differ between exposed workers and controls. Urinary chromium concentrations correlated with erythrocyte chromium concentrations while lymphocyte chromium concentrations correlated with comet tail moment, an indicator of DNA damage. Kuo et al. reported positive correlations between urinary 8-OHdG concentrations and both urinary Cr concentration (P < 0.01) and airborne Cr concentration (P < 0.1) in a study of 50 electroplating workers. Li et al. reported that sperm count and sperm motility were significantly lower (P < 0.05) in the semen of workers exposed to Cr(VI) in comparison with the semen of unexposed control workers. The seminal vol ume and liquefaction time of the semen from the two groups was not significantly different. Workers exposed to Cr(VI) had significantly (P < 0.05) increased serum follicle stimulating hormone levels compared with controls; LH and Cr levels were not significantly different between groups. The seminal fluid of exposed workers contained significantly (P < 0.05) lower levels of lactate dehydrogenase (LDH), lactate dehydrogenase C4 isoenzyme (LDH-x), and zinc; Cr levels were not different.\n\n# Other biomarkers of effect\n\n# Human Health Effects\nMost of the health effects associated with oc cupational hexavalent chromium (Cr) ex posure are well known and have been widely reviewed (see Section 4.1.1,Lung Cancer). The following discussion focuses on quantitative exposure-response studies of those effects and new information not previously reviewed by NIOSH . Comprehensive reviews of welding studies are available from ATSDR ; IARC ;and OSHA . Analyses of epidemiologic stud ies with the most robust data for quantitative risk assessment are described in Chapter 6, \"Assessment of Risk.\"\n\n# Cancer\n\n# Lung Cancer\nHexavalent chromium is a well-established oc cupational carcinogen associated with lung cancer and nasal and sinus cancer. In 1989, the International Agency for Research on Cancer (IARC) critically evaluated the published epi demiologic studies of chromium compounds including Cr(VI) and concluded that \"there is sufficient evidence in humans for the car cinogenicity of chromium compounds as encountered in the chromate production, chro mate pigment production and chromium plat ing industries\" (i.e., IARC category \"Group 1\" carcinogen) . The IARC-reviewed studies of workers in those industries and the ferrochromium industry are presented in Tables 4-1 Additional details and reviews of those stud ies are available in the IARC monograph and elsewhere . Although these studies es tablished an association between occupational exposure to chromium and lung cancer, the specific form of chromium responsible for the excess risk of cancer was usually not identified, nor were the effects of tobacco smoking always taken into account. However, the observed excesses of respiratory cancer (i.e., 2-fold to more than 50-fold in chromium production workers) were likely too high to be solely due to smoking. A retrospective cohort study of 398 current and former workers employed for at least 1 year from 1971 through 1989 was conducted in a large chromate production facility in Cas tle Hayne, North Carolina. The plant opened in 1971 and was designed to reduce the high level of chromium exposure found at the com pany's former production facilities in Ohio and New Jersey. The study was performed to determine if there was early evidence for an increased risk of cancer incidence or m ortal ity and to determine whether any increase was related to the level or duration of exposure to Cr(VI). More than 5,000 personal breathing zone (PBZ) samples collected from 1974 through 1989 were available from company records for 352 of the 398 employees. Concentrations of Cr(VI) ranged from below the limit of detec tion (LOD) to 289 ^g/m 3 , with > 99% of the samples less than 50 ^g/m3. Area samples were used to estimate personal m oni toring concentrations for 1971-1972. (Further description of the exposure data is available in Pastides et al. .) Forty-two of the 45 workers with previous occupational exposure to chromium had transferred from the older Painesville, Ohio plant to Castle Hayne. Es timated airborne chromium concentrations at the Ohio plant ranged from 0.05 m g/m 3 to 1.45 m g/m 3 of total chromium for produc tion workers to a maximum of 5.67 m g/m 3 for maintenance workers (mean not reported).\n\n# Epidemiologic exposureresponse analyses of lung cancer\nMortality of the 311 white male Castle Hayne workers from all causes of death (n = 16), cancer (all sites) (n = 6), or lung cancer (n = 2) did not differ significantly from the mortality experience of eight surrounding North Caro lina counties or the United States white male population. Internal comparisons were used to address an apparent \"healthy worker\" effect in the cohort. Workers with \"high\" cumula tive Cr(VI) exposure (i.e., > 10 \"^g-years\" of Cr) were compared with workers who had \"low\" exposure (i.e., < 10 \"^g-years\" Cr). No significant differences in cancer risk were found between the two groups after consider ing the effects of age, previous chromium expo sure, and smoking. There was a significantly in creased risk of mortality and cancer, including lung cancer, among a subgroup of employees (11% of the cohort) that transferred from older facilities (odds ratio for mortality = 1.27 for each 3 years of previous exposure; 90% CI = 1.07-1.51; OR for cancer = 1.22 for each 3 years of previous exposure; 90% CI = 1.03 1.45, controlling for age, years of previous ex posure, and smoking status and including m a lignances among living and deceased subjects).\n(The authors reported 90% confidence inter vals, rather than 95%. Regression analyses that excluded transferred employees were not re ported.) The results of this study are limited by a small num ber of deaths and cases and a short follow-up period, and the authors stated \"only a large and early-acting cancer risk would have been identifiable\" . The average total years between first employment in any chromate production facility and death was 15.2 years; the maximum was 35.3 years .\n4.1.1.1.2 U.S. chromate production workers, Maryland ; Gibb et al. ) Gibb et al. conducted a retrospective analysis of lung cancer mortality in a cohort of Maryland chromate production workers first studied by . The cohort studied by consisted of 2,101 male salaried and hourly workers (restricted to 1,803 hourly workers) employed for at least 90 days between January 1, 1945, and December 31, 1974, who had worked in new and/or old pro duction sites (Table 4-1). Gibb et al. identified a study cohort of 2,357 male workers first employed between 1950 and 1974. Work ers who started employment before August 1, 1950, were excluded because a new plant was completed on that date and extensive exposure information began to be collected. Workers starting after that date, but with short-term employment (i.e., < 90 days) were included in the study group to increase the size of the low exposure group. The study identified deaths through July 1977. Gibb et al. extended the follow-up period until the end of 1992, and included a detailed ret rospective assessment of Cr(VI) exposure and information about most workers' smoking habits (see Chapter 6, \"Assessment of Risk,\" for further description of the exposure and smok ing data.) The mean length of employment was 3.3 years for white workers (n = 1,205), 3.7 years for nonwhite workers (n = 848), 0.6 years for workers of unknown race (n = 304), and 3.1 years for the total cohort (n = 2,357). The mean follow-up time ranged from 26 years to 32 years; there were 70,736 person-years of observation. The mean cumulative exposures to Cr(VI) were 0.18 m g/m 3-years for nonwhite employees (n = 848) and 0.13 m g/m 3-years for white employees (n = 1,205). The mean expo sure concentration was 43 ^g/m3 .\nLung cancer mortality ratios increased with in creasing cumulative exposure (i.e., mg CrO3/ m 3-years)-from 0.96 in the lowest quartile to 1.57 (95% CI 1.07-2.20; 5-year exposure lag) and 2.24 (95% CI 1.60-3.03; 5-year exposure lag) in the two highest quartiles. The num ber of expected lung cancer deaths was based on age-, race-, and calendar year-specific rates for Maryland. Proportional hazards models that controlled for the effects of smoking predict ed increasing lung cancer risk with increasing Cr(VI) cumulative exposure (relative risks: 1.83 for second exposure quartile, 2.48 for third exposure quartile, and 3.32 for fourth exposure quartile, compared with first quartile of cumulative exposure; confidence intervals not reported; 5-year exposure lag) . For further exploration of time and ex posure variables and lung cancer mortality see Gibb et al. .\nIn an analysis by industry consultants of simu lated cohort data, lung cancer mortality ratios remained statistically significant for white workers and the total cohort regardless of whether city, county, or state reference popu lations were used . The simu lated data were based on descriptive statistics for the entire cohort provided in Gibb et al. , mainly Table 2.\n4.1.1.1.3 U.S. chromate production workers, Ohio ) conducted a retrospec tive cohort study of lung cancer mortality in 482 chromate production workers (four fe male workers) employed > 1 year from 1940 through 1972 in a Painesville, Ohio plant studied earlier by Mancuso ; Proctor et al. stated that 17 workers who transferred to the North Carolina plant had their exposure profiles in corporated. Their mortality was followed from 1941 through 1997 and compared with United States and Ohio rates. Nearly half (i.e., 45%) of the cohort worked in exposed jobs for 1 to 4 years; 16% worked in them > 20 years. Followup length averaged 30 years, ranging from 1 to 58 years. However, of the workers who died from lung cancer (n = 51), 43% worked 20 or more years and 82% began plant employment before 1955. Their follow-up length averaged 31.6 years, ranging from 7 to 52 years and to taling 14,048 person-years. More than 800 area samples of airborne Cr(VI) from 21 industrial hygiene surveys were available for formation of a job-exposure matrix. The surveys were conducted in 1943, 1945, 1948, and every year from 1955 through 1971. Samples were collect ed in impingers and analyzed colorimetrically for Cr(VI). Concentrations tended to decrease over time. The average airborne concentra tion of Cr(VI) in the indoor operating areas of the plant in the 1940s was 0.72 mg/m3, 0.27 mg/ m 3 from 1957 through 1964, and 0.039 mg/ m 3 from 1965 through 1972 . Further details about the exposure data are in Proctor et al. . For the lung can cer deaths, mean cumulative Cr(VI) exposure was 1.58 m g/m 3-years (range: 0.003-23 mg/ m 3-years) for the cohort and 3.28 m g/m 3-years (range: 0.06-23 m g/m 3-years). The effects of smoking could not be assessed because of in sufficient data.\nCumulative Cr(VI) exposure was divided into five categories to allow for nearly equal num bers of expected deaths from cancer of the trachea, bronchus, or lung in each category: 0.00-0.19, 0.20-0.48, 0.49-1.04, 1.05-2.69, and 2.70-23.0 m g/m 3-years ]. Person-years in each category ranged from 2,369 to 3,220, and the number of deaths from trachea, bronchus, or lung cancer ranged from 3 in the lowest exposure category to 20 in the highest (n = 51). The standardized m or tality ratios (SMRs) were statistically signifi cant in the two highest cumulative exposure categories ] and 4.63 , respectively). SMRs were also significantly increased for year of hire before 1960, > 20 years of employment, and > 20 years since first exposure. The tests for trend across increasing categories of cumulative Cr(VI) ex posure, year of hire, and duration of employ ment were statistically significant (P < 0.005).\nA test for departure of the data from linearity was not statistically significant (x2 goodness of fit of linear model; P = 0.23). Van Wijngaarden et al. reported further examination and discussion of cumulative Cr(VI) exposure and lung cancer mortality in this study and Gibb et al. . Luippold et al. conducted a retrospec tive cohort mortality study of 617 male and fe male chromate production workers employed at least 1 year at one of two U.S. plants: 430 workers from the North Carolina plant studied by Pastides et al. (i.e., \"Plant 1\") and 187 workers hired after the 1980 implementa tion of exposure-reducing process changes at \"Plant 2\". The study's prim ary goal was to inves tigate possible cancer mortality risks associat ed with Cr(VI) exposure after production p ro cess changes and enhanced industrial hygiene controls (i.e., the \"postchange environment\"). Employees who had worked less than 1 year in a postchange plant or in a facility using a highlime process were excluded from the cohort. Personal air-monitoring measurements avail able from 1974 to 1988 for Plant 1 and from 1981 through 1998 for Plant 2 indicated that, for most years, overall geometric mean Cr(VI) concentrations for both plants were less than 1.5 ^g/m 3 and area-specific average personal air-sampling values were generally less than 10 ^g/m 3.\nCohort mortality was followed through 1998. The mean time since first exposure was 20.1 years for Plant 1 workers and 10.1 years for Plant 2. Only 27 cohort members (4%) were deceased, and stratified analyses with individ ual exposure estimates and available smoking history data could not be conducted because of the small num ber of deaths. Mortality from all causes was lower than the expected num ber of deaths based on state-specific referent rates, suggesting a strong healthy worker effect (SMR 0.59; 95% CI 0.39-0.85; 27 deaths). Lung cancer mortality was also lower than expected compared with state reference rates (SMR 0.84; 95% CI 0.17-2.44; 3 deaths). However, the study results are limited by a small number of deaths and short follow-up period. The authors stated that the \"absence of an elevated lung cancer risk may be a favorable reflection of the postchange environment,\" but longer followup allowing an appropriate latency period for the entire cohort is needed to confirm this pre liminary conclusion .\n4.1.1.1.5 Chromate production workers, Germany (Birk et al. ) Birk et al. conducted a retrospective co hort study of lung cancer mortality using Cr levels in urine as a biomarker of occupational exposure to Cr(VI). Cohort members were males employed in two German chromate pro duction plants after each plant converted to a no-lime production process, a process believed to result in dusts containing less Cr(VI) . The average duration of Cr(VI) exposure was 9-11 years and mean time since first exposure was 16-19 years, depending on the plant (i.e., Plant A or Plant B). Smoking status from medical examinations/medical re cords was available for > 90% of the cohort as were > 12,000 urinary chromium results col lected during routine employee medical exam inations of workers from both plants.\nMortality was followed through 1998; 130 deaths (22 deaths from cancer of the trachea, bronchus, or lung) were identified among 901 workers employed at least 1 year in the plant with no history of work in a plant before conversion to the no-lime process. The num ber of personyears was 14,684. Although mortality from all causes was significantly less than the expected num ber compared with mortality rates for Germany, the num ber of deaths from cancer of the trachea, bronchus, or lung was greater than expected (SMR = 1.48; 22 deaths observed; 14.83 expected; 95% CI 0.93-2.25). W hen re gional mortality rates were used (i.e., North Rhine-Westphalia), the SMRs were somewhat lower (SMR for all respiratory cancers includ ing trachea, bronchus, and lung = 1.22; 95% CI 0.76-1.85).\nGeometric mean values of Cr in urine varied by work location, plant, and time period, and tended to decrease over the years of plant op eration (both plants are now closed). Results of statistical analysis found lung cancer mortality SMRs > 2.00 in the highest cum ulative C r in-urine exposure category, for no exposure lag, 10-year lag, and 20-year lag (e.g., a statisti cally significant highest SMR was reported in the highest exposure category of > 200 ^g/Lyears Cr in urine: SMR 2.09; 12 lung cancer deaths observed; 95% CI 1.08-3.65; regional rates; no exposure lag). However, few study subjects accrued high cumulative exposures of 20 years or more before the end of the study. Cumulative urinary Cr concentrations of > 200 ^g/L-years compared with concentrations < 200 ^g/L-years were associated with a significantly increased risk of lung cancer mortality (OR = 6.9; 95% CI 2.6-18.2), and the risk was unchanged after controlling for smoking .\nThe use of urinary Cr measurements as a marker for Cr(VI) exposure has limitations, primarily that it may reflect exposure to Cr(VI), Cr(III), or both. In addition, urinary Cr levels may re flect beer consumption or smoking; however, the study authors stated that \". . . workplace ex posures to hexavalent chromium are expected to have a much greater impact on overall uri nary chromium levels than normal variability across individuals due to dietary and metabol ic differences\" . were significantly higher. Lung cancer SMRs tended to increase with years since first expo sure for stainless steel welders and mild steel welders; the trend was statistically significant for the stainless steel welders (P 0.5 mg-years/m3) were not significantly higher than SMRs for the low cumulative exposure subgroup (i.e., < 0.5 mg-years/m3) .\n\n# IARC classifies welding fumes and gases as\nGroup 2B carcinogens-limited evidence of carcinogenicity in humans . Dur ing a 2009 review, IARC found sufficient evi dence for ocular melanoma in welders . NIOSH recommends that \"exposures to all welding emissions be re duced to the lowest feasible concentrations us ing state-of-the-art engineering controls and work practices\" .\n\n# Nasal and Sinus Cancer\nCases or deaths from sinonasal cancers were reported in five IARC-reviewed studies of chromium production workers in the United States, United Kingdom, and Japan, chromate pigment production workers in Norway, and chromium platers in the United Kingdom (see Tables 4-1 through 4-3). IARC concluded that the findings represented a \"pattern of excess risk\" for these rare cancers and in 2009 concluded there is limited evidence for human cancers of the nasal cavity and pa ranasal sinuses from exposure to Cr(VI) com pounds .\nSubsequent mortality studies of chromium or chromate production workers employed in New Jersey from 1937 through 1971 and in the Unit ed Kingdom from 1950 through 1976 reported significant excesses of deaths from nasal and si nus cancer (proportionate cancer mortality ra tio (PCMR) = 5.18 for white males, P < 0.05, six deaths observed and no deaths observed in black males ; SMR ad justed for social class and area = 1,538, P < 0.05, four deaths observed ). Cr(VI) exposure concentrations were not reported.\nHowever, an earlier survey of three chromate production facilities in the U.K. found that aver age air concentrations of Cr(VI) in various phas es of the process ranged from 0.002 to 0.88 mg/ m 3 .\nFour cases of carcinoma of the nasal region were described in male workers with 19 to 32 years of employment in a Japanese chromate factory . No exposure con centrations were reported.\nAlthough increased or statistically significant numbers of cases of nasal or sinonasal cancer have been reported in case-control or inci dence studies of leather workers (e.g., boot and shoe production) or leather tanning workers in Sweden and Italy , a U.S. mortality study did not find an excess number of deaths from cancer of the nasal cavity . The studies did not report quanti tative exposure concentrations of Cr(VI), and a causative agent could not be determined.\nLeather tanning workers may be exposed to several other potential occupational carcino gens, including formaldehyde.\n\n# Nonrespiratory Cancers\nStatistically significant excesses of cancer of the oral region, liver, esophagus, and all cancer sites combined were reported in a few studies reviewed by IARC (Tables 4-1 through 4-4). IARC concluded that \"for cancers other than of the lung and sinonasal cavity, no con sistent pattern of cancer risk has been shown among workers exposed to chromium com pounds.\" More recent reviews by other groups also did not find a consistent pattern of nonrespiratory cancer risk in workers exposed to in haled Cr(VI) . IARC concluded that \"there is little evidence that exposure to chro mium (VI) causes stomach or other cancers.\"\n\n# Cancer Meta-Analyses\nMeta-analysis and other systematic literature re view methods are useful tools for summarizing exposure risk estimates from multiple studies. Meta-analyses or summary reviews of epide miologic studies have been conducted to in vestigate cancer risk in chromium-exposed workers. Steenland et al. reported overall relative risks for specific occupational lung carcino gens, including chromium. Ten epidemiolog ic studies were selected by the authors as the largest and best-designed studies of chromium production workers, chromate pigment pro duction workers, and chromium platers (i.e., Enterline 1974;Alderson et al. 1981;Satoh et al. 1981;Korallus et al. 1982;Frentzel-Beyme 1983;Davies 1984;Sorahan et al. 1987;Hayes et al. 1989;Takahashi and Okubo 1990). The authors stated that statistically significant SMRs for \"all cancer\" mortality were mainly due to lung cancer (all cancer: 40 studies; 6,011 deaths; SMR = 112; 95% CI 109-115). Many of the studies contributing to the meta-analyses did not address bias from the healthy worker effect, and thus the results are likely underes timates of the cancer mortality risks. Other limitations of these meta-analyses include lack of (1) exposure characterization of populations such as the route of exposure (i.e., airborne versus ingestion) and ( 2) detail of criteria used to exclude studies based on \"no or little chrome exposure\" or \"no usable data.\"\nPaddle conducted a meta-analysis of four studies of chromate production w ork ers in plants in the United States ; Pastides et al. ), United King dom (i.e., Davies et al. ), and Germany (i.e., Korallus et al. ) that had undergone modifications to reduce chromium exposure. Most of the modifications occurred around 1960. This meta-analysis of lung cancer \"post modification\" did not find a statistically signifi cant excess of lung cancer (30 deaths observed; 27.2 expected; risk measure and confidence interval not reported). The author surmised that none of the individual studies in the m e ta-analysis or the meta-analysis itself had suf ficient statistical power to detect a lung cancer risk of moderate size because of the need to exclude employees who worked before plant modifications and the need to incorporate a latency period, thus leading to very small ob served and expected numbers. Meta-analyses of gastrointestinal cancer, laryngeal cancer, or any other nonlung cancer were considered in appropriate by the author because of reporting bias and inconsistent descriptions of the can cer sites . Sjögren et al. authored a brief report of their meta-analysis of five lung cancer studies of Canadian and European welders exposed to stainless steel welding fumes. The meta-analy sis found an estimated relative risk of 1.94 (95% CI 1.28-2.93) and accounted for the effects of smoking and asbestos exposure . (Details of each study's exposure assess ment and concentrations were not included.)\n\n# Summary of Cancer and Cr(VI) Exposure\nOccupational exposure to Cr(VI) has long been associated with nasal and sinus cancer and cancers of the lung, trachea, and bronchus.\nNo consistent pattern of nonrespiratory cancer risk has been identified.\nFew studies of Cr(VI) workers had sufficient data to determine the quantitative relationship between cumulative Cr(VI) exposure and lung cancer risk while controlling for the effects of other lung carcinogens, such as tobacco smoke.\nOne such study found a significant relation ship between cumulative Cr(VI) exposure (measured as CrO3) and lung cancer mortality ; the data were reanalyzed by NIOSH to further investigate the exposureresponse relationship (see Chapter 6, \"Assess ment of Risk\").\nThe three meta-analyses and summary reviews of epidemiologic studies with sufficient statis tical power found significantly increased lung cancer risks with chromium exposure.\n\n# Nonmalignant Effects\nCr(VI) exposure is associated with contact der matitis, skin ulcers, irritation and ulceration of the nasal mucosa, and perforation of the na sal septum . Reports of kidney damage, liver damage, pulmonary congestion and edema, epigastric pain, erosion and discol oration of teeth, and perforated ear drums were found in the literature, and NIOSH concluded that \"sufficient contact with any chromium(VI) material could cause these effects\" . Later studies that provided quantitative Cr(VI) information about the occurrence of those effects is discussed here. (Studies of nonmalignant health effects and total chromium concentrations are includ ed in reviews by the Criteria Group for Occu pational Standards and ATSDR .)\n\n# Respiratory Effects\nThe ATSDR review found many re ports and studies published from 1939 to 1991 of workers exposed to Cr(VI) compounds for intermediate (i.e., 15-364 days) to chronic durations that noted these respiratory effects: epistaxis, chronic rhinorrhea, nasal itching and soreness, nasal mucosal atrophy, perforations and ulcerations of the nasal septum, bronchi tis, pneumoconiosis, decreased pulmonary function, and pneumonia.\nFive recent epidemiologic studies of three co horts analyzed quantitative information about occupational exposures to Cr(VI) and re spiratory effects. The three worksite surveys described below provide information about workplace Cr(VI) concentrations and health effects at a particular point in time only and do not include statistical analysis of the quantita tive relationship between specific work expo sures and reported health symptoms; thus they contribute little to evaluation of the exposureresponse association. (Studies and surveys pre viously reviewed by NIOSH are not included.)\n\n# Work site surveys\nA NIOSH HHE of 11 male employees in an Ohio electroplating facility reported that most men had worked in the \"hard-chrome\" area for the majority of their employment (average duration: 7. Huvinen et al. No increased prevalences of respiratory symp toms, lung function deficits, or signs of pneu moconiosis (i.e., small radiographic opacities) were found in a 1993 cross-sectional study of stainless steel production workers . The median personal Cr(VI) con centration measured in the steel smelting shop in 1987 was 0.5 ^g/m 3 (i.e., 0.0005 m g/m 3). A retrospective study of 2,357 males first em ployed from 1950 through 1974 at a chromate production plant included a review of clinic and first aid records for physician findings of nasal irritation, ulceration, perforation; and bleeding, skin irritation and ulceration, der matitis, burns, conjunctivitis, and perforated eardrum . The authors also suggested that the proportional hazards model did not find significant associations with all symptoms because the Cr(VI) concentrations were based on annual averages rather than on shorter, more recent average exposures, which may have been a more relevant choice.\n\n# Summary of respiratory effects studies and surveys\nA few workplace surveys measured Cr(VI) air concentrations and conducted medical evalua tions of workers. These short-term surveys did not include comparison groups or exposureresponse analyses. Two surveys found U.S. electroplaters and Korean welders with na sal perforations or other respiratory effects; the lowest mean Cr(VI) concentrations at the worksites were 0.004 m g/m 3 for U.S. electro platers and 0.0012 m g/m 3 for Korean welders .\nCross-sectional epidemiologic studies of chromeplating workers and stainless steel production workers found no nasal perforations at average chromic acid concentra tions < 2 ^g/m3. The platers experienced nasal ulcerations and/or septal perforations and tran sient reductions in lung function at mean con centrations ranging from 2 ^g/m3 to 20 ^g/m3. Nasal mucosal ulcerations and/or septal perfo rations occurred in plating workers exposed to peak concentrations of 20-46 ^g/m3.\nThe best exposure-response information to date is from the only epidemiologic study with sufficient health and exposure data to estimate the risks of ulcerated nasal septum, ulcerated skin, perforated nasal septum, and perforated eardrum over time . This retrospective study reviewed medical records of more than 2,000 male workers and analyzed thousands of airborne Cr(VI) measurements collected from 1950 through 1985. More than 60% of the cohort had experienced an irritated nasal septum (68.1%) or ulcerated nasal sep tum (62.9%) at some time during their employ ment. The median Cr(VI) exposure (measured as CrO3) at the time of first diagnosis of these findings and all others (i.e., perforated nasal septum, bleeding nasal septum, irritated skin, ulcerated skin, dermatitis, burn, conjunctivitis, perforated eardrum) was 0.020 m g/m 3-0.028 m g/m 3 (20 |ig/m3-28 |ig/m3). O f particular concern is the finding of nasal and ear effects occurring in less than 1 month: the median time from date first employed to date of first diagnosis was less than 1 m onth for irritated nasal septum (20 days), ulcerated nasal septum (22 days), and perforated eardrum (10 days). A proportional hazards model predicted relative risks of 1.20 for ulcerated nasal septum, 1.11 for ulcerated skin, and 1.35 for \"perforated ear\" for each 0.1 m g/m 3 increase in ambient CrO 3.\nThe authors noted that the chrome platers studied by Lindberg and Hedenstierna were exposed to chromic acid, which may be more irritative than the chromate chemicals occurring with chromate production .\n\n# Asthma\nOccupational asthma caused by chromium ex posure occurs infrequently compared with al lergic contact dermatitis .\nThe exposure concentration below which no cases of occupational asthma would occur, including cases induced by chromium com pounds, is not known . Furthermore, that concentration is likely to be lower than the concentration that initially led to the employee's sensitization . Case series of asthma have been report ed in U.K. electroplaters , Finnish stainless steel welders , Russian alumina industry workers ; Korean metal plating, construc tion, and cement manufacturing workers, ; and a cross-sectional study of U.K. electroplaters . However, there are no quantitative exposure-response as sessments of asthma related to Cr(VI) in occu pational cohorts, and further research is needed.\n\n# Dermatologic Effects\nCr .\nNo occupational studies have examined the quantitative exposure-response relationship be tween Cr(VI) exposure and a specific dermatologic effect, such as ACD; thus, an exposure-response relationship has not been clearly established. O ther assessments evaluated the occurrence of ACD from contact with Cr(VI) in soil (e.g., Proctor et al. ; Paustenbach et al. ; Bagdon and Hazen ; Stern et al. ; Nethercott et al. ).\n\n# Reproductive Effects\nThe six available studies of pregnancy occur rence, course, or outcome reported little or no information about total Cr or Cr(VI) concen trations at the workplaces of female chromium production workers [Shmitova 1978[Shmitova , 1980 or male welders that were also spouses [Bonde et al. 1992;Hjollund et al. 1995Hjollund et al. , 1998Hjollund et al. , 2000. The lack of consistent findings and exposureresponse analysis precludes formation of con clusions about occupational Cr(VI) exposure and adverse effects on pregnancy and child birth. Further research is needed.\n\n# Other Health Effects\n\n# Mortality studies\nMore than 30 studies examined numerous non cancer causes of death in jobs with potential chromium exposure, such as chromate produc tion, chromate pigment production, chromium plating, ferrochrom ium production, leather tanning, welding, m etal polishing, cement finishing, stainless steel grinding or produc tion, gas generation utility work, and paint production or spraying. (Studies previously cited by NIOSH [1975NIOSH [ , 1980 are not included.)\nMost studies found no statistically significant increases (i.e., P < 0.05) in deaths from nonmalignant respiratory diseases, cardiovascular diseases, circulatory diseases, accidents, or any other noncancer cause of death that was in cluded . However, these studies did not in clude further investigation of the nonsignifi cant outcomes and therefore do not confirm the absence of an association.\nSome studies did identify significant increases in deaths from various causes . However, the findings were not consistent: no noncancer cause of death was found to be significantly increased in at least five studies. Furthermore, exposureresponse relationships were not examined for those outcomes. Therefore, the results of these studies do not support a causal association between occupational Cr(VI) exposure and a nonmalignant cause of death. NIOSH concluded that Cr(VI) ex posure could cause other health effects such as kidney damage, liver damage, pulmonary congestion and edema, epigastric pain, and erosion and discoloration of the teeth. Other effects of exposure to chromic acid and chro mates not discussed elsewhere in this section include eye injury, leukocytosis, leukopenia, and eosinophilia . Acute renal failure and acute chromi um intoxication occurred in a male worker fol lowing a burn with concentrated chromic acid solution to 1% of his body .\n\n# Other health effects\nThere has been little post-1975 research of those effects in occupational cohorts. Furthermore, there is insufficient evidence to conclude that occupational exposure to respirable Cr(VI) is related to other health effects infrequently reported in the literature after the NIOSH review. These effects included cerebral arachnoiditis in 47 chromium industry work ers and cases of gastric disturbances (e.g., chronic gastritis, polyps, ulcers, and mucous membrane ero sion) in chromium salt workers . Neither study analyzed the relation ship of air Cr(VI) concentrations and health effects, and one had no comparison group . ------------------------------------------------------------------------------------------------------------ ------------------------------------------------------------------------------------------------------------- Davies [1978Davies [ , 1979Davies [ , 1984 1-9 years' 3 2.0f followed to end of employment 1982.\n 10 years' 6 3.2f employment Source: Adapted from IARC . Dash in \"Estimated relative risk\" indicates not reported. ^Significant at 95% level. fP fo r trend < 0.01.\n\n# Experimental Studies\nExperimental studies provide important infor mation about the pharmacokinetics, mecha nisms of toxicity, and potential health effects of hexavalent chromium (Cr) compounds. Studies using cell culture and in vitro tech niques, animal models, and human volunteers provide data about these compounds. The results of these experimental studies, when considered with the results of other health ef fects studies, provide a more comprehensive database for the evaluation of the mechanisms and health effects of occupational exposure to Cr(VI) compounds.\n\n# Pharmacokinetics\nThe absorption of inhaled Cr(VI) depends on the oxidation state, particle size, and solubility of the compound . Large par ticles (> 10 ^m) of inhaled Cr(VI) compounds are deposited in the upper respiratory tract; smaller particles can reach the lower respira tory tract. Some of the inhaled Cr(VI) is re duced to trivalent chromium (Cr) in the epithelial or interstitial lining fluids within the bronchial tree. The extracellular reduction of Cr(VI) to Cr(III) reduces the cellular uptake of chromium because Cr(III) compounds can not enter cells as readily as Cr(VI) compounds. At physiological pH most Cr(VI) compounds are tetrahedral oxyanions that can cross cell membranes. Cr(III) compounds are predom i nantly octahedral structures to which the cell membrane is practically impermeable. Cr(III) can enter the cell only via pinocytosis . The Cr(VI) ions that cross the cell m em brane become a target of intracellular reductants. The Cr(VI) concentration decreases with increasing distance from the point of entry as Cr(VI) is reduced to Cr(III). The Cr(III) ions are transported to the kidneys and excreted.\nInhaled Cr(VI) that is not absorbed in the lungs may enter the gastrointestinal tract fol lowing mucociliary clearance. Much of this Cr(VI) is rapidly reduced to Cr(III) by reductants in the saliva and gastric juice and excret ed in the feces. The remaining 3% to 10% of the Cr(VI) is absorbed from the intestines into the blood stream, distributed throughout the body, transported to the kidneys, and excreted in the urine .\n\n# Mechanisms of Toxicity\nThe possible mechanisms of the genotoxicity and carcinogenicity of Cr(VI) compounds have been reviewed . However, the exact mechanisms of Cr(VI) toxicity and carcinogenicity are not yet fully understood. A significant body of research suggests that Cr(VI) carcinogenicity may result from damage mediated by the bio reactive products of Cr(VI) reduction, which include the Cr(VI) intermediates (Cr and Cr), and reactive oxygen species (ROS). Factors that may affect the toxicity of a chro mium compound include its bioavailability, oxidative properties, and solubility .\nIntracellular Cr(VI) undergoes metabolic re duction to Cr(III) in microsomes, in m ito chondria, and by cellular reductants such as ascorbic acid, lipoic acid, glutathione, cysteine, reduced nicotinamide adenine dinucleotide phosphate (NADPH), ribose, fructose, arabinose and diol-and thiol-containing molecules, as well as NADPH/flavoenzymes. Although the extracellular reduction of Cr(VI) to Cr(III) is a mechanism of detoxification as it decreases the num ber of bioavailable Cr(VI) ions, intracel lular reduction may be an essential element in the mechanism of intracellular Cr(VI) toxicity.\nThe intracellular Cr(VI) reduction process generates products including Cr(V), Cr(IV), Cr(III) molecular oxygen radicals, and other free radicals. The molecular oxygen is reduced to superoxide radical, which is further reduced to hydrogen peroxide (H2O2) by superoxide dismutase (SOD). H2O2 2 rea2cts with Cr(V), Cr(IV) or Cr(III) to generate hydroxyl radi cals ( 'OH) via the Fenton-like reaction, and it undergoes reduction-oxidation cycling . The high concentration of oxy gen radicals and other free radical species gen erated in the process of Cr(VI) reduction may result in a variety of lesions on nuclear chro matin, leading to mutation and possible neo plastic transformation .\nIn the presence of cellular reducing systems that generate chromium intermediates and hydroxyl radicals, Cr(VI) salts induce various types of DNA damage, resulting either from the breakage of existing covalent bonds or the formation of new covalent bonds among molecules, such as DNA interstrand cross links, DNA-protein crosslinking, DNA double strand breaks, and depurination. Such lesions could lead to mutagenesis and ultimately to carcinogenicity . The oxidative damage may result from a direct binding of the reactive Cr(VI) intermediates to the DNA or may be due to the indirect effect of ROS interactions with nuclear chromatin, depending on their intracellular location and proximity to DNA . Cr(VI) does not bind irreversibly to na tive DNA and does not produce DNA lesions in the absence of the microsomal reducing sys tems in vitro .\nIn addition to their oxidative properties, the solubility of Cr(VI) compounds is another im portant factor in the mechanism of their carci nogenicity. Animal studies indicate that insol uble and sparingly soluble Cr(VI) compounds may be more carcinogenic than soluble chro mium compounds .\nParticles of lead chromate, a relatively insoluble Cr(VI) compound, when added directly to the media of mammalian cell culture, induced cell transformation . When injected into whole animals, the particles pro duced tumors at the site of injection . Several hypotheses have been pro posed to explain the effects of insoluble Cr(VI) compounds. One hypothesis proposes that particles dissolve extracellularly, resulting in chronic, localized exposure to ionic chromate. This hypothesis is consistent with studies dem onstrating that extracellular dissolution is re quired for lead chromate-induced clastogenesis . Xie et al. demonstrated that lead chromate clastogenesis in human bronchial cells is medi ated by the extracellular dissolution of the par ticles but not their internalization.\nAnother hypothesis suggests that a high Cr(VI) concentration is created locally inside the cell during internalization of Cr(VI) salt particles by phagocytosis .\nHigh intracellular local Cr(VI) concentrations can generate high concentration of ROS inside the cell, which may overwhelm the local ROS scavenging system and result in cytotoxic ity and genotoxicity . Highly soluble compounds do not generate such high local concentrations of Cr(VI). However, once inside the cell, both soluble (sodium chromate) and insoluble (lead chromate) Cr(VI) com pounds induce similar amounts and types of concentration-dependent chromosomal dam age in exposed cultured mammalian cells [Wise et al. 1993[Wise et al. , 2002[Wise et al. , 2003. Pretreatment of these cells with ROS scavengers such as vitamin E or C prevented the toxic effects of both sodium chromate and lead chromate.\nNumerous studies report a broad spectrum of cellular responses induced by exposure to vari ous Cr(VI) compounds. These cytotoxic and genotoxic responses are consistent with mech anistic events associated with carcinogenesis. Studies in human lung cells provide data regard ing the genotoxicity of many Cr(VI) compounds . Cr(VI) compounds induce transforma tion of human cells, including bronchial epithe lial cells .\nBarium chromate induced concentrationdependent chromosomal damage, including chromatid and chromosomal lesions, in h u m an lung cells after 24 hours of exposure . Lead chromate and soluble sodium chromate induced concentrationdependent chromosomal aberration in h u man bronchial fibroblasts after 24 hours of exposure . Cotreatm ent of cells with vitamin C blocked the chromate induced toxicity. Calcium chro mate induced DNA single-strand breaks and DNA protein cross-links in a dose-dependent m anner in three cell lines. Exposing hum an lung cell cultures to lead chromate induced chrom osom e instability including centrosome amplification and aneuploidy and spindle assembly checkpoint bypass . Sodium dichromate generated ROS that increased the level and ac tivity of the protein p53 in human lung epithe lial cells. In norm al cells the protein p53 is usu ally inactive. It is usually activated to protect cells from tumorigenic alterations in response to oxidative stress and other stimuli such as ultraviolet or gamma radiation. An increased 'OH concentration activated p53; elimination of 'OH by H2O2 scavengers inhibited p53 acti vation .\nThe ROS (mainly H2O2) formed during p o tassium chromate reduction induced the ex pression of vascular endothelial growth factor (VEGF) and hypoxia-induced factor 1 (HIF-1) in DU145 hum an prostate carcinom a cells. VEGF is the essential protein for tum or angiogenesis. HIF-1, a transcription factor, regulates the expression of many genes including VEGF. The level of HIF-1 activity in cells correlates with the tumorigenic response and angiogenesis in nude mice, is induced by the expression of various oncogenes, and is overexpressed in many human cancers .\nEarly stages of apoptosis have been induced in human lung epithelial cells in vitro following exposure to potassium dichromate. Scavengers of ROS, such as catalase, aspirin, and N-acetyl-L-cysteine, decreased apoptosis induced by Cr(VI); reductants such as NADPH and gluta thione enhanced it. Apoptosis can be triggered by oxidative stress. Agents that promote or suppress apoptosis may change the rates of cell division and lead to the neoplastic transform a tion of cells .\nThe treatment of mouse macrophage cells in vitro with sodium chromate induced a dosedependent activation of the transcription en hancement factors NF-kB and AP-1 .\nSodium dichromate increased tyrosine phos phorylation in hum an epithelial cells. The phosphorylation could be inhibited by anti oxidants . Tyrosine phos phorylation is essential in the regulation of many cellular functions, including cancer de velopment .\nHuman lung epithelial A549 cells exposed to potassium dichromate in vitro generated ROSinduced cell arrest at the G2/M phase of the cell proliferation cycle at relatively low con centrations and apoptosis at high concentra tions. Interruption of the proliferation process is usually induced in response to cell damage, particularly DNA damage. The cell remains arrested in a specific cell cycle phase until the damage is repaired. If damage is not repaired, mutations and cell death or cancer may result .\nGene expression profiles indicate that expos ing human lung epithelial cells to potassium dichromate in vitro resulted in up regulation of the expression of 150 genes, and down regu lation of 70 genes. The analysis of gene expres sion profiles indicated that exposure to Cr(VI) may be associated with cellular oxidative stress, protein synthesis, cell cycle regulation, and on cogenesis .\nThese in vitro studies have limitations of m od els of human exposure because they cannot account for the detoxification mechanisms that take place in intact physiological systems.\nHowever, these studies represent a body of data on cellular responses to Cr(VI) that pro vide important information regarding the p o tential genotoxic mechanisms of Cr(VI) com pounds. The cellular damage induced by these compounds is consistent with the mechanisms of carcinogenesis.\n\n# Health Effects in Animals\nChronic inhalation studies provide the best data for extrapolation to airborne occupational exposure. Only a few of these chronic inhala tion studies have been conducted using Cr(VI) compounds. Glaser et al. conducted chronic inhalation studies of chromic acid mist exposure in mice. Glaser et al. conducted chronic inhalation studies of sodium dichromate exposure in rats. Stein hoff et al. conducted an intratracheal study of sodium dichromate exposure in rats. Levy et al. conducted an intrabronchial implantation study of various Cr(VI) materials in rats. The results of these animal studies sup port the classification of Cr(VI) compounds as occupational carcinogens. Glaser et al. exposed male Wistar rats to whole body aerosol exposures of sodium di chromate at 0, 25, 50, 100, or 200 |ig Cr(VI)/m3 for 22 hr/day, 7 days/wk for 28 or 90 days. Twenty rats were exposed at each dose level. An addi tional 10 rats were exposed at 50 ^g for 90 days followed by 2 months of nonexposure before sacrifice. The average mass median diameter (MMD) of the aerosol particles was 0.2 ^m. Significant increases (P < 0.05) occurred in the serum triglyceride, phospholipid contents, and e 2 mitogen-stimulated splenic mean T-lymphocyte count of rats exposed at the 200 ^g/m3 level for 90 days. Serum total immunoglobulins were statistically increased (P < 0.01) for the 50 and 100 ^g exposure groups.\n\n# Subchronic Inhalation Studies\nTo further study the humoral immune effects, half of the rats in each group were immunized with sheep red blood cells 4 days before sac rifice . The prim ary anti body responses for IgM B-lymphocytes were statistically increased (P < 0.05) for the groups exposed to 25 |ig Cr(VI)/m 3 and higher. The mitogen-stimulated T-lymphocyte response of spleen cells to Concanavalin A was significant ly increased (P < 0.05) for the 90-day, 200 |ig/ m 3 group compared with the control group. The mean macrophage cell counts were sig nificantly lower (P < 0.05) than control values for only the 50 and 200 |ig Cr(VI)/m 3, 90-day groups. Alveolar m acrophage phagocytosis was statistically increased in the 50 ^g level of the 28-day study, and the 25 and 50 |ig m g/m 3 Cr(VI) levels of the 90-day study (P < 0.001). A significant depression of phagocytosis oc curred in the 200 ^g/m 3 group of the 90-day study versus controls.\nA group of rats exposed to 200 |ig Cr(VI)/m3 for 42 days and controls received an acute iron oxide particulate challenge to study lung clearance rates during a 49-day nonexposure post-challenge period . Iron oxide clearance was dramatically and increas ingly decreased in a bi-exponential m anner for the group exposed to Cr(VI) compared with the controls. Glaser et al. studied lung toxicity in ani mals exposed to sodium dichromate aerosols. Groups of 30 male Wistar rats were exposed to 0, 50, 100, 200, or 400 |ig Cr(VI)/m 3 for 22 hr/ day, 7 days/week for 30 or 90 days, followed by a 30-day nonexposure recovery period. Aerosol mass median aerodynamic diameter (MMAD) ranged from 0.28 to 0.39 ^m. Sac rifices of 10 rats occurred after experimental days 30, 90, and 120. The only sign or symp tom induced was an obstructive dyspnea pres ent at the 200 and 400 ^g/m3 levels. Statistically significant reductions in body weight gains were present at 30 days for the 200 ^g level, with similar reductions for the 400 |ig level rats at the 30, 90, and 120-day intervals. White blood cell counts were statistically increased (P < 0.05) for all four dichromate exposure groups for the 30-and 90-day intervals, but the white blood cell counts returned to control levels after 30 days of nonexposure. The lung parameters studied had statistically signifi cant dose-related increases after either 30 or 90 days of inhalation exposure to dichromate; some remained elevated despite the nonexpo sure recovery period. A No Observed Adverse Effect Level (NOAEL) was not achieved.\nBronchoalveolar lavage (BAL) provided infor mation about pulmonary irritation induced by sodium dichromate exposure in these rats . Total protein levels present on day 30 progressively decreased at days 90 and 120 but remained above control values. Alveo lar vascular integrity was compromised as BAL albumin levels were increased for all treatment groups, with only the 200 and 400 ^g/m3 levels remaining above those of the controls at the end of the recovery period. Lung cell cytotoxicity as measured by cytosolic lactate dehydrogenase, and lysosomal fi-glucuronidase was increased by dichromate exposure but normalized dur ing the post-exposure period. Mononuclear macrophages comprised 90% of recovered to tal BAL cells. The two highest exposure groups had equal increases throughout the treatment period, but they returned to normal during the recovery period. These macrophages had high er cell division rates, sometimes were multinuclear, and were bigger when compared with control cells. Sodium dichrom ate exposure induced statistically significant increased lung weights for the 100, 200, and 400 ^g/m 3 groups throughout the study, including the nonexpo sure period. Histopathology of lung tissue re vealed an initial bronchoalveolar hyperplasia for all exposure groups at day 30, while only the 200 and 400 ^g/m3 levels retained some lower levels of hyperplasia at study day 120. There was also an initial lung fibrosis observed in some animals at the levels above 50 ^g/m3 on day 30, which was not present during the remainder of the study. Lung histiocytosis re mained elevated throughout the entire study for all treatment groups.\n\n# Chronic Inhalation Studies\nAdachi et al. exposed 50 female ICR/JcI mice to 3.63 mg Cr(VI)/m 3 chromic acid mist (85% of mist measuring < 5 ^m) for 30 m in/ day, 2 days/week for 12 months, followed by a 6-month nonexposure recovery period. Prolif erative changes were observed within the respira tory tract after 26 weeks of chromate exposure. Pin-hole-sized perforations of the nasal septum occurred after 39 weeks at this exposure level. When the incidence rates for histopathological findings (listed below) for chromate-exposed animals were compared for successive study pe riods, the treatment group data were generally similar for weeks 40-61 when compared with weeks 62-78, with the exception of the induction of two adenocarcinomas of the lungs present in two females at the terminal 78-week sacrifice. The total study pathology incidence rates for the 48 chromate-exposed females were the following: perforated nasal septum (n = 6), tracheal (n = 43)/ bronchial (n = 19) epithelial proliferation, and emphysema (n = 11), adenomatous metaplasia (n = 3), adenoma (n = 5), and adenocarcinoma (n = 2) of the lungs. Total control incidence rates for the 20 females examined were confined to the lung: emphysema (n = 1), adenomatous metapla sia (n = 1), and adenoma (n = 2). Adachi exposed 43 female C57BL mice to 1.81 mg Cr(VI)/m 3 chromic acid mist (with 85% of mist measuring ~5 ^m) for 120 m in/ day, 2 days/week for 12 months, followed by a 6-month nonexposure recovery period. Twen ty-three animals were sacrificed at 12 months, with the following nontumorigenic histologi cal changes observed: nasal cavity perforation (n = 3); tracheal hyperplasia (n = 1); and em physema (n = 9) and adenomatous metaplasia (n = 4) of the lungs. A terminal sacrifice of the 20 remaining females occurred at 18 months, which demonstrated perforated nasal sep ta (n = 3) and papillomas (n = 6); laryngeal/ tracheal hyperplasia (n = 4); and emphysema (n = 11), adenomatous metaplasia (n = 5), and adenoma (n = 1) of the lungs. Only emphyse ma (n = 2) and lung metaplasia (n = 1) were observed in control females sacrificed after week 78.\nGlaser et al. exposed groups of 20 male Wistar rats to aerosols of 25, 50, or 102 ^g/m3 sodium dichromate for 22 to 23 hr/day, 7 days/ week for 18 months, followed by a 12-month nonexposure recovery period. Mass median diameter of the sodium dichromate aerosol was 0.36 ^m. No clinical sign of irritation in duced by Cr(VI) was observed in any treated animal. Statistically increased liver weights (+26%) were observed at 30 months for the 102 ^g/m3 dichromate males. Weak accumu lations of pigment-loaded macrophages were present in the lungs of rats exposed to 25 ^g/m3 sodium dichromate; moderate accumulations were present in rats exposed to 50 and 102 ^g/ m 3 sodium dichromate. Three prim ary lung tu mors occurred in the 102 ^g Cr(VI)/m 3 group: two adenomas and one adenocarcinoma. The authors concluded that the 102 ^g Cr(VI)/m3 level of sodium dichromate induced a weak lung carcinogenic effect in rats exposed under these conditions.\n\n# Intratracheal Studies\nSteinhoff et al. dosed Sprague-Dawley rats via intratracheal instillation with equal to tal weekly doses of sodium dichromate for 30 months: either five consecutive daily doses of 0.01, 0.05, or 0.25 mg/kg or one weekly dose of 0.05, 0.25, or 1.25 mg/kg. Each group consisted of 40 male and 40 female rats. Groups left u n treated or given saline were negative controls. Body weight gains were suppressed in males treated with single instillations of 1.25 mg/ kg of sodium dichromate. Chromate-induced nonneoplastic and neoplastic lesions were de tected only in the lungs. The nonneoplastic pulmonary lesions were primarily found at the maximum tolerated irritant concentration lev el for the high dose sodium dichromate group rather than having been dependent upon the total dose administered. The nonneoplastic pulmonary lesions occurred predominantly in the highest dose group and were character ized by fibrotic regions that contained residual distorted bronchiolar lumen or cellular inflam matory foci containing alveolar macrophages, proliferated epithelium, and chronic inflam matory thickening of the alveolar septa plus at electasis. The neoplastic lesions were non-fatal lung tumors found in these chromate-treated animals. Fourteen rats given single weekly in stillations of 1.25 mg sodium dichromate/kg developed a significant (P < 0.01) number of tumors: 12 benign bronchioalveolar adeno mas and 8 malignant tumors including 2 bronchioalveolar adenocarcinomas and 6 squamous cell carcinomas. Only one additional tumor, a bronchioalveolar adenocarcinoma, was found in a rat that had received single weekly instilla tions of 0.25 mg/kg sodium dichromate.\n\n# Intrabronchial Studies\nLevy et al. conducted a 2-year intra bronchial implantation study of 20 chromiumcontaining materials in Porton-W istar rats.\nTest groups consisted of 100 animals with equal numbers of male and female rats. A small, hook-equipped stainless steel wire mesh basket containing 2 mg of cholesterol and test mate rial was inserted into the left bronchus of each animal. Two positive control groups received pellets loaded with 20-methylcholanthrene or calcium chromate. The negative control group received a blank pellet loaded with cholesterol. Pulmonary histopathology was the prim ary parameter studied. There were inflammatory and metaplastic changes present in the lungs and bronchus, with a high level of bronchial irritation induced by the presence of the bas ket alone. A total of 172 tumors were obtained throughout the study, with only 18 found at the terminal sacrifice. Nearly all tumors were large bronchial keratinizing squamous cell carcino mas that affected a major part of the left lung and were the cause of death for most affected animals. The authors noted that no squamous cell carcinomas had been found in 500 of their historical laboratory controls.\nIn Table 5-1, study data from Levi et al. were transformed by NIOSH to present the rank order of tum or induction potential for the test compounds through calculation of the mean ^g of Cr(VI) required to induce a single bronchiolar squamous cell carcinoma. The rank order of tum or induction poten tial for the positive Cr(VI) compounds using these data was the following: strontium > cal cium > zinc > lead, chromic acid > sodium di chromate > barium. The role solubility played in tum or production for these test materials was inconsistent and not able to be determined.\n\n# Chronic Oral Studies\nThe National Toxicology Program (NTP) con ducted 2-year drinking water studies of sodium dichromate dehydrate (SDD) in rodents . Male and female F344/N id en tified also as being a lead chrom ate containing group. §No lung tum ors were previously found in 500 negative historical control rats that h ad basket implants. f21 squam ous cell carcinomas and one anaplastic carcinoma o f the lung.\nrats and female B6C3F1 mice were exposed to 0, 14.3, 57.3, 172, or 516 mg/L SDD, and male mice to 0, 14.3, 28.6, 85.7, or 257.4 mg/L SDD. Statistically significant concentration-related increased incidences of neoplasms of the oral cavity in male and female rats, and of the small intestine in male and female mice, were report ed. The NTP concluded that these results pro vide clear evidence of the carcinogenic activ ity of SDD in rats and mice . This conclusion was reinforced by the similar results reported between the sexes in both rats and mice.\n\n# Reproductive Studies\nReviews and analyses of the animal studies of the reproductive effects of Cr . Negative stud ies have also been reported; potassium dichromate administered in the diet to mice and rats did not result in adverse reproductive effects or outcomes in rats or mice [NTP 1996a,b;. Inhalation studies in male and female rats did not result in adverse reproductive effects [Gla ser et al. 1985[Gla ser et al. , 1986[Gla ser et al. , 1988\n\n# Dermal Studies\nDermal exposure is another important route of exposure to Cr(VI) compounds in the work place. Experimental studies have been conduct ed using human volunteers, animal models, and in vitro systems to investigate the dermal effects of Cr(VI) compounds.\n\n# Human Dermal Studies\nMali et al. reported the permeation of intact epidermis by potassium dichromate in human volunteers in vivo. Sensitization was re ported in humans exposed to this Cr(VI) com pound but not Cr(III) sulfate. Baranowska-Dutkiewicz conducted 27 Cr(VI) absorption experim ents on seven hum an volunteers. The forearm skin absorp tion rate for 0.01 molar solution of sodium chromate was 1.1 |ig/cm2/hr, for 0.1 molar so lution it was 6.5 |ig/cm2/hr, and for 0.2 molar solution it was 10.0 |ig/cm2/hr. The amount of Cr(VI) absorbed as a percent of the applied dose decreased with increasing concentration.\nThe absorption rate increased as the Cr(VI) concentration applied increased, and it de creased as the exposure time increased.\nCorbett et al. immersed four human volunteers below the shoulders in water con taining 22 mg/L potassium dichromate for 3 hours to assess their uptake and elimination of chromium. The concentration of Cr in the urine was used as the measure of systemic up take. The total Cr excretion above historical background ranged from 1.4 to 17.5 |ig. The dermal uptake rates ranged from approximate ly 3.3 x 10-5 to 4.1 x 10-4 ^g/cm2/hr, with an average of 1.5 x 10-4. One subject had a dermal uptake rate approximately seven times higher than the average for the other three subjects.\n\n# Animal Dermal Studies\nMali et al. demonstrated the experi mental sensitization of 13 of 15 guinea pigs by injecting them with 0.5 mg potassium dichromate in Freund adjuvant subdermally twice at 1-week intervals.\nGad et al. conducted standard dermal LD50 tests to evaluate the acute toxicity of sodi um chromate, sodium dichromate, potassium dichromate, and ammonium dichromate salts in New Zealand white rabbits. All salts were tested at 1.0, 1.5, and 2.0 g/kg dosage, with the exception of sodium chromate, which was test ed at the two higher doses only. In males, the dermal LD50 ranged from a mean of 0.96 g/kg (SD = 0.19) for sodium dichromate to 1.86 g/ kg (SD = 0.35) for ammonium dichromate. In females the dermal LD50 ranged from a mean of 1.03 g/kg (SD = 0.15) for sodium dichromate to 1.73 g/kg (SD = 0.28) for sodium chromate. Each of the four salts, when moistened with saline and occluded to the skin for 4 hours, caused marked irritation. Occlusion of each salt on the skin of the rabbit's back for 24 hours caused irreversible cutaneous damage. Liu et al. demonstrated the reduction of an aqueous solution of sodium dichromate to Cr(V) on the skin of Wistar rats using in vivo electron paramagnetic resonance spectroscopy.\nRemoval of the stratum corneum by stripping the skin with surgical tape 10 times before the application of the dichromate solution increased the rates of formation and decay of Cr(V).\n\n# In Vitro Dermal Studies\nGammelgaard et al. conducted chro mium permeation studies on full thickness hu man skin in an in vitro diffusion cell system. Application of 0.034 M potassium chromate to the skin resulted in significantly higher levels of chromium in the epidermis and dermis, com pared with Cr(III) nitrate and Cr(III) chloride. Chromium levels in the epidermis and dermis increased with the application of increasing concentrations of potassium chromate up to 0.034 M Cr. Chromium skin levels increased with the application of potassium chromate solutions with increasing pH. The percentage of Cr(VI) converted to Cr(III) in the skin was largest at low total chromium concentrations and decreased with increasing total concentra tions, indicating a limited ability of the skin to reduce Cr(VI).\nVan Lierde et al. conducted chromium permeation studies on human and porcine skin using a Franz static diffusion cell. Potassium dichromate was determined to permeate hu man and pig skin after 168 hours of exposure, while the Cr(III) compounds tested did not. Exposure of the skin to 5% potassium dichromate resulted in an increased, but not propor tionally increased, amount of total Cr concen tration in the skin, compared with exposure to 0.25% potassium dichromate. Exposure to 5% potassium dichromate compared with 2.5% potassium did not result in much more of an increased Cr skin concentration dichromate, indicating a possible limited binding capacity of the skin. A smaller amount of Cr was bound to the skin when the salts were incubated in simulated sweat before application onto the skin. A larger accumulation of Cr was found in the skin after exposure to potassium dichromate compared with Cr(III) compounds. Rudolf et al. reported a pronounced ef fect of potassium chromate on the morphol ogy and motile activity of human dermal fi broblasts at concentrations ranging from 1.5 to 45 ^M in tissue culture studies. A time and concentration-dependent effect on cell shrink age, reorganization of the cytoskeleton, and inhibition of fibroblast motile activity was re ported. The inhibitory effect on fibroblast m i gration was seen at all concentrations 8 hours after treatment; effects at higher doses were seen by 4 hours after treatment. Cr(VI) expo sure also resulted in oxidative stress, alteration of mitochondrial function, and mitochondriadependent apoptosis in dermal fibroblasts.\n\n# Summary of Animal Studies\nCr(VI) compounds have been tested in animals using many different experimental conditions and exposure routes. Although experimental conditions are often different from occupation al exposures, these studies provide data to as sess the carcinogenicity of the test compounds. Chronic inhalation studies provide the best data for extrapolation to occupational exposure; few have been conducted using Cr(VI) compounds. However, the body of animal studies supports the classification of Cr(VI) compounds as occu pational carcinogens.\nThe few chronic inhalation studies available demonstrate the carcinogenic effects of Cr(VI) compounds in mice and rats . Animal stud ies conducted using other respiratory routes of administration have also produced positive results with some Cr(VI) compounds. Zinc chromate and calcium chromate produced a statistically significant (P < 0.05) number of bronchial carcinomas when administered via an intrabronchial pellet implantation system . Cr(VI) compounds with a range of solubilities were tested using this system. Although soluble Cr(VI) compounds did produce tumors, these results were not statistically significant. Some lead chromate compounds produced squamous carcinomas, which although not statistically significant may be biologically significant because of the historical absence of this cancer in control rats.\nSteinhoff et al. administered the same total dose of sodium dichromate either once per week or five times per week to rats via intra tracheal instillation. No increased incidence of lung tumors was observed in animals dosed five times weekly. However, in animals dosed once per week, a statistically significant (P < 0.01) tum or incidence was reported in the 1.25 mg/ kg exposure group. This study demonstrates a dose-rate effect within the constraints of the ex perimental design. It suggests that limiting ex posure to high Cr(VI) levels may be important in reducing carcinogenicity. However, quanti tative extrapolation of these animal data to the human exposure scenario is difficult.\nAnimal studies conducted using nonrespiratory routes of administration have also produced positive results with some Cr(VI) compounds . These studies pro vide another data set for hazard identification. Crump , Gibb et al. , and EPA . Dose-response data from the Balti more, Maryland chromium chemical produc tion facility were analyzed by Park et al. , K.S. Crump , and Gibb et al. .\nThe epidemiologic studies of these worker populations are described in the human health effects chapter (see Chapter 4). Goldbohm et al. discusses the framework necessary to conduct quantitative risk assessments based on epidemiological studies in a structured, transparent, and reproducible manner.\nThe Baltimore and Painesville cohorts are the best studies for predicting Cr(VI) cancer risks be cause of the quality of the exposure estimation, large amount of worker data available for anal ysis, extent of exposure, and years of follow-up . NIOSH selected the Baltimore cohort for analysis be cause it had the greater num ber of lung cancer deaths, better smoking histories, and a more comprehensive retrospective exposure archive. . These estimates of increased lung cancer risk vary de pending on the data set used, the assumptions made, and the models tested.\nEnvironmental risk assessments of Cr(VI) exposure have also been conducted [ATSDR 2012;EPA 1998EPA , 1999. These analyses assess the risks of nonoccupational Cr(VI) exposure.\n\n# Baltimore Chromate Production Risk Assessments\nNIOSH calculated estimates of excess lifetime risk of lung cancer death resulting from oc cupational exposure to chromium-containing mists and dusts using data from a cohort of chromate chemical produc tion workers . NIOSH de term ined that Gibb et al. was the best data set available for quantitative risk assess ment because of its extensive exposure assess ment and smoking information, strong statis tical power, and its relative lack of potentially confounding exposures. Several aspects of the exposure-response relationship were exam ined. Different model specifications were used permitting nonlinear dependence on cumula tive exposure to be considered, and the possi bility of a nonlinear dose-rate effect was also investigated. All models evaluated fit the data comparably well. The linear (additive) relative rate model was selected as the basis for the risk assessment. It was among the better-fitting models and was also preferred on biological grounds because linear low-dose extrapolation is the default assumption for carcinogenesis.\nThere was some suggestion of a negative dose rate effect, (greater than proportional excess risk at low exposures and less than proportion al risk at high exposures but still a monotic re lationship) but the effect was small. Although lacking statistical power, the analyses examin ing thresholds were consistent with no thresh old on exposure intensity. Some misclassification on exposure in relation to race appeared to be present, but models with and without the exposure-race interaction produced a clear ex posure response. Taken together, the analyses constitute a robust assessment of the risk of chromium carcinogenicity.\nThe excess lifetim e (45 years) risk for lung cancer mortality from exposure to Cr(VI) was estimated to be 255 per thousand workers at the previous OSHA PEL of 52 ^g/m 3 based on the exposure-response estimate for all men in the Baltimore cohort. At the previous NIOSH REL of 1 ^g/m3 for Cr(VI) compounds, the excess lifetime risk was estimated to be 6 lung cancer deaths per 1,000 workers and at the REL of 0.2 ^g/m3 the excess lifetime risk is approxi mately 1 lung cancer death per 1,000 workers.\nThe data analyzed were from the Baltimore, Maryland cohort previously studied by and Gibb et al. . The cohort comprised 2,357 men first hired from 1950 through 1974 whose vital status was followed through 1992. The racial makeup of the study population was 1,205 white (51%), 848 non white (40%) and 304 of unknown race (13%). This cohort had a detailed retrospective expo sure assessment that was used to estimate indi vidual worker current and cumulative Cr(VI) exposures across time. Approximately 70,000 both area and personal airborne Cr(VI) m ea surements of typical exposures were collected and analyzed by the employer from 1950 to 1985, when the plant closed. These samples were used to assign, in successive annual peri ods, average exposure levels to exposure zones that had been defined by the employer. These job title estimated exposures were combined with individual work histories to calculate the Cr(VI) exposure of each member of the cohort.\nSmoking information at hire was available from medical records for 91 percent of the popula tion, including packs per day for 70 percent of the cohort. The cohort was largely free of other potentially confounding exposures. The mean duration of employment of workers in the co hort was 3.1 years, while the median duration was only 0.39 of a year.\nIn this study population of 2,357 workers, 122 lung cancer deaths were documented. This mortality experience was analyzed using Pois son regression methods. Diverse models of exposure-response for Cr(VI) were evaluated by comparing deviances and inspecting cubic splines. The models using cumulative smok ing (as a linear spline) fit significantly better in comparison with models using a simple categorical classification (smoking at hire: yes, no, unknown). For this reason, smoking cu mulative exposure imputed from cigarette use at hire was included as a predictor in the final models despite absence of detailed smoking histories. Lifetime risks of lung cancer death from exposure to Cr(VI) were estimated us ing an actuarial calculation that accounted for competing causes of death.\nAn additive relative rate m odel was selected which fit the data well and which was readily in terpretable for excess lifetime risk calculations: Based on a categorical analysis, the exposurerace interaction was found to be largely due to an inverse trend in lung cancer mortality among whites: an excess in the range 0.03-0.09 m g/m 3-yr of chromium cumulative exposure and a deficit in the range 0.37-1.1 m g/m 3-yr. Park et al. concluded that a biological basis for the chromium-race interaction was unlikely and that more plausible explanations include, but are not limited to, misclassification of smoking status, misclassification of chro mium exposures, or chance. It is doubtful that confounding factors play an important role, be cause it is unlikely that another causal risk factor is strongly and jointly associated with exposure and race. The asbestos exposure that was present was reported to be typical of industry generally at that time. Some asbestos exposure may have been associated with certain chromium process areas wherein workers were not representative of the entire workforce on race. For this to ex plain a significant amount of the observed lung cancer excess would require relatively high as bestos exposures correlated with Cr(VI) levels for non-white workers. It would not explain the relative deficit of lung cancer observed among white workers with high cumulative Cr(VI) ex posures. Furthermore, no mesothelioma deaths were observed, and the observed lung cancer excess would correspond to asbestos exposures at levels seen only in asbestos manufacturing or processing environments.\nExposure misclassification, on the other hand, is plausible given the well-known disparities in exposure by race often observed in occupa tional settings. In this study, average exposure levels were assigned to exposure zones within which there may have been substantial racerelated differences in work assignments and resulting individual exposures. Race-exposure interactions would inevitably follow. If the ra cial disparity was the result of exposure misclassification, then models without the racechromium interaction term would provide an unbiased estimate of the exposure-response, although less precisely than if race had been taken into account in the processing of air sampling results and in the specification of ex posure zone averages. Park and Stayner examined the pos sibility of an exposure threshold in the Balti more cohort by calculating different measures of cumulative exposure in which only concen trations exceeding some specified threshold value were summed over time. The best-fitting models, evaluated with the profile likelihood method, were those with a threshold lower than 1.0 ^g/m3, the lowest threshold tested. The test was lim ited by statistical power but estab lished upper confidence limits for a threshold consistent with the observed data of 16 ^g/ m 3 Cr(VI) for models with the exposure-race interaction or 29 ^g/m 3 Cr(VI), for models without the exposure-race interaction. Other models using a cumulative exposure metric in which concentration raised to some power, Xa, is summed over time, found that the best fit corresponded to a = 0.8. If saturation of some protective process were taking place, one would expect a > 1.0. However, statistical power limited interpretation as a = 1.0 could not be ruled out. Analyses in which a cumula tive exposure threshold was tested found the best-fitting models with thresholds of 0.02 m g/m 3-yr (with exposure-race interaction) or 0.3 m g/m 3-yr Cr(VI)(without exposure-race interaction) but could not rule out no thresh old. The retrospective exposure assessment for the Baltimore cohort, although the best avail able for a chromium-exposed population, has limitations that reduce the certainty of nega tive findings regarding thresholds. Neverthe less, the best estimate at this time is that there is no concentration threshold for the Cr(VI)lung cancer effect.\nCrump KS conducted an analysis of a cohort from the older Baltimore plant reported by . The cumulative exposure estimates of were also used in the risk assessment. From a Poisson regres sion model, the maximum likelihood estimate of fi, the potency parameter (i.e., unit risk), was 7.5 x 10-4 per ^g/m3-yr. Occupational exposure to Cr(VI) for 45 years was estimated to result in 88 excess lung cancer deaths per 1,000 work ers exposed at the previous OSHA PEL and 1.8 excess lung cancer deaths per 1,000 workers exposed at the previous NIOSH REL. Gibb et al. conducted a quantitative as sessment of the Baltimore production workers reported by , whose exposure was reconstructed by . This cohort was divided into six subcohorts based on their period of hire and length of employment . Gibb et al. calculated the lifetime respiratory cancer mortality risk estimates for the four subcohorts who were hired before 1960 and had worked in the old facility. The slopes for these subcohorts ranged from 5.1 x 10-3/^g/m 3 to 2.0 x 10-2/^g/m 3 with a geometric mean of 9.4 x 10-3/^g/m 3.\n\n# Painesville Chromate Production Risk Assessments\nCrump et al. calculated estimates of ex cess lifetime risk of lung cancer death resulting from occupational and environmental expo sure to Cr(VI) in a cohort of chromate chemi cal production workers. The excess lifetime (45 years) risk for lung cancer mortality from occupational exposure to Cr(VI) at 1 ^g/m3 (the previous NIOSH REL) was estimated to be approximately 2 per 1,000 workers for both the relative and additive risk models.\nThe cohort analyzed was a Painesville, Ohio worker population described by . The cohort comprised 493 workers who met the following criteria: first hired from 1940 through 1972, worked for at least 1 year, and did not work in any of the other Cr(VI) facilities owned by the same company, other than the North Carolina plant. The vital status of the cohort was followed through 1997.\nAll but four members of the cohort were male.\nLittle information was available on the racial makeup of the study population other than that available from death certificates. Informa tion on potential confounders such as smok ing histories and other occupational exposures was limited, so this information was not in cluded in the mortality analysis. There were 303 deaths, including 51 lung cancer deaths, reported in the cohort. SMRs were signifi cantly increased for the following: all causes combined, all cancers combined, lung cancer, year of hire before 1960, 20 or more years of ex posed employment, and latency of 20 or more years. A trend test showed a strong relationship between lung cancer mortality and cumulative Cr(VI) exposure. Lung cancer mortality was statistically significantly increased for observa tion groups with cumulative exposures greater than or equal to 1.05 m g/m 3-years.\nThe exposure assessment of the cohort was reported by Proctor et al. . More than 800 Cr(VI) air-sampling measurements from 21 industrial hygiene surveys were identi fied. These data were airborne area samples. Airborne Cr(VI) concentration profiles were constructed for 22 areas of the plant for each month from January 1940 through April 1972. Cr(VI) exposure estimates for each worker were reconstructed by correlating their job titles and work areas with the corresponding area exposure levels for each m onth of their employment. The cumulative exposure and highest average monthly exposure levels were determined for each worker.\nK.S. Crump calculated the risk of Cr(VI) occupational exposure in its analysis of the Mancuso data. Cr(III) and Cr(VI) data from the Painesville, Ohio plant were used to justify a conversion factor of 0.4 to calculate Cr(VI) concentrations from the total chromium concentrations pre sented by Mancuso . The cumulative exposure of workers to Cr(VI) (^g/m 3-yr) was used in the analysis. All of the original expo sure categories presented by Mancuso were used in the analysis, including those that had the greatest cumulative exposure. A sen sitivity analysis using different average values was applied to these exposure categories. U.S. vital statistics data from 1956, 1967, and 1971 were used to calculate the expected numbers of lung cancer deaths. Estimates of excess lung cancer deaths at the previous NIOSH REL ranged from 5.8 to 8.9 per 1,000 workers. Es timates of excess lung cancer deaths at the pre vious OSHA PEL ranged from 246 to 342 per 1.000 workers.\nDECOS used the EPA data to calculate the additional lung cancer mortality risk due to occupational Cr(VI) exposure. The EPA estimate that oc cupational exposure to 8 ^g/m3 total dust re sulted in an additional lung cancer mortality risk of 1.4 x 10-2 was used to calculate occupa tional risk. It was assumed that total dust con centrations were similar to inhalable dust con centrations because of the small aerodynamic diameters of the particulates. Additional can cer mortality risks for 40-year occupational exposure to inhalable dust were calculated as 4 x 10-3 for 2 ^g/m 3 Cr(VI).\nThe EPA used the data of Mancuso \n\n# Other Cancer Risk Assessments\nThe International Chromium Development Association (ICDA) used the overall SMR for lung cancer from 10 Cr(VI) studies to assess the risk of occupational exposure to various levels of Cr(VI) exposure. The 10 stud ies evaluated were those selected by Steenland et al. as the largest and best-designed studies of workers in the chromium produc tion, chromate paint production, and chro mate plating industries. It was assumed that the mean length of employment of all workers was 15 years. Although this assumption may be appropriate for some of the cohorts, for others it is not: the mean duration of employment for the Painesville cohort was less than 10 years, and for the Baltimore cohort it was less than 4 years. Occupational exposures to Cr(VI) were assumed to be 500 |ig/m3, 1,000 |ig/m 3, or 2,000 ^g/m3 TWA. These are very unlikely Cr(VI) ex posure levels. The mean exposure concentra tions in the Painesville cohort were less than 100 ^g/m3 after 1942, and in the Baltimore cohort the mean exposure concentration was 45 ^g/m 3. For these different exposure levels, three different assumptions were tested: (1) the excess SMR was due to only Cr(VI) exposure, ( 2) Cr(VI) exposure was confounded by smok ing or other occupational exposures so that the baseline SMR should be 130, or (3) confounders set the baseline SMR to 160. The investi gators did not adjust for the likely presence of a healthy worker effect in these SMR analyses.\nA baseline SMR of 80 or 90 would have been appropriate based on other industrial cohorts and would have addressed smoking differ ences between industrial worker populations and national reference populations . The reference used for expected deaths was the 1981 life-table for males in England and Wales. The lung cancer mortality risk esti mates ranged from 5 to 28 per 1,000 at exposure to 50 |ig/m3 Cr(VI), to 0.1 to 0.6 per 1,000 at exposure to 1 |ig/m3 Cr(VI). The assumptions made and methods used in this risk assessment make it a weaker analysis than those in which worker exposure data at a particular plant are correlated with their incidence of lung cancer.\nThe excess lung cancer deaths may have been underestimated by at least a factor of 10, given the assumptions used on duration (factor of 1.5-2.0), exposure level (factor of , and healthy worker bias (factor of 1.1-1.2).\n\n# Summary\nThe data sets of the Painesville, Ohio and Balti more, Maryland chromate production workers provide the bases for the quantitative risk as sessments of excess lung cancer deaths due to occupational Cr(VI) exposure. In 1975, M an cuso presented the first data set of the Paines ville, Ohio workers, which was used for quan titative risk analysis. Its deficiencies included very limited exposure data, information on total chromium only, and no reporting of the expected number of deaths from lung can cer. Proctor et al. presented more than 800 airborne Cr(VI) measurements from 23 newly identified surveys conducted from 1943 through 1971 at the Painesville plant. These data and the mortality study of provided the basis for an improved lung cancer risk assessment of the Painesville workers.\nIn 1979, Hayes presented the first data of the Baltimore, Maryland production facility work ers, which were later used for quantitative risk assessment. In 2000, Gibb and coworkers provided additional exposure data for an im proved cancer risk assessment of the Baltimore workers . NIOSH selected the Gibb et al. cohort for quantitative risk analysis rather than the Painesville cohort because of its greater num ber of lung cancer deaths, better smoking his tories, and a more comprehensive retrospective exposure archive .\nIn spite of the different data sets analyzed and the use of different assumptions, models, and calculations, these risk assessments have esti mates of excess risk that are within an order of magnitude of each other (see Tables 6-1, 6- analyzed the most complete data sets available on occupational exposure to Cr(VI). These risk assessments estimated excess risks of lung cancer death of 2 per 1,000 workers and 6 per 1,000 workers , at a working lifetime expo sure to 1 ^g/m3. Park et al. estimated an excess risk of lung cancer death of approxi mately 1 per 1,000 workers at a steady 45-year workplace exposure to 0.2 ^g/m 3 Cr(VI). Park and Stayner evaluated the possibil ity of a threshold concentration for lung cancer in the Baltimore cohort. Although a threshold could not be ruled out because of the lim ita tions of the analysis, the best estimate at this time is that there is no concentration threshold for the Cr(VI)-lung cancer effect. In addition to limiting airborne concentrations of Cr(VI) compounds, NIOSH recommends that dermal exposure to Cr(VI) be prevented in the workplace to reduce the risk of adverse dermal health effects, including irritation, ul cers, skin sensitization, and allergic contact dermatitis.\n\n# Basis for NIOSH Standards\nIn the 1973 Criteria for a Recommended Stan dard: Occupational Exposure to Chromic Acid, NIOSH recommended that the federal stan dard for chromic acid, 0.1 mg/m3 as a 15-minute ceiling concentration, be retained because of reports of nasal ulceration occurring at concentrations only slightly above this con centration . In addition, NIOSH recom m ended supplem enting the ceiling concentration with a TWA of 0.05 m g/m 3 for an 8-hour workday to protect against possible chronic effects, including lung cancer and liv er damage. The association of these chronic effects with chromic acid exposure was not proven at that time, but the possibility of a correlation could not be rejected .\nIn the 1975 Criteria for a Recommended Stan dard: Occupational Exposure to Chromium(VI), NIOSH supported two distinct recommended standards for Cr(VI) com pounds . Some Cr(VI) compounds were consid ered noncarcinogenic at that time, including the chromates and bichromates of hydrogen, lithium, sodium, potassium, rubidium, cesium, and ammonium, and chromic acid anhydride. These Cr(VI) compounds were relatively solu ble in water. It was recommended that a 10-hr TWA limit of 25 ^g Cr(VI)/m 3 and a 15-minute ceiling limit of 50 |ig Cr(VI)/m 3 be applied to these Cr(VI) compounds.\nAll other Cr(VI) compounds were considered carcinogenic . These Cr(VI) compounds were relatively insoluble in water. At that time, NIOSH had a carcinogen policy that called for \"no detectable exposure levels for proven carcinogenic substances\" . Thus the basis for the REL for carci nogenic Cr(VI) compounds, 1 |ig Cr(VI)/m 3 TWA, was the quantitative lim itation of the analytical m ethod available for m easuring workplace exposures to Cr(VI) at that time.\nNIOSH revised its policy on Cr(VI) com pounds in its 1988 Testimony to OSHA on the Proposed Rule on Air Contaminants . NIOSH testified that while insoluble Cr(VI) compounds had previously been dem onstrated to be carcinogenic, there was now sufficient evidence that soluble Cr(VI) com pounds were also carcinogenic. Human studies cited in support of this position included Blair and Mason , Franchini et al. , Royle , Silverstein et al. , Sorahan et al. , and Waterhouse . In addi tion, the animal studies of Glaser et al. and Steinhoff et al. \n\n# Evidence for the Carcinogenicity of Cr(VI) Compounds\nHexavalent chrom ium is a w ell-established occupational carcinogen associated with lung cancer and nasal and sinus cancer . NTP identified Cr(VI) compounds as carcinogens in its first report on carcinogens in 1980 . Toxicologic studies, epidemio logic studies, and lung cancer meta-analyses pro vide evidence for the carcinogenicity of Cr(VI) compounds.\n\n# Epidemiologic Lung Cancer Studies\nIn 1989, the IARC critically evaluated the pub lished epidemiologic studies of chromium compounds including Cr(VI) and concluded that \"there is sufficient evidence in humans for the carcinogenicity of chromium com pounds as encountered in the chromate pro duction, chromate pigment production and chromium plating industries\" (i.e., IARC cat egory \"Group 1\" carcinogen) . Results from two recent lung cancer mortality studies of chromate production workers sup port this evaluation . In 2009, an IARC Working Group reviewed and reaffirmed Cr(VI) com pounds as Group 1 carcinogens (lung) . Gibb et al. conducted a retrospective analysis of lung cancer mortality in a cohort of Maryland chromate production workers. The cohort of 2,357 male workers first employed from 1950 through 1974 was followed until 1992. Workers with short-term employment (i.e., < 90 days) were included in the study group to increase the size of the low exposure group. The mean length of employment was 3.1 years. A detailed retrospective assessment of Cr(VI) exposure based on more than 70,000 personal and area samples (short-term and full-shift) and information about most work ers' smoking habits at hire was available.\nLung cancer standardized mortality ratios in creased with increasing cumulative exposure (i.e., mg CrO3/m 3-years, with 5-year exposure lag)-from 0.96 in the lowest quartile to 1.57 , respectively). SMRs were also significantly increased for year of hire be fore 1960, > 20 years of employment, and > 20 years since first exposure. The tests for trend across increasing categories of cumulative ex posure, year of hire, and duration of employ ment were statistically significant (P < 0.005).\nA test for departure of the data from linearity was not statistically significant (x2 goodness of fit of linear model; P = 0.23).\n\n# Lung Cancer Meta-Analyses\nMeta-analyses of epidemiologic studies have been conducted to investigate cancer risk in chromium-exposed workers. Most of these studies also provide support for the classifi cation of Cr(VI) compounds as occupational lung carcinogens.\nSjogren et al. reported a meta-analysis of five lung cancer studies of Canadian and European welders exposed to stainless steel welding fumes. The meta-analysis found an es timated relative risk of 1.94 (95% CI 1.28-2.93) and accounted for the effects of smoking and asbestos exposure. Steenland et al. reported overall relative risks for specific occupational lung carcino gens identified by IARC, including chromium.\nTen epidemiologic studies were selected by the authors as the largest and best-designed stud ies of chromium production workers, chro mate pigment production workers, and chro mium platers. The summary relative risk for the 10 studies was 2.78 (95% confidence inter val 2.47-3.52; random effects model), which was the second-highest relative risk among the eight carcinogens summarized. Cole and Rodu conducted meta-analyses of epidemiologic studies published in 1950 or later to test for an association of chromium exposure with all causes of death, and death from malignant diseases (i.e., all cancers com bined, lung cancer, stomach cancer, cancer of the central nervous system , kid ney cancer, prostate gland cancer, leukemia, Hodgkin's disease, and other lymphatohematopoietic cancers). Available papers (n = 114) were evaluated independently by both authors on eight criteria that addressed study quality.\nIn addition, papers with data on lung cancer were assessed for control of cigarette smoking effects, and papers with data on stomach can cer were assessed for economic status. Fortynine epidemiologic studies based on 84 papers published were used in the meta-analyses.\nThe number of studies in each meta-analysis ranged from 9 for Hodgkin's disease to 47 for lung cancer. Association was measured by an author-defined \"SMR\" that included odds ra tios, proportionate mortality ratios, and most often, standardized m ortality ratios. M ortal ity risks were not significantly increased for m ost causes of death. However, SMRs were significantly increased in all lung cancer meta-analyses (sm oking controlled: 26 stud ies; 1,325 deaths; SMR = 118; 95% CI 112 125) (sm oking not controlled: 21 studies; 1,129 deaths; SMR = 181; 95% CI 171-192) (lung cancer-all: 47 studies; 2,454 deaths; SMR = 141; 95% CI 135-147). Stomach can cer m ortality risk was significantly increased only in meta-analyses of studies that did not control for effects of economic status (eco nom ic status not controlled: 18 studies; 324 deaths; SMR = 137; 95% 123-153). The au thors stated that statistically significant SMRs for \"all cancer\" m ortality were m ainly due to lung cancer (all cancer: 40 studies; 6,011 deaths; SMR = 112; 95% CI 109-115). Many of the studies contributing to the m eta-anal yses did not address bias from the healthy worker effect, and thus the results are likely underestim ates of the cancer m ortality risks. O ther lim itations of these meta-analyses in clude lack of (1) exposure characterization of populations, such as the route of exposure (i.e., airborne versus ingestion); and (2) detail of criteria used to exclude studies based on \"no or little chrome exposure\" or \"no usable data.\"\n\n# Animal Experimental Studies\nCr(VI) compounds have been tested in ani mals using many different experimental con ditions and exposure routes. Although ex perimental conditions are often different from occupational exposures, these studies provide additional data to assess the carcinogenicity of the test compounds. Chronic inhalation studies provide the best data for extrapolation to oc cupational exposure; few have been conducted using Cr(VI) compounds. However, the body of animal studies support the classification of Cr(VI) compounds as occupational carcinogens.\nThe few chronic inhalation studies available demonstrate the carcinogenic effects of Cr(VI) compounds in mice and rats . Female mice ex posed to 1.8 m g/m 3 chromic acid mist (2 hours per day, 2 days per week for up to 12 months) developed a significant number of nasal papil lomas compared with control animals . Female mice exposed to a higher dose of chromic acid mist, 3.6 m g/m 3 (30 minutes per day, 2 days per week for up to 12 months) developed an increased, but not statistically significant, num ber of lung adenomas . Glaser et al. reported a sta tistically significant num ber of lung tumors in male rats exposed for 18 months to 100 ^g/m3 sodium dichromate; no tumors were reported at lower dose levels.\nAnimal studies conducted using other routes of administration have also produced adverse health effects with some Cr(VI) compounds. Zinc chromate and calcium chromate produced a statistically significant (P < 0.05) number of bronchial carcinomas when administered to rats via an intrabronchial pellet implantation system . Cr(VI) compounds with a range of solubilities were tested using this system. Although some soluble Cr(VI) compounds did produce bronchial carcino mas, these results were not statistically sig nificant. Some lead chromate compounds p ro duced bronchial squamous carcinomas that, although not statistically significant, may be biologically significant because of the absence of this cancer in control rats.\nSteinhoff et al. administered the same total dose of sodium dichromate either once per week or five times per week to male and female rats via intratracheal instillation. No in creased incidence of lung tumors was observed in animals dosed five times weekly. However, in animals dosed once per week, a statisti cally significant tum or incidence was reported in the 1.25 mg/kg exposure group. This study demonstrates a dose-rate effect within the con straints of the experimental design. It suggests that limiting exposure to high Cr(VI) concen trations may be important in reducing carcino genicity. However, quantitative extrapolation of these animal data to the hum an exposure scenario is difficult.\nAnimal studies conducted using nonrespiratory routes of administration have also pro duced injection-site tumors with some Cr(VI) compounds . These studies provide another data set for hazard identification.\nIARC concluded \"there is sufficient evi dence in experimental animals for the carcino genicity of chromium (VI) compounds\".\n\n# Basis for the NIOSH REL\nThe primary basis for the NIOSH REL is the re sults of the Park et al. quantitative risk assessment of lung cancer deaths of Maryland chromate production workers conducted on the data of Gibb et al. . NIOSH determined that this was the best Cr(VI) data set available for analysis because of its extensive exposure as sessment and smoking information, strong sta tistical power, and its relative lack of potentially confounding exposures . The results of the NIOSH risk assessment are sup ported by other quantitative Cr(VI) risk assess ments (see Chapter 6).\nNIOSH selected the revised REL at an excess risk of lung cancer of approximately 1 per 1.000 workers based on the results of Park et al. . Table 7-1 presents the range of risk levels of lung cancer from 1 per 500 to 1 per 100.000 for workers exposed to Cr(VI). Can cer risks greater than 1 per 1,000 are consid ered significant and worthy of intervention by OSHA. This level of risk is consistent with those for other carcinogens in recent OSHA rules . NIOSH has used this risk level in a variety of circum stances, including citing this level as appropri ate for developing authoritative recommenda tions in criteria documents and peer-reviewed risk assessments .\nAdditional considerations in the derivation of the REL include analytical feasibility and the ability to control exposure concentrations to the REL in the workplace. The REL for Cr(VI) compounds is intended to reduce workers' risk of lung cancer over a 45-year working lifetime.\nAlthough the quantitative analysis is based on lung cancer mortality data, it is expected that reducing airborne workplace exposures will also reduce the nonmalignant respiratory ef fects of Cr(VI) compounds, including irritated, ulcerated, or perforated nasal septa, and other potential adverse health effects. The available scientific evidence supports the inclusion of workers exposed to all Cr(VI) compounds into this recommendation. All Cr(VI) compounds studied have dem onstrat ed their carcinogenic potential in animal, in vitro, or human studies . Molecular toxicology studies provide additional support for classifying Cr(VI) com pounds as occupational carcinogens.\nAt this time, there is insufficient data to quan tify a different REL for each specific Cr(VI) compound . Although there are inadequate epidemiologic data to quan tify the risk of hum an exposure to insoluble Cr(VI) compounds, the results of animal stud ies indicate that this risk is likely as great as, if not greater than, exposure to soluble Cr(VI) compounds . Because of the similar mechanisms of action of soluble and insoluble Cr(VI) compounds, and the quan titative risk assessments dem onstrating sig nificant risk of lung cancer death resulting from occupational lifetime exposure to soluble Cr(VI) compounds, NIOSH recommends that the REL apply to all Cr(VI) compounds.\nAt this time, there are inadequate data to con duct a quantitative risk assessment for work ers exposed to Cr(VI), other than chromate production workers. However, epidemiologic studies demonstrate that the health effects of airborne exposure to Cr(VI) are similar across workplaces and industries (see Chapter 4). Therefore, the results of the NIOSH quantita tive risk assessment conducted on chromate production workers are be ing used as the basis of the REL for workplace exposures to all Cr(VI) compounds.\n\n# Park et al. Risk Assessment\nNIOSH calculated estimates of excess lifetime risk of lung cancer death resulting from oc cupational exposure to water-soluble chromi um-containing mists and dusts in a cohort of Baltimore, MD chromate chemical production workers . This cohort, origi nally studied by Gibb et al. , comprised 2,357 men first hired from 1950 through 1974, whose vital status was followed through 1992. The mean duration of employment of workers in the cohort was 3.1 years, and the m edian duration was 0.39 year.\nThis cohort had a detailed retrospective expo sure assessment of approximately 70,000 mea surements, which was used to estimate indi vidual worker current and cumulative Cr(VI) exposures across time. Smoking information at hire was available from medical records for 91% of the population, including packs per day for 70 percent of the cohort. In this study population of 2,357 workers, 122 lung cancer deaths were documented.\nThe excess working lifetime (45 years) risk es timates of lung cancer death associated with occupational exposure to water-soluble Cr(VI) compounds using the linear risk model are 255 (95% CI: 109-416) per 1,000 workers at 52 Cr(VI)/m 3, 6 (95% CI: 3-12) per 1,000 work ers at 1 |ig Cr(V I)/m 3, and approximately 1 per 1.000 workers at 0.2 ^g Cr(VI)/m 3.\n\n# Crump et al. Risk Assessment\nCrump et al. analyzed data from the Painesville, Ohio chromate production work er cohort described by .\nThe cohort comprised 493 workers who met the following criteria: first hired from 1940 through 1972, worked for at least 1 year, and did not work in any of the other Cr(VI) facili ties owned by the same company other than the North Carolina plant. The vital status of the cohort was followed through 1997.\nInformation on potential confounders (e.g., smoking) and other occupational exposures was limited and not included in the mortality analysis. There were 303 deaths reported, in cluding 51 lung cancer deaths. SMRs were sig nificantly increased for the following: all causes combined, all cancers combined, lung cancer, year of hire before 1960, 20 or more years of exposed employment, and latency of 20 or more years. A trend test showed a strong relationship between lung cancer mortality and cumulative Cr(VI) exposure. Lung cancer mortality was in creased for cumulative exposures greater than or equal to 1.05 mg/m3-years.\nThe estimated lifetime additional risk of lung cancer mortality associated with 45 years of occupational exposure to water-soluble Cr(VI) compounds at 1 ^g/m3 was approximately 2 per 1.000 (0.00205 for the relative risk model and 0.00216 for the additive risk model), assuming a linear dose response for cumula tive exposure with a 5-year lag.\nQuantitative risk assessments of the Baltimore, Maryland and Painesville, Ohio chromate pro duction workers consistently demonstrate sig nificant risk of lung cancer mortality to work ers exposed to Cr(VI) at the previous NIOSH REL of 1 |ig Cr(VI)/m 3. These results justify lowering the NIOSH REL to decrease the risk of lung cancer in workers exposed to Cr(VI). NIOSH used the results of the risk assess ment of Park et al. as the basis of the current REL because this assessment analyzes the most extensive database of workplace ex posure measurements, including smoking data on most workers.\n\n# Applicability of the REL to All Cr(VI) Compounds\nNIOSH recommends that the REL of 0.2 Cr(VI)/m3 be applied to all Cr(VI) compounds.\nCurrently, there are inadequate data to exclude any single Cr(VI) compound from this recom mendation. IARC concluded that \"there is sufficient evidence in humans for the carci nogenicity of chromium (VI) compounds\".\nEpidemiologic studies were often unable to iden tify the specific Cr(VI) compound responsible for the excess risk of cancer. However, these stud ies have documented the carcinogenic risk of occupational exposure to soluble Cr(VI). Gibb et al. and report ed the health effects of chromate production workers with sodium dichromate being their prim ary Cr(VI) exposure. These studies, and the risk assessments conducted on their data, demonstrate the carcinogenic effects of this soluble Cr(VI) compound. The NIOSH risk assessment on which the REL is based evalu ated the risk of exposure to sodium dichromate .\n\n# Risk Assessment Summary\nAlthough there are inadequate epidemiologic data to quantify the cancer risk of human ex posure to insoluble Cr(VI) compounds, the re sults of animal studies indicate that this risk is likely as great, if not greater than, exposure to soluble Cr(VI) compounds .\nThe carcinogenicity of insoluble Cr(VI) com pounds has been demonstrated in animal and human studies . Animal stud ies have demonstrated the carcinogenic poten tial of soluble and insoluble Cr(VI) compounds . IARC concluded that \"there is suffi cient evidence in experimental animals for the carcinogencity of chromium (VI) compounds\".\nBased on the current scientific evidence, NIOSH recommends including all Cr(VI) compounds in the revised REL. There are inadequate data to exclude any single Cr(VI) compound from this recommendation. NIOSH acknowledges that the frequent use of PPE, including respirators, may be required by some workers in environments where air borne Cr(VI) concentrations cannot be con trolled below the REL in spite of implementing all other possible measures in the hierarchy of controls. The frequent use of PPE may be re quired during job tasks for which (1) routinely high airborne concentrations of Cr(VI) exist, ( 2) the airborne concentration of Cr(VI) is un known or unpredictable, and ( 3) job tasks are as sociated with highly variable airborne concentra tions because of environmental conditions or the manner in which the job task is performed.\n\n# Analytical Feasibility of the REL\n\n# Preventing Dermal Exposure\nNIOSH recommends that dermal exposure to Cr(VI) be prevented by elimination or substi tution of Cr(VI) compounds. W hen this is not possible, appropriate sanitation and hygiene procedures and appropriate PPE should be used (see Chapter 8). Preventing dermal expo sure is im portant to reduce the risk of adverse dermal health effects, including dermal irri tation, ulcers, skin sensitization, and allergic contact dermatitis. The prevention of dermal exposure to Cr(VI) compounds is critical in preventing skin disorders related to Cr(VI).\n\n# Summary\nNIOSH determined that the data of Gibb et al. is the most comprehensive data set available for assessing the health risk of oc cupational exposure to Cr(VI), including an extensive exposure assessment database and smoking information on workers. The revised REL is a health-based recommendation derived from the results of the NIOSH quantitative risk assessment conducted on these human health effects data . Other consid erations include analytical feasibility and the achievability of engineering controls.\nNIOSH recommends a REL of 0.2 ^g Cr(VI)/ m 3 for an 8-hr TWA exposure within a 40-hr workweek, for all airborne Cr(VI) compounds. The REL is intended to reduce workers' risk of lung cancer over a 45-year working life time. The excess risk of lung cancer death at the revised REL is approximately 1 per 1,000 workers. NIOSH has used this risk level in other authoritative recommendations in crite ria documents and peer-reviewed risk assess ments. Results from epidemiologic and toxico logic studies provide the scientific evidence to classify all Cr(VI) compounds as occupational carcinogens and support the recommendation of having one REL for all Cr(VI) compounds [NIOSH 1988b[NIOSH , 2002[NIOSH , 2005a.\nExposure to Cr(VI) compounds should be eliminated from the workplace where pos sible because of the carcinogenic potential of these compounds. Where possible, less-toxic compounds should be substituted for Cr(VI) compounds. Where elimination or substitution of Cr(VI) compounds is not possible, attempts should be made to control workplace exposures below the REL. Compliance with the REL for Cr(VI) compounds is currently achievable in some industries and for some job tasks. It may be difficult to achieve the REL during certain job tasks including welding, electroplating, spray painting, and atomized-alloy spray-coat ing operations. Where airborne exposures to Cr(VI) cannot be reduced to the REL through using state-of-the-art engineering controls and work practices, the use of respiratory protec tion will be needed.\nThe REL may not be sufficiently protective to prevent all occurrences of lung cancer and other adverse health effects among workers exposed for a working lifetime. NIOSH there fore recommends that worker exposures be maintained as far below the REL as achievable during each work shift. NIOSH also recom mends that a comprehensive safety and health program be implemented that includes worker education and training, exposure monitoring, and medical monitoring.\nIn addition to controlling airborne exposures at the REL, NIOSH recommends that dermal exposures to Cr(VI) compounds be prevented to reduce the risk of adverse dermal health ef fects, including dermal irritation, ulcers, skin sensitization, and allergic contact dermatitis. In addition to limiting airborne concentra tions of Cr(VI) compounds, NIOSH recom mends that dermal exposure to Cr(VI) be prevented in the workplace to reduce the risk of adverse dermal health effects, including irritation, ulcers, allergic contact dermatitis, and skin sensitization.\n\n# Risk Management\n\n# Sampling and Analytical Methods\nThe sampling and analysis of Cr(VI) in work place air should be performed using precise, ac curate, sensitive, and validated methods. All signs should be printed both in English and in the language(s) of non-English-speaking workers. All workers who are unable to read should receive oral instruction on the content and instructions on any written signs. Signs using universal safety symbols should be used wherever possible.\n\n# Exposure Control Measures\nMany exposure control measures are used to protect workers from potentially harmful ex posures to hazardous workplace chemical, physical, or biological agents. These control measures include, in order of priority: elimina tion, substitution, engineering controls, ad m inistrative controls and appropriate work practices, and the use of protective clothing and equipment . The occupa tional exposure routes of prim ary concern for Cr(VI) compounds are the inhalation of air borne Cr(VI) and direct skin contact. This sec tion provides information on general exposure control measures that can be used in many workplaces and specific control measures for controlling Cr(VI) exposures that are effective in some workplaces.\n\n# Elimination and Substitution\nElimination of a hazard from the workplace is the most effective control to protect worker health. Elimination may be difficult to imple ment in an existing process; it may be easier to implement during the design or re-design of a product or process.\nIf elimination is not possible, substitution is the next choice of control to protect worker health. Using substitution as a control measure may include substitution of equipment, mate rials, or less hazardous processes. Equipment substitution is the most common type of sub stitution . It is of ten less costly than process substitution, and it may be easier than finding a suitable substitute material. An example that applies to Cr(VI) ex posure reduction is the substitution of an en closed and automated spray paint booth for a partially enclosed workstation.\nMaterial substitution is the second most com mon type of substitution after equipment sub stitution. It has been used to improve the safety of a process or lower the intrinsic toxicity of the material being used. However, evaluation of the potential adverse health effects of the substitute material is essential to ensure that one hazard is not replaced with a different one . Blade et al. reported material substitu tion in some processes with potential worker exposures to Cr(VI) compounds investigated by NIOSH between 1999 and 2001. A reduc tion in the use of chromate-containing paints was reported in construction (i.e., bridge re painting) and vehicle manufacturing (i.e., the manufacture of automobiles and most trucks reportedly no longer uses chromate paints). However, chromate-containing paints report edly remained without satisfactory substi tute in aircraft manufacture and refurbishing. Chromium electroplating industry represen tatives also reported steady demand for hard chrome finishes for mechanical parts such as gears, molds, etc., because of a lack of econom ical alternatives for this durable finish.\nMany examples of process substitution have been considered. A change from an interm it tent or batch-type process to a continuous-type process often reduces the potential hazard, par ticularly if the latter process is more automat ed .\nDipping objects into a coating material, such as paint, usually causes less airborne material and is less of an inhalation hazard than spray ing the material.\nReducing the Cr(VI) Content o f Portland Ce m ent. One example of substitution is using Portland cement with a reduced Cr(VI) con tent to reduce workers' risk of skin sensitiza tion. The trace amount of Cr(VI) in cement can cause allergic contact dermatitis that can be debilitating and marked by significant, long-term adverse effects . The chromium in cement can originate from a va riety of sources, including raw materials, fuel, refractory brick, grinding media, and additions . The manufacturing process, including the kiln conditions, deter mines how much Cr(VI) forms. The Cr(VI) content of cement can be lowered by using materials with lower chromium content dur ing production and/or by adding agents that reduce Cr(VI). The use of slag, in place of or blended with clinker, may decrease the Cr(VI) content . Fer rous sulfate is the material most often added to cement to reduce its Cr(VI) content. . Limiting the Cr(VI) content of cement in the United States warrants consideration. Further research on the potential impacts of this change in U.S. in dustry is needed.\n\n# Engineering Controls\nIf elimination or substitution are not possible, engineering controls are the next choice for re ducing worker exposure to Cr(VI) compounds. These controls should be considered when new facilities are being designed or when existing facilities are being renovated to maximize their effectiveness, efficiency, and economy. Engi neering measures to control potentially hazard ous workplace exposures to Cr(VI) compounds include isolation and ventilation. OSHA deter mined that the primary engineering control measures most likely to be effective in reduc ing employee exposure to airborne Cr(VI) are local exhaust ventilation (LEV), process enclo sure, process modification, and improved gen eral dilution ventilation . These and other engineering controls are described in the following sections.\n\n# Isolation\nIsolation as an engineering control may in volve the erection of a physical barrier between the worker and the hazard. Isolation may also be achieved by the appropriate use of distance or time . Examples of hazard isola tion include the isolation of potentially hazard ous materials into separate structures, rooms, or cabinets; and the isolation of potentially hazardous process equipment into dedicated areas or rooms that are separate from other work areas . Sepa rate ventilation of the isolated area(s) may be needed to maintain the isolation of the hazard from the rest of the facility . Com plete isolation of an entire process also may be achieved using automated, remote operation methods .\nAn example of an isolation technique to con trol Cr(VI) exposure is the use of a separate, ventilated m ixing room for m ixing batches of powdered m aterials containing chromate pigments.\n\n# Ventilation\nVentilation may be defined as the strategic use of airflow to control the environment within a space-to provide thermal control within the space, remove an air contaminant near its source of release into the space, or dilute the concentration of an air contaminant to an ac ceptable level . W hen controlling a workplace air contaminant such as Cr(VI), a specific dedicated exhaust ventilation system or assembly might need to be designed for the task or process .\nLocal exhaust ventilation (LEV) is primarily intended to capture the contaminant at spe cific points of release into the workroom air through using exhaust hoods, enclosures, or similar assemblies. LEV is appropriate for the control of stationary point sources of contami nant release. It is important to assure proper selection, maintenance, placement, and opera tion of LEV systems to ensure their effective ness .\nGeneral ventilation, often called dilution venti lation, is primarily intended to dilute the con centration of the contam inant w ithin the general workroom air. It controls widespread problems such as generalized or mobile emission sources . Whenever practicable, point-source emissions are most ef fectively controlled by LEV, which is designed to remove the contaminant at the source be fore it emanates throughout the workspace. Dilution ventilation is less effective because it merely reduces the concentration of the con taminant after it enters the workroom air, rath er than preventing much of the emitted con taminant from ever entering the workroom air.\nIt also is much less efficient, requiring much greater volumetric airflow to reduce concen trations. However, for non-point sources of contaminant emission, dilution ventilation may be necessary to reduce exposures.\nThe air exhausted by a LEV system must be re placed, and the replacement air will usually be supplied by a make-up air system that is not as sociated with any particular exhaust inlet and/ or by simple infiltration through building open ings (relying on infiltration for make-up air is not recommended). This supply of replacement air will provide general ventilation to the space even if all the exhaust is considered local. The designation of a particular ventilation system or assembly as local or general, exhaust or sup ply, is governed by the prim ary intent of the de sign .\nPush-pull ventilation may be used to control exposures from open surface tanks such as elec troplating tanks. Push-pull ventilation includes a push jet located on one side of a tank and a lateral exhaust hood on the other side . The jet formed over the tank surface cap tures the emissions and carries them into the hood. Many other types of ventilation systems may be used to control exposures in specific workplace operations .\n\n# Examples of engineering controls to reduce Cr(VI) exposures\nMany types of engineering controls have been used to reduce workplace Cr(VI) exposures. Some of the engineering controls recommend ed by NIOSH in 1975 are still valid and in use today. Some examples are in cluded here, there are many others .\nClosed systems and operations can be used for many processes, but it should be ensured that seals, joints, covers, and similar assemblies fit properly to maintain negative static pressure within the closed equipment, relative to the surroundings.\nThe use of LEV may be needed even with closed systems to prevent workers' exposures during operations such as unloading, charging, and packaging. The use of protective clothing and equipment may also be needed. Ventila tion systems should be regularly inspected and maintained to assure effective operation. Work practices that may obstruct or interfere with ventilation effectiveness must be avoided. Any modifications or additions to the ventilation system should be evaluated by a qualified pro fessional to ensure that the system is operating at design specifications.\nThe use of clean areas, such as control rooms supplied with uncontaminated air, is one m ethod of isolating the workers from the haz ard. An area to which workers may retreat for periods of time when they are not needed at the process equipment also may be configured as a clean area. . Qualitative airflow visualization using smoke tubes suggested that the push-pull ventilation systems were generally effective in moving air away from workers' breathing zones. How ever, maintenance problems with the ventila tion system suggested that the system was not always operating effectively. Floating plastic balls had reportedly been used in the past but proved impractical. M ist suppressants that reduce surface tension were not used because of concerns that they may induce pitting in the hard chrome-plated finish.\nIn contrast with hard chrome plating tanks, control of bright chrome plating tank emis sions is less problematic. Bright chrome plat ing provides a thin chromium coating for appearance and corrosion protection to n on mechanical parts. The use of a wetting agent as a fume suppressant that reduces surface tension provided effective control of emis sions .\nAt another facility, a hard chrome-plating tank was equipped with a layer of a newly devel oped, proprietary viscous liquid and a system to circulate it . This system effectively reduced mist emission containing Cr(VI) from the tank, but it was not durable.\nWelding and therm al cutting involving chro m ium -containing metals. Many welding task variables affect the Cr(VI) content of weld ing fume and the associated Cr(VI) expo sures. Both the base metal of the parts being joined and the consumable metal (welding rod or wire) added to create the joint have vary ing compositions of chromium. The welding process and shield-gas type, and the Cr con tent of both the consumable material and the base metal affect the Cr(VI) content of the fume . W hen pos sible, process and material substitution may be effective in reducing welding Cr(VI) expo sures. Evaluation of an exposure database from The Welding Institute indicated that welding of stainless steel or Inconel (a nickel-chromium alloy containing 14-23% Cr ) resulted in median Cr(VI) exposures of 0.6 ^g/m 3 com pared with the Cr(VI) exposures of the weld ing of other metals, which were less than the LOD (range 0.1-0.2 |ig/m3) . Processes such as gas-tungsten arc weld ing (GTAW), submerged arc welding (SAW), and gas-metal arc welding (GMAW) tend to generate less fume . Whenever appropriate, the selection of GTAW will help to minimize Cr(VI) exposures in welding fume . Cr(VI) exposures during shielded-metal arc welding (SMAW) may be minimized by using consumables (welding rod or wire) containing low chromium con tent (i.e., less than 3% Cr) .\nWelding or thermal-cutting fumes containing Cr(VI) are often controlled using LEV systems . Two common LEV systems are high-volume low-vacuum systems or lowvolume high vacuum systems. High-volume low-vacuum systems have large-diameter hos es or ducts that result in larger capture distanc es . High-vacuum low-volume sys tems use smaller hoses and so have a smaller capture distance; they are often more portable . In controlled welding trials, the use of a portable high-vacuum fume extraction unit reduced Cr(VI) exposures from a median of 1.93 ^g/m 3 to 0.62 ^g/m3 (P = 0.02) .\nWhen welding outdoors, the effect of the wind and the position of the welder are important factors controlling the effectiveness of LEV . In the field setting LEV ef fectiveness is directly related to proper usage . Proper positioning of the ventilation inlet relative to the welding nozzle and the worker's breathing zone is critical to exposure-control performance; this often requires frequent repositioning by the weld er . Welders may keep the LEV inlet too far from the weld site to be effective, or they may be reluctant to use the LEV system because of concerns that the incoming venti lation air could adversely affect the weld qual ity by impairing flux or shield-gas effective ness .\nSpecialized systems called \"fume extraction welding guns\" can be used in many workplaces (e.g., outdoors) to reduce worker exposure to welding fumes. These systems combine the arc-welding gun with a series of small LEV air inlets so that the air inlets are always at a close distance to the welding arc. These systems are heavier and more cumbersome than standard arc-welding guns, so ergonomic issues must be considered .\nSpray application of chromate-containing paints. Blade et al. determined that the most ef fective measure for reducing workers' Cr(VI) exposures at a facility where chromate-containing paints were applied to aircraft parts would be the substitution of paints with lower chromate content (i.e., 1% to 5%) for those with higher content (i.e., 30%) wherever pos sible . Results indicated that partially enclosed paint booths for large-part painting might not provide adequate con taminant capture. The facility also used fully enclosed paint booths with single-pass ventila tion, with air entering one end and exhausted from the other. The average internal air veloci ties within these booths needed to exceed the speed with which the workers walked while spraying paint so that the plume of paint over spray moved away from the workers.\nRemoval o f chromate-containingpaints. At a construction site where a bridge was to be re painted, the removal of the existing chromatecontaining paint was accomplished by abrasive blasting. An enclosure of plastic sheeting was constructed to contain the spent abrasive and paint residue and prevent its release into the sur rounding environment . No mechanical ventilation was provided to the con tainment structure. NIOSH recommended that this type of containment structure be equipped with general-dilution exhaust ventilation that discharges the exhausted air through a high efficiency particulate air (HEPA) filtration unit.\nOther types of specialized engineering mea sures applicable for the control of exposures during chromate-paint removal have been in vestigated and recommended for selected ap plications. These recommendations are often made in the context of lead exposure control , but they are relevant to Cr(VI) control because lead chromate paints may be encountered during paint removal projects. Such control measures include high-pressure water blasting, wet-abrasive blasting, vacuum blasting, and the use of remotely controlled automated blasting devices . High-pressure water blasting uses a blast of extremely focused water at high veloc ity to remove paint and corrosion, but it does not reprofile the underlying metal substrate for repainting. Wet-abrasive blasting uses a con ventional blasting medium that is wetted with water to remove the paint and corrosion and to reprofile the metal. The wetted medium helps suppress the emission of dust that contains re moved chromate-paint particles. Vacuum blast ing uses a blasting nozzle surrounded by a vacu um shroud with a brush-like interfacing surface around its opening, which the operator keeps in contact with the metal surface being blast ed. Large reductions in exposures have been reported with this system, but considerations include the following: good work practices are needed to assure proper contact with the sur face is maintained; the full assembly is heavier than conventional nozzles and thus raises er gonomic concerns; and production (removal) rates reportedly are much lower than with con ventional blast nozzles .\nM ixing o f chromate-containing pigments. At a colored-glass manufacturing facility, pigments containing Cr(VI) were weighed in a separate room with LEV, then moved to a production area for mixing into batches of materials . Cr(VI) exposures at the facility were very low to not detectable.\nAt a screen printing ink manufacturing facil ity, there was no dedicated pigment-mixing room; LEV was used at the ink-batch mixing and weighing operation, but capture velocities were inadequate . Almost all the Cr(VI) exposures of the ink-batch weigh ers exceeded the existing REL.\nOperations creating concrete dust. Portland ce ment contains Cr(VI), so operations that cre ate concrete dust have the potential to expose workers to Cr(VI). In one operation studied by NIOSH, the use of water to suppress dust dur ing cleanup was observed to result in visibly lower dust concentrations . All Cr(VI) exposures at the facility were low. At a construction-rubble crushing and recycling facil ity, a water-spray system was used on the crusher at various locations, and the operator also used a hand-held water hose . All Cr(VI) exposures at this facility also were low.\n\n# Employer Actions\nThe employer should ensure that the qualified health care provider's recommended restric tion of a worker's exposure to Cr(VI) com pounds or other workplace hazards is followed, and that the REL for Cr(VI) compounds is not exceeded without requiring the use of PPE. Ef forts to encourage worker participation in the medical monitoring program and to report any symptoms promptly to the program di rector are important to the program's success. Medical evaluations perform ed as part of the medical monitoring program should be pro vided by the employer at no cost to the partici pating workers. Where medical removal or job reassignment is indicated, the affected worker should not suffer loss of wages, benefits, or seniority.\nThe employer should ensure that the pro gram director regularly collaborates with the employer's safety and health personnel (e.g. industrial hygienists) to identify and control work exposure and activities that pose a risk of adverse health effects.\n\n# Smoking Cessation\nSmoking should be prohibited in all areas of any workplaces in which workers are exposed to Cr(VI) compounds. As cigarette smoking is an important cause of lung cancer, NIOSH recommends that smoking be prohibited in the workplace and all workers who smoke par ticipate in a smoking cessation program. Em ployers are urged to establish smoking cessa tion programs that inform workers about the hazards of cigarette smoking and provide as sistance and encouragement for workers who want to quit smoking. These programs should be offered at no cost to the participants. Infor mation about the carcinogenic effects of smok ing should be disseminated. Activities prom ot ing physical fitness and other health lifestyle practices that affect respiratory and overall health should be encouraged through training, employee assistance programs, and/or health education campaigns.\n\n# Record Keeping\nEmployers should keep employee records on exposure and medical monitoring according to the requirements of 29 CFR 1910.20(d), Pres ervation of Records.\nAccurate records of all sampling and analysis of airborne Cr(VI) conducted in a workplace should be maintained by the employer for at least 30 years. These records should include the name of the worker being monitored; Social Security number; duties perform ed and job locations; dates and times of measurements; sampling and analytical methods used; type of personal protection used; and number, dura tion, and results of samples taken.\nAccurate records of all medical monitoring conducted in a workplace should be m ain tained by the employer for 30 years beyond the employee's termination of employment. Any half mask particulate air-purifying respirator with a N100*, R100, or P100 filter worn in combination with eye protection.\nIf chromyl chloride is present, any half mask air-purifying respirator with can isters providing organic vapor (OV) and acid gas (AG) protection with a N100, R100, or P100 filter worn in combination with eye protection.\nAny supplied-air respirator with loose-fitting hood or helmet operated in a continuous-flow mode; any powered air-purifying respirator (PAPR) with a HEPA filter with loose-fitting hood or helmet.\nIf chromyl chloride is present, any PAPR providing OV and AG protec tion with a HEPA filter with loose-fitting hood or helmet.\nAny full facepiece particulate air-purifying respirator with a N100, R100, or P100 filter; any PAPR with full facepiece and HEPA filter; any full facepiece supplied-air respirator operated in a continuous-flow mode.\nIf chromyl chloride is present, any full facepiece air-purifying respirator pro viding OV and AG protection with a N100, R100, or P100 filter; any full face piece PAPR providing OV and AG protection and a HEPA filter.\nAny supplied-air, pressure-demand respirator with full facepiece.\nAny self-contained breathing apparatus that is operated in a pressure-demand or other positive-pressure mode, or any supplied-air respirator with a full fa cepiece that is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained positive-pressure breathing apparatus.\nAny self-contained breathing apparatus that has a full facepiece and is oper ated in a pressure-demand or other positive-pressure mode.\nAny air-purifying, full-facepiece respirator with a N100, R100, or P100 filter or any appropriate escape-type, self-contained breathing apparatus.\nIf chromyl chloride is present, any full facepiece gas m ask (14G) with a canis ter providing OV and AG protection with a N100, R100, or P100 filter or any appropriate escape-type, self-contained breathing apparatus.\nAbbreviations: AG= acid gas; APF = assigned protection factor; Cr(VI) = hexavalent chrom ium ; HEPA = high efficiency particulate air; IDLH = im mediately dangerous to life or health; OV=organic vapor; PAPR = powered air-purifying respirator. fThe protection offered by a given respirator is contingent upon (1) the respirator user adhering to complete program requirem ents (such as those required by OSHA in 29 CFR 1910.134), ( 2) the use of NIOSH-certified respirators in their approved configuration, and (3) individual fit testing to rule out those respirators with tight-fitting facepieces that cannot achieve a good fit on individual workers. *N-100 series particulate filters should n o t be used in environm ents w here there is potential for exposure to oil mists.\n\n# INTRODUCTION History of Hexavalent Chromium Hazard\nChromium is commercially important in metallurgy, electroplating, and in diverse chemical ap plications such as pigments, biocides and strong oxidizing agents. Adverse health effects have long been known and include skin ulceration, perforated nasal septum, nasal bleeding, and conjuncti vitis. Reports of bronchogenic carcinoma appeared prior to World War II in Germany and were subsequently confirmed in multiple studies.1 The International Agency for Research on Cancer (IARC) declared in 1980 that chromium and certain of its compounds are carcinogenic and, in 1987, concluded that hexavalent chromium is a hum an carcinogen but that trivalent chromium was not yet classifiable. Recent studies updating chromium worker cohorts in Ohio2,3 and Marylandi demonstrated an excess lung cancer risk from exposure to hexavalent chromium.\n\n# Regulation of Chromium Exposures\nThe current Permissible Exposure Limit (PEL) of the U.S. O ccupational Safety and Health A dm inistration (ÜSHA) is 0.1 mg/m3 for soluble hexavalent chrom ium (as CrÜ3) as an 8 hour time-weighted average. 4 The American Conference of Governmental Industrial Hygienists has a similar recommendation.5 The U.S. National Institute for Occupational Safety and Health recom mends a limit of 0.001 m g/m 3 (as Cr).6 Due to continuing concerns over lung cancer risks from hexavalent chromium, OSHA is currently reviewing the distribution of chromium exposures in the U.S. workforce and the available estimates of excess risk.\n\n# Present Objective\nThe goal of this investigation was to evaluate various models of exposure-response for lung cancer mortality and exposure to hexavalent chromium compounds and then conduct a risk assessment for lung cancer based on these models. The cohort of chromate workers analyzed by Hayes et al.7 and later updated and modified by Gibb et al.1 was used for the analysis. In addition to a detailed retrospective exposure assessment for chromium, this cohort had smoking information and is be lieved to be largely free of other potentially confounding exposures from this plant. Using logtransformed cumulative exposure estimates within a proportional hazards regression model, Gibb et al. observed the rate of lung cancer mortality in these chromate workers to increase by a factor of 1.38 for each 10-fold increase in cumulative exposure to hexavalent chromium (p=0.0001).i\n\n# METHODS\nThe description of the cohort can be found in Gibb et al. and comprised 2372men hired between August 1, 1950and December 31, 1974 at a plant in Baltimore, MD.1,7 Fifteen workers lost to followup were excluded, leaving 2357 subjects for analysis. Followup began with date of hire and con tinued until December 31, 1992 or the date of death, whichever occurred first. The cohort consisted of 1205 men known to be white (51%), 848 known to be nonwhite (36%)-believed to be mostly African Americans-and 304 with unknown race (13%). The mean duration of employment was 3.1 yr., but the median was 0.39 yr. Some smoking information was available at hire for 91% of the study population, including smoking level in packs per day for 70%. For those of unknown smok ing status (9%), average levels were assigned; for known cigarette smokers with unknown cigarette usage (21%), the average level among known smokers was assigned. Cumulative smoking expo sure, as packs/day-years, was calculated assuming workers smoked from age 18 until the end of followup, and using a 5 year lag (same as for chromium exposure).\n\n# Chromium Exposure History\nThis chromate manufacturing facility began operation in 1845 and continued until 1985. Because of facility and process changes and the limited availability of detailed early air sampling data, the study population was restricted to those who worked in the \"new\" plant and were hired between August 1, 1950 andDecember 31, 1974. A detailed retrospective exposure assessment was con ducted for this populationi using contemporaneous exposure measurements. During 1950-61, short-term personal samples were collected using high volume pumps. From 1961 until 1985 ap proximately 70,000 systematic area air samples were collected at 154 fixed sites (27 sites after 1977). Based on these air samples and recorded observations of the fraction of time spent in these exposure zones by each job title, the employer calculated exposures by job title. After 1977, fullshift personal samples were collected as well. Hexavalent chromium concentrations (as CrÜ3) were based on laboratory determinations of water-soluble chromate perform ed by the employer; results of the area sampling/time-in-zone system of calculating exposures were adjusted to the personal sample results. Exposure histories were then calculated for each worker based on the jobs held (defined by dates) and corresponding hexavalent chromium exposure estimate for that job title and time period. Total cumulative exposures to hexavalent chromium averaged 0.134 m g/m 3-yr, with a maximum value of 5.3 mg/m3-yr.1\n\n# Mortality Analyses\nA classification table for Poisson Regression analysis was calculated using a FORTRAN program developed previously8 which classified followup in 16 age (<20, 20-24, 25-29, 30-34,... , 85+), 9 calendar (1950-54, 1955-59,...1990-94), and three race categories (0=nonwhite, 1=white, 2= unknown), together with 50 levels of time-dependent cumulative hexavalent chromium exposure and 10 levels of time-dependent cumulative smoking exposure and employment duration. The 50 intervals of cumulative exposure were defined to be narrower at the low exposure end compared to the high end because observation time was concentrated at the low end. Although classified in dis crete levels, cumulative exposures for chromium and smoking were entered into regression models as a continuous variable defined by the person-year weighted mean values of cumulative exposure in each of the classification strata. Cumulative exposure is a standard metric used in modeling car cinogenic risk in human populations. The unit of followup in this procedure was 30 days, i.e., every 30-day interval of a worker's observed person-time (and lung cancer death outcome) was classified as described above. To address latency, different lag periods were used and, for some analyses, cu mulative exposures were calculated in three time periods: 5-9.99, 10-19.99, 20 or more years prior to observation.\nRelative rate models of the following forms (1a-1f) were evaluated for the effect of cumulative chromium exposure on lung cancer mortality: where, â0 (intercept), â, â1, and â2 are parameters to be estimated.\n\n# Log-linear models\nExternal standardization on age, race and calendar time was accomplished using U.S. rates for lung cancer mortality during 1950-1994 9 as a multiplier of person-years. This approach makes use of well-known population rates and yields models of standardized rate ratios in which the intercept is an estimate of the (log) standardized mortality ratio (SMR) for workers without chromium or smoking exposures. The m ethod permits departures from the reference rates by including explicit terms (e.g., age or race) in the model, and it enables internal comparisons on exposure. Those with unknown race (n=304) were assigned a composite expected rate as a weighted average of the exter nal race-specific rates based on the distribution of race in their year of hire.\nPoisson regression models were fit using Epicure software.10 Descriptive categorical analyses for chromium exposure-response were conducted using five levels of cumulative exposure defined to produce equal numbers of lung cancer cases in the upper levels for both races combined. The lowest category encompassed the most observation time and observed deaths because of the large num ber of short duration employees in this study population (median duration: 4.7 mos.). Files were also constructed for Cox proportional hazards models with continuous cumulative exposures and risk sets based on the attained age of the lung cancer case at death. Results using Cox propor tional hazard analyses were similar to the Poisson analyses and are not shown.\nThe models with the largest decrease in deviance (i.e., decrease in -2log (likelihood) with addi tion of exposure terms) were considered to be the \"best\" fitting. The adequacy of the parametric forms for exposure and for smoking duration in these models was also investigated by fitting cubic splines11. The spline models were fit as generalized additive models with three degrees of freedom for the effect of exposure using S-Plus, version 4.5. 12 Unlagged and lagged cumulative exposures were considered. Models with exposures lagged by 5 yrs or 10 yrs provided statistically equivalent fits to the data (based on minimizing the deviance) which were better than that obtained with the unlagged model; a 5 yr lag was chosen to conform to previ ous analyses of this cohort.1 The cumulative smoking variable was included in the log-linear or linear terms of different models. However, in estimating the chromium effect for calculating excess lifetime risk, the smoking variable was placed in the loglinear term in order to produce a chromium risk esti mate relative to an unexposed population without regard to smoking status. Finally, to better model the smoking exposure-response, a piece-wise linear spline was used with a knot chosen at 30 packs/ day-yrs). This choice was motivated by a cubic spline analysis of the smoking effect exhibiting a pla teau above 30 pack-years. The final model chosen for estimating excess lifetime lung cancer risk had the following form, consisting of the product of \"loglinear\" and \"linear\" terms:\nRate = x where: Ind() are indicators of race (white or unknown), Smk1 and Smk2 are variables speci fied for the piece-wise linear terms on cumulative smoking, and CumCr6 is cumulative hexavalent chromium exposure.\n\n# Estimation of Working Lifetime Risks\nExcess lifetime risk of death from lung cancer was estimated for a range of chromium air concen trations using an actuarial m ethod that accounts for competing risks and was originally developed for a risk analysis of radon.13 Excess lifetime risk was estimated by first applying cause-specific rates from an exposure-response model to obtain lifetime risk, and then subtracting the same expression with exposures set to zero:\nExcess lifetime risk = Zi { x S(X,i) x } -Zi { x S(0,i) x \nwhere R+i (X)= all cause age-specific m ortality rate for exposed population; qi = Pr(death in year i given alive at the start of year i); and S(X,i) = (1-q1) x (1-q2) x ... x (1-qi 1), probability of survival to year i For specified hexavalent chromium concentrations, excess lifetime risks were estimated making the assumption that workers were occupationally exposed to constant concentrations between the ages of 20 and 65, or 45 years (less if dying before age 65). Annual excess risks were accumulated up to age 85; risk among those surviving past age 85 was not calculated because of small numbers and unstable rates. Rate ratios for lung cancer mortality corresponding to work at various chromium concentrations were derived from the final linear relative rate Poisson regression model. Agespecific all-cause death rates came from a life table for the U.S. population.14\n\n# RESULTS\n\n# Lung Cancer Mortality\nLung cancer was the underlying cause for 122 deaths in the chromate cohort. Fitting a Poisson regression model with indicator terms for race produced similar lung cancer SMRs for white (SMR=1.85, 95%CI=1.45-2.31) and nonwhite (SMR=1.87, 95%CI=1.39-2.46) workers that were close to those reported by Gibb et al. (1.86,1.88, respectively, using different reference rates).i\nResults from fitting models with five categorical chromium exposure levels and unadjusted for smoking reveal a clear upward trend for the lung cancer SMR with cumulative chromium exposure but the trends differed by race (Table 1). The same patterns were observed using internally stan dardized rate ratios (SRRs, Table 1). The nonwhite workers exhibited a strong overall increasing trend of lung cancer risk except for a deficit in the 2nd exposure category (based on two deaths). The white workers exhibited an erratic exposure-response relationship, with elevated risks in the 1st, 2nd and 5th categories, but a declining trend across the 2nd, 3rd and 4th categories.\nInitially several specifications of exposure-response were examined within the family of log-linear models: 1a-1d above. Models with linear, square root, quadratic and log-transformed representa tions of cumulative chromium exposure performed about the same (Table 2, models 1-3,4.1) but a model in which smoking cumulative exposure was log-transformed performed considerably bet ter (Table 2, model 4.2). Use of a piece-wise linear specification for smoking exposure resulted in further improvement (Table 2 , model 4.3). For a saturated model containing both the logtransform ed and piece-wise linear smoking terms, the model deviance was almost identical to that with the piece-wise term s alone (1931.39 vs. 1931.57). Cubic splines applied to cumulative chromium exposure in log-linear models did not detect significant smooth departures from any of the specified models.\n(X2=10.6, p=0.001) (Table 4, m odel 1 vs. 2). This interaction was observed w hether age, race and calendar tim e were adjusted by stratification (internal adjustm ent) or by using external population rates. The chromium exposure-response for white men was diminished with the in teraction (RR=1.18, 95% CI=0.43-1.92, for 1 mg/m3-yr cumulative exposure) but an overall lung cancer excess remained for that group.\nCumulative smoking was used in the final models despite absence of detailed smoking histories because, in comparison with models using a simple categorical classification (smoking at hire: yes, no, unknown), the models using cumulative smoking fit better. The changes in -2ln(Likelihood) for the cumulative smoking piece-wise linear terms versus the categorical terms (both with two degrees of freedom) were 28.42 and 25.83 respectively in the final model.\nA significant departure of the estimated background rate (for unexposed workers) from the U.S. reference rate was observed with age and with race, but not with calendar time. The age effect corre sponded to a reduction of 8-10% (RR=0.92, 0.90) for each 5 yr. of age (Table 4, models 1, 2 respec tively). W hen chromium cumulative exposure was partitioned into three distinct latency intervals (5-9.99,10-19.99, 20 or more yrs), there was no improvement in fit, and the chromium exposure interaction with race remained.\n\n# Estimates of Excess Lifetime Risk\nEstimates of excess lifetime mortality from lung cancer resulting from up to 45 years of chromium exposure at concentrations 0.001-0.10 mg/m3 were calculated based on the preferred model with out the chromium-race interaction (Table 4, model 1). At 0.10 mg/m3 (the current OSHA standard for total hexavalent chromium as CrO3), 45 years of exposure corresponds to a cumulative expo sure of 4.5 mg/m3-yr and a predicted lifetime excess risk for lung cancer mortality of 255 per thou sand workers (95% CI: 109-416) (Table 5). At 0.01 mg/m3, one tenth of the current standard, 45 years of exposure corresponds to a lifetime excess risk of 31 per thousand workers (95% CI: 12-59). W hen the alternate log-linear model (Table 2, model 4.3) was used, the estimates of lifetime excess risk for lung cancer mortality were very similar (Table 5).\n\n# DISCUSSION Model Choice\nAfter consideration of a variety of log-linear and additive relative rate forms for modeling both smoking and chromium effects, a linear relative rate model with highly statistically significant ex posure effects was selected to describe the lung cancer-chromium exposure response and for cal culating excess lifetime risk. An equivalently fitting power model produced a slightly larger but less precise estimate of lifetime risk at the current PEL. The current findings are consistent with but not directly comparable to the results of Gibb et al. in the same population/ Gibb et al. used a log trans formation of cumulative exposure: ln(cumX+d), where d was the smallest measured background exposure in the study (d=1.4x10-6 mg/m3-yr). That metric was then used in a log-linear Cox regres sion model to estimate exposure-response.\nExtensive and systematic historical environmental air-sampling data were available covering the entire period of employment for this study population. Over 70,000 measurements collected be tween 1950 and 1985 were available for the exposure assessment.1 These measurements were taken with the objective of characterizing typical rather than highest exposure scenarios, the latter being more commonly measured in industrial settings. The extent and quality of the exposure data are unique among chromium exposed populations and far exceed what is typically available for his torical cohort studies of occupational groups. Although the exposure information in this study has clear advantages over previous studies of chromium workers, it also has its limitations including a lack of information on particle size and also on variability of exposures of individual workers hav ing the same job title. Nonetheless, the measurement methodology used in the exposure surveys was generally consistent with what has been required by OSHA.\n\n# Potential Confounding\nAlthough asbestos was identified as a potential exposure in this cohort, we do not believe that it is likely to have been an important confounder in this investigation. As in most plants of this pe riod, asbestos was widely used and might have resulted in exposures among part of the workforce, particularly among skilled trades and maintenance workers (e.g., pipefitters, steamfitters, furnace or kiln repair and laborers). Asbestos exposure would not be expected to be generally correlated with chromium exposure in this population and thus should not have biased the internal exposureresponse analysis. Furthermore, no cases of mesothelioma were reported.\nAlthough cigarette smoking was controlled for in this analysis, there is a possibility of residual confounding by smoking because of the crudeness of the smoking data which pertained only to the time of hire. However, this was considerably more smoking information than is usually found in occupational studies. Furthermore, for smoking to have been a strong confounder in this analysis, its intensity (packs per day) would have needed to vary by level of hexavalent chromium exposure concentration. O ur assumption that smokers started at 18 years of age and continued until the end of follow-up permitted the estimation of a time-dependent smoking cumulative exposure. A piece wise linear fitting of smoking cumulative exposure considerably improved model fit. It also indi cated that cumulative smoking greater than 30 pack-years, where smoking misclassification would be greater due to unknown lifetime smoking history, was not a significant predictor of further increased risk (Tables 2-4). Observing a plateau in the smoking cumulative exposure response was consistent with the pattern observed in previous studies of smoking.16 W hen smoking was modeled using the piece-wise linear terms, the parameter estimate of the chromium affect was increased by 10 percent, compared with use of the categorical specification for smoking.\n\n# Exposure-Race Interaction\nAs indicated above, an exposure-race interaction was observed in our analyses. Because the source of this interaction is unknown, we chose not to include an interaction term in the final risk assess ment model. Discussion in the scientific literature of differential cancer rates and risks by race, focuses almost exclusively on socioeconomic, occupational and life-style risk factor differences Exposure Assessment and diagnostic bias. 17 We are not aware of examples establishing that occupational lung cancer susceptibility varies between African-Americans (majority of the nonwhite study population) and white Americans, and thus, in our opinion, it is unlikely that the chromium-race interaction that we observed has a biological basis. More plausible explanations include, but are not limited to: mis classification of smoking status, misclassification of chromium exposures, or chance. We have no evidence to support any of these explanations, however, and we believe that the exposure-response relationship derived for the entire study population provides the best basis for predicting risk.\n\n# Excess Lifetime Risk and Prior Risk Assessments\nOur analysis predicts, based on the preferred model (Table 4, Model 1), that workers exposed at the current OSHA PEL of 0.1 m g/m 3 for 45 years will have approximately 25% excess risk of dying from lung cancer due to their exposure. Very few workers in this study had cumulative exposures cor responding to 45 years at the PEL, and thus our estimates of risk are based on an upward extrapola tion from most of the data (less than 2% of person-years but 10% of lung cancer deaths occurred with cumulative exposures greater than 1.0 mg/m3-yr (Table 1)). However, even workers exposed at one tenth of the PEL (i.e., to 0.01 m g/m 3) would experience 3% excess deaths (Table 5).\nThere have been several other risk assessments for hexavalent chromium exposure and lung can cer, and it is informative to compare the predictions from these assessments with those from this investigation. In a 1995 review that included an earlier assessment of this cohort and the Mancuso study2, OSHA identified point estimates of lifetime risk at the current PEL (0.1 mg/m3) in the range of 88 to 342 per thousand.18 Conversion' of a U.S. Environmental Protection Agency risk as-sessment19 for ambient chromium exposures based on the Mancuso study, to predict occupational risks, produces estimated lifetime risks of 90 per thousand for 45 years of exposure to 0.1 mg/ m3. The State of California EPA published a risk assessment based on best estimates also from the Mancuso study with different assumptions about chromium exposures which, when converted for occupational exposures, result in a predicted lifetime occupational risk of 90 to 591 per thousand for exposure at the PEL.20 Thus the predicted occupational risks for lifetime exposure to the current OSHA PEL developed from these previous risk assessments, which ranged from 88 to 591 per 1000 workers, are quite consistent and bracket the estimate presented in this paper of 255 per 1000 work ers. Thus the estimates of risk for 45 years of exposure at the current OSHA PEL from previous risk assessments are all within a factor of 3 of the estimates provided in this paper, which is reasonably consistent given the uncertainties involved in the risk assessment process.\n\n# CONCLUSION\nThis study clearly identifies a linear trend of increasing risk of lung cancer mortality with increasing cumulative exposure to water-soluble hexavalent chromium. O ur analysis predicts that exposure"}}},{"rowIdx":89,"cells":{"id":{"kind":"string","value":"214aec5355b6d9cda5a9e03f854dbb3b04e40600"},"source":{"kind":"string","value":"nice"},"text":{"kind":"string","value":"Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion\n\n# Guidance \nRanibizumab is recommended as an option for treating visual impairment caused by macular oedema:\nfollowing central retinal vein occlusion or\nfollowing branch retinal vein occlusion only if treatment with laser photocoagulation has not been beneficial, or when laser photocoagulation is not suitable because of the extent of macular haemorrhage and\n-nly if the manufacturer provides ranibizumab with the discount agreed in the patient access scheme revised in the context of NICE technology appraisal guidance 274.\nPeople currently receiving ranibizumab whose disease does not meet the criteria in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.# The technology \nRanibizumab (Lucentis, Novartis) belongs to a class of drugs that block the action of vascular endothelial growth factor (VEGF)‑A. Retinal vein occlusion (RVO) is a common cause of reduced vision as a result of retinal vascular disease. Thrombosis in the retinal veins causes an increase in retinal capillary pressure, resulting in increased capillary permeability and the discharge of blood and plasma into the retina. This leads to macular oedema and varying levels of ischaemia through reduced perfusion of capillaries. These changes trigger an increase in VEGF, which increases vascular permeability and new vessel proliferation. By inhibiting the action of VEGF‑A, ranibizumab reduces oedema and limits visual loss or improves vision. Ranibizumab has a UK marketing authorisation for 'the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO)'.\nThe summary of product characteristics states that treatment should be given monthly and continued until maximum visual acuity is reached – that is, until visual acuity has been stable for 3 consecutive months. Thereafter, visual acuity should be monitored monthly. Treatment should be resumed if monitoring indicates a loss of visual acuity caused by macular oedema secondary to RVO, and continued until visual acuity has remained stable for 3 consecutive months. The interval between doses should not be shorter than 1 month. If there is no improvement in visual acuity over the course of the first 3 injections, continued treatment is not recommended.\nContraindications to ranibizumab include known hypersensitivity to the active substance or to any of its excipients, active or suspected ocular or periocular infections, and active severe intraocular inflammation. Adverse reactions to treatment are mostly limited to the eye. Those commonly reported in clinical trials include vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, sensation of a foreign body in the eye, increased production of tears, blepharitis, dry eye, ocular hyperaemia, itching of the eye and increased intraocular pressure. Nasopharyngitis, arthralgia and headaches are also commonly reported. For full details of adverse reactions and contraindications, see the summary of product characteristics.\nRanibizumab is administered as a single 0.5 mg intravitreal injection. Each vial of ranibizumab contains 2.3 mg in 0.23 ml; overfilling is considered necessary to achieve an injectable dose of 0.5 mg. The list price of ranibizumab is £742.17 per vial (excluding VAT; 'British national formulary' edition 64). The manufacturer of ranibizumab (Novartis) has agreed a patient access scheme with the Department of Health, revised in the context of technology appraisal guidance 274, which makes ranibizumab available with a discount applied to all invoices. The level of the discount is commercial‑in‑confidence (see section 5.3). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The manufacturer has agreed that the patient access scheme will remain in place until any review of this technology by NICE is published.# The manufacturer's submission\nThe Appraisal Committee (section 9) considered evidence submitted by the manufacturer of ranibizumab and a review of this submission by the Evidence Review Group (ERG; section 10).\nThe manufacturer submitted evidence of clinical and cost effectiveness for ranibizumab compared with grid laser photocoagulation in people with visual impairment caused by macular oedema secondary to branch retinal vein occlusion (BRVO) and for ranibizumab compared with best supportive care in people with visual impairment caused by macular oedema secondary to central retinal vein occlusion (CRVO). The manufacturer stated that there was no direct or indirect evidence comparing the clinical effectiveness of ranibizumab with bevacizumab or dexamethasone intravitreal implant (which were defined as comparators in the scope for the appraisal). However, a comparison of the cost effectiveness of ranibizumab with dexamethasone intravitreal implant was included in the manufacturer's submission; this was not the case for bevacizumab (see sections 3.9 and 3.10).\nThe main sources of evidence presented in the manufacturer's submission came from the BRAVO and CRUISE randomised controlled trials (RCTs). These evaluated the efficacy of ranibizumab, compared with a sham procedure, for treating visual impairment caused by macular oedema secondary to BRVO and to CRVO respectively. The BRAVO (n=397) and CRUISE (n=392) trials were both 3‑armed RCTs carried out at multiple centres in the USA. Patients were randomised equally to sham injection, monthly intraocular ranibizumab 0.3 mg or monthly intraocular ranibizumab 0.5 mg. Both trials included people with visual impairment caused by macular oedema who had been diagnosed in the 12 months before study initiation. Patients entered a 6‑month treatment phase during which monthly injections were given, beginning on day 0. In the treatment phase of BRAVO, patients in both the sham injection and ranibizumab groups could receive grid laser photocoagulation for rescue treatment from 3 months. In both BRAVO and CRUISE, the treatment phase was followed by a 6‑month observation phase during which all groups (that is, the sham group and the 2 ranibizumab groups) could receive ranibizumab as needed. Patients in the observation phase of BRAVO (but not CRUISE) could receive grid laser photocoagulation for rescue treatment from 3 months (that is, at month 9 of the study). The final treatment in both BRAVO and CRUISE was given at month 11, with a final study visit at month 12. Patients who completed the 12‑month BRAVO and CRUISE trials could enter an open‑label extension study (HORIZON).\nThe primary outcome in both BRAVO and CRUISE was the mean change from baseline in best corrected visual acuity (BCVA) score in the study eye at 6 months. BCVA score was measured using the Early Treatment of Diabetic Retinopathy Study (ETDRS) eye chart, in which a score of 85 letters corresponds to normal visual acuity ('20/20 vision'). Secondary outcomes reported in both BRAVO and CRUISE included mean change from baseline in BCVA score over time up to 6 and 12 months, and the proportion of patients gaining or losing more than 15 letters in BCVA score at 6 and 12 months compared with baseline. The trials also reported results for several exploratory outcomes, including the mean change from baseline in the National Eye Institute Visual Function Questionnaire‑25 (NEI VFQ‑25) composite score up to 6 months. The NEI VFQ‑25 has 25 questions that are designed to measure the effect of visual impairment on daily functioning and quality of life.\nThis appraisal considered the 0.5 mg dose of ranibizumab, which is the only dose with a UK marketing authorisation. In BRAVO, 91.7% of patients in the sham group and 95.4% in the ranibizumab group were treated in the 'worse‑seeing eye' (that is, the eye affected by RVO). In CRUISE, 90.0% of patients in the sham group and 92.3% in the ranibizumab group were treated in their 'worse‑seeing eye'. The mean number of ranibizumab injections in the treatment phase was 5.7 (BRAVO) and 5.6 (CRUISE). The average number of ranibizumab injections in the observation phase was 2.7 (BRAVO) and 3.3 (CRUISE). More than 80% of patients from the sham injection group in both BRAVO and CRUISE received ranibizumab as needed during the observation phase. During the first 6 months of the BRAVO trial, grid laser photocoagulation was used in 57.6% of patients in the sham injection group and in 21.4% of the patients in the ranibizumab group. Over the 12‑month study period in BRAVO, 61.4% of patients in the sham (plus ranibizumab) group and 34.4% of patients in the ranibizumab group received rescue treatment with grid laser photocoagulation.\nIn BRAVO, at month 6, patients in the ranibizumab group had gained an average of 18.3 letters (95% confidence interval 16.0 to 20.6) from baseline BCVA score. This gain was statistically significant compared with the gain of 7.3 letters (95% CI 5.1 to 9.5) in the group receiving sham injection (p<0.0001). At month 12 of the BRAVO trial (that is, at the end of the 6‑month observation period, during which all patients could receive ranibizumab as needed), the 0.5 mg ranibizumab group reported an average gain in BCVA baseline score of 18.3 letters (95% CI 15.8 to 20.9) compared with the sham (plus ranibizumab) group, which had gained 12.1 letters (95% CI 9.6 to 14.6, p<0.01). The observed improvement at month 6 from baseline in the NEI VFQ‑25 composite score was statistically significantly greater in patients receiving ranibizumab (10.4 points, 95% CI 8.3 to 12.4) than in patients receiving sham injection (5.4 points, 95% CI 3.6 to 7.3; p<0.005). The manufacturer reported that overall the BRAVO trial showed a clinically meaningful and statistically significant effect of ranibizumab on visual acuity and patient‑reported outcomes based on the NEI VFQ‑25 at 6 months. The manufacturer carried out a post‑hoc analysis stratified by rescue treatment with grid laser photocoagulation to investigate the effects of adding this treatment to ranibizumab. The manufacturer concluded that treating patients with grid laser photocoagulation as well as ranibizumab did not lead to the efficacy of ranibizumab being overestimated.\nAt month 6 in the CRUISE trial, patients in the ranibizumab group achieved a statistically significant mean gain in BCVA score from baseline of 14.9 letters (95% CI 12.6 to 17.2) compared with the sham group, who gained 0.8 letters (95% CI −2.0 to 3.6, p<0.0001). The manufacturer reported that the improvements in BCVA in the ranibizumab group at month 6 were generally maintained through to month 12 with treatment as needed (13.9 letters for ranibizumab; 7.3 letters for sham group; p<0.001). Patients receiving ranibizumab 0.5 mg showed statistically significantly greater improvements in patient‑reported outcomes as measured by the NEI VFQ‑25 (6.2 points, 95% CI 4.3 to 8.0) than patients receiving sham injection (2.8 points, 95% CI 0.8 to 4.7; p<0.05).\nFor patients who entered the open‑label extension study (HORIZON), ranibizumab 0.5 mg was given at intervals of at least 30 days. Sixty‑seven per cent of patients from BRAVO and 60% of patients from CRUISE completed month 12 of HORIZON. The primary outcome for the HORIZON extension study was mean change from HORIZON baseline in BCVA score up to 24 months. The manufacturer presented results from the first 12 months. From the BRAVO trial baseline, patients receiving sham (plus ranibizumab) and those receiving 0.5 mg ranibizumab had mean gains in BCVA score of 15.6 letters and 17.5 letters respectively. From the CRUISE trial baseline, patients receiving sham (plus ranibizumab) and those receiving 0.5 mg ranibizumab had mean gains in BCVA score of 7.6 and 12.0 letters respectively (no confidence intervals reported).\nAdverse events were reported at 6 months and 12 months in both BRAVO and CRUISE trials, and for a further 12 months' follow‑up in the HORIZON extension study. In BRAVO, at 6 months there were 7 ocular adverse events (5.4%) in the ranibizumab group compared with 17 (13%) in the sham group, excluding occurrences of raised intraocular pressure. Non‑ocular serious adverse events (potentially related to vascular endothelial growth factor inhibition) at 6 months were higher in the ranibizumab group (5 events ) than in the sham group (1 event ). In CRUISE, at 6 months there were 13 ocular adverse events (10.1%) in the ranibizumab group compared with 25 (19.4%) in the sham group, excluding occurrences of raised intraocular pressure. In CRUISE, non‑ocular serious adverse events (potentially related to VEGF inhibition) were similar in both the ranibizumab and sham groups (3 and 2 respectively). The most common adverse event reported in BRAVO and CRUISE at 12 months was cataract, with 8 (6.2%) and 9 (7%) instances associated with ranibizumab treatment respectively; in the sham (plus ranibizumab) group, 3 (2.6%) and 2 (1.8%) instances of cataract were reported for the treatment period of 6 to 12 months. Instances of raised intraocular pressure were reported in both BRAVO and CRUISE at 6 months but were academic in confidence, and therefore not reported here. In the HORIZON extension study, the incidence of any adverse event in the sham (plus ranibizumab) and ranibizumab groups was 2.2% and 5.8% respectively for the patients (with BRVO) recruited from BRAVO, 5.2% and 3% respectively for the patients (with CRVO) recruited from CRUISE.\nA systematic review was undertaken to identify RCTs involving potential comparators for ranibizumab in the treatment of visual impairment caused by macular oedema secondary to RVO. The manufacturer discussed the feasibility of conducting a formal indirect comparison of ranibizumab with dexamethasone intravitreal implant or bevacizumab in CRVO, and an indirect comparison of ranibizumab with dexamethasone intravitreal implant, bevacizumab or grid laser photocoagulation in BRVO. For a comparison of ranibizumab and bevacizumab in CRVO, the manufacturer identified a study by Faghihi et al. (2008) but stated that there was not enough information about the baseline characteristics of patients in the study. For a comparison with bevacizumab in BRVO, studies by Moradian et al. (2011) and Russo et al. (2009) were identified. The manufacturer stated that an indirect comparison could not be conducted without bias because the length of time since diagnosis of macular oedema differed in Moradian et al. (2011) and BRAVO, and because the trial duration was different in all 3 studies. The manufacturer also considered that bevacizumab was not an appropriate comparator because it did not consider that its use in the NHS was routine or best practice. The manufacturer stated that an indirect comparison of ranibizumab and dexamethasone intravitreal implant could not be undertaken for CRVO or BRVO because of the population differences in trials involving these 2 treatments: patients had different lengths of time since diagnosis of macular oedema, different baseline ranges of BCVA and different retinal thickness in the BRAVO and CRUISE trials compared with the GENEVA studies (which compared dexamethasone with sham injection). The manufacturer also stated that ranibizumab could not be compared indirectly with grid laser photocoagulation because of fundamental differences in trial design between BRAVO, which was sham‑injection‑controlled, and the laser studies BVOS (1984) and Battaglia et al. (1999), which were not.\nAlthough no formal indirect comparison of ranibizumab with other drug treatments was performed, the relative systemic safety profiles of ranibizumab and bevacizumab were discussed in the manufacturer's submission. The manufacturer stated that ranibizumab was associated with a better safety profile than bevacizumab. The manufacturer provided data from 3 large retrospective studies by Carneiro et al. (2011), Curtis et al. (2010) and Gower et al. (2011) in support of this statement, but these studies compared bevacizumab with ranibizumab for the treatment of age‑related macular degeneration (AMD) rather than RVO. The manufacturer acknowledged that AMD manifests later in life than RVO, and so the average age of patients in the BRAVO and CRUISE trials was lower than in the studies of AMD.\nFor evidence of cost effectiveness, the manufacturer submitted a Markov state transition model comparing treatment with ranibizumab with grid laser photocoagulation (standard care) for visual impairment caused by macular oedema secondary to BRVO and with best supportive care for CRVO. Treatment was modelled over a 15‑year time horizon for a hypothetical cohort of 1000 patients with visual impairment because of macular oedema secondary to RVO, with a starting age of around 66 years. Eight BCVA health states and death are included in the model structure, with each health state having an associated utility and mortality risk depending on whether the 'better‑seeing eye' or 'worse‑seeing eye' is treated. In the manufacturer's base‑case analysis, it was assumed that all patients are treated in their 'better‑seeing eye'. People move through the model in monthly cycles, accumulating the utility associated with each health state they enter, together with the costs of treatment and subsequent monitoring. Additional costs and disutility associated with blindness were applied for people with a visual acuity equal to or less than 35 letters in the 'better‑seeing eye'. The model assumed that a person's risk of mortality would increase with worsening visual acuity in the 'better‑seeing eye'. A published study by Christ et al. (2008) was used to provide the risk levels by ETDRS bands. The manufacturer asserted that mortality associated with RVO would not be expected to result in any additional risk of mortality over and above that of the general population and as a consequence, the model did not include an assumption of excess mortality associated with RVO.\nTransition probabilities were determined monthly and subsequently used to calculate overall monthly transition probabilities for months 0 to 1, months 2 to 6 and months 7 to 12. For CRVO, the probabilities derived from the sham group of the CRUISE trial for months 2 to 6 were applied to months 2 to 6, 7 to 12 and 13 to 24 in the best supportive care arm of the model. The manufacturer stated that this was because there were no comparative data beyond month 6; from this point in the trial treatment with ranibizumab could be given to people in either arm as needed. Similarly for BRVO, no comparative data existed beyond month 6. However, this was further complicated by the use of grid laser photocoagulation as a rescue treatment in both arms of the trial beyond month 3. Therefore the probabilities for months 7 to 12 were pooled from the sham and ranibizumab groups of BRAVO and applied to months 7 to 12 and months 13 to 24 in both arms of the model. Dexamethasone intravitreal implant was incorporated into the model by a combination of applying relative risks from 2 trials (GENEVA studies) and assigning probabilities observed in the control groups of the BRAVO and CRUISE trials.\nThe manufacturer conducted a systematic review of the literature to identify utility values for populations with visual impairment because of RVO, with priority given to populations with macular oedema secondary to BRVO or CRVO. From the results of this review, the manufacturer chose a study by Brown (1999) as the source of utilities for the model, stating that this was the only relevant study that reported utility values related to visual acuity. This is a US study assessing preferences for different levels of visual acuity in patients with vision loss from various causes, 7% of whom had RVO. The manufacturer's model applies different utility values to each BCVA health state, depending on whether the 'better‑seeing eye' or 'worse‑seeing eye' is treated. Although separate utility values for visual acuity in the 'better‑seeing eye' and 'worse‑seeing eye' were available from the study by Brown, the manufacturer stated that there was little difference between the worst and best health states for people treated in their 'worse‑seeing eye' and therefore assumed a value of 0.85 for all BCVA health states for people treated in the 'worse‑seeing eye' (that is, no gain from treatment). In addition, the base‑case model assumed all people would be treated in their best‑seeing eye and therefore this issue of utility gain for people treated in their 'worse‑seeing eye' was not relevant to the base case. For people treated in their 'best‑seeing eye' the maximum utility gain from treatment was 0.41 (that is, the difference between the best visual health state of 0.92 and the worst visual health state of 0.51). Utilities were not adjusted for age.\nCosts included intervention and comparator costs, administration costs and follow‑up visits. Grid laser photocoagulation (BRVO only) was assumed to incur no cost but an administration cost as an outpatient procedure was applied. The ranibizumab injection administration visit was costed as an office‑based outpatient procedure, whereas the dexamethasone intravitreal implant injection was based on a weighted average of the cost of an outpatient procedure (25%) and day case procedure (75%) to account for its greater complexity. For ranibizumab, the frequency of injections was taken from the BRAVO and CRUISE trials. In addition, patients experiencing adverse events had an associated cost applied, and patients considered to be blind had the additional costs associated with blindness.\nAll of the manufacturer's base‑case incremental cost‑effectiveness ratios (ICERs) that were presented included an approved patient access scheme, which was offered by the manufacturer at the time of submission (and which was subsequently superseded). In the base case for BRVO, the ICER for ranibizumab compared with grid laser photocoagulation was £20,494 per quality‑adjusted life year (QALY) gained. In the base case for CRVO, the ICER for ranibizumab compared with best supportive care was £8643 per QALY gained. The base‑case ICERs for ranibizumab compared with dexamethasone for BRVO and CRVO were £5486 and £7174 per QALY gained respectively. Incremental costs and QALYs for the base‑case results were commercial in confidence and therefore cannot be presented here.\nThe manufacturer performed a deterministic sensitivity analysis and found the model to be sensitive to the frequency of injections and follow‑up visits. The manufacturer performed scenario analyses to assess the impact of varying the proportion of people treated in their 'worse‑seeing eye' and commented that this was a key driver of cost effectiveness. The manufacturer also presented probabilistic sensitivity analyses and concluded that the probability that ranibizumab was cost effective when compared with grid laser photocoagulation in BRVO was 45.5% and 57.2% at thresholds of £20,000 and £30,000 per QALY gained respectively. For ranibizumab compared with best supportive care in CRVO, the probability of cost effectiveness was estimated by the manufacturer to be 74.5% and 83.3% at thresholds of £20,000 and £30,000 per QALY gained respectively.\n\n# Evidence Review Group comments on the manufacturer's submission\nThe ERG noted that most patients with retinal ischaemia were excluded from the BRAVO and CRUISE trials, because one of the exclusion criteria was brisk afferent pupillary defect, which, as the manufacturer stated, equates to severe retinal ischaemia. Therefore, the ERG considered that the results of any analyses could only be applied to people without retinal ischaemia.\nThe ERG considered that the concomitant use of grid laser photocoagulation from month 3 confounded the results of the BRAVO study and that definite conclusions could not be drawn about the effects of ranibizumab compared with sham injection or grid laser photocoagulation alone. The ERG noted that there was not enough evidence to conclude that grid laser photocoagulation had no effect in the ranibizumab group. It also noted that the treatment period of the BRAVO trial was not long enough to capture any benefits of grid laser photocoagulation on patient outcomes, which may last longer than 3 years. Furthermore, clinical advice to the ERG suggested that ranibizumab and grid laser photocoagulation would not be used together to treat patients in clinical practice.\nThe ERG noted that from month 6 onwards people were allowed to have ranibizumab as needed and therefore considered the data up to month 6 to be the most relevant data for determining the comparative effectiveness of ranibizumab in treating visual impairment caused by macular oedema secondary to RVO. However, the ERG noted that this period may not be long enough to determine the long‑term effects of ranibizumab.\nThe ERG questioned the manufacturer's view that an indirect estimate of the efficacy of ranibizumab compared with bevacizumab, dexamethasone and grid laser photocoagulation (for BRVO only) was not possible. Although the ERG accepted that there were differences in baseline characteristics between patients in the CRUISE, BRAVO and GENEVA trials (see section 3.9), it stated that this would not prevent an indirect comparison between ranibizumab and dexamethasone, and would likely favour ranibizumab. This was because at baseline the mean duration of macular oedema secondary to CRVO was 3 months in CRUISE and 5 months in GENEVA, and a greater mean duration of RVO tends to result in a poorer response to treatment. The ERG suggested that the impact of any bias could have been explored through critical assessment. The ERG agreed with the manufacturer that it was not possible to incorporate bevacizumab for people with CRVO into an adjusted indirect comparison because only 1 study of bevacizumab for CRVO had been identified in the manufacturer's submission (Faghihi et al. 2008), and this did not adequately report baseline characteristics. For BRVO, the ERG considered that studies of bevacizumab reported in the manufacturer's submission (see section 3.9) were suitable for inclusion in an indirect comparison with the first 3 months of data from BRAVO (that is, before rescue treatment with grid laser photocoagulation was permitted). Again, the ERG accepted that there would be some bias in this comparison, but overall the biases would likely favour ranibizumab because the duration of macular oedema in BRAVO was longer than in the study by Moradian et al. and because the Moradian study included more patients with ischaemia than BRAVO. The ERG highlighted that this could be explored in critical assessment.\nFrom the trials reported in the manufacturer's submission, the ERG was able to construct a linear network of trials using BRAVO (ranibizumab compared with sham), Moradian et al. 2011 (bevacizumab compared with sham) and Russo et al. 2009 (bevacizumab compared with grid laser photocoagulation). The ERG commented that although the results should be treated with caution because they are exploratory, they estimated an approximately 3‑letter improvement in visual acuity with ranibizumab over bevacizumab and an 8‑letter improvement with ranibizumab over grid laser photocoagulation at month 3. However, the ERG did not consider the difference between bevacizumab and ranibizumab to be clinically meaningful from this analysis.\nThe ERG noted that in the base‑case analysis the model assumed all patients were treated in the 'better‑seeing eye', despite the fact that over 90% of patients in the BRAVO and CRUISE trials were treated in their 'worse‑seeing eye'. The ERG considered that it was not reasonable to assume equivalent gains in utility and reductions in costs when treating a patient in their 'worse‑seeing eye'. The ERG considered the manufacturer's use of a 'better‑seeing eye' model to be inappropriate because RVO is predominantly a unilateral condition, and therefore most patients would receive treatment in their 'worse‑seeing eye' only.\nThe ERG considered the pooled transition probabilities for ranibizumab, which the manufacturer stated had been necessary to account for the effect of grid laser photocoagulation in people with BRVO. The ERG commented that pooling would lead to an overestimate of the efficacy of ranibizumab because the benefit seen in patients in the sham group who received ranibizumab after the first 6 months would be added to the continued effect of ranibizumab in those patients initially randomised to receive ranibizumab. The ERG conducted sensitivity analyses using unpooled transition probabilities. It noted that the ICER for ranibizumab compared with grid laser photocoagulation (for BRVO) with this change alone increased the manufacturer's original base‑case from £20,494 to £52,004 per QALY gained for months 7 to 12, and ranibizumab was dominated (was less clinically effective and more expensive) for months 13 to 24, and months 7 to 12 plus months 13 to 24 together. Incremental costs and QALYs for the base‑case results were commercial in confidence and therefore cannot be presented here.\nThe ERG considered the manufacturer's exploratory economic analysis that incorporated dexamethasone intravitreal implant. The ERG commented that there was a potential bias towards ranibizumab in the manufacturer's approach (see section 3.20). The ERG conducted an exploratory indirect comparison of ranibizumab with dexamethasone intravitreal implant, which provided relative risks of an improvement in visual acuity of 10 letters (2 lines) or more for patients with macular oedema secondary to BRVO and CRVO (a relative risk of less than 1 favours ranibizumab). The relative risks increased from 0.55 to 0.79 for ranibizumab compared with dexamethasone in BRVO. For CRVO, the corresponding figures were 0.30 to 0.40. The ERG commented that the relative risks calculated from the manufacturer's model were more favourable to ranibizumab in both BRVO and CRVO. Moreover, because the ERG's indirect comparison was known to be biased towards ranibizumab, the manufacturer's approach to modelling dexamethasone was largely biased towards ranibizumab. However, the ERG commented that these results were exploratory and should therefore be interpreted with caution.\nThe ERG noted the manufacturer's assumption in the economic model that there is no mortality risk attributable to RVO. The ERG identified a UK‑based study (Tsaloumas et al. 2000) that concluded that patients with RVO were at a significantly greater risk of death from myocardial infarction than the general population. The ERG was of the opinion that it would have been appropriate to include the relative risk of 1.6 reported by Tsaloumas in the manufacturer's base‑case analysis.\nThe ERG noted the manufacturer had applied a mortality risk associated with the visual acuity level in the patient's 'better‑seeing eye' using data from Christ et al. (2008). The ERG noted that this mortality risk would only apply to patients being treated in their 'better‑seeing eye'. The ERG commented that if the model was amended to treat those with visual impairment in their 'worse‑seeing eye' it would be appropriate to use a mortality risk associated with 'some' visual impairment in these patients.\nThe ERG noted that the utility values for visual acuity in the 'better‑seeing eye' were taken from Brown (1999) rather than Czoski‑Murray et al. (2009), an earlier version of which had been used (referred to as Brazier et al. 2006) in Ranibizumab and pegaptanib for the treatment of age\\u2011\\related macular degeneration (NICE technology appraisal guidance 155). The ERG noted that the manufacturer's model assumes utilities are independent of age, although age adjustment is expected to have minimal impact on the ICERs. However, the ERG commented that age adjustment of the utilities presented by Czoski‑Murray et al. (2009) was not necessary because age had already been adjusted for. The ERG commented that the study by Czoski‑Murray et al. (2009) should therefore be used as the source for utility associated with visual acuity in the 'better‑seeing eye' in this assessment. For the 'worse‑seeing eye' the ERG was of the opinion that the available evidence from the Brown publication (which reported utilities by worse‑ and better‑seeing eyes) suggested the maximum gain from treating a person's 'worse‑seeing eye' would be 0.1.\nThe ERG carried out exploratory analyses varying several parameters. Assuming that only 10% (and not 100%) of people are treated in their 'better‑seeing eye', applying utilities derived from Czoski‑Murray et al. (2009), a 0.1 overall benefit associated with treating the 'worse‑seeing eye' and an increased risk of mortality associated with RVO, the ICERs for ranibizumab compared with best supportive care and with dexamethasone in CRVO were £43,760 and £37,443 per QALY gained respectively. This formed the ERG's base‑case estimate for CRVO. The ERG did not present further economic evaluation of ranibizumab compared with grid laser photocoagulation because it considered that the confounded data from BRAVO (in which grid laser photocoagulation was permitted in the ranibizumab arm after 3 months of treatment) was insufficient to inform an indirect comparison and be used in the economic model. When the ERG applied their preferred assumptions as above for ranibizumab compared with dexamethasone intravitreal implant in BRVO, this increased the manufacturer's base‑case ICER from £5486 to £31,122 per QALY gained. The ERG's exploratory analyses highlighted that the key drivers that increased the manufacturer's base‑case ICERs were amending the proportion of patients treated in their 'better‑seeing eye' (10% instead of 100%) and the assumption of some benefit associated with treating the 'worse‑seeing eye'.\nThe ERG commented that its comparisons of ranibizumab with dexamethasone intravitreal implant for both BRVO and CRVO used relative risks derived from the manufacturer's model (0.55 for BRVO and 0.30 for CRVO) rather than those derived from the ERG's indirect comparison (0.79 and 0.40 respectively). The ERG commented that this would bias the results in favour of ranibizumab and if the ERG's suggested relative risks were applied, the ICER would increase further. The ERG also commented that the efficacy of dexamethasone was potentially underestimated because of differing patient characteristics in the trials that informed the comparison (patients had differing durations of macular oedema from diagnosis in the GENEVA trials compared with BRAVO and CRUISE). Therefore, the manufacturer's base‑case ICERs may be underestimates. The ERG also highlighted that the ICER generated for ranibizumab compared with dexamethasone from the BRAVO trial is derived using the pooled transition probabilities in the original submission. Using the unpooled transition probabilities would increase the ICER further.\nThe ERG conducted an exploratory cost‑minimisation analysis for ranibizumab compared with bevacizumab, assuming equivalent efficacy for the 2 treatments (in BRVO and CRVO) and an acquisition cost of £50 per month for bevacizumab. The ERG presented data on the incremental costs of ranibizumab compared with bevacizumab that included commercial‑in‑confidence information and so cannot be presented here. The ERG's analysis using the manufacturer's model suggested that ranibizumab would need to generate 1.5 times more QALYs than bevacizumab (each month between months 2 and 6) in macular oedema secondary to BRVO (without considering the revised patient access scheme implemented in NICE technology appraisal guidance 274) to give an ICER at the top end of the range usually considered cost effective. Ranibizumab would need to generate 1.7 times more QALYs than bevacizumab for macular oedema secondary to CRVO (without considering the revised patient access scheme implemented in NICE technology appraisal guidance 274) to give an ICER at the top end of the range usually considered cost effective.\n\n# Revised economic model submitted by the manufacturer during consultation\nIn response to the consultation on the appraisal consultation document the manufacturer submitted a revised cost–utility analysis addressing the Committee's concerns about the original model. The revised economic model included the ERG's preferred assumptions relating to 10% of patients being treated in their 'better‑seeing eye', utilities from Czoski‑Murray et al. (2009). The manufacturer also applied some alternative assumptions (see sections 3.33 to 3.36) to present revised base‑case cost‑effectiveness estimates for ranibizumab compared with dexamethasone in both BRVO and CRVO.\nThe manufacturer considered that the ERG's approach to deriving utilities from Czoski‑Murray et al. (2009) underestimated the utility gains associated with improving visual acuity. The manufacturer therefore provided an alternative to the ERG's derivation of utilities by applying a regression equation from the Czoski‑Murray et al. (2009) publication to derive utilities for each of the 8 BCVA health states in a similar way to that employed in the guidance on Ranibizumab and pegaptanib in age\\u2011\\related macular degeneration (NICE technology appraisal guidance 155). The manufacturer also applied a 0.3 overall benefit of treating the 'worse‑seeing eye' because it felt that a 0.1 benefit, as applied by the ERG, did not capture the difference in utility for people with blindness in their 'worse‑seeing eye'.\nThe manufacturer did not apply an excess mortality risk specifically associated with RVO in its revised model because the available evidence was conflicting, and it considered the evidence base to be inconclusive. In addition, the manufacturer highlighted that an excess mortality risk had not been included in the evidence submitted for the published guidance on Dexamethasone intravitreal implant in macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 229). However, the manufacturer did amend the model to include mortality risk associated with visual impairment in the 'worse‑seeing eye' as originally suggested by the ERG (see section 3.26).\nThe manufacturer acknowledged the Committee's concerns about the use of pooled transition probabilities during months 7–24 of the BRAVO trial, which were originally used to account for the confounding effect of patients being treated with grid laser photocoagulation at the same time as treatment with ranibizumab. In its revised model, the manufacturer applied data for months 7–24 from only the ranibizumab arm of BRAVO to inform the transitions of all BRAVO patients.\nThe manufacturer's revised model included updated adverse event rates for year 2 for ranibizumab as well as updated adverse event rates for dexamethasone for year 1, based on 12‑month outcomes from the GENEVA studies published since the manufacturer's original submission. In addition, the manufacturer considered that the dexamethasone re‑treatment frequency included in the original model (every 6 months) was conservative and therefore applied a re‑treatment frequency of 4 months to the revised model.\nFinally, the manufacturer applied a lifetime time horizon instead of the 15‑year time horizon included in the original submission in order to derive its base‑case cost‑effectiveness estimates. The manufacturer stated that this was consistent with the approach taken in the guidance on Dexamethasone intravitreal implant in macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 229).\nThe manufacturer highlighted in its consultation response that although patients with brisk afferent pupillary defect were excluded from the BRAVO and CRUISE studies, this only represents those at the more severe end of the ischaemic spectrum and therefore did not exclude those with milder ischaemia.\nAfter consultation on the appraisal consultation document, the manufacturer responded to the Committee's concerns regarding the extent of bias generated by the differences in the duration of macular oedema between GENEVA and BRAVO/CRUISE. The manufacturer commented that the extent of bias was not known and that the implications for the ICER may be minimal. They also re‑examined the reported mean durations of macular oedema in the GENEVA (dexamethasone) and BRAVO and CRUISE (ranibizumab) studies noting that in the GENEVA studies, the mean duration of macular oedema was assessed at a screening visit which occurred at least 1 month earlier than in the BRAVO and CRUISE studies. The manufacturer further noted that its cost‑effectiveness analysis of ranibizumab compared with dexamethasone was already favourable to dexamethasone because the relative effectiveness of ranibizumab and dexamethasone was assessed at 3 months, and conservative assumptions related to the number of dexamethasone injections and the rate of adverse events associated with dexamethasone were used.\nIn their response to the appraisal consultation document consultation the manufacturer reiterated their view that bevacizumab is not a valid comparator because it does not satisfy the definition of a comparator as set out in the NICE Guide to the methods of technology appraisal because, in their view, the use of bevacizumab is not routine or best practice, and because bevacizumab is not licensed for RVO. The manufacturer further highlighted that the studies included in the ERG's indirect comparison of ranibizumab with bevacizumab had methodological shortcomings and that the inclusion of the study by Russo et al. (2009) was inappropriate because standard deviations were not reported in this study for the values of change from baseline. The manufacturer considered the ERG's conclusion about the direction of bias in the indirect comparison to be overly speculative and not evidence‑based. In addition the manufacturer reiterated its concerns over comparisons with an unlicensed drug that might compromise patient safety, further noting that the absence of a full pharmacovigilance programme (normally funded by the drug sponsor), would mean that the cost of safety surveillance would be a significant burden to the NHS and was not included in the ERG's cost‑minimisation analysis. The manufacturer provided an estimate of the per‑patient cost of a basic pharmacovigilance programme, which was submitted as commercial in confidence and cannot therefore be reported. Finally, the manufacturer highlighted that the ERG's use of a cost‑minimisation analysis is fundamentally flawed and that it was not appropriate to assume equivalent safety and efficacy of ranibizumab and bevacizumab, an assumption required for cost‑minimisation methodology, when this has not been established.\n\n# Evidence Review Group's comments on the manufacturer's revised model\nThe ERG noted the manufacturer's approach to applying the 'better‑seeing eye' utilities from Czoski‑Murray et al. (2009) to the model and agreed that this was appropriate because it provided utilities for each of the health states in the model rather than the ERG's smaller set of utility values (see section 3.32), and was consistent with the approach taken by the Assessment Group for the guidance on Ranibizumab and pegaptanib in age\\u2011\\related macular degeneration (NICE technology appraisal guidance 155). The ERG considered the manufacturer's approach of applying a maximum utility gain of 0.3 from treatment of the 'worse‑seeing eye'. The ERG noted that the manufacturer extrapolated the 0.1 utility loss estimated by Brown et al. (2001) to apply further loss in the 'worse‑seeing eye'. However, the ERG considered that the evidence presented by Brown et al. (2001) suggested that further deterioration in visual acuity in the 'worse‑seeing eye' did not affect utility and therefore applying a 0.3 utility gain was not evidence‑based. They also considered that it lacked face validity.\nThe ERG noted the manufacturer's response suggesting that the extent of bias towards ranibizumab in comparison with dexamethasone was overestimated (in the original ERG report). The ERG acknowledged that there is uncertainty surrounding the extent of bias but that this is difficult to quantify. With respect to duration of macular oedema at baseline, the ERG did not have access to data from BRAVO and CRUISE to adjust for the difference in the timing of measurement of duration of macular oedema compared with GENEVA. The ERG also noted that although the manufacturer's revised model uses data from months 7–12 of the ranibizumab arm of BRAVO to inform all transition probabilities from month 7 to 24, this assumes equivalent efficacy between dexamethasone and ranibizumab when given as needed. The ERG noted that it is not clear whether this assumption is conservative, and that evidence provided by the manufacturer from the BRAVO trial showed that there is a decline in ranibizumab's efficacy when given as needed rather than as monthly treatment.\nThe ERG considered the manufacturer's consultation response to dexamethasone re‑treatment frequency and adverse events associated with dexamethasone. The ERG noted that the manufacturer's approach should have also modelled the effectiveness of dexamethasone re‑treatment given less frequently than every 4 months (for example, every 5 months) and that the manufacturer did not take into account that a higher re‑treatment frequency would result in a more stable efficacy for dexamethasone. In addition, the ERG agreed that a higher re‑treatment frequency for dexamethasone would have the impact of increasing the number and severity of adverse events.\nThe ERG noted the manufacturer's response to the issue of ischaemic disease. The ERG agreed that the exclusion criterion in BRAVO and CRUISE of brisk afferent pupillary defect would not exclude patients with minor ischaemic disease. However, the ERG noted that none of the key trials used in the ERG's exploratory analysis, including BRAVO and CRUISE, reported data on the number of patients with baseline macular ischaemia. Therefore, the ERG highlighted that it could not be assumed that patients with ischaemia could have been included in BRAVO and CRUISE and stated that the effects of ranibizumab in the subgroup of patients with macular oedema secondary to ischaemic RVO were unknown.\n\n# Patient access scheme as revised in the context of NICE technology appraisal guidance 274\nThe manufacturer submitted a revised patient access scheme in 2013 for consideration in this appraisal (as revised in the context of NICE technology appraisal guidance 274), in which it applied a revised discount to ranibizumab for all indications (see section 2.4). The manufacturer did not submit any additional clinical‑effectiveness data but submitted an economic model that incorporated the revised patient access scheme discount and employed all of the revised assumptions from the manufacturer's response to consultation (outlined in more detail in sections 3.31 to 3.39). In summary these were as follows:\nderiving utilities from Czoski‑Murray et al. (2009) for each of the 8 BCVA health states in a similar way to that employed in the guidance on Ranibizumab and pegaptanib in age\\u2011\\related macular degeneration (NICE technology appraisal guidance 155) by applying a regression equation from Czoski‑Murray et al. (2009)\napplying a 0.3 overall utility benefit for treating the 'worse‑seeing eye'\nincluding mortality risk associated with visual impairment as suggested by the ERG\napplying data for months 7–24 from only the ranibizumab arm of BRAVO to inform the transition probabilities of all BRAVO patients\nincluding updated adverse event rates for year 2 for ranibizumab as well as updated adverse event rates for dexamethasone for year 1\napplying a lifetime time horizon to be consistent with the published guidance for Dexamethasone intravitreal implant for macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 229).\nBy applying all of their revised assumptions (see section 3.44), the manufacturer's revised base‑case ICERs (with the revised patient access scheme as implemented in NICE technology appraisal guidance 274) for ranibizumab compared with dexamethasone were £2370 and £6995 per QALY gained for BRVO and CRVO respectively. For ranibizumab compared with best supportive care in CRVO the ICER was £13,851 per QALY gained, whereas for ranibizumab compared with grid laser photocoagulation in BRVO, the ICER was £23,073 per QALY gained.\nThe manufacturer performed a deterministic sensitivity analysis and found the model to be sensitive to the frequency of injections and follow‑up visits; for example in BRVO, increasing the number of injections in year 2 (from 2.5 to 6) increased the ICER for ranibizumab compared with dexamethasone from £2370 to £9892 per QALY gained.\nThe manufacturer provided scenario analyses (one‑way sensitivity analysis) which explored the effect of changing some of the parameters in the model individually. The manufacturer explored the effect of applying a 0.2 overall utility gain for treating the 'worse‑seeing eye'. This increased the base‑case ICERs of ranibizumab compared with dexamethasone from £2370 to £3029 per QALY gained for BRVO, and from £6995 to £9005 per QALY gained for CRVO. For ranibizumab compared with best supportive care in CRVO, the ICER increased from £13,851 to £18,332 per QALY gained. For ranibizumab compared with grid laser photocoagulation, the manufacturer's ICER increased from £23,073 to £30,778 per QALY gained.\nOther scenario analyses included reducing the mean number of ranibizumab injections in year 2 (the revised number of mean injections was submitted as academic in confidence and cannot be presented). This reduced the ICERs of ranibizumab compared with dexamethasone by 54% in BRVO and by 58% in CRVO. A scenario which included longer follow‑up data based on year 2 of the HORIZON extension study reduced the ICERs for ranibizumab compared with dexamethasone from £2370 to £1599 per QALY gained and from £23,073 to £20,911 per QALY gained for ranibizumab compared with grid laser photocoagulation in BRVO. The corresponding scenario analysis for CRVO was not presented.\nThe manufacturer also presented probabilistic sensitivity analyses and concluded that from the base‑case results the probability that ranibizumab was cost effective when compared with grid laser photocoagulation in BRVO was 44.2% at a threshold of £20,000 per QALY gained and 58.6% at a threshold of £30,000 per QALY gained. For ranibizumab compared with best supportive care in CRVO, the probability of cost effectiveness was estimated by the manufacturer to be 67.9% and 82.0% at thresholds of £20,000 and £30,000 per QALY gained respectively.\n\n# ERG critique of manufacturer's revised base case with the patient access scheme as revised in the context of NICE technology appraisal guidance 274\nThe ERG noted that the revised model used to inform the current patient access scheme submission is the same as that submitted as part of the manufacturer's response to the original consultation, but that not all issues raised by the Committee have been addressed. Therefore, the ERG's views outlined in sections 3.40 to 3.43 (relating to deriving utilities, transition probabilities, re‑treatment frequency and adverse events associated with dexamethasone and ischaemic disease) still apply. Overall, the ERG accepted the manufacturer's approach to:\nmodelling 90% of people in the model as being treated in their 'worse‑seeing eye'\nthe use and implementation of the 'better‑seeing eye' utilities derived from Czoski‑Murray et al. (2009)\nexcess mortality associated with visual impairment in the 'worse‑seeing eye'\nupdated adverse events. However, the ERG maintained that the available evidence relating to utility gain from treating the 'worse‑seeing eye' suggests a utility decrement of 0.1 (rather than the manufacturer's assumption of 0.3) between the best and worst 'worse‑seeing eye' BCVA health states. Therefore, the ERG provided amended exploratory cost‑effectiveness estimates to include the assumption of a 0.1 utility decrement. For BRVO, this increased the manufacturer's base‑case ICER for ranibizumab compared with grid laser photocoagulation from £23,073 to £44,713 per QALY gained. In the ERG's incremental analysis in BRVO, dexamethasone was extendedly dominated by ranibizumab (that is, the ICER for dexamethasone compared with grid laser photocoagulation was higher than for ranibizumab compared with grid laser photocoagulation) and the ICER compared with best supportive care was £44,713 per QALY gained. The ERG highlighted that there is considerable uncertainty in the comparisons of ranibizumab with grid laser photocoagulation and with dexamethasone as a result of the confounded data from BRAVO (grid laser photocoagulation was permitted in the ranibizumab arm after 3 months of treatment) used to inform the comparison with grid laser photocoagulation and the absence of a direct comparison with dexamethasone.\nFor ranibizumab compared with dexamethasone in BRVO, the ERG's amendment of including a 0.1 utility decrement increased the manufacturer's base‑case ICER from £2370 to £4092 per QALY gained. The ERG performed the same amendment for CRVO, and the ICER for ranibizumab compared with best supportive care increased from £13,851 to £26,263 per QALY gained, and for ranibizumab compared with dexamethasone the ICER increased from £6995 to £12,306 per QALY gained. In the ERG's incremental analysis for CRVO, dexamethasone was extendedly dominated by ranibizumab (that is, the ICER for dexamethasone compared with best supportive care was higher than for ranibizumab compared with grid laser photocoagulation) and the ICER for ranibizumab compared with best supportive care was £26,263 per QALY gained. The ERG highlighted that the absence of a direct comparison of ranibizumab with dexamethasone generates considerable uncertainty in these results. In particular, the manufacturer assumed that from month 7 onwards, the efficacy of dexamethasone is equivalent to ranibizumab when given as needed (rather than monthly). The ERG note that it remains unclear whether this assumption would lead to bias towards or against ranibizumab.\n\n# NICE Decision Support Unit report\nFollowing the Committee's consideration of comparators in this appraisal, and in line with NICE processes (specifically section 3.5.49 of the Guide to the single technology appraisals process), the NICE Board asked for additional work to be commissioned from the NICE Decision Support Unit (DSU) related specifically to the consideration of intravitreal bevacizumab as a comparator.\nThe DSU report considered 4 questions:\nWhat evidence is there relating to the pharmaceutical quality of reformulated bevacizumab as used in eye conditions in general?\nHow widespread is intravitreal bevacizumab use in the UK?\nWhat is the evidence for efficacy of intravitreal bevacizumab in adults with RVO (and diabetic macular oedema) specifically?\nWhat evidence is there regarding adverse events for intravitreal bevacizumab in eye conditions in general?\nThe DSU report noted that the process of diluting and aliquoting bevacizumab into the smaller doses required for intravitreal injections requires a 'specials' licence issued by the Medicines and Healthcare products Regulatory Agency (MHRA) and can be performed by hospital pharmacists or on a larger scale by specialist units under tightly controlled conditions. The DSU identified Moorfields Pharmaceuticals (a manufacturing arm of Moorfields Eye Hospital NHS Foundation Trust) and Liverpool and Broadgreen University Hospitals pharmacy as the 2 major suppliers of intravitreal bevacizumab in the UK, both of which hold 'specials' licences. The DSU report highlighted that the greatest risk from reformulation of bevacizumab is infection such as endophthalmitis, which can lead to loss of vision or even the eye itself, and that there has been a warning issued about this by the US Food and Drug Administration (FDA). Reports of sterile endophthalmitis or uveitis by Moorfields to the MHRA have resulted in the recall of 27 batches of bevacizumab.\nThe DSU report investigated the extent of use of intravitreal bevacizumab in the UK by reviewing commissioning policy documents, data from the 2 major suppliers of intravitreal bevacizumab, and a survey of consultant ophthalmologists. The findings suggested that there is substantial use of intravitreal bevacizumab across the UK in eye conditions in general and that its use is even more widespread in private practice.\nThe report also reviewed the evidence relating to efficacy of intravitreal bevacizumab specifically in RVO. The DSU identified 5 RCTs that examined the effectiveness of bevacizumab on BCVA in people with RVO, 3 of which were in populations with CRVO; the remaining 2 studies were in BRVO. The studies all suggested that intravitreal bevacizumab appeared to confer some improvement in BCVA in both BRVO and CRVO compared with sham injection. However, because 3 of the studies were only available as conference abstracts, detailed data were not available. In addition, the DSU highlighted that interpretations of the findings should be made with caution because of the small number of studies with relatively small sample sizes and differences in participants' age, gender distribution and type of RVO. The studies also had relatively short follow‑up durations (the maximum was 24 weeks).\nThe report assessed the evidence relating to adverse events associated with intravitreal bevacizumab in eye conditions in general. A total of 22 RCTs were identified, which evaluated the safety of bevacizumab compared with laser therapy, sham injection, triamcinolone, ranibizumab, pegaptanib and observational control. In addition, 67 observational non‑RCT studies were included in the safety review of intravitreal bevacizumab. Overall, the DSU report commented that adverse event rates following intravitreal bevacizumab treatment were low when compared with other intravitreal treatments, sham injection and laser therapy and most of these studies were in people with AMD, diabetic macular oedema or RVO. Most outcomes were not significantly different between groups. The DSU report noted that higher rates of adverse events have been reported in the bevacizumab group in the head‑to‑head studies of intravitreal bevacizumab and ranibizumab (CATT and IVAN trials in AMD) and although this was not significant in the IVAN trial, when added to the meta‑analysis with the CATT trial, the overall finding was statistically significant. Overall the DSU considered that the 22 RCTs offer the most robust assessment of adverse events. The DSU commented that the evidence on safety of intravitreal bevacizumab from observational studies was inconclusive. However, with respect to larger studies, observational data from Curtis et al. suggested no difference in the risk of adverse events between bevacizumab and ranibizumab, and another population‑based case–control study reported no relationship between the risk of systemic events such as myocardial infarction, venous thromboembolism, stroke or congestive heart failure and the administration of intravitreal bevacizumab or ranibizumab.\nComments on the DSU report consultation highlighted that the quality of reformulated bevacizumab might vary between studies and in clinical practice, and there are concerns about the reports of endophthalmitis. However it is unclear how this compares with ranibizumab. Consultees commented that there was insufficient evidence to evaluate the safety of intravitreal bevacizumab, while other consultees noted that the pooled analysis of IVAN and CATT trials, which compared ranibizumab and bevacizumab directly (in people with AMD), showed significantly higher serious systemic adverse events in the bevacizumab group. Some consultees noted that although there is some favourable evidence for efficacy of intravitreal bevacizumab for RVO in comparison with sham injection, the evidence is limited. However, some consultees noted that the use of intravitreal bevacizumab could be substantial but may have declined since the publication of Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 229).\nFull details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ranibizumab, having considered evidence on the nature of visual impairment caused by macular oedema secondary to retinal vein occlusion (RVO) and the value placed on the benefits of ranibizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\nThe Committee heard from patient experts about the problems associated with visual impairment caused by macular oedema. It heard that the loss of vision has a significant effect on the independence of people with the condition. The patient experts also stated that the condition affects ability to work and hobbies such as reading and gardening. The patient experts acknowledged that although people may be worried about having an injection in the eye, they are willing to receive injections in order to keep their sight. The Committee agreed that loss of vision caused by macular oedema secondary to retinal vein occlusion seriously impairs health‑related quality of life.\nThe Committee heard from clinical specialists that the current standard treatment for visual impairment caused by macular oedema secondary to branch RVO (BRVO) is grid laser photocoagulation but that in interim guidelines from the Royal College of Ophthalmologists it is only recommended after a period of 3 to 6 months following the initial event (obstruction of retinal veins) and following the absorption of the majority of the haemorrhage. The Committee heard from the clinical specialists that grid laser photocoagulation is not an option for people with central RVO (CRVO), because CRVO does not respond to grid laser photocoagulation (as outlined in the Royal College of Ophthalmologists' interim guidelines on RVO) and the current standard treatment is dexamethasone or anti‑vascular endothelial growth factor (VEGF) drugs such as bevacizumab.\nThe Committee considered the comparators for the appraisal, and specifically bevacizumab intravitreal injection. It was aware that bevacizumab does not have a UK marketing authorisation for the treatment of RVO and heard from patient experts that they were concerned about using unlicensed treatments for which there was no formal post‑marketing surveillance, particularly if there were alternatives that have a UK marketing authorisation. The Committee noted that a marketing authorisation is not a prerequisite for a comparator in a NICE technology appraisal. It noted that NICE's Guide to the methods of technology appraisal, in recommending comparison with technologies that are 'best practice' or in 'routine use', is not intended to be restrictive but to emphasise the need for comparison with all relevant comparators; any medicine in routine use or considered to be best practice should be considered a comparator. The Committee was minded to conclude that bevacizumab fulfils the requirements for inclusion as a comparator but noted the advice from the NICE Board that this decision should be based on a careful consideration of its use in clinical practice for the condition concerned and, critically, a thorough assessment of its efficacy and safety.\nThe Committee considered the information in the Decision Support Unit (DSU) report on the product quality of reformulated bevacizumab. It was aware of consultation comments on the DSU report raising concerns on quality and reports of endophthalmitis and uveitis with intravitreal bevacizumab, although it was not clear how the number of reports compared with those observed with ranibizumab. The Committee also noted the comments from consultation on the DSU report that reformulation of pharmaceutical products is not an unusual practice and is routinely performed in many other circumstances under a 'specials' licence. The Committee noted that reformulating bevacizumab for intravitreal use requires a 'specials' licence from the Medicines and Healthcare products Regulatory Agency (MHRA) and that this means manufacturers must adhere to a range of conditions and inspections. The Committee was satisfied that there is some level of good manufacturing practice in place when pharmaceutical products are reformulated under a 'specials' licence and that such practice is not exceptional.\nThe Committee considered the evidence relating to the safety of bevacizumab as reported by the DSU. It was aware that in the 22 randomised controlled trials (RCTs) identified for age‑related macular degeneration (AMD), diabetic macular oedema and RVO, adverse events were few compared with sham injection, laser photocoagulation and other intravitreal treatments. The Committee noted the pooled analysis from the IVAN and CATT trials (both in patients with AMD), which showed a statistically significantly higher rate of systemic adverse events in the bevacizumab group than in the ranibizumab group. However, it also noted observational data from a large study by Curtis et al. suggesting no difference in the risk of adverse events between bevacizumab and ranibizumab. It also noted a population‑based case–control study, including over 90,000 patients, that reported no relationship between the risk of systemic events such as myocardial infarction, venous thromboembolism, stroke or congestive heart failure and the administration of intravitreal bevacizumab or ranibizumab. The Committee concluded that the evidence base relating to the safety of bevacizumab was sufficient to inform judgement of whether bevacizumab is an appropriate comparator.\nThe Committee considered the evidence base for the efficacy of bevacizumab in treating visual impairment caused by macular oedema secondary to BRVO and CRVO. It noted the small trials (2 in BRVO, 3 in CRVO) identified in the DSU report, of which 3 were published only as abstracts. The Committee agreed that all trials reported significant mean improvements in best corrected visual acuity (BCVA) for bevacizumab compared with sham injections, but because no direct comparisons of ranibizumab with intravitreal bevacizumab are currently available, a mixed treatment comparison would be needed to answer the question of relative effectiveness between the 2 treatments. The Committee noted that the DSU was not asked to address this question specifically. The Committee concluded that the available evidence was limited with small sample sizes and differences in study populations but on balance sufficient to inform judgement of whether bevacizumab is an appropriate comparator.\nHaving noted the available evidence and comments from consultation on the safety, efficacy and quality of intravitreal bevacizumab, the Committee concluded that bevacizumab is an appropriate potential comparator in this appraisal. However, the Committee further concluded that there is currently insufficient evidence to make robust comparisons with ranibizumab needed for a cost‑effectiveness analysis.\n\n# Clinical effectiveness\nThe Committee considered the evidence presented by the manufacturer on the clinical effectiveness of ranibizumab. It noted that the main sources of evidence came from the BRAVO and CRUISE RCTs, which included patients with macular oedema secondary to BRVO and CRVO respectively. It also noted the evidence from the 12‑month open‑label extension of both trials, the HORIZON study. The Committee noted that the decision problem for the appraisal included people with or without retinal ischaemia. However it was aware that most patients with retinal ischaemia were excluded from the BRAVO and CRUISE trials, because patients with a brisk afferent pupillary defect (which equates to severe retinal ischaemia) were excluded. It heard from the clinical specialists and the manufacturer that this meant that there was no evidence of ranibizumab for treating visual impairment caused by RVO in patients with significant ischaemia.\nThe Committee noted that in both BRAVO and CRUISE ranibizumab was associated with statistically significant mean gains in BCVA in the treated eye compared with sham injection for the 6‑month treatment phase. It also noted that ranibizumab was associated with sustained gains in BCVA at 12 months in both BRAVO and CRUISE, and that these were statistically significant (p<0.01 and p<0.001 respectively). The Committee was aware that ranibizumab could be used as needed in both arms of both trials from 6 months. In addition, the Committee was aware that in the BRAVO trial, grid laser photocoagulation was permitted after 3 months in both the sham group and the ranibizumab group, confounding the results of the treatment phase from month 3 onwards. Despite this, the Committee concluded that ranibizumab is a clinically effective treatment for visual impairment caused by macular oedema secondary to BRVO and CRVO compared with sham injection, if there is no significant retinal ischaemia.\nThe Committee considered the evidence for adverse effects associated with ranibizumab. It noted that the safety of ranibizumab had been shown previously in patients with wet AMD (NICE technology appraisal guidance 155) and diabetic macular oedema (NICE technology appraisal guidance 274 – rapid review of TA237). The Committee also noted that the overall frequency of adverse effects in the BRAVO and CRUISE trials at month 6 was low. It agreed that ranibizumab was safe and well tolerated in patients with macular oedema secondary to RVO.\nThe Committee noted that the BRAVO and CRUISE trials collected data on the effect of visual impairment on quality of life using the National Eye Institute Visual Function Questionnaire‑25 (NEI VFQ‑25) questionnaire. It noted that both trials reported a statistically significant difference in NEI VFQ‑25 score at month 6 between the ranibizumab and sham injection groups. The Committee concluded that treating patients with ranibizumab improves the quality of life of people with visual impairment caused by macular oedema secondary to RVO.\n\n# Cost effectiveness\nThe Committee considered the manufacturer's original economic model and the critique and exploratory analyses performed by the Evidence Review Group (ERG). It noted the manufacturer's original base‑case incremental cost‑effectiveness ratios (ICERs) of £8600 and £20,500 per quality‑adjusted life year (QALY) gained for ranibizumab compared with standard care for CRVO and BRVO respectively and the ICERs for ranibizumab compared with dexamethasone in CRVO and BRVO which were £7200 and £5500 per QALY gained respectively. The Committee broadly accepted the model structure, but was concerned by some of the uncertainties highlighted by the ERG around the assumptions used by the manufacturer. In particular, the Committee did not accept:\nthe assumption that all patients would be treated in their 'better‑seeing eye', having heard from clinical specialists that this is not the case in clinical practice, and that most patients in the CRUISE and BRAVO trials were treated in their 'worse‑seeing eye' (see section 3.22)\nthe manufacturer's use of 'better‑seeing eye' utility values from the Brown study, without age adjustment (see section 3.27)\nthe absence of a mortality risk associated with RVO in the model (see section 3.25)\nthe use of pooled transition probabilities during months 7–12 of the BRAVO trial, which overestimated the efficacy of ranibizumab compared with sham injection (see section 3.23)\nthe potential bias in the indirect comparison between ranibizumab and dexamethasone (both BRVO and CRVO), with different exclusion rules for ischaemia, patients with different durations of macular oedema and different severities in the trials of each drug (see section 3.24).The Committee concluded that the most plausible ICERs for ranibizumab compared with standard care and dexamethasone intravitreal implant, based on the manufacturer's base case modified appropriately by the ERG, were likely to range from £31,100 to £52,000 per QALY gained and would therefore be well in excess of £20,000 to £30,000 per QALY gained. It also noted that there was additional uncertainty about the cost‑effectiveness estimates for ranibizumab in people with BRVO because grid laser photocoagulation was permitted after 3 months in both the sham and the ranibizumab groups, confounding the results of the treatment phase from month 3 onwards. The Committee proceeded to consider the revised model submitted by the manufacturer.\nThe Committee noted the manufacturer's revisions to its economic model submitted in response to consultation. It first noted the amendment to reflect the fact that most patients (90%) would be treated in their 'worse‑seeing eye'. The Committee considered that this was consistent with the BRAVO and CRUISE trials and clinical practice, and concluded that this amendment was appropriate.\nThe Committee next considered the manufacturer's revised approach to deriving utilities for the 'better‑seeing eye' from Czoski‑Murray et al. (2009) for use in the economic model. It understood that these utilities would only apply to 10% of the people in the revised economic model which now assumed that 90% of people would be treated in their 'worse‑seeing eye' (section 4.14). The Committee noted that the manufacturer had applied a regression equation from Czoski‑Murray et al. (2009) to produce a finer degradation of the utilities. The Committee noted that the ERG accepted the manufacturer's use and implementation of the utilities as applied using the Czoski‑Murray equation and further noted the provisional guidance from the rapid review of NICE technology appraisal guidance 237 (now published as NICE technology appraisal guidance 274) in which the range of utility values was accepted to lie somewhere in between those estimated by Czoski‑Murray and those from the Brown study. The Committee concluded that although uncertain, the use of utilities as applied using the Czoski‑Murray equation was acceptable.\nThe Committee understood that the manufacturer's submission initially assumed that all people in the economic model would be treated in their 'better‑seeing eye' and therefore did not apply a utility gain associated with treating the 'worse‑seeing eye'. It noted that in the revised economic model (submitted in response to the appraisal consultation document) it was assumed that most people (90%) would be treated in their 'worse‑seeing eye' in line with the ERG's suggestion. The Committee therefore considered the manufacturer's revised assumption of applying a 0.3 utility gain associated with treating the 'worse‑seeing eye'. The Committee heard from the ERG that the manufacturer's assumption was based on an extrapolation of evidence from Brown et al. (2001). It understood that the ERG had used a gain of 0.1 from the Brown study in which utility values were collected separately for the 'worse‑seeing' and 'better‑seeing' eyes. The Committee considered that a 0.3 utility gain associated with treating the 'worse‑seeing eye' seems high given that utility is driven primarily by the 'better‑seeing eye', and therefore lacked face validity. It further noted that the manufacturer had originally suggested that no gain in utility would be obtained from treating the 'worse‑seeing eye'. The Committee was also aware of the results of an analysis from NICE technology appraisal guidance 229 (Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion) the details of which are commercial in confidence. The Committee concluded that a utility gain of 0.1 associated with treating the 'worse‑seeing eye' was appropriate.\nThe Committee considered evidence supplied by the manufacturer during consultation relating to excess cardiovascular mortality associated with RVO, that is, the additional risk caused by cardiovascular complications associated with RVO, compared with the general population. The Committee noted that the excess mortality risk incorporated in the ERG base case was based on a paper from 2000 (Tsaloumas), which suggested that a person with RVO would have 1.6 times that of the general population. It noted that, of the papers referenced by the manufacturer in response to the original consultation, none suggested that overall mortality was lower for RVO patients than for the population at large. Some suggested it was greater. But the Committee was also aware that excess cardiovascular mortality had not been applied in Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 229). The Committee concluded that the evidence on the risk of cardiovascular mortality associated with RVO was unclear, and therefore it need not be included in the base‑case model to the degree applied in the original ERG report. However, it would remain an uncertainty in the analysis.\nThe Committee considered the manufacturer's response to the Committee's concerns about the use of pooled transition probabilities. The Committee was aware that the revised model used data from the ranibizumab arm of BRAVO to inform the transitions of all BRVO patients from month 7–24 which, in the view of the manufacturer, was a more conservative approach. The Committee noted that this had the effect of boosting the model's mean efficacy of the ranibizumab group after 6 months of treatment, because it assumes the same response to treatment for a person previously treated with ranibizumab as for a person naïve to ranibizumab treatment. It also noted that patients treated with grid laser photocoagulation or dexamethasone will experience the same benefit as patients treated with ranibizumab who are moving onto treatment with ranibizumab given as needed. The Committee heard from the ERG that because of the decline in efficacy of ranibizumab when given as needed in the extension arm of the trial, compared with monthly ranibizumab, it was unclear if the manufacturer's assumption was conservative. The Committee noted that the manufacturer's approach had minimal impact on the revised ICER for ranibizumab compared with dexamethasone in BRVO. The Committee acknowledged that there were advantages and disadvantages to the manufacturer and ERG's approaches. But it concluded that, given the lack of clear data, the approach taken by the manufacturer was appropriate.\nThe Committee discussed the manufacturer's revised assumption relating to adverse events. The Committee noted that the revised model included updated adverse event rates in year 2, which included iris neovascularisation as an adverse event for ranibizumab and dexamethasone and an updated estimate of the rate of cataract development for dexamethasone (based on 12‑month outcomes from the GENEVA studies). The Committee noted the ERG's concern that it is not clear how the rate of iris neovascularisation was calculated for year 2. Although it acknowledged the ERG's concerns with the methods used to estimate adverse events in year 2, it cautiously accepted the updated safety data in the model.\nThe Committee considered the manufacturer's consultation response to the ERG's opinion that its exploratory economic comparison of ranibizumab with dexamethasone was biased in favour of ranibizumab. The Committee considered the manufacturer's points that the duration of macular oedema may have been underestimated by up to 1 month and that the rates of ischaemic disease were higher in the ranibizumab studies, and that the comparison at 3 months does not take into consideration the declining efficacy of dexamethasone. The Committee heard from the ERG that there may still be greater bias in favour of ranibizumab. This was because dexamethasone's efficacy starts declining at 2 months (which was incorporated in the analysis at 3 months) so in the first cycle of treatment dexamethasone's efficacy was in between that of the sham and ranibizumab treatment and was assumed to be equivalent to best supportive care in months 2–6, after which the same efficacy as ranibizumab was assumed. The Committee accepted that the relative effectiveness of ranibizumab and dexamethasone was uncertain and concluded that it was difficult to quantify any bias.\nHaving discussed the assumptions in the manufacturer's revised base‑case model the Committee went on to discuss the ICERs produced from this model. It was aware that the manufacturer's revised model included the patient access scheme as revised in the context of NICE technology appraisal 274. It noted the ICERs for BRVO of £23,100 and £2400 per QALY gained for ranibizumab compared with standard care (grid laser photocoagulation) and with dexamethasone respectively, and the base‑case ICERs for CRVO of £13,900 and £7000 per QALY gained for ranibizumab compared with best supportive care and dexamethasone respectively. The Committee noted that the ERG had accepted the manufacturer's assumptions relating to 90% of patients being treated in the 'worse‑seeing eye', use of the 'better‑seeing eye' utilities from Czoski‑Murray et al. (2009) as modelled by the manufacturer, excess mortality associated with visual impairment in the 'worse‑seeing eye', updated adverse events for year 2, and a lifetime time horizon. However, the Committee was aware that the ERG had undertaken an exploratory analysis on the revised model in which a maximum utility benefit of 0.1 from treating the 'worse‑seeing eye', instead of the manufacturer's value of 0.3, had been applied. The Committee understood that this was the only difference in the calculation of the ICERs between the analyses. On the basis of its discussions relating to the maximum possible gain in utility from treating the 'worse‑seeing eye' (section 4.16), the Committee concluded that its decision should be made on the basis of the ERG's adjustment to the manufacturer's calculations.\nThe Committee considered the ICERs for ranibizumab for CRVO calculated in the ERG's exploratory analyses. It noted that in this incremental analysis dexamethasone was extendedly dominated (that is, dexamethasone is dominated by a combination of 2 other alternatives, in this case best supportive care and ranibizumab) and therefore can be discounted from the analysis. Therefore, the Committee went on to consider the comparison of ranibizumab with best supportive care. It noted that, incorporating the patient access scheme (as revised in the context of NICE technology appraisal 274), ranibizumab was associated with an ICER of £26,200 per QALY gained compared with best supportive care in CRVO. The Committee was aware of remaining uncertainties regarding the possible confounding in the data resulting from both groups in the CRUISE trial receiving ranibizumab as needed from month 7 (section 4.10). It was also aware of the remaining uncertainty because of the absence of a direct comparison with dexamethasone, however on balance the Committee considered that the most plausible ICER for ranibizumab for visual impairment caused by macular oedema secondary to CRVO was between the £20,000 and £30,000 per QALY gained thresholds. It could therefore be considered a cost‑effective use of NHS resources. The Committee therefore concluded that ranibizumab should be recommended as an option for treating visual impairment caused by macular oedema following CRVO. However, there remained uncertainties because of the absence of a direct comparison with dexamethasone.\nThe Committee considered the ICERs calculated in the ERG's exploratory analyses for ranibizumab for BRVO. The Committee noted that the key comparison was standard care with laser photocoagulation, rather than with dexamethasone, which is only recommended when laser treatment is inappropriate (NICE technology appraisal guidance 229). The Committee therefore considered the ERG's exploratory ICER of £44,800 per QALY gained for ranibizumab compared with standard care. The Committee was aware that people receiving ranibizumab in the BRAVO trial could receive grid laser photocoagulation from month 3 and that this represented a significant confounding factor in both the manufacturer's and the ERG's calculations of the ICER for BRVO compared with standard care. It therefore considered that this ICER would be an underestimate of the most plausible ICER. The Committee concluded that the most plausible ICER for ranibizumab compared with standard care in treating BRVO was in excess of £44,800 per QALY gained. It further concluded that ranibizumab could not be recommended as an option for treating visual impairment caused macular oedema following BRVO when laser photocoagulation is an appropriate treatment option.\nThe Committee next considered the population with BRVO for whom grid laser photocoagulation is not an option. It considered that this population would include both those for whom grid laser photocoagulation has not been beneficial and those for whom grid laser photocoagulation is not a suitable treatment. It was aware that the NICE appraisal of dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion (NICE technology appraisal guidance 229) had accepted the extent of macular haemorrhage as the definition for the subgroup of people for whom grid laser photocoagulation is not a suitable treatment option. Noting the Royal College of Ophthalmologists' 2010 Interim Guidelines on Retinal Vein Occlusion in which grid laser photocoagulation is only recommended following absorption of the majority of haemorrhage (section 4.3), the Committee accepted the extent of macular haemorrhage as the definition of the group of people for whom grid laser photocoagulation is not an option. The Committee understood that, when grid laser photocoagulation is not an option, the comparator in this analysis would be dexamethasone. It considered the ERG's exploratory analysis in which the ICER was £4100 per QALY gained for ranibizumab compared with dexamethasone. Consistent with its previous conclusions it recognised that this ICER would be subject to uncertainty because of the absence of a direct comparison between ranibizumab and dexamethasone and because of confounding in the BRAVO trial. However, the Committee remained satisfied that the most plausible ICER would be below £20,000 per QALY gained. The Committee therefore concluded that ranibizumab should be recommended as an option for treating visual impairment caused by macular oedema following BRVO when grid laser photocoagulation has not been beneficial or is not suitable because of the extent of macular haemorrhage.\nThe Committee discussed how innovative ranibizumab is in its potential to make a significant and substantial impact on health‑related benefits. It agreed that anti‑VEGF treatments were a substantial improvement over previous treatments, but considered that this improvement applied to the class of drugs, including bevacizumab. It stated that the innovation was in the scientific step forward, not the act of licensing. In addition the Committee was not aware of any substantial benefits of ranibizumab over its comparators that would not be already captured into the QALY estimation in the modelling.\nThe Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal in the guidance.\n\n# Summary of Appraisal Committee's key conclusions\nTA283\nAppraisal title: Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion\nSection\nKey conclusion\nRanibizumab is recommended as an option for treating visual impairment caused by macular oedema:\nfollowing central retinal vein occlusion or\nfollowing branch retinal vein occlusion only if treatment with laser photocoagulation has not been beneficial, or when laser photocoagulation is not suitable because of the extent of macular haemorrhage and\n-nly if the manufacturer provides ranibizumab with the discount agreed in the patient access scheme revised in the context of NICE technology appraisal guidance 274.\nCurrent practice\nClinical need of patients, including the availability of alternative treatments\nThe Committee heard that the loss of vision has a significant effect on the independence of people with the condition. The Committee agreed that loss of vision caused by macular oedema secondary to retinal vein occlusion seriously impairs health‑related quality of life.\nThe Committee heard from clinical specialists that the current standard treatment for visual impairment caused by macular oedema secondary to branch retinal vein occlusion (BRVO) is grid laser photocoagulation but that in interim guidelines from the Royal College of Ophthalmologists it is only recommended after a period of 3 to 6 months following the initial event (obstruction of retinal veins) and following the absorption of the majority of the haemorrhage. The Committee heard from the clinical specialists that grid laser photocoagulation is not an option for people with central retinal vein occlusion (CRVO) and the current standard treatment is dexamethasone or anti‑vascular endothelial growth factor (VEGF) drugs such as bevacizumab.\nThe technology\nProposed benefits of the technology\nHow innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?\nThe Committee was not aware of any substantial benefits of ranibizumab over its comparators that would not be already captured into the quality‑adjusted life year (QALY) estimation in the modelling.\nWhat is the position of the treatment in the pathway of care for the condition?\nRanibizumab has a marketing authorisation for 'the treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO)'.\nAdverse reactions\nThe Committee noted that the overall frequency of adverse effects in the BRAVO and CRUISE trials at month 6 was low. It agreed that ranibizumab was safe and well tolerated in patients with macular oedema secondary to RVO.\nEvidence for clinical effectiveness\nAvailability, nature and quality of evidence\nThe Committee was aware that most patients with retinal ischaemia were excluded from the BRAVO and CRUISE trials, because patients with a brisk afferent pupillary defect (which equates to severe retinal ischaemia) were excluded. It heard from the clinical specialists and the manufacturer that this meant that there was no evidence of ranibizumab for treating visual impairment caused by RVO in patients with significant ischaemia.\nHaving noted the available evidence and comments from consultation (of the Decision Support Unit report) on the safety, efficacy and quality of intravitreal bevacizumab, the Committee concluded that bevacizumab is an appropriate potential comparator in this appraisal. However, the Committee further concluded that there is currently insufficient evidence to make the robust comparisons with ranibizumab needed for a cost‑effectiveness analysis.\nRelevance to general clinical practice in the NHS\nThe Committee heard from clinical specialists that the current standard treatment for visual impairment caused by macular oedema secondary to branch RVO is grid laser photocoagulation but that it is only recommended after a period of 3 to 6 months following the initial event (obstruction of retinal veins) and following the absorption of the majority of the haemorrhage. The Committee heard from the clinical specialists that grid laser photocoagulation is not an option for people with central RVO because CRVO does not respond to grid laser photocoagulation and the current standard treatment is dexamethasone or anti‑vascular endothelial growth factor (VEGF) drugs such as bevacizumab.\nUncertainties generated by the evidence\nThe Committee was aware that ranibizumab could be used as needed in both arms of the BRAVO and CRUISE trials from 6 months, and that in the BRAVO trial, grid laser photocoagulation was permitted after 3 months in both the sham and the ranibizumab groups, confounding the results of the treatment phase from month 3 onwards.\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\nThe Committee concluded that ranibizumab is a clinically effective treatment for visual impairment caused by macular oedema secondary to BRVO and CRVO compared with sham injection, if there is no significant retinal ischaemia.\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\nThe Committee noted that in both BRAVO and CRUISE ranibizumab was associated with statistically significant mean gains in BCVA in the treated eye compared with sham injection for the 6‑month treatment phase. It also noted that ranibizumab was associated with sustained gains in BCVA at 12 months in both BRAVO and CRUISE, and that these were statistically significant (p<0.01 and p<0.001 respectively). The Committee concluded that ranibizumab is a clinically effective treatment for visual impairment caused by macular oedema secondary to BRVO and CRVO compared with sham injection, if there is no significant retinal ischaemia.\nEvidence for cost effectiveness\nAvailability and nature of evidence\nThe Committee considered the manufacturer's original economic model and the critique and exploratory analyses performed by the Evidence Review Group (ERG). It broadly accepted the model structure, but was aware of the uncertainties highlighted by the ERG around the assumptions used by the manufacturer.\nThe Committee also considered the manufacturer's revisions to its economic model submitted in response to consultation and broadly accepted the manufacturer's approach to:\nreflecting that most patients (90%) would be treated in their 'worse‑seeing eye'\nthe use of utilities as applied using the Czoski‑Murray equation, in absence of further evidence\napplying unpooled transition probabilities although there was a lack of clear data\nthe inclusion of updated adverse event rates in year 2, albeit cautiously.\nUncertainties around and plausibility of assumptions and inputs in the economic model\nThe Committee considered that a 0.3 utility gain associated with treating the 'worse‑seeing eye' seems high given that utility is driven primarily by the 'better‑seeing eye', and therefore lacked face validity.\nThe Committee concluded that a utility gain of 0.1 associated with treating the 'worse‑seeing eye' was appropriate.\nThe Committee concluded that the evidence on the risk of cardiovascular mortality associated with RVO was unclear, and therefore it need not be included in the base‑case model to the degree applied in the original ERG report. However it would remain an uncertainty in the analysis.\nThe Committee acknowledged that there were advantages and disadvantages to the manufacturer and ERG's approaches (to applying unpooled transition probabilities). But it concluded that, given the lack of clear data, the approach taken by the manufacturer was appropriate.\nAlthough the Committee acknowledged the ERG's concerns with the methods used to estimate adverse events in year 2, it cautiously accepted the updated safety data in the model.\nThe Committee accepted that the relative effectiveness of ranibizumab and dexamethasone was uncertain and concluded that it was difficult to quantify any bias.\nThe Committee was aware of the remaining uncertainty because of the absence of a direct comparison with dexamethasone.\nThe Committee was aware that people receiving ranibizumab in the BRAVO trial could receive grid laser photocoagulation from month 3 and that this represented a significant confounding factor in both the manufacturer's and the ERG's calculations of the ICER for BRVO compared with standard care. It therefore considered that this ICER would be an underestimate of the most plausible ICER.\nIncorporation of health‑related quality‑of‑life benefits and utility values\nHave any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?\nThe Committee noted that the BRAVO and CRUISE trials reported a statistically significant difference in NEI VFQ‑25 score at month 6 between the ranibizumab and sham injection groups. The Committee concluded that treating patients with ranibizumab improved the quality of life of people with macular oedema secondary to RVO.\nThe Committee concluded that although uncertain, the use of utilities as applied using the Czoski‑Murray equation was acceptable.\nThe Committee concluded that a utility gain of 0.1 associated with treating the 'worse‑seeing eye' was appropriate.\nThe Committee was not aware of any substantial benefits of ranibizumab over its comparators that would not be already captured into the QALY estimation in the modelling.\nAre there specific groups of people for whom the technology is particularly cost effective?\nThe Committee concluded that ranibizumab should be recommended as an option for treating visual impairment caused by macular oedema following BRVO if grid laser photocoagulation has not been beneficial or is not suitable because of the extent of macular haemorrhage.\nWhat are the key drivers of cost effectiveness?\nThe ERG exploratory analyses highlighted that the key drivers that increased the manufacturer's base‑case ICERs were amending the proportion of patients treated in their 'better‑seeing eye' (10% instead of 100%) and the assumption of some benefit associated with treating the 'worse‑seeing eye'.\nThe Committee considered that a 0.3 utility gain associated with treating the 'worse‑seeing eye' seems high given that utility is driven primarily by the 'better‑seeing eye', and therefore lacked face validity.\nMost likely cost‑effectiveness estimate (given as an ICER)\nRanibizumab was associated with an ICER of £26,200 per QALY gained compared with best supportive care in CRVO.\nThe Committee concluded that the most plausible ICER for ranibizumab compared with standard care in treating BRVO was in excess of £44,800 per QALY gained.\nAdditional factors taken into account\nPatient access schemes (PPRS)\nThe Department of Health and the manufacturer have agreed that ranibizumab will be available to the NHS with a patient access scheme which makes ranibizumab available with a discount. The level of the discount is commercial in confidence.\nEnd‑of‑life considerations\nNot applicable.\nEqualities considerations and social value judgements\nThe Committee considered whether there were any equalities considerations affecting population groups protected by equality legislation and concluded that there were no equality issues relating to this appraisal that needed addressing in the guidance.\n\n# Recommendations for further research \nThe Committee concluded that further research directly comparing the clinical and cost effectiveness of ranibizumab and bevacizumab in people with macular oedema secondary to retinal vein occlusion should be conducted.# Related NICE guidance\nDetails are correct at the time of publication. Further information is available on the NICE website.\nPublished\nRanibizumab for treating diabetic macular oedema (rapid review of technology appraisal 237). NICE technology appraisal guidance 274 (2013).\nFluocinolone acetonide intravitreal implant for the treatment of chronic diabetic macular oedema after an inadequate response to prior therapy. NICE technology appraisal guidance 271 (2013).\nDexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion. NICE technology appraisal guidance 229 (2011).\nRanibizumab and pegaptanib for the treatment of age\\u2011\\related macular degeneration. NICE technology appraisal guidance 155 (2008).\nUnder development\nAflibercept solution for injection for the treatment of macular oedema caused by central retinal vein occlusion. NICE technology appraisal. Publication date to be confirmed.# Review of guidance\nThe guidance on this technology will be considered for review in March 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\nAndrew DillonChief ExecutiveMay 2013# Changes after publication\nJanuary 2014:\n minor maintenance.# About this guidance\nNICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\nThis guidance was developed using the NICE single technology appraisal process.\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\nCopyright© National Institute for Health and Care Excellence 2013. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\nISBN 978-1-4731-0134-0"}}},{"rowIdx":90,"cells":{"id":{"kind":"string","value":"7bfbf3d1b5d4b21cfbf987ae9d33dd91e6e4826b"},"source":{"kind":"string","value":"who"},"text":{"kind":"string","value":"Fortification of industrially processed flour, when appropriately designed and implemented, is an efficient, simple and inexpensive strategy for supplying vitamins and minerals to the diets of large segments of the population. Wheat is cultivated and consumed in many parts of the world and its domestication contributed to the development of farming and human civilization. Industrial fortification of wheat flour with at least iron has been practised for many years in several countries where the flour is used in the preparation of different types of bread and national dishes.\nDecisions about which nutrients to add to fortified wheat flour and how much of each nutrient to use should be based on the nutritional needs and intake gaps of the target populations; the usual level of consumption of wheat flour and products made from this staple; the sensory and physical effects of the fortificant on the flour and on flour products; the type of wheat and the extraction rate 1 of the flour; the availability and coverage of fortification of other staple food vehicles in addition to other commercially available fortified products; the population use of vitamin and mineral supplements; costs; feasibility; and acceptability of the fortified product by the consumers.\nWheat flour can be fortified with several micronutrients, such as iron, folic acid and other B-complex vitamins 2 vitamin A and zinc. Some micronutrients are incorporated for restitution of the original nutritional contents of unrefined wheat flour, and others are used for correcting inadequacies and associated deficiencies of public health significance. The bioavailability of the added micronutrients will partially depend on the grain type and the extraction rate of the flour.\n\n# PURPOSE OF THE GUIDELINE\nThe main objective of this guideline is to provide locally adaptable, clear, evidence-informed global recommendations on the fortification of wheat flour with vitamins and minerals as a public health strategy to improve the micronutrient status of populations, which are grounded in gender, equity and human rights approaches with the aim of leaving no one behind. The focus of this document is on the use of this intervention as a public health strategy and not on market-driven fortification of wheat flour or products 3. This guideline aims to help Member States and their partners to make informed decisions on the appropriate nutrition actions to achieve the 2030 Sustainable Development Goals and the global targets set in the World Health Organization (WHO) Comprehensive implementation plan on maternal, infant and young child nutrition.\nThe recommendations in this guideline are intended for a wide audience, including policymakers, expert advisers, and technical and programme staff in ministries and organizations involved in the design, implementation and scaling-up of nutrition actions for public health. The recommendations are particularly relevant to the design and implementation of appropriate food-fortification programmes, as part of a comprehensive food-based strategy for combating micronutrient inadequacies and deficiencies.\nThese recommendations supersede the previous WHO recommendation on fortification of wheat flour1. The guideline complements the WHO/FAO (Food and Agriculture Organization of the United Nations) Guidelines on food fortification with micronutrients2 and the Pan American Health Organization (PAHO) Iron compounds for food fortification: guidelines for Latin America and the Caribbean 20023. These two documents are not WHO standard guidelines but contain information still current that is not covered in this guideline. Because of the important aspects covered, the WHO Nutrition and Food Safety Department plans to update both documents.\n\n# GUIDELINE DEVELOPMENT METHODOLOGY\nWHO developed the present evidence-informed recommendations using the procedures outlined in the WHO handbook for guideline development. The steps in this process included: (i) identification of the priority questions and outcomes; (ii) retrieval of the evidence; (iii) assessment and synthesis of the evidence; (iv) formulation of recommendations, including research priorities; and planning for (v) dissemination; (vi), equity, human rights, implementation, regulatory and ethical considerations; as well as (vii) impact evaluation and updating of the guideline. The Grading of Recommendations Assessment, Development and Evaluation (GRADE)4 methodology was followed to prepare evidence profiles related to preselected topics, based on up-to-date systematic reviews and other narrative syntheses of the evidence.\nThe guideline development group consisted of content experts, methodologists and representatives of potential beneficiaries. One guideline group participated in a meeting where the guideline was scoped, and a second WHO guideline development group -nutrition actions, was convened to discuss the evidence and finalize the recommendations. The members of the first guideline development group meeting identified five priority areas for guidelines on food fortification: wheat, maize, rice, sugar, and oil and condiments. For each item the group prioritized the nutrients based on the prevalence of deficiency and the feasibility of fortification based on nutrients to add and the characteristics of the food vehicle(s). For wheat flour the group prioritized iron, folic acid and zinc.\nRecommendations on wheat and maize flour fortification. Meeting report: interim consensus statement. Geneva: World Health Organization; 2009 (, accessed 1 February 2022).\nThe GRADE approach defines the overall rating of confidence in the body of evidence from systematic reviews as the extent to which one can be confident of an estimate of effect across all outcomes considered critical to the recommendation. Each critical outcome had a confidence rating based on certainty of evidence -high, moderate, low or very low. High-certainty evidence indicates that we are very confident that the true effect lies close to that of the estimate of the effect. Moderate-certainty evidence indicates that we are moderately confident in the effect estimate and that the true estimate is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low-certainty evidence indicates that our confidence in the effect estimate is limited and the true effect may be substantially different from the estimate of the effect. Very low-certainty evidence indicates that we have very little confidence in the effect estimate and the true effect is likely to be substantially different from the estimate of effect.\nSystematic reviews team members participated in the guideline development process as resource persons by presenting evidence and identifying research priorities. While developing recommendations, the guideline development group considered additional factors in the implementation of wheat flour fortification as a public health strategy, including equitable access and universal coverage. Four technical experts were invited to peer-review the draft guideline.\n\n# SUMMARY OF THE EVIDENCE\nSeveral systematic reviews were included in the evidence to decision document presented to the guidelines development group to inform recommendations.\n- For iron, seven systematic reviews were included that aimed to determine the benefits and harms of wheat flour fortification with iron on anaemia, iron status and health-related outcomes.\n- For folic acid, one systematic review was commissioned to evaluate the effect of fortification of wheat and maize flour with folic acid on population health outcomes.\n- For zinc, two systematic reviews evaluated the effects of the fortification of staple foods on health-related outcomes and biomarkers of zinc status in the general population.\n- For vitamin A, one systematic review assessed the effects of fortifying staple foods on vitamin A deficiency and health-related outcomes in the general population.\nA systematic review was commissioned to determine the benefits and harms of wheat flour fortification, with iron alone or with other vitamins and minerals, on anaemia, iron status and health-related outcomes. Ten trials, involving 3319 participants, were included in the review and assessment of different iron compounds, doses and duration of fortification. In comparison to unfortified flour, wheat flour fortified with iron alone or with other micronutrients may reduce anaemia and probably makes little or no difference in the risk of iron deficiency. The effect of wheat flour fortified with iron on haemoglobin concentrations is uncertain.\n\n# FOLIC ACID\nA systematic review from 2019 concluded that fortification of wheat flour with folic acid alone or with other micronutrients may increase erythrocyte and serum/plasma folate concentrations and may reduce the risk of neural tube defects compared to unfortified flour.\nTwo systematic reviews aimed to evaluate the beneficial and adverse effects of fortification of staple foods with zinc on health-related outcomes and biomarkers of zinc status in the general population.\nBoth reviews show that zinc may improve the serum zinc status of populations, reducing the prevalence of zinc deficiency and may provide health and functional benefits, including a reduced incidence of diarrhoea.\n\n# VITAMIN A\nA systematic review assessed the effects of fortifying staple foods with vitamin A for reducing vitamin A deficiency and improving health-related outcomes in the general population older than 2 years of age. Out of ten studies, two were on wheat flour and showed that vitamin A, with or without other micronutrients, made little or no difference to the serum retinol levels in children and adolescents after six months of intervention.\nOverarching principle for recommendations -Fortification of cereal flours, in this case industrially processed/produced wheat flour fortification, should be considered when wheat flour is regularly consumed by large population groups in a country. The fortification scheme in terms of which nutrients to add and in what amounts should be based on the nutritional needs of the population, usual consumption of fortifiable flour, sensory and physical effects of the added nutrients on flour and flour products, type of wheat and the extraction rate of flour, other fortified food items or ongoing micronutrient programmes, and fortification costs, feasibility and acceptance.\nBased on available evidence, the recommendations to fortify wheat flour are as follows.\n- Fortification of wheat flour with highly bioavailable iron is recommended as a public health strategy to improve haemoglobin concentrations and iron status, and to prevent anaemia and iron deficiency in populations, particularly for vulnerable groups such as children and women (strong recommendation, low certainty of evidence).\n- Fortification of wheat flour with folic acid is recommended as a public health strategy to reduce the risk of occurrence of pregnancies affected by neural tube defects among women of reproductive age and to improve folate status in populations (strong recommendation, low and very low certainty of evidence).\n- Fortification of wheat flour with zinc may be used as a public health strategy to improve serum/ plasma zinc status of populations (conditional recommendation, low certainty of evidence).\n\n# KEY REMARKS\nThe remarks in this section are suggestions intended to give some considerations for implementation of the recommendations, based on the discussions of the guideline development group.\n- When vitamin A deficiency constitutes a public health problem and no other/insufficient strategies to address it are in place, fortification of wheat flour with vitamin A could be considered as a public health strategy to improve vitamin A status or to reduce the risk of subclinical vitamin A deficiency.\n- In countries with a high prevalence of vitamin B 12 depletion and deficiency, the inclusion of vitamin B 12 could be considered when staples are fortified with folic acid, to prevent unintended consequences of imbalances caused by the addition of folic acid alone.\n- Since some of the B-complex vitamins naturally present in the wheat kernel are removed during milling, especially with low-extraction (i.e. refined) wheat flour, the restoration of thiamine, riboflavin, niacin and pyridoxine in wheat flour could be considered as a regular practice in fortification.\n- The choice of iron compound is a compromise between cost, bioavailability, micronutrient interactions and the acceptance of texture, taste, smell and/or colour.\n- The removal of phytates in wheat flour could increase the bioavailability of iron and zinc.\n- Addition of vitamins and minerals to wheat flour should be based on evidence about inadequacy of micronutrient intakes and/or the prevalence of deficiency. This pre-fortification data will also serve for measuring impact of the fortification programme.\n- Countries that fortify wheat flour may also fortify other food items. A combined fortification strategy using multiple vehicles appears to be a suitably effective option for reaching all segments of the population. Fortification of wheat flour should be integrated and monitored as part of their national programmes for prevention and control of micronutrient deficiencies and insufficiencies.\n- Food fortification should be guided by national standards, with quality-assurance and qualitycontrol systems to ensure quality fortification. Continuous programme monitoring should be in place as part of a process to ensure high-quality implementation. Monitoring consumption patterns and evaluation of micronutrient status in the population can inform adjustment of fortification levels over time.\n- Populations should be encouraged to receive adequate nutrition, which is best achieved through consumption of a healthy balanced diet. Fortified foods only complement the diet when feasible and required.\n- Although evidence is limited, fortification of wheat flour could potentially decrease inequity in population access to and consumption of micronutrient required to achieve good health and to prevent adverse health outcomes.\n- The following table contains a list of nutrients and levels that could be added to wheat flour for fortification and/or restitution of contents based on extraction rate, chemical form and estimated per capita flour consumption. Note: This table is for general guidance and is partially based on the 2009 Recommendations on wheat and maize flour fortification. The number and amounts of nutrients should be adapted according to the needs of the country. These estimated target levels consider only wheat flour as the main fortification vehicle in a public health programme. If other large-scale food fortification programmes are implemented effectively, these suggested fortification levels may need to be adjusted downwards as needed.\na Nutrient levels were adapted from the 2009 Recommendations on wheat and maize flour fortification and the evidence presented and discussed at the guideline development group meeting.\nb High-extraction flour (>80%) is also known as whole flour. It retains high levels of natural phytates, which inhibit the body's ability to absorb iron and zinc. High-extraction flours contain a naturally higher content of vitamins and minerals than low-extraction flours.\nc Estimated per capita consumption of <75 g/day does not allow for the addition of sufficient amounts of fortificant to cover the needs of some micronutrients for women of reproductive age. Fortification of additional food vehicles and other interventions may need to be considered.\nd The amounts of micronutrients such as iron, zinc and calcium presented here are in mg of the elemental micronutrient. The amount of a micronutrient compound to add should be calculated depending on the molecular weight of the compound.\ne These amounts of zinc fortification assume 5 mg zinc intake and no additional phytate intake from other dietary sources. As with iron, the phytate concentration of high-extraction flour will affect the bioavailability of zinc.\nf Consider fortifying wheat flour with vitamin A when deficiency constitutes a public health problem and no other strategies to address it are in place.\ng Inclusion of vitamin B 12 is recommended when its deficiency is a public health problem or when wheat flour is fortified with folic acid.\nh Restitution of some B-complex vitamins should be achieved as a regular practice in all settings. The B-vitamins contents vary between types of whole wheat flours.\ni Compounds and amounts indicated in this section are seldom used and constitute only rough estimates. Including them will depend on country needs, wheat type and other ongoing nutrition programmes.\nj Level used in Jordan and Mongolia, with consumptions above 300 g/day. For lower levels of wheat flour consumption, consider increasing the amount of vitamin D.\n\n# EVIDENCE GAPS\nThe WHO guideline development groups and the systematic reviews teams highlighted the limited evidence available in some areas. Further research on wheat flour fortification is merited, particularly in:\n- the bioavailability of different iron compounds for use in wheat flour fortification, including mixtures of different compounds;\n- the bioavailability and stability of added folic acid, vitamin A and vitamin D in wheat flour;\n- fortification of wheat flour with zinc only in comparison with fortification with a mix of micronutrients;\n- the effects of different phytate contents on the absorption of iron and zinc from the premix formulation;\n- biomarkers of individual micronutrient status under different conditions of infection and inflammation;\n- stability of different micronutrients and compounds in different cooking processes that are context specific;\n- relative bioavailability among different chemical forms of various micronutrients that can be used in wheat flour fortification, including nutrient-nutrient interactions;\n- the most appropriate delivery platforms of the fortified flour/fortified flour products for reaching the intended target population;\n- the impact of wheat flour fortification on micronutrient status and health outcomes to prevent excessive supplies of micronutrients to certain groups and identify situations where complementary interventions are needed to reduce inequity in populations.\n\n# PLANS FOR UPDATING THE GUIDELINE\nThe WHO Secretariat will continue to follow research developments in wheat flour fortification, particularly for questions in which the certainty of evidence was found to be low or very low. If the guideline merits an update, or if there are concerns about the validity of the guideline, the Department of Nutrition and Food Safety, in collaboration with other WHO departments or programmes, will coordinate the guideline update, following the formal procedures of the WHO handbook for guideline development.\n\n# WHO GUIDELINE 1 : FORTIFICATION OF WHEAT FLOUR WITH VITAMINS AND MINERALS AS A PUBLIC HEALTH STRATEGY\n\n# SCOPE AND PURPOSE\nWHO is committed to increasing the impact of public health measures in every country, ensuring healthy lives and promoting well-being for all at all ages. As part of its unique normative function in public health, WHO aims to provide global, evidence-informed recommendations on the fortification of wheat flour with vitamins and minerals to improve health outcomes associated with micronutrient status. This guideline will support the work of WHO regional and country offices and will help Member States and their partners to make evidence-informed decisions on the appropriate actions in their efforts to improve access to quality essential health services, support countries to be prepared for health emergencies, and address the determinants of health. It will also help in increasing capacity in the countries to respond to their needs on improving micronutrient status and to prioritize essential nutrition actions in national health policies, strategies and plans.\nThe guideline aims to help Member States and their partners in their efforts to make informed decisions on the appropriate nutrition actions to achieve the 2030 Sustainable Development Goals (1), in particular, Goal 2: End hunger, achieve food security and improved nutrition and promote sustainable agriculture and Goal 3: Ensure healthy lives and promote well-being for all at all ages. It will also support Member States in their efforts to achieve the global targets of the Comprehensive implementation plan on maternal, infant and young child nutrition (2) and The global strategy for women's, children's and adolescents' health (2016-2030) (3).\nThe recommendations in this guideline are intended for a wide audience, including policymakers, their expert advisers and technical and programme staff at ministries and organizations involved in the design, implementation and scaling-up of nutrition actions for public health. This guideline is intended to contribute to discussions among stakeholders when selecting or prioritizing interventions to be undertaken in their specific context. The document presents the key recommendations and a summary of the supporting evidence. Further details of the evidence base are provided in Annex 1 and other documents listed in the references.\nThe most studied and more prevalent nutritional problems -anaemia and iron, folate, zinc, vitamin A and iodine deficiencies -are serious public health issues that particularly affect young children and women. The most common causes of micronutrient deficiencies are related to inadequate intakes, utilization or increased losses.\nAnaemia is a condition in which the number of red blood cells or the haemoglobin concentration within them is lower than normal. The most common causes of anaemia include nutritional deficiencies, particularly of iron, although deficiencies in folate, vitamin B 12 and vitamin A are also important causes; inherited haemoglobinopathies; and infectious diseases, such as malaria, tuberculosis, HIV and parasitic infections. Anaemia is a serious global public health problem that particularly affects young children and pregnant women. WHO estimates that 40% of children aged 6-59 months and 37% of pregnant women worldwide are anaemic (4).\nLow folate status in women of reproductive age can lead to adverse health consequences of public health significance, such as megaloblastic anaemia (folate deficiency) and an increased risk of pregnancies affected by neural tube defects. A review, which involved searching eight databases and the WHO Micronutrients Database, identified surveys of population prevalence of folate deficiency or insufficiency in women of reproductive age. Between 2000 and 2014, 45 relevant surveys in 39 countries were published. Prevalence of folate deficiency was >20% in many countries with lowerincome economies but was typically 40% in most countries (5).\nZinc deficiency is largely related to inadequate intake or absorption of zinc from the diet, although excess losses of zinc during diarrhoea may also contribute. Severe zinc deficiency was defined in the early 1900s as a condition characterized by short stature, hypogonadism, impaired immune function, skin disorders, cognitive dysfunction, and anorexia. Estimates based on food availability data indicate that zinc inadequacy (i.e. intakes that do not satisfy the nutrient requirements) affects about one third of the world's population, with estimates ranging from 4% to 73% across subregions. Although severe zinc deficiency is rare, mild-to-moderate zinc deficiency is quite common throughout the world. At least 17% of the world's population is at risk of inadequate zinc intake with the highest risk occurring in sub-Saharan Africa and south Asia (6). Worldwide, it is estimated that zinc deficiency is associated with approximately 16% of lower respiratory tract infections, 18% of malaria and 10% of diarrhoeal disease.\nVitamin A deficiency is the leading cause of preventable blindness in children and increases the risk of disease and death from severe infections. In pregnant women, vitamin A deficiency causes night blindness and may increase the risk of maternal mortality. Vitamin A deficiency is a public health problem in more than half of all countries, especially in Africa and south-east Asia, affecting young children and pregnant women in low-income countries the most (7).\nEmerging, unexpected situations that affect health, food safety or trade have a deep impact on micronutrient status, especially of vulnerable populations such as children, women and elderly people. The COVID-19 pandemic is likely worsening the already high prevalence of micronutrient deficiencies worldwide. Lockdowns and physical distancing may lead to decreased family income and reduced access to crops, food, services, health care and social protection programmes that could result in increased rates of malnutrition and micronutrient deficiency. Modelling predicts that the COVID-19 pandemic will have a significant impact on maternal and child undernutrition and child mortality in the current generation, with large long-term negative consequences on productivity (8).\nWheat is cultivated and consumed in many parts of the world, and its domestication contributed to the development of farming and human civilization. It was first cultivated 9000 years ago in the Euphrates Valley of the Middle East. An estimated 65% of the global wheat crop is used for human consumption, 17% is used for animal feed and 12% is used in industrial applications, including biofuel production (9). China, India and the Russian Federation are the top three producers of wheat (10). Low-income countries consume 77% of wheat produced globally and are generally wheat importers, with wheat accounting for 24% of imported food commodities in these countries (11,12). In 2019, the annual production of wheat was 765 769 635 tonnes, being the second most produced cereal after maize and before rice (12).\nWheat is a staple in many countries due to its agronomic adaptability, ease of grain storage and milling, and suitability for making edible, palatable, acceptable and satisfying foods (13). Doughs produced from wheat flour differ from those made from other cereals in their unique viscoelastic properties. Wheat varieties, including hard/soft, winter/spring, and red, white and durum, are grown at a variety of altitudes and in various types of soil throughout the world.\nAll types of wheat belong to the genus Triticum aestivum, subspecies vulgare. In addition, three other species are cultivated and traded: T. durum T. compactum and T. spelta. Because of its quality, durum wheat is used by the pasta industry, and non-durum wheat is used for milling, livestock feed or ethanol production. Wheat kernels have three components: bran, germ, and endosperm. Most wheat is milled into flour through mechanical extraction of the endosperm, the core part of the kernel containing mainly carbohydrates and some proteins (14,15). The nutrient-rich germ and bran are usually removed in refined flours and therefore the micronutrient content of these flours is lower than that of whole wheat flour.\nThe production of wheat flour is a multi-step process to isolate the endosperm and subsequent sifting into flour (16). The extraction rate of a flour is the extent to which it has been sifted to separate the fine-grain endosperm, with a higher extraction rate indicating higher retention of the bran and germ. Most vitamins and minerals in wheat are found in the bran or germ, and flours of 80% or lower extraction rates have a significantly reduced micronutrient content (14). However, high-extraction flour also contains higher levels of phytates, which interfere with intestinal absorption of iron and other minerals as zinc and copper (17,18).\nFortification is the practice of deliberately increasing the content of one or more micronutrients, i.e. vitamins and minerals, in a food to improve the nutritional quality of the food supply and provide a public health benefit with minimal risk to health. Fortification of staple foods is one of the strategies used to safely and effectively prevent vitamin and mineral inadequacies and their associated deficiencies in populations (19).\nFortification of industrially processed wheat flour, when appropriately designed and implemented, can be an efficient, simple and inexpensive strategy for supplying vitamins and minerals to the diets of large segments of the population. Industrial fortification of wheat flour has been practised for many years in several countries where the flour is used in the preparation of different types of bread and national dishes. Based on data from the Food Fortification Initiative, 86 countries in 2021 had legislation on fortification of wheat flour alone or in combination with other grains. Table 1 shows the most common levels and chemical forms of micronutrient compounds included in standards for wheat flour fortification around the world.\nDecisions about which nutrients to add to fortified wheat flour and how much of each nutrient to use should be based on the nutritional needs and intake gaps of the target populations; usual level of consumption of wheat flour and products made from this staple; sensory and physical effects of the fortificant on the flour and on flour products; type of wheat and the extraction rate of the grain; availability and coverage of other fortified staple foods, in addition to other commercially available fortified products; population use of vitamin and mineral supplements; costs; feasibility; and acceptability by the producers and consumers (19)(20)(21).\nWheat flour can be fortified with several micronutrients, such as iron, folic acid and other B-complex vitamins 1 vitamin A and zinc. Some micronutrients are incorporated for restitution of original nutritional contents of unrefined wheat flour, and others are used for correcting inadequacies and their associated deficiencies of public health significance. The bioavailability of the added micronutrients will depend in part on the grain type and the extraction rate of the flour.\nIn many cases, procedures for the fortification of wheat and maize flours have been viewed and managed similarly, and many of the conclusions on the impact of fortification programmes are based on experiences with wheat flour, or on programmes simultaneously fortifying wheat and maize flour (22). It is now recognized that there are differences and that the principles that apply to fortification of wheat flour may not necessarily apply to fortification of other flours (23). The whole fortification process and supply chain in a given country is an intricate network of public and private entities that link farmers, collectors, traders, millers, retailers and food processors to the final consumers. Other stakeholders include transporters; companies that supply seeds, agrochemicals, and agricultural equipment; irrigation companies; inspection agencies; government departments of commerce, tax, and agriculture; and other state agencies that control the flow in this chain according to individual governmental policies (24).\nFortification programmes should include appropriate quality-assurance and quality-control programmes at mills, as well as regulatory and public health monitoring of the nutrient content of fortified foods and assessment of the nutritional and health impacts of the fortification strategies. There are also specific country or community settings to evaluate and decisions to make. For example, from a quality-control point of view, it is desirable that milling is centralized in few mills, although this is not the case in some countries.\nThe main objective of this guideline is to provide locally adaptable, clear, evidence-informed global recommendations on the fortification of wheat flour with vitamins and minerals as a public health strategy to improve the micronutrient status of populations, which are grounded in gender, equity and human rights approaches with the aim of leaving no one behind. These recommendations supersede the previous WHO recommendation on fortification of wheat flour 1.The guideline complements the WHO/FAO Guidelines on food fortification with micronutrients (19) and the PAHO 2002 document, Iron compounds for food fortification: guidelines for Latin America and the Caribbean (25). These two documents are not WHO standard guidelines but contain information still current that is not covered in this guideline. Because of the important aspects covered, the WHO Nutrition and Food Safety Department plans to update both documents.\n\n# SUMMARY OF THE EVIDENCE\n\n# WHEAT FLOUR FORTIFICATION AND POPULATION MICRONUTRIENT STATUS AND HEALTH-RELATED OUTCOMES\nSeveral systematic reviews were included in the evidence to decision document presented to the guidelines development group to inform recommendations.\n- For iron, seven systematic reviews were included that aimed to determine the benefits and harms of wheat flour fortification with iron on anaemia, iron status and health-related outcomes. One of the reviews was commissioned, and results from six additional systematic reviews were discussed to complement findings from the commissioned review.\n- For folic acid, one systematic review was commissioned to evaluate the effect of fortification of wheat and maize flour with folic acid on population health outcomes.\n- For zinc, two systematic reviews evaluated the effects of the fortification of staple foods on health-related outcomes and biomarkers of zinc status in the general population.\n- For vitamin A, one systematic review assessed the effects of fortifying staple foods on vitamin A deficiency and health-related outcomes in the general population.\nThe evidence from systematic reviews was used to prepare the evidence-to-decision framework and draft this guideline. The GRADE summary of findings tables for each of the critical outcomes were prepared from commissioned (Cochrane) systematic reviews.\nA systematic review was commissioned to determine the benefits and harms of wheat flour fortification with iron alone or with other vitamins and minerals on anaemia, iron status and health-related outcomes (18). The systematic review included cluster and individual randomized controlled trials done among general populations in any country aged 2 years and above. Ten trials, involving 3319 participants, were included in the review. The duration of interventions varied from 3 to 24 months. In comparison to unfortified flour, wheat flour fortified with iron alone or with other micronutrients may reduce anaemia and probably makes little or no difference in iron deficiency. The effect of wheat flour fortified with iron increasing haemoglobin concentrations is uncertain (18).\nA group of six systematic reviews on food fortification, which included wheat flour fortified with iron and other micronutrients were also reviewed (26)(27)(28)(29)(30)(31). Studies of populations from all socioeconomic strata showed that fortification of flours with iron is an effective strategy to improve the iron status of populations (26); this includes large-scale food fortification programmes in lowand middle-income countries (27). The impact of flour fortification on iron status and anaemia has also been demonstrated government-supported fortification programmes in children and women of reproductive age, showing statistically significant decreases in the prevalence of anaemia and in low serum/plasma ferritin concentrations (28).\nThe review of randomized controlled trials on food fortification with iron, including wheat flour consumed as bread, snacks, noodles and biscuits in children aged <10 years, showed a significant increase of haemoglobin concentration in the fortification group compared with the control group (29). A systematic review of studies of the effect of fortification of staple foods in women of reproductive age and pregnant women reported a significant increase in serum ferritin and haemoglobin levels (30). Finally, a systematic review of 60 randomized and pseudorandomized controlled trials found that, compared with non-fortified food intake, consumption of foods fortified or biofortified with iron (31) resulted in significant improvements in haemoglobin, serum ferritin and iron status, and a reduced risk of remaining anaemic and iron deficient.\n\n# FOLIC ACID\nA systematic review was commissioned to evaluate the effect of fortification of wheat and maize flour with folic acid on population health outcomes. Seven studies included fortified wheat flour (32). Adults consuming bread rolls made with wheat flour fortified with folic acid had higher erythrocyte folate (mean difference 0.66 nmol/L, 95% confidence interval 0.13 to 1.19; 1 study, 30 participants; very low-certainty evidence) and plasma folate (MD 27.00 nmol/L, 95% CI 15.63 to 38.37; 1 study, 30 participants; very low-certainty evidence) than those consuming bread made with unfortified flour. The authors conclude that folic acid, alone or with other micronutrients, may increase erythrocyte and serum/plasma folate concentrations. In one non-randomized controlled trial of women of reproductive age and pregnant women, wheat flour fortified with folic acid and other micronutrients was associated with significantly lower occurrence of total neural tube defects, spina bifida, and encephalocele compared to unfortified flour (total neural tube defects: risk ratio 0.32, 95% CI 0.21 to 0.48; 8037 births; low-certainty evidence) (32).\nA systematic review evaluated the beneficial and adverse effects of the fortification of staple foods with zinc on health-related outcomes and biomarkers of zinc status in the general population. Eight trials with 709 participants were included. Five of the included studies were on wheat flour or wheat products. The analysis of the wheat flour products showed the same trend as the main analysis: foods fortified with zinc increased the serum or plasma zinc levels in comparison to foods without added zinc (MD 2.46 µmol/L, 95% CI 2.05 to 2.87 µmol/L; 2 studies; 99 participants; low-certainty evidence). There was no difference in serum or plasma zinc levels in participants consuming foods fortified with zinc plus other micronutrients when compared with participants consuming the same foods with micronutrients but no added zinc (MD -0.01 µmol/L, 95% CI -1.01 to 0.98 µmol/L; 3 studies; 201 participants; low-certainty evidence). The authors concluded that fortification of foods with zinc may improve the serum zinc status of populations if zinc is the only micronutrient used for fortification. If zinc is added to foods in combination with other micronutrients, it may make little or no difference to serum zinc concentrations (33).\nA 2021 systematic review on the effect of zinc fortification, alone or with multiple micronutrients, on zinc-related biomarkers showed that zinc fortification with and without multiple micronutrients increased plasma zinc concentrations (efficacy, n = 27: 4.68 μg/dL; 95% CI: 2.62-6.75; effectiveness, n = 13: 6.28 μg/dL; 95% CI: 5.03-7.77 μg/dL) and reduced the prevalence of zinc deficiency (efficacy, n = 11: odds ratio : 0.76, 95% CI: 0.60-0.96; effectiveness, n = 10: OR: 0.45, 95% CI: 0.31-0.64). There was no statistical difference in the effect on plasma zinc concentration or zinc deficiency by food vehicle group (cereal grains, beverages, and condiments). When analysing studies only on wheat flour/products, there was no effect of zinc fortification on prevalence of zinc deficiency (34).\n\n# VITAMIN A\nA systematic review assessed the effects of fortifying staple foods with vitamin A for reducing vitamin A deficiency and improving health-related outcomes in the general population older than two years of age (35). The authors included interventions that fortified staple foods with vitamin A alone or in combination with other vitamins and minerals. Only two studies reported on wheat flour as the intervention vehicle for fortification -in chapati (36) and in wheat flour buns (37). The duration of interventions ranged from 3 to 9 months. In the study with chapati, the intervention made little or no difference to mean serum retinol levels in participants (1. Table 2 compiles the concentrations and chemical forms of compounds that were used both in the studies included in the systematic reviews described previously and by the WHO guideline development group as a base for discussions to establish the recommendations of this guideline.\nThe outcomes that were considered by the WHO guideline development group to be critical for decision-making were iron status (as defined by trialists), iron deficiency and anaemia, neural tube defects and other congenital anomalies, folate status (as measured by serum or red cell folate) in women of reproductive age and older adults, zinc deficiency, zinc status (as measured by plasma zinc), and growth (as defined by stunting, wasting or underweight). The presence of adverse effects was an outcome for all micronutrients (Annexes 1-3).\nOn application of the GRADE methodology, the certainty of the direct evidence for the critical outcomes was low and very low (38,39). The GRADE summary of findings table for the fortification of wheat flour is shown in Annexes 1A to 1I. In addition to the direct and indirect evidence (delivered using food vehicles other than wheat flour) and its overall certainty, other considerations were taken into account by the guideline development group to define the direction and strength of the recommendations.\nThe overarching principle of these recommendations is that fortification of cereal flours, in this case industrially processed/produced wheat flour fortification, should be considered when flour is regularly consumed by large population groups in a country. The fortification scheme, in terms of which nutrients to add and in what amounts, should be based on the nutritional needs of the population; usual consumption of fortifiable flour; sensory and physical effects of the added nutrients on flour and flour products; type of wheat and the extraction rate of flour; other fortified food items or ongoing micronutrient programmes; and fortification costs, feasibility and acceptance.\nBased on available evidence the recommendations to fortify wheat flour are as follows.\n- Fortification of wheat flour with highly bioavailable iron is recommended as a public health strategy to improve haemoglobin concentrations and iron status and to prevent anaemia and iron deficiency in populations, particularly in vulnerable groups such as children and women (strong recommendation, low certainty of evidence).\n- Fortification of wheat flour with folic acid is recommended as a public health strategy to reduce the risk of occurrence of neural tube defects in pregnancies in women of reproductive age and to improve folate status in populations (strong recommendation, low and very low certainty of evidence).\n- Fortification of wheat flour with zinc may be used as a public health strategy to improve serum/ plasma zinc status of populations (conditional recommendation, low certainty of evidence).\nThe guideline development group considered wheat flour fortification with iron and folic acid as strong recommendations despite the low certainty of the evidence after discussing other considerations like the priority of the problem and the clear benefits of fortification. Other considerations included feasibility and acceptability of the intervention.\nThe remarks in this section are suggestions intended to give some considerations for implementation of the recommendations, based on the discussion of the guideline development group.\n- When vitamin A deficiency constitutes a public health problem and no other/insufficient strategies to address it are in place, fortification of wheat flour with vitamin A could be considered as a public health strategy to improve vitamin A status or to reduce the risk of subclinical vitamin A deficiency.\n- In countries with a high prevalence of vitamin B 12 depletion and deficiency, the inclusion of vitamin B 12 could be considered when staples are fortified with folic acid, to prevent unintended imbalances resulting from addition of folic acid alone.\n- Since some of the B-complex vitamins naturally present in the wheat kernel are removed during milling, especially with low-extraction (i.e. refined) wheat flour, the restoration of thiamine, riboflavin, niacin and pyridoxine in wheat flour could be considered as a regular practice in fortification.\n- The choice of iron compound is a compromise between cost; bioavailability; micronutrient interactions; and the acceptance of texture, taste, smell, and/or colour.\n- The removal of phytates in wheat flour could increase the bioavailability of iron and zinc.\n- Addition of vitamins and minerals in wheat flour should be based on evidence about inadequacy of micronutrient intakes and/or the prevalence of deficiency. These pre-fortification data are also used for measuring impact of the fortification programme.\n- Countries that fortify wheat flour may also fortify other food items. A combined fortification strategy using multiple vehicles appears to be an effective option for reaching all segments of the population. Fortification of wheat flour should be integrated and monitored as part of national programmes for prevention and control of micronutrient deficiencies and insufficiencies.\n- Food fortification should be guided by national standards, with quality-assurance and qualitycontrol systems to ensure quality fortification. Continuous programme monitoring should be in place as part of a process to ensure high-quality implementation. Monitoring consumption patterns and evaluation of micronutrient status in the population can inform adjustment of fortification levels over time.\n- Populations should be encouraged to receive adequate nutrition, which is best achieved through consumption of a healthy balanced diet. Fortified foods only complement the diet when feasible and required.\n- Although evidence is limited, fortification of wheat flour could potentially decrease inequity in population access to and consumption of micronutrients required to achieve good health and to prevent adverse health outcomes.\n- Table 3 contains a list of nutrients and levels that could be added to wheat flour for fortification and/or restitution of contents based on extraction rate, chemical form and estimated per capita flour consumption. This is a reference table based on a WHO interim consensus statement from 2009 (22); the levels used in included studies from the systematic reviews (Table 2); and in available standards from country legislations (Table 1). Note: This table is for general guidance. The number and amounts of nutrients should be adapted according to the needs of the country. These estimated target levels consider only wheat flour as the main fortification vehicle in a public health programme. If other large-scale food fortification programmes are implemented effectively, these suggested fortification levels may need to be adjusted downwards as needed.\na Nutrient levels were adapted from the 2009 Recommendations on wheat and maize flour fortification (22) and the evidence presented and discussed at the guideline development group meeting. b High-extraction flour (>80%) is also known as whole flour. It retains high levels of natural phytates, which inhibit the body's ability to absorb iron and zinc. High-extraction flours contain a naturally higher content of vitamins and minerals than low-extraction flours.\nEstimated per capita consumption of <75 g/day does not allow for the addition of sufficient amounts of fortificant to cover the needs of some micronutrients for women of reproductive age. Fortification of additional food vehicles and other interventions may need to be considered. d The amounts of micronutrients such as iron, zinc and calcium presented here are in milligrams of the elemental micronutrient. The amount of a micronutrient compound to add should be calculated depending on the molecular weight of the compound. e These amounts of zinc fortification assume 5 mg zinc intake and no additional phytate intake from other dietary sources. As with iron, the phytate concentration in high-extraction flour will affect the bioavailability of zinc.\nf Consider fortifying wheat flour with vitamin A when deficiency constitutes a public health problem and no other strategies to address it are in place. g Inclusion of vitamin B 12 is recommended when its deficiency is a public health problem or when wheat flour is fortified with folic acid.\nh Restitution of some B-complex vitamins should be achieved as a regular practice in all settings. The B-vitamins contents vary between types of whole wheat flours (15,41,42).\n\n# SUMMARY OF THE CONSIDERATIONS TO DETERMINE THE DIRECTION AND STRENGTH OF THE RECOMMENDATIONS\nIn addition to the certainty of the scientific evidence described in the reviews, the other factors that the guideline development group considered in determining the strength and direction of the recommendations included: the priority of the problem, the balance of benefits and harms, equity and human rights, acceptability, feasibility and costs. Annex 3 presents a summary of these considerations.\n\n# CERTAINTY OF THE EVIDENCE\nThe certainty of direct evidence was moderate, low (for most of the included studies), and very low.\nTwo of the recommendations were considered strong and one was considered as moderate, although the certainty of the evidence was low or very low for the priority critical outcomes.\n\n# PRIORITY OF THE PROBLEM\nAll guideline development group members considered that micronutrient deficiencies are important public health problems and that health-care providers, policy-makers and family members in all settings are likely to place a high value on food fortification, especially with iron and folic acid, to combat micronutrient deficiencies.\n\n# BALANCE OF EFFECTS\nBased on the available evidence, the guideline development group concluded that there are benefits in wheat flour fortification with iron, folic acid and zinc, while the benefits were uncertain for fortification with vitamin A. The evidence for undesirable effects was uncertain for iron, folic acid, zinc and vitamin A, since studies were limited in number and quality and some showed inconsistent results. The group concluded that the overall benefits for fortifying wheat flour overweighed the harms.\n\n# EQUITY AND HUMAN RIGHTS\nThe guideline development group discussed how flour fortification might affect equity and human rights and whether flour fortification could reduce inequalities and increase equity and accessibility. The group considered how the ability to choose fortified flour is affected by a person's location (e.g. urban versus rural), educational attainment, and level of agency in making food choices.\nThe group concluded that effective interventions to improve nutrition in disadvantaged populations could help to reduce health inequalities. Strategies for fortification need to be aligned with relevant programmes, especially poverty reduction and other social interventions. In general, effective nutrition interventions are more likely to decrease health inequities only if they are accompanied by concurrent interventions that address the root cause of the problem.\nInequities in access to fortified flours, where these are staples, can perpetuate inequalities among communities and individuals with respect to cognitive abilities, work skills and capacities for protecting self and/or family health. Programmes to date may not favour increased equity, although the guideline development group considers they have potential to increase equity, especially if made mandatory.\nAcceptability is affected by several factors, such as who benefits from flour fortification and who may be harmed; who pays or who saves money as a result; and when the benefits, harms and costs occur. The group's discussion was centered on acceptability to the end users, i.e. those who buy the flour and its products. Fortification requires less behaviour change than other interventions, thus acceptability and feasibility are favoured.\nThe group considered that wheat flour fortification is a well-accepted intervention, although the existence of sectors that are against adding anything to foods was recognized. Additionally, changes in organoleptic properties of the final product and acceptability by millers were also discussed as factors that could affect the overall acceptability of this intervention.\nFeasibility is influenced by the resources available, programmatic considerations, existing and additional necessary infrastructure and training, among other factors. Wheat flour fortification was considered a feasible intervention where implemented by millers and monitored by governments. The evidence is robust regarding feasibility where wheat flour is produced by a small number of large mills, but was recognized to be more complex and difficult for small millers. Education is important to enhance stakeholder value, and for this reason any intervention needs to be promoted and have an education component that does not increase consumption of the fortification vehicle.\nIn comparison with other nutrition interventions, fortification represents a negligible cost to governments and might be affordable for the end users. The group recognized the need for investment at the milling/industry and government levels to implement and maintain fortification programmes.\nFor this guideline, the guideline development group was presented with the evidence-todecision frameworks that considered the above-mentioned factors. This approach is in agreement with the WHO guideline development procedures, specifically with guidance on developing recommendations integrating evidence across multiple domains WHO handbook for guideline development (40).\n\n# EVIDENCE GAPS\nThe WHO guideline development groups and the systematic reviews teams highlighted the limited evidence available in some areas. Further research on wheat flour fortification is merited, particularly regarding:\n- the bioavailability of different iron compounds for use in wheat flour fortification, including mixtures of different compounds;\n- the bioavailability and stability of added folic acid, vitamin A and vitamin D in wheat flour;\n- fortification of wheat flour with zinc only compared to fortification with a mix of micronutrients;\n- the effects of different phytate contents on the absorption of iron and zinc from premix formulations;\n- biomarkers of individual micronutrient status under different conditions of infection and inflammation;\n- stability of different micronutrients and compounds in different, context-specific, cooking processes;\n- relative bioavailability among different chemical forms of various micronutrients that can be used in wheat flour fortification, including nutrient-nutrient interactions;\n- the most appropriate delivery platforms for reaching the intended target population;\n- the impact of wheat flour fortification on micronutrient status and health outcomes in preventing the need for excessive supplies of micronutrients to certain groups;\n- identifying situations where complementary interventions are needed to reduce inequity in populations.\n\n# DISSEMINATION, IMPLEMENTATION AND ETHICAL CONSIDERATIONS\nThis guideline will be disseminated through electronic media such as slide presentations and the World Wide Web, through the WHO Nutrition mailing lists, social media, the WHO nutrition website (43), or the WHO e-Library of Evidence for Nutrition Actions (eLENA) (44). eLENA compiles and displays WHO guidelines related to nutrition, along with complementary documents such as systematic reviews and other evidence that informed the guidelines; biological and behavioural rationales; and additional resources produced by Member States and global partners. In addition, the guideline will be disseminated through a broad network of international partners, including WHO country and regional offices, ministries of health, WHO collaborating centres, universities, other United Nations agencies and nongovernmental organizations. Derivative products that are useful for end users, such as summaries and collation of recommendations related to food fortification, may be developed.\nParticular attention will be given to improving access to these guidelines for stakeholders that face high, or specific, barriers in access to information, or to those that play a crucial role in the implementation of the guideline recommendations, for example, policy-makers and decision-makers at subnational level that disseminate the contents of the guideline. Disseminated information may emphasize the benefits of food fortification programmes in populations or regions where micronutrient deficiencies and their consequences are of public health significance. This is particularly important in rural communities or highly isolated settings where access to fortified foods is often limited or difficult.\nThe executive summary of the guideline may be translated into the other five United Nations languages and disseminated through the WHO regional offices. Specialized technical assistance will be provided to any WHO regional office willing to translate the full guidelines into any of these languages and support countries in implementation for impact.\n\n# EQUITY, HUMAN RIGHTS AND IMPLEMENTATION CONSIDERATIONS\nThis guideline provides Member States with evidence-informed recommendations on the effects and safety of fortifying wheat flour with micronutrients, as a strategy to improve the health status of populations, specifically for reducing anaemia and the risk of occurrence of neural tube defects, and the improvement of iron, folate and zinc status. This guideline is intended to help Member States and their partners make informed decisions about what interventions are best suited to their context, needs, resources and ongoing programmes, observing existing human rights standards and pursuing health equity 1. Currently, fortification of wheat flour with micronutrients is already taking place in several Member States, and up to 86 countries have developed mandatory legislation to fortify wheat flour alone or in combination with other fortification vehicles (21). If Member States decide to adopt the recommendations contained in this guideline at either the national or subnational level, a thorough assessment of the policy implications concerning this decision is needed. The following illustrative considerations seek to support Member States that are considering fortification of wheat flour with micronutrients.\nThe adoption and adaptation of this recommendation should be framed under the existing national strategy on prevention and control of micronutrient deficiencies. The choice of an intervention to prevent micronutrient deficiencies should be considered in the context of that strategy, including consideration of the costs, feasibility, accessibility and acceptability among the different stakeholders (e.g. decision-makers, law-makers, programme managers, farmers, manufacturers, industry organizations, importers, exporters, retailers, consumers' organizations, organizations with opposing views). A mapping exercise of the different stakeholders and their interests and form of involvement in the intervention is a useful practice (45).\nSound dietary intake data and a robust baseline or database on the prevalence of micronutrient inadequacies and deficiencies across the population is the optimal foundation for any programme. Data should be disaggregated as much as possible, in order to identify health inequities across population groups, which is also needed for monitoring. Some of the most useful and common stratifiers include those grouped under the acronym PROGRESS-Plus: Place of residence; Race, ethnicity, culture and language; Occupation; Gender and sex; Religion; Socioeconomic status; and Social capital; plus other relevant social determinants (e.g. age, disability status, migration status, health-system configuration, political environment) (46). The disaggregation of data is also useful for monitoring and evaluation of the programme. WHO has developed guidance on health equity in order to support Member States in this respect: the WHO Handbook on health inequality monitoring with a special focus on low-and middle-income countries (47) and the WHO Health equity assessment toolkit (HEAT) (48). These resources will assist Member States in the assessment of within-country health inequalities and can inform Member States adopting this guideline in the process of adaptation.\nAn analysis is recommended during pre-implementation stages regarding capacities for wheat flour production, imports and industrialization, the nutrients needed and consumption of wheat flour/products. Accurate and robust data on the prevalence of micronutrient deficiencies in population groups is needed to inform cost estimates and the formulation of the fortification premix. It is also recommended the pathways and distribution channels required to reach and benefit hard-to-reach population groups should be carefully identified. Policy-makers and programme managers may consider appropriate measures to guarantee that the intervention is implemented as it was designed, so that fidelity 1 can also be measured and monitored.\nAccess to and availability of fortified wheat flour should be promoted when the need is identified irrespective of geographical, cultural or economic factors. In the context of staple foods made from wheat flour, even slight changes in geographical placement, culturally adapted communication strategies, and variations in the price of the food could affect accessibility. For example, in low-income and rural settings, households may often purchase wheat flour at local markets, from local hammer or small mills, or grind their own. These households may not benefit from large-scale fortification of wheat flour. In that scenario, concurrent measures can contribute to prevent and mitigate health inequities that are produced as a result of differential access to fortified wheat flour. Those concurrent measures include awareness-raising campaigns, food subsidies, cash-transfer programmes, direct distribution of culturally appropriate fortified foods, and the coordinated use of other interventions such as point-of-use fortification or supplementation.\nTo counteract misunderstandings, culturally appropriate communication strategies should be developed to disseminate accurate and evidence-based information on what fortified wheat flour is and why it is important for health and nutrition. Likewise, programmes at national and subnational levels should be culturally appropriate to the target populations, to increase their acceptability, adoption and sustainability. Programmes should also identify any resistance, via actions or behaviours, based on well-established practices or social beliefs that affect adoption of and adherence to fortified wheat flour. The involvement of local leaders and use of local languages and culturally relevant representations is a reasonable strategy.\nAcceptability and adoption are more likely if accompanied by simple and easy-to-access information that can be understood by different population groups. Dissemination of information must be carried out in a manner that aims to ensure that these recommendations are perceived as appropriate by all actors involved, including the population expected to consume fortified wheat flour products, the industries in charge of milling and fortifying the wheat, and the organizations in charge of measuring the impact of the programme and its monitoring and evaluation.\nThe programme should have well-defined objectives that consider available resources, existing policies, suitable delivery platforms and suppliers, communication channels and potential stakeholders. Ideally, a programme for the fortification of wheat flour should be implemented as part of a coordinated and comprehensive programme aiming to address micronutrient deficiencies. A comprehensive fortification programme may include several food items. The selection of the foods to be fortified and the levels of nutrients to be added to those different foods must be carried out in a coordinated manner. Some countries offer suitable case studies, such as Costa Rica, where the national fortification programme includes a basket of foods: wheat flour, maize flour, rice, milk, sugar and salt. The levels of nutrients added to these foods are determined in a coordinated manner (50). Fortification programmes should be coordinated with antenatal care programmes that supplement pregnant women with iron and folic acid. Likewise, when a malaria prevention and treatment programme is in place, the coexistence of a public health programme distributing iron is feasible, provided that coordinating measures between both programmes are formulated and observed (51,52).\n1 \"Fidelity\" is an implementation outcome variable that indicates the degree to which an intervention is or was implemented as designed in the original policy, plan or protocol. A full description of different implementation outcomes (e.g. acceptability, adoption, appropriateness, feasibility, fidelity, implementation cost, coverage and sustainability) can be found in reference (49).\nMoreover, food-fortification programmes should not be considered as replacements for adequate and diverse diets; hence, food-fortification efforts should coincide with initiatives for the improvement of diets, especially in population groups with more monotonous diets, and with other dietary counselling programmes in place. To achieve this form of coordination, policy-makers need to determine what multisectoral approaches represent the most appropriate allocation of resources, produce greater benefits, and optimize the results of the programme objectives.\n\n# REGULATORY CONSIDERATIONS\nA general legislation framework and technical specifications, which are included in standards and regulations, could be placed at different levels of the wheat flour fortification programme. Regulations and standards might include (i) recommended nutrients, fortification target levels, minimum and/or maximum levels and chemical forms of nutrients in the fortified foods; (ii) labelling, claims and advertising; and (iii) regulatory monitoring, sampling procedures and enforcement measures to assure compliance. Other specifications might include physical, microbiological and contaminants limits (53). Several Codex Alimentarius standards provide general guidance that may be helpful to regulators, such as on the addition of essential nutrients; labelling and claims; and composition, quality and food safety factors in wheat flour (53,54).\nCompetent authorities should determine whether the standards of fortification for wheat flour should be mandatory or voluntary. This decision may be based on the severity and extent of public health need. Input from all involved sectors when developing the regulations and standards, including producers, public institutions, academia, research organizations and consumer protection groups, will help to ensure a realistic approach.\nThe Code of practice for food premix operations was created by the Pan American Health Organization as a first step to assure premix quality for fortification programmes, not only in terms of adequate types and levels of nutrients added, but also in relation to hygiene, food safety, and good manufacturing practices, thereby assuring that the premix meets the minimum requirements for human consumption (55). Purity criteria for these compounds will also need to be stipulated and reference to texts such as the Food chemicals codex (56).\nFor implementing a wheat flour fortification programme, a well-designed regulatory monitoring system is an essential component to ensure nutrient, quality and safety standards are followed as set out in the regulations and standards. WHO and FAO have developed guidelines on fortification that describe key functions of regulatory monitoring and that identify criteria for evaluating monitoring systems, including the role of national authorities in establishing procedures, methodologies and reporting requirements to evaluate the fortification programme; allocation of responsibilities between the different actors; and a monitoring mechanism (19,57). Regulatory monitoring encompasses all monitoring activities conducted at the production level, as well as monitoring at customs warehouses and at retail stores, by the relevant regulatory authorities as well as by producers themselves as part of self-regulation programmes. Production level regulatory monitoring comprises both internal and external monitoring and refers to the quality control and quality assurance practices conducted by producers, importers and packers. External monitoring refers to the inspection and auditing activities carried out by governmental authorities (19).\nGovernments should also consider regulations about trade. Mandatory fortification may impose trade restrictions on imported products based on health criteria, because either they are unfortified or they have been fortified differently. On the other hand, nations with similar needs may benefit from a common agreement on fortification policies and regulations that could be regionally adopted (19,57,58).\n\n# ETHICAL CONSIDERATIONS\nEthics refers to standards of what is right or wrong and fair or unfair, which can advise people on what to do and not do in terms of rights, obligations and benefits to society and individuals. Ethics is central to science, research, policy-making and implementation. Every field of human action, including public health nutrition, is subject to ethical challenges.\nThe delivery of micronutrients to populations with micronutrient deficiencies must be informed by the right to health, and duty-bearers should consider the corresponding human-rights instruments when designing the intervention and its implementation. Large-scale fortification of a staple food may raise ethical challenges about how to best benefit populations, avoid unintended harms, and promote the principles of equity and social justice.\nFor example, the question of whether application of food fortification standards should be voluntary or mandatory can be approached as an ethically challenging question: which of the two policy options is likely to produce greater benefit in the population, reduce micronutrient deficiencies and be feasible within available resources, policy frameworks, and supply and demand? Member States may need to consider several issues when deciding on the type of fortification (i.e. mandatory or voluntary) of wheat flour. For instance, the configuration of the industry within the country must be examined. Mandatory fortification is more feasible when the existing industry consists of large and formal mills (59). Data on wheat flour fortification around the world shows that mandatory fortification reaches a greater proportion of the population and is easier to monitor. Conversely, when the configuration of the industry within a country consists mainly of small, formal and informal businesses, mandatory fortification becomes more difficult. The decision of mandatory versus voluntary fortification must also observe international agreements of the World Trade Organization, so countries that export wheat flour may not claim that a mandatory standard or regulation is a technical barrier to trade. Therefore, mandatory fortification programmes must be supported by strong health criteria and epidemiological data. A sound, ethically informed decision must be grounded in the consideration of all relevant factors and robust evidence.\nAn additional ethical consideration could arise regarding the provision of iron through wheat flour fortification to groups in the population that are not affected by iron deficiency, raising questions on how to avoid causing harm. Large-scale food fortification with iron is not likely to pose a risk to an entire population because the amount of iron in fortified foods is usually well below the recommended daily allowance. Nevertheless, a public health programme on fortification of wheat flour must be carefully designed so that the selected contents are within appropriate limits. Thus, technical expertise and proper training are essential for all staff involved in the food fortification programme. Likewise, coordination is fundamental between different food fortification initiatives taking place in the same setting and between public health programmes distributing micronutrients to the same populations. The provision of folic acid through food fortification to prevent neural tube defects may also pose concerns about the safety of this intervention for other groups in the population not affected by folate deficiency or insufficiency, thus raising ethical questions on how to avoid causing harm.\nAnother concern that may arise is the potential effects of iron-fortified foods on individuals with thalassaemia. Since the resemblance between thalassaemia and iron deficiency can confuse the diagnosis of either disorder (60), appropriate clinical procedures and services should be designed to identify and treat individuals with this condition (61). Iron overload in individuals with thalassaemia comes from both their diet and the blood transfusions. Therefore, these individuals take iron chelators to remove excessive iron from the body. Public authorities in charge of a public health programme distributing iron through fortified foods should make sure that food items with added iron are properly labelled. This ensure that both patients with thalassaemia and the clinical staff treating them are provided with all the information needed to enable patients to adapt their diet to reduce iron absorption and clinicians to plan for quality care (62).\nOther challenges that may arise when adopting fortification of wheat flour with iron is its relationship with corn-soy blends (CSBs), which are designed to provide protein to prevent malnutrition and address micronutrient deficiencies (63). They are mixed with water and cooked as porridge and are often used in food aid, especially in emergency settings (64). The composition 1 of CSB usually includes iron, folic acid and other nutrients (63). Therefore, in settings where CSBs are distributed to affected populations, careful coordination is essential if fortified wheat flour or products become available or are distributed. The aim is to avoid the potential risk of excess intake, although this is likely to be within tolerable levels. Furthermore, a human-rights-based approach to development suggests that the involvement of potential beneficiaries in nutrition interventions in emergency settings has been associated with improvements in their nutritional status (65).\nSound implementation of this guideline, as informed by these considerations, can contribute to systematic detection of facilitators and barriers to achieving the programme goals, and to better design any scaling-up strategy (66).\n\n# MONITORING AND EVALUATION OF GUIDELINE IMPLEMENTATION\nA plan for monitoring and evaluation with appropriate indicators, including equity-oriented indicators, is encouraged at all stages (67). The impact of this guideline can be evaluated within countries (i.e. monitoring and evaluation of the programmes implemented at national or regional scale) and across countries (i.e. the adoption and adaptation of the guideline globally). The WHO Department of Nutrition and Food Safety has developed a logic model for fortification of maize flour and corn meal with vitamins and minerals as a public health strategy to depict the plausible relationships between inputs and expected Sustainable Development Goals, especially goals 2 and 3, by applying the micronutrient-programme evaluation theory. This maize flour fortification logic model is adapted from the WHO/CDC logic model for micronutrient interventions and could be adapted and applied to wheat flour fortification (68) (Annex 4).\nMember States can adjust the model and use it in combination with appropriate indicators, for designing, implementing, monitoring and evaluating the successful escalation of nutrition actions in public health programmes. Additionally, the WHO/CDC eCatalogue of indicators for micronutrient programmes (69) and the manual of flour fortification (57) utilize this logic model, which can be customized for programmes of fortification of wheat flour with vitamins and minerals in public\nThe following is the usual nutritional value for fortified blended foods, including CSB, as per information from the World Food Programme (59): energy, minimum 380 kcal; protein, minimum 18%; fat, minimum 6%; micronutrients, vitamins A, B 6, B 12 C, D, E, K, calcium, folic acid plus zinc, iron, niacin, pantothenic acid, potassium, riboflavin, thiamine.\nhealth. This eCatalogue is a user-friendly, non-comprehensive web resource for those actively engaged in providing technical assistance in monitoring, evaluation and surveillance of public health programmes implementing micronutrient interventions. It provides potential indicators with standard definitions that can be selected, downloaded and adapted to a local programme context. Since 1991, WHO has hosted the Micronutrients Database as part of the Vitamin and Mineral Nutrition Information System (VMNIS) (70). Part of WHO's mandate is to assess the micronutrient status of populations, monitor and evaluate the impact of strategies for the prevention and control of micronutrient malnutrition, and track related trends over time. The WHO Department of Nutrition and Food Safety manages the VMNIS Micronutrient Database through a network of regional and country offices, and in close collaboration with national health authorities.\nFor evaluation at the global level, the WHO Department of Nutrition for Health and Food Safety has developed a web-based WHO Global targets tracking tool (71) that allows users to explore different scenarios to achieve the rates of progress required to meet the 2025 global nutrition targets, including target 2: 50% reduction of anaemia in women of reproductive age (72), as well as a centralized platform for sharing information on nutrition actions in public health practice implemented around the world. By sharing programmatic details, specific country adaptations and lessons learnt, this platform will provide examples of how guidelines are being translated into actions. The Global database on the Implementation of Nutrition Actions (GINA) (73) provides valuable information on the implementation of numerous nutrition policies and interventions. The use of GINA has grown steadily since its launch in November 2012.\n\n# GUIDELINE DEVELOPMENT PROCESS\nThis guideline was developed in accordance with the WHO evidence-informed guideline development procedures, as outlined in the WHO handbook for guideline development (40).\nThe development of this guideline started in February 2010. The project included the development of guidelines on fortification of five staple foods (wheat, maize, rice, condiments, sugar and oil) and a group of micronutrients involved in maintaining health and development and whose deficiencies have severe consequences at the individual and the public health level (iron, folates, vitamin A, zinc, iodine). This fortification guideline is the third of this project. During this period, the Nutrition Department has published two fortification guidelines (maize and rice).\nA WHO steering committee (Annex 5), led by the Department of Nutrition and Food Safety, was established with representatives from relevant WHO departments with an interest in the provision of scientific nutrition advice. The steering committee guided and provided overall supervision to the guideline development process. Two additional groups were formed: a guideline development group and a systematic reviews team.\nThe WHO guideline development group -micronutrients, was established for the biennium 2010-2011 (Annex 6A). Its role was to advise WHO on the choice of critical outcomes for decisionmaking within the scope of this guideline. Another guideline group, the WHO guideline development group -nutrition actions (Annex 6B) was convened for a second guideline development group meeting held virtually on 16 and 17 September 2020, to discuss the evidence and finalize the recommendations. WHO guideline development groups include experts from various WHO expert advisory panels (74) and those identified through open calls for specialists, taking into consideration a balanced gender mix, multiple disciplinary areas of expertise, and representation from all WHO regions. Efforts were made to include content experts, methodologists, representatives of potential stakeholders (such as managers and other health professionals involved in the health-care process) and technical staff from WHO and ministries of health from Member States. Representatives of commercial organizations may not be members of a WHO guideline group. Systematic review teams participated only in the open meetings and were not allowed to participate in the decisionmaking process. (Annex 7).\nThe final draft guideline was peer-reviewed by four content experts, who provided technical feedback (Annex 8). These peer-reviewers were identified through various expert panels within and outside WHO.\nPeer-reviewers are not involved in the guideline development process (40) and are only asked to provide comments on the final draft guideline. Their role is to identify any errors or missing data and to comment on clarity, setting-specific issues and implications for implementation; they may not change the recommendations formulated by the guideline development group. Reviews from such individuals or organizations on a draft guideline may be helpful in anticipating and dealing with controversy, improving the clarity of the final document and promoting engagement with all stakeholders.\nThis document is a WHO guideline and, after executive clearance, represents the decisions, policy or views of WHO.\n\n# SCOPE OF THE GUIDELINE, EVIDENCE APPRAISAL AND DECISION-MAKING\nAn initial set of questions (and the components of the questions) to be addressed in the guideline was the starting point for formulating the recommendations. The questions were drafted by technical staff at the Department of Nutrition and Food Safety, based on the policy and programme guidance needs of Member States and their partners. The population, intervention, control, outcomes (PICO) format was used. The questions were discussed and reviewed by the WHO steering committee and the guideline development group -micronutrients 2010-2011 and were modified as needed. The guideline development group scored the relative importance of each outcome from 1 to 9 (where 7-9 indicated that the outcome was critical for a decision, 4-6 indicated that it was important, and 1-3 indicated that it was not important). The final key questions on this intervention, along with the outcomes that were identified as critical for decision-making, are listed in PICO format in Annex 2.\nThis guideline builds on a body of previous work. The Flour Fortification Initiative, CDC and the Mexican Institute of Public Health held a first technical workshop entitled: \"Wheat flour fortification: current knowledge and practical applications\", in Cuernavaca, Mexico in December 2004. A followup technical workshop entitled: \"Wheat flour fortification: practical recommendations for national application\", was held in Stone Mountain, GA, United States of America in April 2008 by WHO, in collaboration with nearly 100 leading nutrition, pharmaceutical and cereal scientists and milling experts from the public and private sectors worldwide (22). The purpose of this second workshop was to provide guidance on national fortification of wheat and maize flours, milled in industrial roller mills (i.e. >20 metric tons/day milling capacity), with iron, zinc, folic acid, vitamin B 12 and vitamin A and to develop guidelines on formulations of premix based on common ranges of flour consumption. Expert work groups prepared technical documents that reviewed published efficacy and effectiveness studies as well as the form and levels of fortificants currently being added to flour in different countries. The full reviews were published in a supplement of the Food and Nutrition Bulletin in 2010 (75).\nTo inform this guideline, and as detailed in the available evidence section, WHO commissioned Cochrane systematic reviews of the evidence to determine the benefits and harms of wheat flour fortification with vitamins and minerals (iron, folic acid, zinc or vitamin A) on micronutrient status and health-related outcomes in the general population. The Cochrane methodology for systematic reviews of interventions1 (76) was followed. For identification of unpublished studies or studies still in progress, a standard procedure was followed to contact more than ten international organizations working on micronutrient interventions. In addition, clinicaltrials.gov (National Library of Medicine United States of America) and the International Clinical Trials Registry Platform (77), hosted at WHO, were systematically searched for any trials still in progress. No language restrictions were applied in the search. Evidence summaries were prepared according to the GRADE approach, to assess the overall certainty of the evidence (38,39). GRADE considers: the study design; the limitations of the studies in terms of their conduct and analysis; the consistency of the results across the available studies; the directness (or applicability and external validity) of the evidence with respect to the populations, interventions and settings where the proposed intervention may be used; and the precision of the summary estimate of the effect.\nBoth the systematic review and the GRADE summary of findings tables for each of the critical outcomes were used for drafting this guideline (Annex 1). The draft recommendations were discussed by the WHO steering committee and the guideline development group, at a second guideline development group meeting, held virtually on 16-17 September 2020, where the guideline development group members received and filled out an online consensusbuilding form prepared using survey software (QuestionPro Inc., San Francisco, United States of America). On this form, members could indicate their positions on the recommendation, and the judgements on harms and benefits. They also noted the strength of the recommendation, taking into account: (i) the desirable and undesirable effects of the intervention; (ii) the certainty of the available evidence; (iii) values and preferences related to the intervention in different settings; and (iv) the cost and feasibility of the intervention in different settings (Annex 3). These aspects were discussed openly in the meeting, followed by notation on individual forms of each member's primary considerations in these areas. Subsequent deliberations among the members of the guideline development group were private. The WHO Secretariat (Annex 9) gathered and disclosed a summary of the results to the guideline development group. If there was no unanimous consensus (primary decision rule), more time was given for deliberations and a second round of online balloting took place. If no unanimous agreement was reached, a two thirds vote of the guideline development group was required for approval of the proposed recommendations (secondary decision rule). Divergent opinions could be recorded in the guideline. The results from voting forms are kept on file by WHO for up to 5 years. WHO staff present at the meeting, as well as the systematic reviews teams involved in the collection and grading of the evidence, did not participate in the consensus-building process. Two cochairs with expertise in managing group processes and interpreting evidence were nominated at the opening of each consultation, and the guideline development group approved their nomination. Members of the WHO Secretariat were always available to help guide the overall meeting process but did not vote and did not have veto power.\n\n# MANAGEMENT OF COMPETING INTERESTS\nAccording to the processes recommended in the WHO handbook for guideline development (40), all experts participating in WHO meetings must declare any interest relevant to the meeting, prior to their participation. The responsible technical officer and the relevant departments reviewed the declaration-of-interest statements for all guideline development group members, before finalization of the group composition and invitation to attend a guideline development group meeting. All participants, members of the guideline development group, and systematic reviews teams of the guideline development meetings, submitted a declaration-of-interests form, along with their curriculum vitae, before each meeting. Participants of these meetings participated in their individual capacity and not as institutional representatives. In addition, they verbally declared any interests that could be perceived to affect their objectivity and independence in providing advice to WHO at the beginning of each meeting. The procedures for management of competing interests strictly followed the WHO Guidelines for declaration of interests (78). The management of the perceived or real conflicts of interest declared by the members of the guideline development group that are relevant to this guideline is summarized next. Because Danone does not manufacture products or make claims related to the fortification of wheat flour, it was agreed that he could participate fully in the deliberations and decision-making on this guideline.\nDr Luz Maria De-Regil worked for an international nongovernmental agency, Nutrition International (formerly Micronutrient Initiative), which supports food-fortification programmes and was also a Member of the Executive Management Team of the Food Fortification Initiative. For the second guideline development group meeting she participated fully in decision making but was asked to verbally disclose to the other meeting participants at the start of the meeting, her previous employment at Nutrition International and her participation as member of the Executive Management Team of the Food Fortification Initiative at the start of the meeting.\n\n# Dr Maria Elena del Socorro Jefferds works for the International Micronutrient Malnutrition\nPrevention and Control Program (IMMPaCt), that financially supports the secretariat of the Food Fortification Initiative whose work includes supporting wheat flour fortification with vitamin and minerals. The leaders of her Division also participate as observers on the Executive Management Team of the Food Fortification Initiative. For the second guideline development group meeting, Dr Jefferds fully participated in decision making and was asked to verbally disclose to the other meeting participants her employer's involvement in financial support to the secretariat of the Food Fortification Initiative and the participation as observers in the Executive Management Team.\nDr Lynette Neufeld declared that her employer, the Global Alliance for Improved Nutrition, supports food-fortification programmes and that she has led research and authored several publications in the area of food fortification. For the second guideline development group meeting, Dr Neufeld declared that the organization she works for has received funding for research and programming related to food fortification, but she was not leading any of these initiatives, although she has publications in the area of food fortification. For the second guideline development group meeting Dr Neufeld fully participated in decision making and was asked to verbally disclose to the other meeting participants her personal interests in food fortification and her employer's involvement in projects related to food fortification.\nMs Carol Tom declared being employed by the United States Agency for International Development (USAID)/A2Z on a project related to child blindness and micronutrients, and being a consultant (technical and other adviser) for the East, Central and Southern African Health Community (ECSA-HC) on food fortification. It was felt that her employment did not present any conflict of interest for the meeting, as USAID is a government agency of the United States of America and ECSA-HC is a regional association of ministries of health, and it was agreed that she could participate fully in the deliberations and decision-making on this guideline.\nThe systematic reviews teams also declared that they had no conflict of interest and did not participate in the deliberations or decision-making process.\n\n# PLANS FOR UPDATING THE GUIDELINE\nThe WHO Secretariat will continue to follow research developments in the area of wheat fortification, particularly for areas in which the evidence was limited and the quality of evidence was found to be very low. If the guideline merits an update, or if there are concerns about the validity of the guideline, the Department of Nutrition and Food Safety, in collaboration with other WHO departments or programmes, will coordinate the guideline update, following the formal procedures of the WHO handbook for guideline development (40).\n\n# ANNEX 1 1C. WHEAT FLOUR OR WHEAT FLOUR PRODUCTS FORTIFIED WITH FOLIC ACID ALONE COMPARED TO UNFORTIFIED WHEAT FLOURS OR WHEAT FLOUR PRODUCTS (NOT CONTAINING FOLIC ACID NOR ANY OTHER VITAMINS AND MINERALS) FOR POPULATION HEALTH OUTCOMES\nPatient or population: general population above two years of age Setting: any country (location for study providing data for this comparison: Canada) Intervention: wheat flour or wheat flour products fortified with folic acid alone Comparison: unfortified wheat flours or wheat flour products (no micronutrients added) Included study: Green 2013 The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RCT: randomized controlled trial; RR: risk ratio.\n\n# GRADE Working Group grades of evidence High certainty:\nWe are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect a Downgraded 1 level for limitations in the study design or execution (risk of bias). b Downgraded 1 level for indirectness, the participants were healthy men and women, aged 18-45 years who received a high dose of folic acid (400 µg folic acid/bread) which is not commonly used by the general population. c Downgraded 1 level for imprecision; only one study informing these outcomes with few patients and few events, wide confidence intervals.\n\n# ANNEX 1\n\n# 1D. WHEAT FLOUR OR WHEAT FLOUR PRODUCTS FORTIFIED WITH FOLIC ACID PLUS OTHER VITAMINS AND MINERALS COMPARED TO UNFORTIFIED WHEAT FLOURS OR WHEAT FLOUR PRODUCTS (NOT CONTAINING FOLIC ACID NOR ANY OTHER VITAMINS AND MINERALS) FOR POPULATION HEALTH OUTCOMES\nPatient or population: general population above two years of age Setting: any country (location of the study providing data for this comparison: Bangladesh) Intervention: folic acid-fortified wheat flour or wheat flour products plus other vitamins and minerals Comparison: unfortified wheat flour (no micronutrients added) Included study: Rahman 2015 (C) The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).\n(C): denotes cluster RCT; CI: confidence interval; MD: mean difference; RCT: randomized controlled trial; RR: risk ratio.\n\n# GRADE Working Group grades of evidence High certainty:\nWe are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect a Downgraded 1 level for indirectness, the only study informing this outcome included children aged 6 to 15 years who received daily chapatis made with wheat flour fortified with folic acid and other nutrients and minerals; food intake was supervized by an adult.\nb Downgraded 1 level for imprecision, there was only one study informing this outcome, and wide confidence intervals. Included study: Lopez de Romaña 2005 The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RCT: randomized controlled trial; RR: risk ratio.\n\n# GRADE Working Group grades of evidence High certainty:\nWe are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.\na Downgraded 1 level for imprecision and inconsistency. The confidence intervals are wide and the direction varies in the included studies.\nb Downgraded 1 level for indirectness. One study contributing data was conducted among stunted, moderately anaemic children aged 3-4 years, residing in a poor community on the periphery of Lima, Peru, and who were considered as at high risk for zinc deficiency.\nc Downgraded 1 level for imprecision. The confidence interval is very broad and data is coming from only one study among stunted, moderately anaemic children aged 3-4 years, residing in a poor community on the periphery of Lima, Peru, and who were considered as at high risk for zinc deficiency. d Downgraded 1 level for limitations in the study design or execution (risk of bias). In one study they were divided into five groups based on the order in which they visited hospital for antenatal care with no sequence generation."}}},{"rowIdx":91,"cells":{"id":{"kind":"string","value":"2f85d6ec392675d75b60506cc999bf8e19e39343"},"source":{"kind":"string","value":"nice"},"text":{"kind":"string","value":"Pixantrone monotherapy for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma\n\nEvidence-based recommendations on pixantrone (Pixuvri) for treating relapsed or refractory aggressive non-Hodgkin's B-cell lymphoma in adults.\n\n# Guidance\nPixantrone monotherapy is recommended as an option for treating adults with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma only if:\nthe person has previously been treated with rituximab and\nthe person is receiving third- or fourth-line treatment and\nthe manufacturer provides pixantrone with the discount agreed in the patient access scheme.\nPeople currently receiving treatment initiated within the NHS with pixantrone monotherapy that is not recommended for them by NICE in this guidance should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.# The technology\nPixantrone (Pixuvri, Cell Therapeutics) is an aza‑anthracenedione analogue and inhibitor of topoisomerase II. The recommended dosage is pixantrone 50 mg/m2 on days 1, 8 and 15 of each 28-day cycle for up to 6 cycles. It is administered intravenously. Pixantrone has a conditional marketing authorisation 'as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin B‑cell lymphomas (NHL). The benefit of pixantrone treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy'. The European public assessment report noted pixantrone had a reduced benefit in patients pretreated with rituximab. The marketing authorisation is linked to results being provided from the phase III PIX306 trial, which is investigating pixantrone plus rituximab compared with gemcitabine plus rituximab in patients with relapsed or refractory aggressive non-Hodgkin's B‑cell lymphomas who have previously received a rituximab-containing regimen. Results are expected in 2015.\nThe summary of product characteristics states that the most common toxicity with pixantrone is bone marrow suppression (particularly the neutrophil lineage) and that other toxicities such as nausea, vomiting and diarrhoea are generally infrequent, mild, reversible, manageable and as expected in patients treated with cytotoxic agents. Although the occurrence of cardiac toxicity indicated by congestive heart failure appears to be lower than that expected with related drugs like anthracyclines, the summary of product characteristics recommends monitoring left ventricular ejection fraction. For full details of adverse reactions and contraindications, see the summary of product characteristics.\nPixantrone is priced at £553.50 per 20‑ml vial containing 29 mg free base pixantrone, which is equivalent to 50 mg pixantrone dimaleate (excluding VAT; 'British national formulary' edition 66). The estimated cost of a course of treatment is £19,926 (costs calculated over 4 cycles using an average of 3 vials per dose based on the median length of treatment in the PIX301 trial, described in section 3.2). Costs may vary in different settings because of negotiated procurement discounts. The manufacturer of pixantrone has agreed a patient access scheme with the Department of Health that makes pixantrone available with a discount. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.# The manufacturer's submission\nThe Appraisal Committee (section 8) considered evidence submitted by the manufacturer of pixantrone and a review of the submissions by the Evidence Review Group (ERG; section 9). The manufacturer submitted additional evidence (about the patient population, trial design and clinical effectiveness, a revised model, and support for consideration of end-of-life criteria) after consultation on the appraisal consultation document. The submission and the additional evidence did not incorporate a patient access scheme. The manufacturer later made a confidential simple discount patient access scheme submission in July 2013, which was superseded by an updated patient access scheme submitted in November 2013. The Committee's considerations and decision-making are based on the November 2013 patient access scheme.\n\n# Clinical effectiveness\n\n## Manufacturer's original submission\nThe manufacturer's systematic review identified 1 randomised controlled trial, which was included in its original submission. No other relevant randomised controlled trials or non-randomised controlled trials were identified. The manufacturer also included some supporting cardiotoxicity data from a randomised phase II study that did not meet the inclusion criteria of the literature review (because it evaluated pixantrone in combination with other drugs, not as monotherapy).\nPIX301 is a randomised, controlled, open-label phase III study conducted in 66 centres, including the USA and Europe. Eligible patients were adults with aggressive de novo or transformed non-Hodgkin's lymphoma that had relapsed after 2 or more chemotherapy regimens, including at least 1 standard anthracycline-containing regimen with a response that had lasted at least 24 weeks. Seventy patients were randomised to pixantrone and 70 patients to a physician's choice of single-agent comparators. The full publication of PIX301 described how 67 patients went on to receive vinorelbine (n=11), oxaliplatin (n=30), ifosfamide (n=12), etoposide (n=9), mitoxantrone (n=4) or gemcitabine (n=1). Pixantrone was administered at a dosage of 85 mg/m2 on days 1, 8 and 15 of a 28‑day cycle for up to 6 cycles. Comparators were administered at predefined standard dosages for up to 6 cycles. Follow-up was for 18 months after completing study treatment.\nThe primary outcome was complete and unconfirmed complete response, which was determined by a blinded independent assessment panel. Secondary outcomes were overall survival, response lasting at least 4 months and progression-free survival. Other predefined end points were overall response rate, time to response, time to complete response, duration of response and relative dose intensity. Health-related quality of life was not assessed. The primary analysis was the intention-to-treat population. Secondary analyses included a prespecified analysis of the response and survival end points for the histologically confirmed intention-to-treat population (that is, if the lymphoma had been classified according to retrospective independent central pathological assessment).\nIt was initially planned that 320 patients would be recruited to PIX301 but study enrolment was closed early because of slow accrual. The manufacturer's original submission stated that, with a final enrolment of 140 patients, the study was considered to be sufficiently powered (about 80%) to detect a 15% difference in the complete or unconfirmed complete response rate, assuming a rate of at least 18% in the pixantrone arm. In contrast, the full publication of PIX301 reported that the study was originally powered to detect a difference of 10% in the proportion of patients who achieved a complete or unconfirmed complete response. The publication further stated that, according to the original sample size assumptions, a sample of 70 patients per group would have about 40% power. It added that, to achieve 81% power with 70 patients per group, the true proportion of patients with a complete or unconfirmed complete response would have to be 22% in the pixantrone group and 5% in the comparator group.\nThe manufacturer's original submission reported that baseline demographic and disease characteristics were similar in the 2 arms. Previous treatment for non-Hodgkin's lymphoma was broadly similar for both groups, including number of chemotherapy regimens (median 8 regimens in both arms). Aggressive histological features were identified onsite in all patients before treatment was given and confirmed by central independent pathological review in 54 (77%) of 70 patients in the pixantrone arm and 50 (71%) of 70 patients in the comparator arm receiving treatment of physician's choice. Of the remaining 36 patients, reasons for non-confirmation were low-grade histology (n=13), lack of consensus (n=10), shortage of specimen (n=6), confirmation of a non-aggressive subtype other than non-Hodgkin's lymphoma (n=5), and the specimen reviewed by only 1 pathologist (n=2). Out of 140 patients, 36 patients completed 6 cycles of protocol treatment, and 104 patients discontinued early. The most common reason for early discontinuation in both groups was disease progression or relapse. After completing study treatment, 95 patients entered follow-up and 26 of these completed 18 months of follow-up.\nThe manufacturer's original submission reported that, at the end of treatment, confirmed and unconfirmed response rates for the intention-to-treat population (70 patients in each arm) were statistically significantly higher for the pixantrone group than the comparator group receiving treatment of physician's choice (20% compared with 5.7%; p=0.021). This was also the case at the end of the study after 18 months of follow-up (24.3% compared with 7.1%; p=0.009).\nThe manufacturer's original submission described the results for progression-free and overall survival in the intention-to-treat population. Median progression-free survival was statistically significantly longer for the group receiving pixantrone than the comparator group receiving treatment of physician's choice at 5.3 months compared with 2.6 months (hazard ratio 0.60 and 95% confidence interval 0.42 to 0.82; p=0.005). However, there was no statistically significant difference in median overall survival between the 2 groups (10.2 months in the pixantrone arm compared with 7.6 months in the comparator arm receiving treatment of physician's choice (hazard ratio 0.79 ; p=0.251).\nIn addition to the results for the intention-to-treat population of PIX301, the manufacturer included clinical-effectiveness data for several post-hoc subgroups in its original submission for patients with aggressive B‑cell lymphoma (classed as diffuse large B‑cell lymphoma, transformed indolent lymphoma or follicular lymphoma ):\nDisease confirmed by onsite pathological review (all lines of treatment, and third- or fourth-line treatment only).\nDisease confirmed by central independent pathological review (all lines of treatment, and third- or fourth-line treatment only).\nDisease confirmed by central independent pathological review in patients who had previously received rituximab treatment.The manufacturer also presented the results for a subgroup of patients with diffuse large B‑cell lymphoma confirmed by onsite pathological review (over 80% of the total number of patients with aggressive B‑cell lymphoma). The results of the subgroup analyses that were incorporated into the manufacturer's original economic model are described below. The results of other subgroup analyses included in the manufacturer's original submission have been previously reported in the appraisal consultation document.\nIn its original submission, the manufacturer considered the post-hoc subgroup of patients with aggressive B‑cell lymphoma confirmed by onsite pathological review to be similar to the population eligible for treatment according to pixantrone's European marketing authorisation, and indicated that this formed the basis of the population in the original base case of its cost-effectiveness analysis (however, it should be noted that the manufacturer stated that its economic evaluation focused on those who had received 2 or 3 previous therapies; see section 3.20 for details). This subgroup excluded patients with peripheral T‑cell lymphoma not otherwise characterised and other disease subtypes not included in pixantrone's European marketing authorisation. Compared with the group that received treatment of physician's choice (n=62), complete or unconfirmed complete response rates at the end of the study in the pixantrone group (n=64) were statistically significantly higher (23.4% compared with 8.1%; p=0.027). Overall response rates were also statistically significantly higher in the pixantrone group (40.6% compared with 16.1%; p=0.003). Median progression-free survival was statistically significantly longer in patients who had received pixantrone than those who had received a comparator drug (5.7 months compared with 2.5 months, hazard ratio 0.56 ; p=0.002). The manufacturer advised that median overall survival was not included because the aggressive B‑cell lymphoma analyses were exploratory.\nIn its original submission, the manufacturer presented a further analysis of patients with aggressive B‑cell lymphoma confirmed by onsite pathological review who received pixantrone (n=50) or a comparator (n=49) as third- or fourth-line treatment, which it stated was more closely aligned with pixantrone's marketing authorisation. It is not clear from the manufacturer's submission how this population differs from that in the base case of its cost-effectiveness analyses (see section 3.20 for details). The group receiving pixantrone had a statistically significantly higher complete response or unconfirmed complete response rate (28.0% compared with 4.0%; p=0.002) and overall response rate (48.0% compared with 12.2%; p<0.001), and statistically significantly longer progression-free survival (5.8 months compared with 2.8 months, hazard ratio not stated; p=0.002) than the comparator group receiving treatment of physician's choice. Median overall survival in this population was numerically higher in the pixantrone arm than the comparator arm but this difference was not statistically significant (13.9 months compared with 7.8 months, hazard ratio 0.76 ; p=0.275). The manufacturer's submission did not state whether the results were for end of treatment or end of study.\nIn addition to the histologically defined subgroups of the PIX301 population in its original submission, the manufacturer also supplied subgroup analyses that showed the influence of previous rituximab treatment on pixantrone's efficacy in the subgroup of patients who had aggressive non-Hodgkin's B‑cell lymphoma confirmed by central independent pathological review. In this subgroup of patients who had previously received rituximab, there was no statistically significant difference between pixantrone (n=30) and the comparator arm (n=26) in the proportion of patients who had a complete or unconfirmed complete response at the end of treatment (16.7% compared with 7.7%; p=0.431). Median progression-free survival was longer in the pixantrone group than in the comparator group receiving treatment of physician's choice for this subgroup of patients but the difference did not reach statistical significance (3.5 months compared with 2.3 months, hazard ratio 0.66 ). Similarly, median overall survival was longer in the pixantrone group than in the comparator group receiving treatment of physician's choice but the between-group difference was not statistically significant (6.0 months compared with 4.6 months, hazard ratio 0.85 ).\nThe manufacturer's original submission described the adverse events in PIX301 for 68 patients in the pixantrone group and 67 patients in the comparator group who received treatment of physician's choice. One dose reduction was allowed for patients who had neutropenia during treatment, and reductions were similar in the pixantrone and comparator groups (18% compared with 15%). Dose delay was more frequent with pixantrone (40% compared with 22%).\nA similar number of patients had an adverse event of any grade but there was a higher incidence of grade 3 and 4 adverse events in the pixantrone group than in the comparator group (76.5% compared with 52.2%). Neutropenia occurred more frequently in the pixantrone group and was the most common adverse event of any grade (50.0% compared with 23.9%) and the most common grade 3 or 4 adverse event (41.2% compared with 19.4%). Grade 3 or 4 febrile neutropenia was also more common in the pixantrone group than in the comparator group (7.4% compared with 3.0%), and more patients in the pixantrone group than in the comparator group received an immunostimulant (51.5% compared with 26.9%). The manufacturer reported that severity of neutropenia did not increase with increasing cycle number and that the overall rates of grade 3 and 4 infections were similar in the 2 groups. It further stated that the common adverse events were similar to those expected in a heavily pretreated patient population, which reflected pixantrone's intended use in clinical practice in England and Wales (that is, third and subsequent lines of treatment).\nApproximately 40% of patients in both treatment arms presented with a history of cardiac disease at study enrolment, and cardiac risk factors were also similar in the 2 groups. The manufacturer stated that pixantrone is an innovative treatment because it has been specifically designed to reduce cardiotoxicity associated with anthracyclines without compromising efficacy. More cardiac adverse events occurred in the pixantrone group (24 patients than in the comparator group who received treatment of physician's choice (14 patients ). Thirteen (19.1%) patients in the pixantrone group experienced decreased left ventricular ejection fraction compared with 7 patients in the comparator group. The manufacturer provided supporting cardiotoxicity data from the randomised open-label phase II PIX203 trial, which closed before enrolment completed. This trial compared the combination of cyclophosphamide, pixantrone, vincristine, prednisone and rituximab with the standard of care (that is, rituximab in combination with a regimen of cyclophosphamide, doxorubicin, vincristine and prednisone) as first-line treatment in patients with diffuse large B‑cell lymphoma. The cardiotoxicity results of PIX203 broadly supported those of PIX301.\n\n## Manufacturer's additional evidence in response to consultation on the first appraisal consultation document\nIn response to consultation on the first appraisal consultation document, the manufacturer requested and received permission from NICE to submit additional evidence. The additional evidence contained the results for 4 subgroups and showed the effect of treatment in patients who had previously received rituximab. Two of the subgroups were patients who had aggressive non-Hodgkin's B‑cell lymphoma confirmed by central independent pathological review for all lines of therapy, and the other 2 subgroups were patients with aggressive B‑cell lymphoma confirmed by central independent pathological review who were receiving third- or fourth-line treatment. During the second Committee meeting, the manufacturer clarified that the subgroups of all patients regardless of rituximab status (those patients who had previously received rituximab plus those who had not) were labelled as 'without rituximab' in its response to consultation.\nIn its additional evidence, the manufacturer presented amended results for the subgroup of patients who had aggressive non-Hodgkin's B‑cell lymphoma confirmed by central independent pathological review and had previously received rituximab (see section 3.11). Complete or unconfirmed complete response rates were higher in the pixantrone arm than in the comparator arm (20% compared with 11%) but this difference was not statistically significant. Results for progression-free survival and overall survival were as before, except for median progression-free survival in the comparator arm, which the manufacturer confirmed was an error. In its consultation response, the manufacturer also reiterated data for the subgroup of all patients who had aggressive non-Hodgkin's B‑cell lymphoma confirmed by central independent pathological review regardless of whether they had previously received rituximab or not (n=50 in the pixantrone group, n=47 in the comparator group). At the end of the study, there was no statistically significant difference in complete or unconfirmed complete response rates between the pixantrone and comparator groups (9 patients compared with 4 patients; p=0.236). However, the overall response rate was statistically significantly higher in the pixantrone group (18 patients compared with 8 patients; p=0.041). Median progression-free survival was statistically significantly longer in the pixantrone arm than in the comparator arm (5.6 months compared with 2.5 months, hazard ratio 0.51 ; p value not stated) but there was no statistically significant difference in median overall survival between the 2 groups (8.1 months compared with 6.3 months, hazard ratio 0.72 ; p value not stated).\nIn its additional evidence, the manufacturer reiterated subgroup analyses for all patients (that is, patients who had previously received rituximab plus those who had not) with aggressive B‑cell lymphoma confirmed by central independent pathological review who were receiving third- or fourth-line treatment with pixantrone (n=39) or treatment of physician's choice (n=39). Compared with the group receiving treatment of physician's choice, the pixantrone group had a statistically significantly higher complete or unconfirmed complete response rate (23.1% compared with 5.1%; p=0.047) and overall response rate (43.6% compared with 12.8%; p=0.005). Median progression-free survival was statistically significantly longer with pixantrone than with treatment of physician's choice (5.7 months compared with 2.8 months, hazard ratio 0.44 ) but there was no statistically significant difference in median overall survival between treatment groups (11.9 months with pixantrone compared with 7.0 months with treatment of physician's choice, hazard ratio 0.67 ).\nIn its additional evidence, the manufacturer also provided results for a subgroup described as patients with aggressive B‑cell lymphoma confirmed by central independent pathological review who were receiving third- or fourth-line treatment who had previously received rituximab (n=25 in both study arms), but confirmed at the second Committee meeting that this population was in fact a subgroup of patients whose disease had been confirmed by onsite (not central) pathological review. The correct population (that is, with pathology confirmed by central independent review), whose results had previously been included as part of the manufacturer's clarification response, showed an increase in complete response or unconfirmed complete response in the pixantrone arm (n=20) compared with the comparator arm (n=18; 30% compared with 5.6%; p=0.093). There was no statistically significant difference between treatment arms in median progression-free survival (5.4 months in the pixantrone group and 2.8 months in the comparator group, hazard ratio 0.52 ). Similarly, there was no statistically significant difference in median or mean overall survival between treatment arms (hazard ratio 0.76 ). Median overall survival was 7.5 months in the pixantrone group and 5.4 months in the comparator group. Mean overall survival was 9.9 months in the pixantrone arm and 7.9 months in the comparator group (difference of 2.0 months).\n\n# Cost effectiveness\nThe manufacturer did not identify any published economic evaluations or costing studies that were relevant to the decision problem. Consequently, it submitted a de novo economic analysis that assessed the cost effectiveness of pixantrone compared with treatment of physician's choice in treating multiply relapsed or refractory aggressive B‑cell lymphoma, which was later revised as part of the manufacturer's response to consultation (see section 3.31 for details of changes in the revised model). Further minor updates were made in the manufacturer's model that formed part of a patient access scheme submission which was submitted in July 2013. In November 2013, this was superseded by another patient access scheme submission, which applied a further simple discount to the model (see sections 3.34–3.38 for details).\n\n## Manufacturer's submission\nThe manufacturer advised that the base-case model considered patients who had received 2 or 3 prior therapies and whose disease was sensitive to treatment with anthracyclines because this population was consistent with pixantrone's European marketing authorisation for treating multiply relapsed or refractory aggressive non-Hodgkin's lymphoma (the marketing authorisation notes that a treatment benefit has not been established 'when used as fifth line or greater chemotherapy in patients who are refractory to last therapy'). The clinical data for this population were derived from PIX301. The analysis was conducted from an NHS and personal and social services perspective and a lifetime horizon of 23 years was used. Weekly cycles were chosen to capture the 4‑week treatment cycles of pixantrone and 3‑week treatment cycles of some of the comparator treatments and a half-cycle correction was applied. Costs and benefits were discounted at 3.5% per annum.\nThe manufacturer created a semi-Markov model that contained 3 health states: stable or no progression, progressive or relapsed disease, and death. The stable or no progression health state had 2 distinct subpopulations. The first of these was patients on initial third- or fourth-line treatment. The second was patients who had discontinued third- or fourth-line treatment (because of complete response, adverse event, completion of 6 months' treatment or a non-clinical reason) but had not experienced progression. All patients entered the model in the on-treatment subpopulation within the stable or no progression health state. During each cycle, patients could remain in the on-treatment subpopulation of this health state, discontinue treatment and move into the other subpopulation in this health state, progress and move into the progressive disease health state, or die. Patients who discontinued treatment before progression remained at risk of progression or death. Following progression, patients were at risk of death and unable to return to the stable or no progression health state. It was assumed that the original treatment was stopped following disease progression and patients received further treatment or palliative care. Adverse events were captured as events within the model by applying a utility decrement (disutility).\nThe manufacturer outlined how the transition between health states was calculated from the clinical data for any given weekly cycle. It noted that semi-Markov models allow the use of a partition approach, which has been used extensively in oncology because it is particularly suited to progressive conditions that have ongoing risks that may vary over time. The distribution of the patient group between the different health states was estimated by calculating the area under the survival curves at each cycle. The progression-free survival curve defined the stable or no progression state, while the progressed state was defined by subtracting those patients who remained progression free from all surviving patients.\nClinical parameters for progression-free survival and overall survival were incorporated into the base case of the manufacturer's economic model by statistical analysis of patient-level data from the aggressive B‑cell population of PIX301. Predictive equations for progression-free survival and overall survival were derived by fitting the patient-level data and extrapolating beyond the data from PIX301 (around 2 years). A log-normal distribution was used in the base case for both progression-free survival and overall survival.\nFurther clinical parameters were incorporated into the base case of the manufacturer's economic model. The cycle probability of treatment discontinuation distinguished between patients remaining on initial treatment and those who discontinued while stable. The frequency and duration of adverse events (grades 2–4) before progression while taking initial treatment were based on PIX301. Grade 3 and 4 adverse events occurring in at least 5% of the total patient population were considered to have cost and utility consequences. Some grade 2, and rarer grade 3 and 4, adverse events were included if considered important by clinical specialists in England. Other data from PIX301 that were used to inform the model were mean dose for the comparator treatments plus sex and body surface area.\nThere were no patient-reported outcomes in PIX301 and the manufacturer did not identify any utility data for any line of treatment in aggressive non-Hodgkin's lymphoma in its systematic literature review for studies on health-related quality of life. Utility data were identified from published sources for similar patient populations, and for disease areas with similar expected survival, disease progression, nature of the disease and quality of life. These were diffuse large B‑cell lymphoma, chronic myelogenous leukaemia, chronic lymphocytic leukaemia, follicular lymphoma, renal cell carcinoma and melanoma. For its original model, the manufacturer considered the self-reported quality of life in older patients with aggressive diffuse large B‑cell lymphoma to give the estimation closest to the PIX301 trial population and used these values (pre-progression 0.81, post-progression 0.60) in its base-case analysis. The manufacturer did not provide a rationale for this decision. Utility values were assumed to depend only on the health state and any adverse events experienced, but not the treatment arm. Based on expert clinical opinion, the manufacturer assumed no difference in baseline health-related quality of life between the 2 subpopulations in the stable or no progression health state. All stable/no progression patients were assumed to have similar quality of life (that is, there was no difference according to complete response, partial response or stable disease).\nThe manufacturer determined disutilities associated with each adverse event that was included in the original model from relevant literature from other oncology indications. If no utility decrements were available, the maximum value of the range identified was assumed by the manufacturer to keep the calculations conservative (that is, so that pixantrone was not favoured).\nAdverse events were modelled by the manufacturer as events rather than as health states and were assumed to be time independent because adverse events are likely to be experienced at different stages of treatment. Any grade 1–4 adverse event that occurred in less than 5% of the trial population was assumed to have no impact on quality of life. After consulting some clinical specialists in England, the manufacturer included some rarer grade 3 and 4 adverse events and some grade 2 adverse events that the clinical specialists considered to be important. Because no disutility values were available specifically for grade 2 and grade 3 or 4 adverse events, they were assumed to be the same for each grade. Within a health state, disutilities relating to an adverse event were applied to the proportion of patients assumed to experience the adverse event as weighted average disutilities. For each treatment, the manufacturer calculated a weighted average of grade-specific disutilities that were weighted by the number of effects of that particular grade. The disutility for each adverse event was then applied for the duration of that specific type of effect. The manufacturer's model limited the consideration of adverse events to patients on original treatment upon entering the model (pixantrone or treatment of physician's choice).\nCosts captured in the manufacturer's model included drugs and their administration, plus those associated with health state and disease management, including adverse events. Drug and administration costs in the original model were calculated based on average dose per administration from the PIX301 trial using the British national formulary (BNF) edition 62 (published in September 2011) and the NHS reference costs. No patient access scheme was incorporated in the original model. From the second attendance onwards, administration costs were £206 for each attendance for all drugs except etoposide 50 mg (£163). At clarification, the manufacturer corrected an error in the vial price, which had been mistakenly quoted as £343.80 (based on the vial size given for pixantrone base) instead of £553.50 (equivalent to 50 mg pixantrone dimaleate). It advised that this error had a minimal impact on the cost-effectiveness estimates (which increased by 0.3%) because the drug costs in the model had been calculated based on cost per administration. The total number of administrations varied according to the dosing schedule for each drug. Drug wastage was incorporated in the base case. Personal and social services costs were £476.42 per 28 days for stable health state on treatment, £119.10 for stable health state on palliative care and £1993.89 for progressive health state. Disease management costs (comprising healthcare professional contact, disease follow-up and hospital-related costs) were different for active treatment and palliative care. For active treatment, health professional contact costs were £788.96 on treatment and £220.38 after treatment (per 28 days), disease follow-up costs were £86.63 per 28 days and annual hospital-related costs were £2357.28. For palliative care, health professional contact costs were £990.74 per 28 days, disease follow-up costs were £18.44 per 28 days and annual hospital-related costs were £1982.03. End-of-life care was excluded from the calculations because it affected only the last few weeks of life and estimates would be similar for pixantrone and its comparators. Within a health state, costs for managing an adverse event were applied to the proportion of patients assumed to experience the adverse event.\nThe manufacturer advised that the predicted median progression-free survival and predicted median overall survival were similar to the results reported in PIX301. Compared with the clinical trial results, the manufacturer noted that the original model slightly underestimated the median overall survival with pixantrone (13.1 months compared with 13.8 months) while overestimating it for the comparator (9.2 months compared with 7.6 months). It reported that, conversely, the original model overestimated the median progression-free survival for the pixantrone arm (7.8 months compared with 6.4 months) and slightly underestimated it for the comparator arm (3.2 months compared with 3.5 months).\nUsing the original model, the manufacturer's base-case analyses for pixantrone compared with treatment of physician's choice in patients with aggressive B‑cell lymphoma confirmed by onsite pathological review (third- or fourth-line treatment) produced a deterministic incremental cost-effectiveness ratio (ICER) of £28,423 per quality-adjusted life year (QALY) gained. Incremental costs were £17,638 and incremental QALYs were 0.62. Using the correct vial price supplied at clarification increased the ICER to £28,503 per QALY gained. No probabilistic base-case ICER was presented. All economic analysis results generated using the manufacturer's original model have been superseded by those using the model provided with the patient access scheme submission submitted in November 2013 (see sections 3.34–3.38).\n\n## Manufacturer's additional evidence in response to consultation on the first appraisal consultation document\nIn response to the first appraisal consultation document, the manufacturer provided a revised economic model, which contained these amendments:\nThe adverse-event disutilities used in the ERG's exploratory analyses were incorporated.\nDrug costs for comparator treatments were taken from the NHS Commercial Medicines Unit's Electronic Marketing Information Tool (eMIT) database instead of the BNF in line with NICE's Guide to the methods of technology appraisal (2013).\nUtility values were changed from self-reported quality of life in older patients with aggressive diffuse large B‑cell lymphoma (0.81 for the pre-progression health state, 0.60 for the post-progression health state) to those for second- and subsequent-line treatment of renal cell carcinoma (0.76 for the pre-progression health state and 0.68 for the post-progression health state). This was in response to the Committee's conclusion in the first Committee meeting that the original utility values had overestimated quality of life for patients with multiply relapsed or refractory non-Hodgkin's lymphoma.The revised model did not incorporate a patient access scheme.\nUsing its revised model, the manufacturer provided cost-effectiveness estimates of pixantrone compared with treatment of physician's choice for several subgroups, including patients with aggressive B‑cell lymphoma confirmed by central independent pathological review who were receiving third- or fourth-line treatment and had previously had rituximab. The deterministic ICER for this subgroup was £45,282 per QALY gained (incremental costs £9170; incremental QALYs 0.20). No probabilistic ICER was provided. All economic analysis results generated using the manufacturer's revised model have been superseded by those using the model provided with the patient access scheme submission submitted in November 2013 (see sections 3.34–3.38).\n\n## Manufacturer's patient access scheme submissions\nThe manufacturer agreed a patient access scheme in July 2013, which was a confidential simple discount on the list price of pixantrone. It further updated its economic model so that costs for treating adverse events and the cost for methotrexate were in line with the Committee's preferred values decided at the second Committee meeting. All economic analysis results generated using the manufacturer's model provided with the patient access scheme submitted in July 2013 have been superseded by those using the model provided with the patient access scheme submission submitted in November 2013 (see sections 3.34–3.38).\nIn response to the second appraisal consultation document, the manufacturer submitted a patient access scheme in November 2013 that contained an additional discount to the patient access scheme proposed in July 2013. The November 2013 patient access scheme is a simple discount on the list price of pixantrone, and the economic model was further updated with this additional discount as part of this submission. The manufacturer advised that the patient access scheme would apply to patients with histologically confirmed aggressive non-Hodgkin's B‑cell lymphoma who had previously received rituximab and would be receiving pixantrone as a third- or fourth-line treatment. The manufacturer made no other revisions to the economic model.\nThe manufacturer provided cost-effectiveness estimates incorporating the patient access scheme submitted in November 2013 for pixantrone compared with treatment of physician's choice for patients with aggressive B‑cell lymphoma confirmed by central independent pathological review who were receiving third- or fourth-line treatment and had previously received rituximab. This additional discount reduced the deterministic ICER to £18,462 per QALY gained (incremental costs are commercial in confidence and so cannot be shown here; incremental QALYs 0.20).\nThe manufacturer tested the robustness of the model using one-way sensitivity analyses and reported that the key drivers of the cost-effectiveness estimates produced using its economic model were the parametric fitting methodology for progression-free survival and overall survival, and the utility estimate for the stable or no progression health state. The manufacturer noted that the ICER was sensitive to changes in the estimates for progression-free survival.\nIn its base-case patient access scheme submission provided in November 2013, the manufacturer used the same utility values as the revised version of the model, which were for patients receiving second- and subsequent-line treatment for renal cell carcinoma (0.76 for the pre-progression health state and 0.68 for the post-progression health state). The manufacturer provided alternative utility scenarios using data from published sources for similar patient populations, and for disease areas with similar characteristics. These were second-line treatment in patients with chronic myelogenous leukaemia, third-line treatment in patients with chronic lymphocytic leukaemia, first-line maintenance treatment in patients with follicular lymphoma, first-line treatment in patients with metastatic renal cell carcinoma, self-reported quality of life during chemotherapy in elderly patients with aggressive non-Hodgkin's lymphoma and second-line treatment in patients with malignant melanoma. The ICERs ranged from £14,607 per QALY gained to £18,871 per QALY gained.\nTo explore uncertainty, the manufacturer undertook a probabilistic sensitivity analysis that incorporated the patient access scheme submitted in November 2013. The probabilistic mean ICER was £22,024 per QALY gained (incremental costs are commercial in confidence and so cannot be shown here; incremental QALYs 0.18). However the manufacturer asserted that there was structural uncertainty inherent in the probabilistic sensitivity analysis that reduced the advantage of pixantrone and skewed the probabilistic results. It explained that the model assumed that overall survival and progression-free survival were independent, leading to the survival curves crossing (that is, more patients were in the progression-free survival state than alive) and the model artificially reduced progression-free survival to avoid this, and that this applied to around 30% of the simulations. In order to illustrate the structural uncertainty arising from the probabilistic ICER, the manufacturer provided additional analyses; for example, if it is assumed that overall survival and progression-free survival are not independent (by assuming the same random numbers for progression-free survival and overall survival using the Cholesky decomposition), the probabilistic mean ICER is £9938 per QALY gained (incremental costs are commercial in confidence and so cannot be shown here; incremental QALYs 0.21). The manufacturer also noted that the joint uncertainty of incremental QALYs and incremental costs did not follow a normal distribution, and reported that the median probabilistic ICER was £14,692 per QALY gained (incremental costs are commercial in confidence and so cannot be shown here; incremental QALYs 0.18). The manufacturer reported that pixantrone was more likely to be cost effective compared with treatment of physician's choice in patients with aggressive B‑cell lymphoma confirmed by central pathological review who were receiving third- or fourth-line treatment at a maximum acceptable ICER of £25,000 per QALY gained.\n\n# Evidence Review Group's comments\nThe ERG considered the evidence included by the manufacturer to be relevant to the decision problem in its analysis. No additional relevant trials were identified and the ERG found that the manufacturer's systematic review followed standard practices.\nThe ERG had concerns about the generalisability of the PIX301 population to clinical practice in England and Wales, particularly the potential effect of previous rituximab treatment on the response to pixantrone because rituximab is given as part of standard first-line treatment in the UK. The ERG noted that about 50% of patients in PIX301 had previously received treatment with a biological agent (for example, rituximab). The ERG considered the clinical benefit of pixantrone in patients who have previously been treated with rituximab to be a key area of uncertainty, given that there were no statistically significant differences between the pixantrone and comparator arms for complete or unconfirmed complete response, progression-free survival or overall survival in the subgroup of patients with aggressive B‑cell lymphoma confirmed by central independent pathological review who had previously received rituximab.\nThe ERG considered whether the treatments of physician's choice in PIX301 represented clinical practice in England and Wales. Following input from its clinical specialists, the ERG noted that there is no consensus on which chemotherapy regimens should be used after second-line treatment fails and that there is a lack of comparative data on their clinical effectiveness. The ERG concluded that this meant the choice of treatment in the comparator arm of PIX301 was unlikely to be a key issue. It also concluded that the small number of patients receiving each treatment meant that the choice of treatment in the comparator group could not be reliably analysed.\nThe ERG was concerned about the statistical power of PIX301 to detect a difference between treatment groups. According to the manufacturer's revised power calculation, 81% power with 70 patients per group (the intention-to-treat population) would be achieved if the true proportion of patients with complete or unconfirmed complete response was 22% in the pixantrone group and 5% in the comparator group. However, the observed proportions of patients with a complete or unconfirmed complete response in the intention-to-treat population were 20.0% in the pixantrone group and 5.7% in the comparator group. The ERG noted that the difference between groups did not always reach statistical significance, and that results of the analyses in the subgroups confirmed by central independent pathological review should be interpreted with caution because they are likely to be underpowered to detect a difference between treatment groups. For these reasons, the ERG had reservations about whether pixantrone had been shown to have superior efficacy in PIX301.\nThe ERG was concerned about the reliability of the diagnosis of aggressive non-Hodgkin's lymphoma at study entry. It noted that central independent pathological review by consensus was undertaken retrospectively (that is, after the trial), rather than at enrolment, and that aggressive disease was subsequently confirmed in only 104 of the 140 patients who were randomised. Consequently, it felt that results from the full trial population might not reflect the benefit of pixantrone in patients with aggressive B‑cell lymphoma. The ERG acknowledged that the manufacturer said it had not been practical to confirm aggressive disease by central independent pathological review at enrolment, but considered it was important to evaluate data from the subgroup of patients with disease confirmed by central independent pathological review. The ERG noted that, as a subgroup analysis, the statistical power of PIX301 would be less than the intention-to-treat population.\nThe ERG considered the different patient populations in the subgroup analyses presented by the manufacturer. The ERG viewed the data from the post-hoc subgroup of patients with aggressive non-Hodgkin's B‑cell lymphoma that was histologically confirmed by central independent pathological review to be more relevant to the marketing authorisation and the decision problem in the NICE scope than the other 2 subgroups categorised according to type of lymphoma determined by onsite pathological review (patients with aggressive non-Hodgkin's B‑cell lymphoma and patients with diffuse large B‑cell lymphoma). The ERG noted that retrospective central independent pathological review revealed 23% of patients receiving pixantrone and 29% of patients receiving a comparator in the intention-to-treat population had disease that was not subsequently confirmed as being aggressive. The ERG was aware that disease severity is an important factor in deciding treatment strategy because patients without aggressive disease are likely to have a more favourable response than those with aggressive disease.\nThe ERG considered the statistical robustness of the subgroup analyses. It observed that the comparative clinical-effectiveness results for most of the subgroups were based on post-hoc subgroup analyses. It also noted that the number of patients in the analysis was generally small, increasing uncertainty around the results. For subgroups based on retrospective histological confirmation of aggressive disease and previous rituximab treatment, the ERG noted the potential for unbalanced groups because randomisation had not been stratified by these factors. The ERG concluded that the results of the subgroup analyses should be interpreted with caution.\nThe ERG considered the adverse events reported to occur more often in the pixantrone group than the comparator group receiving treatment of physician's choice to be consistent with the common adverse events associated with pixantrone reported in the summary of product characteristics.\nOverall, the ERG considered the manufacturer's original model to be in line with current best practice recommendations, generally well constructed and largely transparent. The ERG considered that an important limitation of the manufacturer's original base-case analysis was that it used data from patients whose disease had not been histologically confirmed as aggressive. The ERG indicated that the subgroup of patients with aggressive non-Hodgkin's B‑cell lymphoma confirmed by central independent pathological review for all lines of treatment in PIX301 was the most informative to the decision problem because it excluded patients who were later found to have disease that was irrelevant to the decision problem (for example, indolent disease). However, the ERG noted that the manufacturer's estimate of cost effectiveness in this patient population was highly uncertain because it used post-hoc subgroup data and because the subgroups were not powered to detect a difference in efficacy between treatment with pixantrone and the comparators.\nThe ERG considered the utility weights used by the manufacturer in its original economic model to be potentially inappropriate. It noted that the utility values were from a population of patients receiving first-line treatment for aggressive non-Hodgkin's lymphoma and were derived from a study that had initially been rejected by the manufacturer in its systematic review. It further noted that the manufacturer's reported utility values were higher than those that have been derived for healthy older patients in the UK.\nThe ERG noted that the results of the manufacturer's original economic model may potentially be biased towards pixantrone because of an overestimation of pixantrone's relative progression-free survival benefit compared with treatment of physician's choice for the populations with aggressive B‑cell lymphoma (whether confirmed by onsite or central independent pathological review). Clinical specialist opinion received by the ERG expressed concern that the data used in the model may not be sufficient to reach reasonable conclusions about the clinical or cost effectiveness of pixantrone.\nThe ERG identified other areas of inaccuracy or uncertainty in the assumptions and parameter estimates used in the manufacturer's original model and indicated the most significant of these were structural assumptions made about treatment discontinuation, disutility, and the cost parameters used:\nThe potential double-counting of treatment discontinuation because of disease progression.\nExcluding adverse event disutilities for patients on further lines of treatment.\nDiscrepancies between the manufacturer's and ERG's interpretation of the literature on disutilities for adverse events.\nUsing weighted average adverse event rates to inform costs and disutilities associated with adverse events for patients on original treatment.\nMissing data from data used to inform average adverse event costs.\nExcluding costs associated with treating leukopenia and thrombocytopenia.\nUsing costs from BNF 62 (published September 2011) rather than BNF 64 (published September 2012).\nThe ERG critiqued the manufacturer's additional evidence submitted in response to the first consultation. Although there were some uncertainties in the definition and labelling of the manufacturer's subgroups, the ERG was able to validate the terminology used and check that the changes the manufacturer had made to its model were appropriate. The ERG indicated that, based on the European marketing authorisation and clinical practice in England and Wales, it was important to evaluate patients with aggressive B‑cell lymphoma confirmed by retrospective central independent pathological review who had previously received rituximab. However, it noted that it was also appropriate to evaluate a subgroup of these patients receiving third- or fourth-line treatment.\nThe ERG critiqued the manufacturer's patient access scheme submission. It validated the changes made to the economic model in the July 2013 and November 2013 submissions and agreed that the subgroup of patients covered by the patient access scheme was characteristic of patients in England and Wales who were likely to be eligible for treatment with pixantrone.\nThe ERG validated the manufacturer's deterministic and probabilistic sensitivity analyses on the updated base case in the patient access scheme submitted in November 2013, which were conducted in the same way as in the manufacturer's original submission. The ERG had commented in its critique of the manufacturer's original submission that the manufacturer's assessment of uncertainty was very detailed and that the probabilistic and one-way sensitivity analyses, including various scenario analyses, were satisfactorily reported.\nThe ERG commented that the absence of utility data in patients with relapsed or refractory aggressive non-Hodgkin's lymphoma results in a great deal of uncertainty. The ERG stated that although the utility values derived from patients receiving second-line treatment for renal cell carcinoma were less favourable than those used in the manufacturer's original submission, they may still overestimate the utility of patients with aggressive non-Hodgkin's B‑cell lymphoma receiving third- or fourth-line treatment.\nThe ERG stated that the manufacturer's original base-case cost-effectiveness results (before inclusion of any patient access scheme) were generated deterministically rather than probabilistically (that is, mean values rather than distributions were used to inform the value of each parameter). However, the ERG noted that probabilistic cost-effectiveness results could be assessed using the manufacturer's original model. It noted a wide range in the 95% confidence interval for the mean probabilistic ICER. The ERG considered this showed substantial uncertainty in the manufacturer's cost-effectiveness results.\nUsing the manufacturer's original model (before inclusion of any patient access scheme), the ERG carried out exploratory sensitivity analyses to investigate the impact of alternative assumptions or parameters on the manufacturer's cost-effectiveness results. The ERG judged the population with aggressive B‑cell lymphoma confirmed by central independent pathological review for all lines of treatment in PIX301 to be the most relevant to the decision problem (because it excluded patients who were later found to have disease that was not relevant to the decision problem ) and used it in all its exploratory analyses with the original model.\nBecause it had concluded that the utility values used by the manufacturer in its original model (before inclusion of any patient access scheme) may have been inappropriate, the ERG investigated how alternative utility values affected the manufacturer's original base case. The ERG presented a markedly increased ICER for pixantrone compared with treatment of physician's choice when it used utility data from chronic lymphocytic leukaemia patients receiving third- or later-line treatment to inform the utility of progression-free survival and progressive disease (0.428 for the pre-progression health state and 0.279 for the post-progression health state).\nThe ERG discussed the probabilistic cost-effectiveness results generated by the manufacturer using the patient access scheme submitted in November 2013, and validated the changes by the manufacturer to the economic model. The ERG commented that the manufacturer's probabilistic analysis showed that, after incorporating the patient access scheme, the probability of pixantrone being cost-effective compared with treatment of physician's choice was 49.3% at up to £20,000 per QALY gained and 55.7% at up to £30,000 per QALY gained. The ERG considered it important to note that, although 68% of probabilistic iterations showed a greater benefit for pixantrone than treatment of physician's choice, around 32% of probabilistic iterations indicated that patients treated with pixantrone fared worse than those who received treatment of physician's choice.\nFull details of all the evidence are in the evaluation report.# Consideration of the evidence\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of pixantrone, having considered evidence on the nature of multiply relapsed or refractory non-Hodgkin's B‑cell lymphoma and the value placed on the benefits of pixantrone by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\nThe Committee discussed the treatment pathway for multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. It heard from the clinical specialists that rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone (also known as R‑CHOP) was the standard first-line treatment in England and Wales, and that most patients would also receive a rituximab-containing regimen second line. If their disease did not relapse within 6 months of first-line treatment, patients would be treated with rituximab. The Committee also noted that the clinical specialists stated that people treated with rituximab were less likely to respond to any subsequent treatment. The Committee heard that a platinum-based regimen was offered as second-line treatment but that there was no consensus on third- or fourth-line treatment. The Committee heard from the clinical specialists and the patient expert that the aim of treatment at this disease stage was to reduce the impact of symptoms on quality of life, as well as extending life, and could include chemotherapy or participating in clinical trials. The clinical specialists highlighted that fifth-line options include palliative care or participating in clinical trials. The Committee also noted that the marketing authorisation states that the benefit of pixantrone treatment has not been established in patients when used as fifth-line or further chemotherapy in patients whose disease is refractory to last therapy.\nThe Committee heard from the patient expert about the impact of multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma on daily life and that the symptoms of the disease can reduce quality of life. It heard that patients are normally told at the start of their treatment that they are being treated with curative intent and that experiencing multiple relapses can be devastating; consequently, they would value any new treatment that could offer symptom relief, have a positive impact on quality of life and increase survival. The Committee acknowledged the demands that living with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma can place on patients and accepted that a treatment option for these patients is important.\n\n# Clinical effectiveness\nThe Committee reviewed the suitability of the clinical trial evidence submitted by the manufacturer and expressed several concerns about the PIX301 trial. It considered PIX301 to be underpowered because it had failed to recruit the planned number of patients. It also noted that European regulators prefer a primary end point of overall survival or progression-free survival for clinical trials of anticancer drugs, but the primary end point for PIX301 was complete or unconfirmed complete response. The Committee heard from the clinical specialists that although this end point would have been acceptable when the trial began in 2004, positron emission tomography (PET) scans have made unconfirmed complete response obsolete in trials that have begun more recently. The Committee also heard from the clinical specialists that they considered studies that were powered to detect a difference in overall survival to be more useful for clinical decision-making. The Committee concluded that these fundamental concerns about the design of PIX301 meant that there was considerable uncertainty in the validity and robustness of its results.\nThe Committee discussed the relationship between the marketing authorisation, the PIX301 population and clinical practice in England and Wales. The Committee was aware that the intention-to-treat population included around 10% of patients who did not have aggressive B‑cell lymphoma, making them ineligible for treatment with pixantrone according to the terms of the marketing authorisation. The Committee further noted that the marketing authorisation is for multiply relapsed or refractory disease (that is, it is approved for patients who have received at least 2 previous lines of treatment) and that this does not necessarily restrict its use to third- and fourth-line treatment. However, it also noted the comments received during consultation stating that patients receiving fifth-line or further treatment would likely have palliative treatment or participate in a clinical trial. The Committee was persuaded that pixantrone would most likely be used, within its marketing authorisation, as a third- or fourth-line treatment in clinical practice in England and Wales. The Committee concluded that, when assessing the PIX301 results, it would be more appropriate to consider the population with aggressive B‑cell lymphoma who had received third- or fourth-line treatment.\nThe Committee discussed how the tumour histologies were determined in the PIX301 population and whether this was generalisable to clinical practice in England and Wales. It was aware that tumour histology in the intention-to-treat population of PIX301 had been determined by onsite review by a single pathologist. The Committee heard from the clinical specialists that this was not representative of clinical practice in England and Wales, in which multidisciplinary team review is routine and specimens are examined by 2 or 3 pathologists. It noted that the Evidence Review Group (ERG) had also been advised by clinical specialists that a population with disease confirmed by central independent pathological review was more relevant to clinical practice in England and Wales. It also noted that a considerable proportion of patients were excluded after the central independent pathological review (for example, if indolent disease had been confirmed). The Committee concluded that it would be more appropriate to consider the PIX301 population with tumour histology confirmed by retrospective central independent pathological review by consensus than by onsite review by a single pathologist.\nThe Committee discussed whether the comparator arm (treatment of physician's choice) in PIX301 was relevant to clinical practice in England and Wales. It heard from clinical specialists that, apart from PIX301, there was no evidence base for selecting a third- or fourth-line treatment for multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma and that there was wide variation in the treatments used in clinical practice in England and Wales. The Committee concluded that all of the comparators used in the treatment of physician's choice arm in PIX301 were clinically relevant (although there was some uncertainty in the proportions in PIX301 compared with clinical practice in England and Wales), and the comparator arm was therefore acceptable for decision-making.\nThe Committee discussed the generalisability of previous treatments received by the PIX301 population to clinical practice in England and Wales. The Committee heard from the clinical specialists that rituximab is an integral part of standard first-line treatment in the NHS and is also often used as a second-line treatment. The Committee noted that the manufacturer's subgroup analyses showed a reduced benefit of pixantrone in patients who had previously received rituximab, and that many of the results showed no statistically significant difference between treatment arms (see sections 3.11 and 3.16–3.18). It also noted a clinical specialist's concern that statistical significance was not reached for the parameters complete or unconfirmed complete response, progression-free survival and overall survival for this subgroup. The Committee accepted the non statistically significant results because of the positive trend in all 3 outcomes for this subgroup. It was aware from comments received during consultation that this reduced benefit applied to other drugs in clinical development and was not specific to pixantrone. It was also aware of the obligation to the European Medicines Agency in pixantrone's European marketing authorisation requiring a trial to confirm the clinical benefit in patients who have previously received rituximab. However, the Committee acknowledged the comments received in response to consultation that the complete response rates with pixantrone in PIX301 were among the highest reported to date in trials for patients with diffuse large B‑cell lymphoma who had previously received rituximab. The Committee concluded that it was appropriate to evaluate the subgroup of patients in PIX301 who had previously received rituximab because this would apply to almost all patients with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma in England and Wales.\nThe Committee considered the clinical-effectiveness results for the whole intention-to-treat trial population and all the post-hoc subgroups. It noted that in the intention-to-treat population, PIX301 was inadequately powered to detect a difference between treatment groups because it had accrued less than half of the planned 320 patients. It noted that the difference in response rates, progression-free survival and overall survival between treatment groups did not always reach statistical significance in the intention-to-treat population (see section 3.17) and the post-hoc subgroups, and that there was no statistically significant difference in overall survival between treatment arms for any groups presented by the manufacturer. The Committee had reservations about whether superior efficacy of pixantrone had been shown for the intention-to-treat trial population.\nThe Committee then discussed the clinical effectiveness for the subgroup of patients it considered to be most appropriate for decision making (those receiving third- or fourth-line treatment and who had previously received rituximab ). It concluded that there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice, and that the mean survival advantage of pixantrone compared with treatment of physician's choice was 2.0 months. However, these results were not statistically significant (see section 3.18). The Committee also concluded that there was limited and non-robust evidence to show that pixantrone was more clinically effective than treatments currently used in the Committee's preferred subgroup.\nThe Committee discussed the adverse events associated with pixantrone. It noted the manufacturer's assertion that pixantrone was associated with less cardiotoxicity than anthracyclines. The Committee was aware that the final scope issued by NICE did not include any anthracyclines as comparators and that mitoxantrone was the only anthracenedione out of the 6 comparators. It heard from clinical specialists that doxorubicin (an anthracycline) was used as first-line treatment, and that none of the comparators for third- or fourth-line treatment were associated with the similarly raised cardiovascular risk associated with anthracyclines. The Committee was aware that there were more cardiac adverse events in the pixantrone group than in the comparator group, who received treatment of physician's choice (35% compared with 21%). However, it heard from the clinical specialists that efficacy is considered key in this patient population and that, because of its cardiovascular safety profile compared with anthracyclines, pixantrone offered an opportunity for response in patients who had previously shown sensitivity to anthracyclines but who could not receive further lines of anthracycline treatment after relapse because they had reached the maximum lifetime dose. It concluded that pixantrone had an acceptable adverse-effect profile although it was associated with more cardiotoxicity than treatments such as oxaliplatin and gemcitabine that are routinely used in this population in clinical practice in England and Wales.\n\n# Cost effectiveness\nThe Committee discussed the manufacturer's general approach to developing the submitted pixantrone economic models. It noted that the ERG considered the manufacturer's approach to follow current best practice and was largely transparent. The Committee concluded that the outlined structure of the models adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of pixantrone.\nThe Committee considered the manufacturer's cost-effectiveness analyses that included the patient access scheme for the Committee's preferred patient subgroup (that is, the subgroup with aggressive B‑cell lymphoma confirmed by central independent pathological review for third- or fourth-line treatment and who had previously received rituximab ). In particular the Committee discussed how quality of life had been incorporated into the manufacturer's economic modelling. It was aware that the base-case analysis in the manufacturer's patient access scheme submitted in November 2013 used utility values for patients receiving second- and subsequent-line treatment for renal cell carcinoma (0.76 for the pre-progression health state and 0.68 for the post-progression health state). It noted the absence of published utility values in the relevant patient population and that the manufacturer intends to fund additional research in this area. The Committee noted that the utility value for the pre-progression health state (0.76) was similar to that expected for a healthy older population in the UK, and it considered that the quality of life of patients receiving third- or fourth-line treatment for aggressive non-Hodgkin's B‑cell lymphoma could be lower than this. The Committee then reviewed the utility values selected by the ERG for its exploratory analyses using the manufacturer's original model and the revised model supplied with the patient access scheme submission, which were for patients receiving final-line treatment for chronic lymphocytic leukaemia (0.428 for the pre-progression health state and 0.279 for the post-progression health state). The Committee heard from the clinical specialists that there were differences between the 2 conditions that could mean these utility values were too low, and decided that the ERG's utility values were likely to underestimate the quality of life for this population. Having excluded the ERG's low utility values, the Committee considered that the manufacturer's deterministic sensitivity analysis on the base case in the patient access scheme submission using various utility values (see section 3.37) showed that utility values were not a key driver of cost effectiveness. The Committee concluded that, although there was some uncertainty as to the true utility value, the utility values used in the manufacturer's revised model with the patient access scheme were acceptable for use in the Committee's decision-making.\nThe Committee considered the incremental cost-effectiveness ratios (ICERs) and considered those presented in the manufacturer's most recent cost-effectiveness analyses, which included the patient access scheme for the Committee's preferred patient subgroup. For the comparison of pixantrone with treatment of physician's choice, it noted that the manufacturer's deterministic and mean probabilistic ICERs incorporating the patient access scheme for this population were £18,500 and £22,000 per quality-adjusted life year (QALY) gained respectively. The Committee noted that the ERG had validated the changes made to the manufacturer's model as part of the patient access scheme submission in November 2013. The Committee concluded that the manufacturer's analysis was appropriate for its decision-making.\nThe Committee discussed the amount of uncertainty in the cost-effectiveness estimates for the Committee's preferred subgroup of patients, that is people with aggressive B‑cell lymphoma confirmed by central pathological review receiving third- or fourth-line treatment and who have previously received rituximab. The Committee was persuaded that the manufacturer's mean probabilistic ICER of £22,000 per QALY gained could overestimate the uncertainty associated with the survival modelling and that the true value of the ICER might be lower. It was aware that the median probabilistic ICER was £14,700 per QALY gained and that the probabilistic ICER reduced to £10,000 per QALY gained when assuming that progression-free survival and overall survival did not change independently of each other. The Committee noted that the manufacturer's exploratory probabilistic sensitivity analysis showed that the probability of pixantrone being cost effective compared with treatment of physician's choice was 56% at a maximum acceptable ICER of £30,000 per QALY gained, and approximately 50% at a maximum acceptable ICER of £20,000 per QALY gained. Additionally, although pixantrone was less clinically effective in 32% of simulations, it was less expensive than treatment of physician's choice in a high proportion of these at a maximum acceptable ICER of £20,000 per QALY gained. The Committee therefore agreed that the probability of pixantrone being cost-effective compared with treatment of physician's choice was acceptable. The Committee concluded that the most plausible ICER was likely to be less than £22,000 per QALY gained, and it concluded that pixantrone was recommended as a cost-effective use of NHS resources.\nThe Committee discussed whether pixantrone was innovative in its potential to make a significant and substantial impact on health-related benefits. It observed that pixantrone is the first drug that has been tested in a randomised phase III trial in patients with multiply relapsed or refractory aggressive non-Hodgkin's lymphoma. It examined whether pixantrone had the potential to make a significant and substantial impact on health-related benefits but heard from the clinical specialists that it was uncertain whether pixantrone could be considered a step change in treatment. On the basis of currently available evidence, the Committee did not consider pixantrone to be a step change in managing multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. The Committee observed that there were no additional gains in health-related quality of life over those already included in the QALY calculations. The Committee concluded that there were no additional QALYs that had not been incorporated into the economic model and the cost-effectiveness estimates.\nThe Committee understood that pixantrone's conditional marketing authorisation is linked to results from the ongoing PIX306 study, which should be available in 2015. It noted that this larger randomised phase III study (n=350) will compare the effectiveness of pixantrone plus rituximab with gemcitabine plus rituximab in patients with relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma who have already received a rituximab-containing regimen. Given the relevance of the patient population (because virtually all patients with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma in England and Wales will have previously received rituximab ), the Committee recommended that the technology appraisal guidance on pixantrone for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma should be considered for review by NICE once the PIX306 results are available in 2015.\nThe Committee considered whether NICE's duties under the equality legislation required it to alter or to add to its recommendations. It noted that no equality issues had been raised during scoping, in any of the consultees' submissions, during consultation or during the Committee meetings. The Committee concluded that its decision on the use of pixantrone does not have a particular impact on any group with a protected characteristic in the equality legislation and that there was no need to alter or add to its recommendations.\n\n# Summary of Appraisal Committee's key conclusions\nTA306\nAppraisal title: Pixantrone monotherapy for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma\nSection\nKey conclusion\nPixantrone monotherapy is recommended as an option for treating adults with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma only if:\nthe person has previously been treated with rituximab and\nthe person is receiving third- or fourth-line treatment and\nthe manufacturer provides pixantrone with the discount agreed in the patient access scheme.\nThe Committee concluded that there was limited and non-robust evidence to show that pixantrone was more clinically effective than treatments currently used in clinical practice for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. It further concluded that there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice. However, these results were not statistically significant.\nThe Committee noted that using the revised model that incorporated the patient access scheme, the manufacturer's deterministic ICER was £18,500 per quality-adjusted life year (QALY) gained and that the mean probabilistic ICER was £22,000 per QALY gained. The Committee agreed that the probability of pixantrone being cost effective compared with treatment of physician's choice was acceptable and that the most plausible ICER was likely to be less than £22,000 per QALY gained. It therefore concluded that pixantrone could be recommended as a cost-effective use of NHS resources.\nCurrent practice\nClinical need of patients, including the availability of alternative treatments\nThe Committee heard from the clinical specialists and the patient expert that the aim of treatment at this disease stage was to reduce the impact of symptoms on quality of life, as well as extending life, and could include chemotherapy and participating in clinical trials. The Committee heard from the patient expert that patients would value any new treatment that could offer symptom relief, have a positive impact on quality of life and increase survival. The Committee acknowledged the demands that living with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma can place on patients and accepted that a treatment option for these patients is important.\nThe technology\nProposed benefits of the technology\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\nPixantrone (Pixuvri, Cell Therapeutics) is an aza‑anthracenedione analogue and inhibitor of topoisomerase II. The Committee concluded that there was limited and non-robust evidence to show that pixantrone was more clinically effective than treatments currently used in clinical practice to treat multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. It further concluded that there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice. However, these results were not statistically significant.\nThe Committee examined whether pixantrone had the potential to make a significant and substantial impact on health-related benefits. On the basis of currently available evidence, the Committee concluded that using pixantrone would not be a step change in managing multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma and that there were no additional QALYs that had not been incorporated into the economic model and the cost-effectiveness estimates.\nWhat is the position of the treatment in the pathway of care for the condition?\nPixantrone has a conditional marketing authorisation 'as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin B‑cell lymphomas (NHL). The benefit of pixantrone treatment has not been established in patients when used as fifth line or greater chemotherapy in patients who are refractory to last therapy'.\nIn light of consultee and commentator responses to consultation, the Committee considered that it was appropriate to restrict its assessment of pixantrone to third- and fourth-line treatment. The Committee concluded that the subgroup in PIX301 with aggressive B‑cell lymphoma confirmed by central independent pathological review receiving third- or fourth-line treatment and who had previously received rituximab was the most appropriate for decision-making.\nAdverse reactions\nThe summary of product characteristics states that the most common toxicity with pixantrone is bone marrow suppression (particularly the neutrophil lineage) and that other toxicities such as nausea, vomiting and diarrhoea are generally infrequent, mild, reversible, manageable and as expected in patients treated with cytotoxic agents. Although the occurrence of cardiac toxicity indicated by congestive heart failure appears to be lower than that expected with related drugs like anthracyclines, the summary of product characteristics recommends monitoring left ventricular ejection fraction.\nThe Committee concluded that pixantrone had an acceptable adverse-event profile although it was associated with more cardiotoxicity than treatments such as oxaliplatin and gemcitabine that are routinely used in this population in clinical practice in England and Wales.\nEvidence for clinical effectiveness\nAvailability, nature and quality of evidence\nThe Committee considered that the PIX301 trial was underpowered because it had failed to recruit the planned number of patients. It also noted that European regulators prefer a primary end point of overall survival or progression-free survival for clinical trials of anticancer drugs, but the primary end point for PIX301 was complete or unconfirmed complete response. The Committee considered that although the PIX301 study had included a high proportion of patients who would be eligible for treatment under the terms of the marketing authorisation, the intention-to-treat population was not appropriate for evaluation and decision-making. The Committee concluded that these fundamental concerns about the design of PIX301 meant that there was considerable uncertainty in the validity and robustness of its results.\nRelevance to general clinical practice in the NHS\nBecause tumour specimens would be examined by 2 or 3 pathologists in clinical practice in England and Wales, the Committee concluded that it would be more appropriate to consider results from the PIX301 trial using a population with tumour histology confirmed by retrospective central independent pathological review by consensus than by onsite review by a single pathologist.\nUncertainties generated by the evidence\nThe Committee was concerned that only just over half of patients in the PIX301 trial had previously received rituximab because it heard from the clinical specialists that rituximab is an integral part of standard first-line treatment in the NHS and also often used as a second-line treatment. It was aware of the obligation to the European Medicines Agency in pixantrone's marketing authorisation requiring a trial to confirm the clinical benefit in patients who have previously received rituximab. The Committee noted a reduced benefit of pixantrone in the subgroup of patients who had previously received rituximab, but concluded that it was appropriate to evaluate this subgroup because this would apply to almost all patients with multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma in England and Wales.\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\nThe Committee was aware that the intention-to-treat population included patients whose tumour histology would make them ineligible for treatment with pixantrone according to the terms of the European marketing authorisation. The Committee concluded that the subgroup of patients in PIX301 with aggressive B‑cell lymphoma confirmed by central independent pathological review receiving third- or fourth-line treatment and who had previously received rituximab was the most appropriate for decision-making.\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\nThe Committee concluded that for the subgroup of patients it considered to be most appropriate for decision making (those receiving third- or fourth-line treatment and who had previously received rituximab) there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice, and that the mean survival advantage of pixantrone compared with treatment of physician's choice was 2.0 months. However, these results were not statistically significant. The Committee concluded that there was limited and non-robust evidence to show pixantrone was more clinically effective than treatments currently used in clinical practice for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma.\nEvidence for cost effectiveness\nAvailability and nature of evidence\nThe Committee concluded that the outlined structure of the models adhered to the NICE reference case for economic analysis and was acceptable for assessing the cost effectiveness of pixantrone.\nUncertainties around and plausibility of assumptions and inputs in the economic model\nThe Committee was persuaded that the manufacturer's mean probabilistic ICER of £22,000 per QALY gained could overestimate the uncertainty associated with the survival modelling and that the true value of the ICER might be lower. It further concluded that there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice. However, these results were not statistically significant.\nIncorporation of health-related quality-of-life benefits and utility values\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\nThe Committee was aware that the utility value used by the manufacturer in its revised model incorporating the patient access scheme for the pre-progression health state was similar to that expected for an older population in the UK. The Committee considered that the quality of life of patients receiving third- or fourth-line treatment for aggressive non-Hodgkin's B‑cell lymphoma could be lower than this. The Committee concluded that, although there was some uncertainty as to the true utility value, the utility values used in the manufacturer's revised model that was part of the patient access scheme submission were appropriate for use in the Committee's decision-making. The Committee observed that there were no additional gains in health-related quality of life over those already included in the QALY calculations and concluded that there were no additional QALYs that had not been incorporated into the economic model and the cost-effectiveness estimates.\nAre there specific groups of people for whom the technology is particularly cost effective?\nThe patient access scheme applies to patients with histologically confirmed aggressive non-Hodgkin's B‑cell lymphoma who have previously received rituximab and are receiving pixantrone as a third- or fourth-line treatment.\nWhat are the key drivers of cost effectiveness?\nThe Committee concluded that there was limited and non-robust evidence to show pixantrone was more clinically effective than treatments currently used in clinical practice for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma. It further concluded that there was an increase in response rates, progression-free survival, and overall survival for pixantrone compared with treatment of physician's choice. However, these results were not statistically significant.\nThe patient access scheme reduced the mean probabilistic ICER to £22,000 per QALY gained. The Committee was persuaded that this ICER could overestimate the uncertainty associated with the survival modelling and that the true value of the ICER might be lower.\nMost likely cost-effectiveness estimate (given as an ICER)\nThe Committee noted that, for the subgroup of patients with aggressive B‑cell lymphoma confirmed by central independent pathological review for third- or fourth-line treatment and who had previously received rituximab, the manufacturer's deterministic ICER incorporating the patient access scheme was £18,500 per QALY gained and the manufacturer's mean probabilistic ICER was £22,000 per QALY gained. The Committee noted that the exploratory analysis showed a high level of uncertainty around the ICER. However, the Committee was persuaded that this analysis could overestimate the uncertainty associated with the survival modelling and that the true value of the ICER might be lower. The Committee concluded that because the probabilistic ICER was likely to be less than £22,000 per QALY gained pixantrone was recommended as a cost-effective use of NHS resources.\nAdditional factors taken into account\nPatient access schemes (PPRS)\nThe manufacturer of pixantrone has agreed a patient access scheme with the Department of Health that makes pixantrone available with a discount. The size of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.\nEnd-of-life considerations\nNot appropriate.\nEqualities considerations and social value judgements\nThe Committee concluded that its decision on the use of pixantrone does not have a particular impact on any group with a protected characteristic in the equality legislation and that there was no need to alter or add to its recommendations.\n\n# Related NICE guidance\nDetails are correct at the time of publication. Further information is available on the NICE website.\nRituximab for aggressive non-Hodgkin's lymphoma. NICE technology appraisal guidance 65 (2003).\nImproving outcomes in haematological cancers. NICE cancer service guidance (2003).# Review of guidance\nThe guidance on this technology will be considered for review when the PIX306 trial results are available and at the latest in November 2016. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\nAndrew DillonChief ExecutiveFebruary 2014# Changes after publication\nApril 2014: Wording changes in sections 4.8 and 4.9.# About this guidance\nNICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\nThis guidance was developed using the NICE single technology appraisal process.\nIt has been incorporated into the NICE pathway on blood and bone marrow cancers along with other related guidance and products.\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\nYour responsibilityThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\nCopyright© National Institute for Health and Care Excellence 2014. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\nISBN: 978-1-4731-0448-8"}}},{"rowIdx":92,"cells":{"id":{"kind":"string","value":"2a8ce388e7d1c0bf619852c859fd1f7a3d18bce2"},"source":{"kind":"string","value":"nice"},"text":{"kind":"string","value":"Mannitol dry powder for inhalation for treating cystic fibrosis\n\n# Guidance\nMannitol dry powder for inhalation is recommended as an option for treating cystic fibrosis in adults:\nwho cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and\nwhose lung function is rapidly declining (forced expiratory volume in 1 second decline greater than 2% annually) and\nfor whom other osmotic agents are not considered appropriate.\nPeople currently receiving mannitol whose cystic fibrosis does not meet the criteria in 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.# The technology\nMannitol (Bronchitol, Pharmaxis) is a mucoactive agent that causes water to enter the airway lumen and hydrate airway secretions. This reduces the viscosity of secretions and stimulates cough, thereby increasing the clearance of secretions and pathogenic bacteria. Mannitol dry powder is inhaled from a hand-held, breath-activated device. Mannitol has a marketing authorisation as an add-on therapy to best standard of care in adults with cystic fibrosis. The summary of product characteristics states that the recommended dose is 400 mg twice a day.\nThe most common and important adverse reactions associated with mannitol as stated in the summary of product characteristics are hyperresponsiveness to mannitol, cough, bronchospasm, exacerbation of cystic fibrosis, chest discomfort, wheezing, throat irritation, vomiting, headache and pharyngolaryngeal pain. The most clinically significant adverse reaction associated with mannitol use is haemoptysis (coughing up of blood).\nMannitol is available as a 40 mg powder capsule for inhalation. The list price for a 14-day pack of 280 capsules and 2 inhalers is £231.66 (excluding VAT; 'Monthly Index of Medical Specialities' September 2012). This equates to £0.83 per 40 mg capsule, or an average cost of £16.55 per day, including the cost of the inhaler. These prices do not include VAT. Costs may vary in different settings because of negotiated procurement discounts.# The manufacturer's submission\nThe Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of mannitol and a review of this submission by the Evidence Review Group (ERG; appendix B).\n\n# Clinical effectiveness\nThe manufacturer presented clinical-effectiveness data from 2 randomised multinational double-blind controlled trials (DPM-CF-301 and DPM-CF-302). The trials were designed to assess the effectiveness of twice-daily mannitol at a dose of 400 mg compared with a 50 mg dose of mannitol twice daily, assumed to be sub-therapeutic. Patients in both arms also received best supportive care with or without rhDNase. Best supportive care included, but was not limited to, inhaled antibiotics, anti-inflammatory agents, bronchodilators, vitamin supplements, pancreatic enzymes, and antidiabetic agents for people with diabetes. The trials had 26-week double-blind phases, followed by further unblinded phases of 26–52 weeks. The inclusion and exclusion criteria for the 2 trials were similar but differed in the lower cut-off for 'FEV1% predicted' (FEV1% of the patient adjusted for the average FEV1% in the population for any person without cystic fibrosis of similar age, sex and body composition); this was 30% in DPM-CF-301 and 40% in DPM-CF-302.\nDPM-CF-301 included 295 patients (190 adults) and took place at 40 centres in Australia, New Zealand, the UK and Ireland. The manufacturer presented results for adults only, in line with the marketing authorisation. There were 114 adults in the mannitol arm, of whom 58 used rhDNase and 56 did not use rhDNase, and 76 adults in the control arm, of whom 44 used rhDNase and 32 did not use rhDNase. There were 30 adults in the mannitol arm and 13 in the control arm (43 in total) who could not take rhDNase because of ineligibility, intolerance, or inadequate response to rhDNase. The remaining 45 patients did not use rhDNase for other reasons that were not recorded.\nDPM-CF-302 included 305 patients (151 adults) and took place at 53 centres in the USA, Canada, Argentina, Germany, Belgium, France and the Netherlands. The manufacturer presented results for adults only. There were 93 adults in the mannitol arm, of whom 64 used rhDNase and 29 did not use rhDNase, and 58 adults in the control arm, of whom 41 used rhDNase and 17 did not use rhDNase. There were 15 adults in the mannitol arm and 7 in the control arm (22 in total) who could not take rhDNase because of ineligibility, intolerance, or inadequate response to rhDNase. The remaining 24 patients did not use rhDNase for other reasons that were not recorded. After a request by the ERG for clarification, the manufacturer submitted information on 2 groups defined by their use of rhDNase: (1) people using rhDNase and (2) people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase.\nThe trial protocols for DPM-CF-301 and DPM-CF-302 were similar. Because mannitol and hypertonic saline have similar modes of actions, patients taking nebulised hypertonic saline were excluded from DPM-CF-301 and, in DPM-CF-302, patients could use nebulised hypertonic saline at initial assessment but had to stop 4 weeks before the baseline assessment. Potential participants were screened for bronchial hyperresponsiveness to mannitol, and those with hyperresponsiveness were excluded before randomisation. Randomisation was stratified by region and rhDNase use. The studies were powered to show an improvement in FEV1 in both patients who took rhDNase and also the total trial population. There were 4 follow-up visits after the screening visit, at week 0 (start of treatment with mannitol or control) and at weeks 6, 14, and 26. In both trials, patients were offered the opportunity to continue or start mannitol treatment in an open-label phase for a further 26 weeks to gain more information on adverse reactions; in DPM-CF-301, there was an additional open-label extension phase of 26 weeks, giving a total of 78 weeks.\nThe primary outcome in both trials was the absolute FEV1 as measured in millilitres over 26 weeks. Both trials reported changes in FEV1 from baseline in the mannitol group compared with the control group.\nSecondary outcomes included the proportion of patients who responded by FEV1 criteria defined as achieving an increase from baseline of at least 100 ml in FEV1, or at least a 5% increase in absolute FEV1 in millilitres, or at least a 5 percentage point increase in FEV1% predicted. Protocol-defined pulmonary exacerbations (PDPE) were defined as pulmonary events with 4 or more pre-defined symptoms or signs needing intravenous antibiotics. Reductions in the frequency of both PDPE and hospital care were measured in both trials.\nBoth trials measured quality of life using the Cystic Fibrosis Questionnaire – Revised (CFQ-R); DPM-CF-302 also used the Health Utility Index 2 (HUI2). The CFQ-R was administered to patients at week 0 and then at weeks 14 and 26. Antibiotic use and adverse events were also measured in both trials.\nIn the manufacturer's original submission, lung function was reported only for the subgroup of adults using rhDNase, in line with the fact that only 1 subgroup was pre-specified in the statistical plan of the study protocol. After a request by the ERG for clarification, the manufacturer submitted data on change in FEV1 and exacerbations for adults using rhDNase and also for adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase.\nIn the DPM-CF-301 trial, mannitol statistically significantly improved lung function over 26 weeks compared with the control, as measured by a change in FEV1 from baseline of 109.3 ml (95% confidence interval 52.8 to 165.8; p<0.001) in adults using rhDNase. This difference was evident at 6 weeks of treatment and was maintained over the 26-week double-blind phase. For the other measures of lung function, the mean difference from baseline between adults randomised to receive mannitol plus rhDNase compared with the control group were: mean percentage change in FEV1 from baseline of 4.2% (95% CI 0.3 to 8.1); change in FEV1% predicted of 2.7% (95% CI 0.6 to 4.7) and change in forced vital capacity (FVC) of 117.4 ml (95% CI 1.0 to 233.9). After a request for clarification, the manufacturer provided the change in FEV1 over 26 weeks for the 43 adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase; this was 147.0 ml, a difference that was statistically significant between the mannitol and control group (95% CI 23.2 to 270.7, p=0.02).\nIn the DPM-CF-301 trial, for people using rhDNase, the incidence of PDPE (over the 26-week time horizon of the trial) was 27.6% for adults randomised to mannitol compared with 36.4% in the control group. For adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the incidence of PDPE was 16.7% in the mannitol group compared with 30.8% in the control group. The rate of PDPE per year was 1.41 for adults receiving mannitol plus rhDNase compared with 1.58 in the control group. The estimated PDPE rate per year was 0.41 for adults randomised to receive mannitol who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase compared with an estimated 0.64 in the control group. There was a 36.5% reduction in the rate of exacerbations in the mannitol group compared with the control group for patients who could not use rhDNase, but this was not statistically significant. The trials were not powered to demonstrate statistically significant differences for PDPE outcomes in these subgroups.\nIn the DPM-CF-302 trial, the mean change in FEV1 over 26 weeks for adults using rhDNase and randomised to receive mannitol was not statistically significantly different from the control group (88.5 ml, 95% CI −8.5 to 185.4). For the other measures of lung function in adults using rhDNase randomised to receive mannitol compared with the control group, the mean difference in the changes from baseline were 5.4% (95% CI −0.4 to 11.3) for FEV1, 3.0% (95% CI −0.6 to 6.5) for change in FEV1% predicted and 96.9 ml (95% CI −7.7 to 201.6) for changes in FVC. After clarification, the manufacturer provided the difference in the change in FEV1 over 26 weeks for mannitol in 22 adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase compared with the control group; this was 208.6 ml (95% CI −9.3 to 426.5, p=0.061).\nIn the DPM-CF-302 trial, the incidence of PDPE (over the 26 weeks of the trial) was 18.8% in adults using rhDNase alone compared with 9.8% for adults receiving mannitol plus rhDNase. For adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the PDPE incidence was 13.3% for adults randomised to mannitol compared with 42.9% in the control group. The estimated PDPE rate per year was 0.83 for adults randomised to mannitol plus rhDNase compared with 0.19 in the control group. The estimated PDPE rate per year was 0.26 for adults randomised to receive mannitol who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase compared with an estimated 0.86 in the control group. However, the trials were not powered to demonstrate statistically significant differences for these outcomes in patients not receiving rhDNase or patients who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase.\nIn response to the appraisal consultation document (ACD), the manufacturer presented analyses pooling the results of the DPM-CF-301 and DPM-CF-302 trials. The outcomes in the pooled analyses did not include the primary outcome, absolute FEV1, but instead were FEV1% predicted, the proportion responding according to FEV1 criteria, and the estimated rate of PDPE per patient per year. For the pooled adult population of people using rhDNase, the mean change in FEV1 over 26 weeks for patients receiving mannitol plus rhDNase was 94.1 ml (95% CI 29.7 to 158.42). For people who received mannitol but did not take rhDNase (irrespective of the reason), the change was 110.3 ml (95% CI not given, p<0.005). The change was 166.7 ml (95% CI 52.0 to 280.6) for the subgroup of adults receiving mannitol who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The pooled results for both trials for adults who could not use rhDNase were 0.27 PDPE per year in the mannitol group compared with 0.96 PDPE per year in the control group (not statistically significant).\nThe manufacturer reported on adverse events for the whole adult population, but not for the rhDNase subgroups based on rhDNase use. Overall, 87% of all adults experienced at least 1 adverse event, the most common adverse event being cough (the only adverse event that occurred in more than 10% of adults). However, the manufacturer considered productive cough a desired effect of treatment with mannitol. Other adverse events with an incidence of between 1% and 10% over 26 weeks were decreased appetite, headache, haemoptysis, bronchospasm, wheezing, asthma, condition aggravated, pharyngolaryngeal pain, and chest discomfort.\nHaemoptysis was the most clinically significant adverse event in both studies and was observed in 11.9% of adults on treatment with mannitol and 8.5% in the control group in the DPM-CF-301 trial, and in 7.1% in the mannitol group and 2.5% in the control group in the DPM-CF-302 trial. In response to the ACD, the manufacturer submitted pooled analyses on haemoptysis events based on the protocol-defined criteria for PDPE. For all adults using rhDNase, 16.4% experienced haemoptysis in the mannitol group and 20.0% in the control group. For adults not using rhDNase, these figures were 14.1% in the mannitol group and 14.3% in the control group.\nHealth-related quality of life was only presented for the whole adult population in the original manufacturer's submission. There were no statistically significant changes in the CFQ-R domains in either trial for adults randomised to receive mannitol relative to the control group. The results suggested some improvement in the respiratory, physical and vitality domains of CFQ-R, but these did not achieve statistical significance. In DPM-CF-302, there was no statistically significant difference in HUI2 measurements between adults randomised to receive mannitol and the control group.\nIn response to the ACD, the manufacturer submitted the proportion of adults whose condition was considered to respond to treatment based on FEV1 criteria for both trials. In the DPM-CF-301 trial, for adults using rhDNase, the condition responded in 41.4% in the mannitol group and 27.3% in the control group; for adults not using rhDNase, these figures were 60.7% in the mannitol group and 40.6% in the control group. In the DPM-CF-302 trial, for adults using rhDNase, the condition responded in 45.3% in the mannitol group and 39.0% in the control group; for adults not using rhDNase, these figures were 44.8% in the mannitol group and 44.8% in the control group.\n\n# Cost effectiveness\nThe manufacturer developed a Markov health-state transition model, implemented as a patient-level simulation model evolving over the lifetime of the patient, and modelling 2 treatment options: treatment with inhaled mannitol and treatment without inhaled mannitol. The manufacturer did not model inhaled hypertonic saline as a treatment that a patient may use with, or instead of, mannitol. The model assumed treatment with mannitol for lifetime or until drop-out (according to the rate modelled on the trials). The analysis had a time horizon of 100 years, at which point all patients would have died. The cycle lengths were taken from the time between visits in the 2 trials, and were 6 weeks for the first cycle, 8 weeks for the second cycle and 12 weeks for each subsequent cycle. The transition parameters between the health states depended on characteristics derived from the clinical trial such as age, history of pulmonary exacerbations and use of mannitol.\nThe health states in the model include cystic fibrosis, cystic fibrosis with improved respiratory symptoms, lung transplantation, death from cystic fibrosis, and death from an unrelated cause. At baseline, all patients enter the cystic fibrosis health state. As patients progress, if their FEV1% predicted falls below 30%, they enter the lung transplantation state in which they have a probability of receiving a transplant in subsequent cycles. The model includes a discontinuation rule under which patients whose condition does not respond to mannitol treatment within 6 weeks stop mannitol and switch to best standard of care. Modelled to mirror the clinical trial, the definition of a response is either a relative increase of 5% or more in absolute FEV1 or an absolute increase of 100 ml or more in FEV1 at week 6 from baseline. In subsequent cycles, a patient may switch between the health states of cystic fibrosis and cystic fibrosis with improved respiratory symptoms and back again, and patients in either state may experience a pulmonary exacerbation. Patient characteristics such as body mass index (BMI), age and FEV1% predicted are updated.\nThe manufacturer used clinical-effectiveness data from the DPM-CF-301 and DPM-CF-302 trials to obtain baseline values and some, but not all, transition parameters used in the model, such as FEV1% predicted at week 26, the probability of being a 'responder' at 26 weeks and the relative risk of pulmonary exacerbations for 'responders' to treatment. Other transition parameters were derived from the literature and from the commissioned BioGrid study using regression analysis, such as FEV1% predicted over time, the rate of exacerbations and mortality after lung transplant. The baseline characteristics (age, sex, BMI and FEV1% predicted) were taken from the pooled adult population from the DPM-CF-301 and DPM-CF-302 trials. The manufacturer also used data from the trials to estimate the probability of response to mannitol, FEV1% predicted after 26 weeks of treatment, the effect of treatment on pulmonary exacerbations, and the probability of improvement in respiratory symptoms. The manufacturer estimated changes in FEV1% predicted and the risk of an exacerbation after baseline from the BioGrid retrospective observational study of disease progression in cystic fibrosis, which used data from Australia (the BioGrid data) and was commissioned by the manufacturer. The decline over time in FEV1% predicted was modelled dependent on age, age above 30 years, and pulmonary exacerbations (using hospital admissions as a proxy). The manufacturer estimated the relationship between FEV1% predicted and mortality rate from the BioGrid data using survival analyses. In the model, mortality depended on FEV1, exacerbations, age, sex, concurrent infection with Burkholderia cepacia and lung transplantation. After a request for clarification from the ERG, data on these variables were provided to update the model for patients who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase.\nUtility values were drawn largely from HUI2 data collected during the DPM-CF-302 trial; the manufacturer also included values from the literature for lung transplantation and pulmonary exacerbations. The baseline utility was taken as the mean overall HUI2 global utility score at baseline (0.899). The manufacturer calculated the change in utility between baseline and visit 3 or in week 14, or between baseline and the last visit in the case of early withdrawal. The manufacturer calculated the HUI2 global utility scores for each health state by adding the average change to the baseline utility. The increase in utility value for patients with improved symptoms was 0.009 in the control group and 0.019 in the mannitol group. The decrease in utility for patients without improved symptoms was 0.046 for patients in the control group and 0.022 in the mannitol group. Utility values were not linked directly to lung function. The HUI2 questionnaire was administered in the trial at weeks 0, 12 and 26, but had a recall period of 1 week, and so did not necessarily capture the effect of PDPEs on health-related quality of life at the time they occurred. Therefore, the manufacturer took utility data for PDPEs and post-lung transplantation from the literature. Adverse events had a negative impact on CFQ-R data in both trials.\nThe manufacturer calculated the costs of treatment with or without mannitol accumulated up to 26 weeks, but made no distinction between patients whose lung function improved and those whose did not. The model included costs related to pulmonary exacerbation and for the time periods before and after lung transplantation. Costs were taken from national reference costs. The manufacturer included costs for concomitant medications (mostly antibiotics) for both groups, and used a mean cost of £3253 in the mannitol group and £2972 in the control group (with a cost of £0 for the subclinical trial dose). In the trials, most patients were admitted to hospital at least once, and approximately 40% had a community visit during the 26-week randomised phase of the trial. Costs of pulmonary exacerbation were taken from the trial data. For patients receiving mannitol, the mean total cost of medications, community visits and hospitalisations without a PDPE in the 26-week trial period was £4391, and taking into account PDPE the cost was £12,852. From the trial, for patients in the control group, the mean total costs without PDPE were £4664 and with at least 1 PDPE were £10,354. The manufacturer used peri-transplant costs from the UK literature and resource use from the trial and patient records. The manufacturer applied a discount rate of 3.5% to both costs and benefits.\nThe manufacturer's base-case results indicated an incremental cost-effectiveness ratio (ICER) for mannitol compared with treatment without mannitol (best supportive care) of £47,095 per quality-adjusted life year (QALY) gained in adults using rhDNase and £41,074 per QALY gained in adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase.\nThe manufacturer undertook extensive scenario analyses and deterministic sensitivity analyses for the treatment of adults using rhDNase and for adults not using rhDNase (irrespective of the reason for non-use). The parameters that changed the ICER by more than 10% were:\nFEV1% predicted at baseline\nthe regression parameter estimate for mannitol treatment used to predict the FEV1% predicted after 26 weeks of treatment (that is, the effect of treatment)\nthe relative risk of an exacerbation with mannitol relative to not using mannitol for people whose condition was considered to respond to treatment\nthe relative risk of a subsequent exacerbation if there had been an exacerbation in the previous year\nhazard rate of death for the FEV1% predicted\nthe utility decrement associated with an exacerbation\nthe utility associated with no improvement in respiratory symptoms among patients using or not using mannitol\nthe cost of an exacerbation.\nThe manufacturer also performed sensitivity analyses showing the effect of several parameters, including treatment failure after 1, 5, 10 and 20 years. The base-case model assumed that patients using mannitol maintained the difference in lung function over their lifetime. Not maintaining the improvements in FEV1% predicted over the long term had a large effect on the ICER. If the improvements in FEV1% predicted were maintained for only 1 year the ICER was £149,587 per QALY gained; if improvements were maintained for 5, 10 and 20 years, the ICERs were £86,981, £63,539 and £49,907 per QALY gained respectively. Other factors that had an impact on the ICER were the rate ratio of pulmonary exacerbations between people receiving and those not receiving mannitol, whether the discontinuation rule was applied, the relative risk of a PDPE if the patient experienced an exacerbation in the previous year, costs and utilities. The manufacturer concluded that the main factors affecting the ICER were:\nthe cost of mannitol\nthe relative risk of pulmonary exacerbations in the mannitol group\nthe impact of pulmonary exacerbations on quality of life\nthe FEV1% predicted when starting mannitol\nthe improvement in FEV1% predicted on mannitol treatment\nthe hazard rate of death for FEV1% predicted\nutility for patients whose symptoms do not improve.\nAfter a request from the ERG, the manufacturer provided scenario analyses taking into account reduced adherence to treatments, which reduced the costs in the mannitol group. Using a lower mean adherence gave an ICER of £37,387 per QALY gained for mannitol compared with the control in adults using rhDNase, and £33,934 per QALY gained for mannitol compared with the control in adults not using rhDNase.\nThere was uncertainty around the relative risk of PDPE, and the model was sensitive to fluctuation in this parameter. Using the relative risk of exacerbation of 0.7 associated with treatment with mannitol for the total adult population (provided by the manufacturer in response to a request for clarification from the ERG), the ICER for mannitol compared with not using mannitol was £54,329 per QALY gained in adults using rhDNase and £27,673 per QALY gained in adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. Using a relative risk of exacerbations based on adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the ICER per QALY gained was £19,828.\nIn the manufacturer's probabilistic sensitivity analyses, as an add-on therapy to best standard of care, mannitol had a 16.4% probability of being cost effective at an ICER of £30,000 per QALY gained and a 7.4% probability at an ICER of £20,000 per QALY gained. For non-users of rhDNase, mannitol had a 25.8% probability of being cost effective at an ICER of £30,000 per QALY gained and a 10.9% probability at an ICER of £20,000 per QALY gained. In response to a request from the ERG to estimate the cost effectiveness separately for adults using rhDNase and adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the manufacturer re-ran the probabilistic sensitivity analysis. This resulted in mean ICERs of £53,796 per QALY gained for adults using rhDNase and £30,080 per QALY gained for adults ineligible for rhDNase.\nThe manufacturer conducted 2 further subgroup analyses, one by baseline FEV1% predicted and the other among patients whose condition responded to treatment with mannitol by 6 weeks. The analyses showed that, as baseline FEV1% predicted declines, the ICER decreases. For FEV1% predicted 80% or more, the ICERs were £56,228 per QALY gained for adults using rhDNase and £50,688 per QALY gained for adults not using rhDNase. For FEV1% predicted less than 40%, the corresponding ICERs were £30,746 per QALY gained for adults using rhDNase and £23,704 per QALY gained for adults not using rhDNase.\nIn response to the ACD, the manufacturer submitted a revised model for people with cystic fibrosis not using rhDNase, including people whose reason for not using rhDNase was not reported in the trials and is not known. In addition, the manufacturer changed several key parameters in the model. The health states in the model more closely model health states rather than treatment states. The costs and utility values in the revised model no longer depend on treatment, but rather on whether the simulated patient has improved respiratory symptoms or not. The utility values are no longer directly tied to lung function. The manufacturer also included a new stopping rule, centred on the Committee's concerns that a stopping rule based on an FEV1 improvement as defined would be unlikely to be implemented in practice. In the new stopping rule, people are permitted to continue using mannitol if their FEV1 improves by more than 0%, that is, if their FEV1 improves at all. The manufacturer continued to base its model on the BioGrid data, but submitted evidence in an effort to show that the BioGrid population was similar to the UK population with cystic fibrosis. For people not using rhDNase, the manufacturer used a revised utility value of 0.896. In the original model, the change in utility value was 0.015 for people using mannitol who had improved respiratory symptoms, and 0.031 for people using mannitol who did not have improved respiratory symptoms. In the revised model, the change in utility value for people not using rhDNase and who took mannitol and had improved respiratory symptoms increased to 0.025 and for people who did not use rhDNase who took mannitol and had no improvement it decreased to 0.001. In the ERG's analyses, treatment for people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase had costs of £3885 if they improved and £4385 if they did not improve, a difference of £500. In the model developed in response to the ACD, treatment for people who did not use rhDNase had costs of £2307 if they improved and £3255 if they did not improve, a difference of £948. The manufacturer chose a baseline PDPE rate of 1.01, based on the ERG's critique of the original model.\nThe manufacturer did not provide revised estimates of cost effectiveness for the whole population. The revised ICER for mannitol compared with best supportive care was £19,993 per QALY gained in people not using rhDNase, and had an 82.2% probability of being cost effective at an ICER of £30,000 per QALY gained and a 46.5% probability at an ICER of £20,000 per QALY gained. Furthermore, the manufacturer provided a new analysis based on adherence rates of 30% and 70%. Keeping the QALYs constant, the ICER per QALY gained was £6327 at a compliance of 30% and £14,137 at a compliance of 70%.\nThe manufacturer submitted additional clinical evidence indicating that the relative benefit with respect to FEV1 associated with taking mannitol was maintained over 78 weeks. This evidence derived from an extension of the 2 trials. The manufacturer also provided scenario analyses showing the ICERs for shortening the model's time horizon from lifetime (100 years) to 5, 10 and 50 years to be £45,329, £25,151 and £20,018 per QALY gained respectively.\nIn response to the ACD, the manufacturer also conducted a survey defining the treatment pathway for managing sputum in cystic fibrosis. The manufacturer noted that this survey showed 82% of people with cystic fibrosis have trialled hypertonic saline before age 18 years. The manufacturer stated that clinicians would be reluctant to change treatments for people with well-controlled cystic fibrosis. They also noted that approximately a third of people currently using hypertonic saline did not have well-controlled cystic fibrosis and may be able to benefit from mannitol.\n\n# Evidence Review Group comments\nThe ERG regarded DPM-CF-301 and DPM-CF-302 as well designed, high-quality trials, with a large combined study population. The ERG noted the change in therapeutic indication of mannitol limiting it to adults, which reduced the combined study population to 341 and consequently reduced the statistical power of all the analyses.\nThe ERG conducted pooled analyses on the results of the DPM-CF-301 and DPM-CF-302 trials. These showed statistically significant differences between mannitol and the control with all outcomes related to lung function. Among adults using rhDNase, the differences between mannitol and control over 26 weeks were as follows: 91.8 ml (95% CI 30.9 to 152.7) for change in FEV1, 4.6 (95% CI 1.3 to 7.8) for percentage change in FEV1, 2.7 (95% CI 0.9 to 4.5) for FEV1% predicted and 106.1 ml (95% CI 28.3 to 183.9) for FVC. The ERG analysed data from adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, rather than from the broader group of adults not using rhDNase because that reflected the anticipated marketing authorisation at that time, but the marketing authorisation was eventually not restricted to this group. For adults who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the change in FEV1 from baseline was 162.3 ml (95% CI 51.8 to 272.9).\nThe ERG's pooled analyses showed that, for the adults using rhDNase, there were no statistically significant differences between the mannitol and control arm in incident PDPE over the 26 week trial period (relative risk 1.00, 95% CI 0.61 to 1.66), and no statistically significant difference in the estimated rate of PDPE per year (RR 1.14, 95% CI 0.75 to 1.73). In the group of people who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, there were also no statistically significant differences between mannitol and the control in the incidence of PDPE (RR 0.44, 95% CI 0.18 to 1.10) over the course of the trial. The ERG stated that restriction of the therapeutic indication to adults meant that the analysis was under-powered, a problem compounded by the post-hoc subgroup analyses of the pooled trial data, and contributed to the uncertainty around the results.\nThe ERG conducted an indirect comparison of mannitol with hypertonic saline, in line with the scope. The 2 measures common to the identified study of hypertonic saline (0.9% saline) (Elkins et al. 2006) and the DPM-CF-301 and DPM-CF-302 trials were measurements of FEV1 and pulmonary exacerbations. The ERG found that mannitol improved FEV1 compared with hypertonic saline, although this was statistically significant only for the subgroup that could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. FEV1 was 94.3 ml (95% CI 29.0 to 159.6) higher with mannitol than with hypertonic saline, regardless of rhDNase use, and for adults using rhDNase FEV1 was 23.8 ml (95% CI −65.0 to 112.5) higher with mannitol than with hypertonic saline.\nIn the ERG's view, the basic structure of the manufacturer's Markov model was appropriate for the research question, sufficiently inclusive and diverse to model the complexities of cystic fibrosis, but the ERG expressed concerns about the cost-effectiveness model.\nThe ERG questioned the assumption by the manufacturer in the model that mannitol use was completely independent of rhDNase use (that is, that any benefit of mannitol did not depend on whether a patient used, or did not use, rhDNase). This led the ERG to re-analyse the data according to rhDNase use and to divide the group not using rhDNase into those who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and those who could use rhDNase but did not do so for unknown reasons.\nThe ERG indicated that there was statistically significant heterogeneity in the overall group of people not using rhDNase. Patients who were able to take rhDNase but did not do so had different characteristics than those who were unable to take rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The ERG noted that mannitol is more likely to provide effective treatment to people who cannot rather than do not take rhDNase and who do not take hypertonic saline.\nThe ERG noted that the manufacturer had not used the results of the trials in the model, but instead had developed regression equations to estimate lung function. The ERG felt that the use of regression was appropriate for this Markov patient-level model, and noted that the manufacturer had consulted with experts on cystic fibrosis and modelling. The manufacturer also ran a microsimulation (100,000 trials) to compare the model output with the pooled results of the DPM-CF-301 and DPM-CF-302 trials. The ERG found small mistakes in the manufacturer's model, but noted that the validation checks matched the results of the clinical studies at a time point of 26 weeks.\nThe ERG noted that one of the most important assumptions made by the manufacturer was that any absolute improvement in FEV1% predicted relative to patients not using mannitol would be maintained throughout the lifetime of the patient, and would directly translate into lower rates of morbidity and mortality. That is, a patient on mannitol would experience a decline in lung function over time consistent with the natural history of disease but, on cessation of mannitol treatment, would start the decline at a higher level of FEV1% predicted than a patient not taking mannitol. The ERG was concerned that there were no long-term data to support this assumption. The ERG questioned the manufacturer's use of Australian BioGrid data for transition parameters, which may not be generalisable to the UK.\nThe ERG was concerned about several assumptions made by the manufacturer in the original model about pulmonary exacerbations, namely the narrow confidence intervals around the baseline rate based on the BioGrid data used in the deterministic sensitivity analysis, and questioned whether it applied to a UK population.\nThe ERG was concerned about assumptions made by the manufacturer in the original model that HUI2 utility and cost parameters depended on treatment, but not on health state. The ERG questioned that there was no direct link between lung function and utility and suggested that a model linking lung function to utility could have altered the cost effectiveness and could have decreased the ICER.\nThe ERG conducted exploratory analyses to examine the effect on the ICER of varying the model assumptions and the input parameters, including the difference in costs and utilities associated with respiratory symptoms and exacerbations, and the mortality rate of cystic fibrosis by varying the FEV1% predicted. However, because of a lack of data, the ERG could not investigate the manufacturer's assumption that the probability of moving between health states remained the same over the lifetime of the patient.\nThe ERG amended the model to include treatment-independent and improvement-specific values for costs and utilities; using rhDNase subgroup-specific relative risks associating treatment with exacerbations, changing the cost of rhDNase from £16.88 to the most recent price of £16.55 (British national formulary 61); and adjusting model parameters, probabilities and distributions.\nThe ERG's exploratory cost-effectiveness analysis included the treatment options of best standard of care, rhDNase and mannitol, but not hypertonic saline. The ERG compared best standard of care with mannitol plus best standard of care. In people using rhDNase, best standard of care included rhDNase, and in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, best standard of care did not include rhDNase. These amendments resulted in the ERG's ICER for mannitol plus best supportive care compared with best supportive care of £80,098 per QALY gained in adults using rhDNase and £29,883 per QALY gained in adults who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The main reasons for the changes to the ICERs were the use of health-state specific costs and utilities used by the ERG rather than treatment specific costs and utilities used by the manufacturer, and the population specific relative risks for exacerbations.\nThe ERG investigated the relationship between improvements in FEV1% predicted and survival, and found evidence to support the assumption that a 1 percentage point improvement in FEV1% predicted was related to an approximate 5% reduction in mortality.\nThe ERG examined the assumption that the improvement in FEV1% predicted caused by mannitol would be maintained over the lifetime of the patient by reducing the time horizon of the model as a proxy for a shorter duration of effectiveness. This was similar to a scenario analysis conducted by the manufacturer. The ERG's analyses in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase resulted in ICERs for a time horizon of 5 years of £90,126 per QALY gained. For a time horizon of 10 years, the ICER was £49,854 per QALY gained for people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase.\nThe ERG pointed out that the manufacturer had generated cost data based on whether a patient received mannitol or not, rather than whether the patient was in a given health state. The manufacturer divided costs according to respiratory symptoms or according to rhDNase use, but did not estimate costs by both factors simultaneously. However, the ERG acknowledged that, in its revised model in response to the ACD, the manufacturer derived costs using patient-level data. The ERG used the information available to calculate the ratio of the improvement-specific costs to the overall mean costs as an estimate of the difference in costs by health state. The ERG calculated that patients with improved respiratory symptoms have 93% of the overall costs, whereas patients without improved symptoms have 105% of the overall costs. The ERG assumed these percentages also applied to mean costs with rhDNase. The ERG estimated 6-month treatment costs for improved and not improved respiratory symptoms in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The ERG decided that health-state specific costs should be used rather than treatment specific costs. The ERG confirmed that the manufacturer used treatment specific values in its revised analysis of people not using rhDNase.\nThe ERG re-ran the probabilistic sensitivity analyses with assumptions based on its exploratory analyses, varying the exacerbation rate in the control group, making the costs and utilities improvement specific rather than treatment specific, and using shorter time horizons. The ERG calculated that there was a zero probability that the ICER for mannitol would lie below £30,000 per QALY gained for people using rhDNase. For those who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, the probability that the ICER would be below £20,000 per QALY gained was 5%, and the probability it would be below £30,000 per QALY gained was 50%.\nThe ERG considered the health-related quality-of-life data provided by the manufacturer in the form of HUI2 data collected in the DPM-CF-302 trial, and questioned the use of treatment-dependent values for utility. For its own sensitivity analyses, the ERG used values for utilities received from the manufacturer in response to a request for clarification and assumed that these values were independent of treatment. The ERG did not identify any other substantial health-related benefits not included in the QALY.\nThe factors identified by the ERG as causing substantial differences in the ICERs generated by the ERG and the manufacturer included whether or not someone took rhDNase alongside mannitol, the assumption that any improvement in FEV1% predicted caused by mannitol would be sustained over the patient's lifetime, the assumption that patients whose condition did not respond to mannitol would discontinue therapy, and the effect of pulmonary exacerbations on utility. The manufacturer addressed these in their response to the ACD and in the second Committee meeting by changing these assumptions to be in line with those used by the ERG.\nIn their response to the ACD, the manufacturer provided evidence to suggest that the BioGrid data were similar to the UK population with cystic fibrosis. The ERG explained to the Committee that there was a clinically meaningful difference in the FEV1% predicted values for the BioGrid data and the UK data (of 60.2% for the BioGrid data and 66.3% for the UK data) because every percentage point decrease in predicted FEV1% predicted has an impact on mortality.\nThe ERG highlighted the additional analyses in the manufacturer's response to the ACD, which supported its assumption that improvements in FEV1% predicted would be maintained throughout the lifetime of the patient. In the second Committee meeting, the ERG stated that there was uncertainty about whether the benefit of mannitol would persist over time, decrease at the same rate as that of the control group, or decrease at a slower rate. The ERG commented that a time horizon of 50 years was likely to accurately represent the lifetime horizon of the adult UK population with cystic fibrosis.\nIn examining the manufacturer's revised analysis in people who do not use rhDNase, the ERG identified 3 drivers that decreased the ICER from that in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase (as originally modelled): including the exacerbation rate chosen for the model; acknowledging that some people treated with mannitol stop taking it ('drop-outs'); and the change in the estimated price for best supportive care, with the difference between best supportive care and mannitol being smaller in the original model (£500) than in the revised model (£948).\nFull details of all the evidence are in the manufacturer's submission and the ERG report.# Consideration of the evidence\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of mannitol, having considered evidence on the nature of cystic fibrosis and the value placed on the benefits of mannitol by people with cystic fibrosis, the people who represent them, and clinical specialists. It also took into account the effective use of NHS resources.\n\n# Clinical practice\nThe Committee discussed the clinical needs of people with cystic fibrosis. It heard from clinical specialists that cystic fibrosis leads to considerable morbidity and early mortality, and that there is no single standard care pathway in the UK. Clinicians and patients working with cystic fibrosis centres decide on treatment according to each patient's needs. The clinical specialists added that the aim of treatment in adults is to maintain lung function (as measured primarily by the absolute volume of FEV1 in millilitres), particularly after the age of 30 years. In response to the consultation, the clinical specialists added that it is particularly important to manage cystic fibrosis to prevent a further decline in lung function in patients with rapidly declining lung function (that is, more than 2% per year decline in FEV1% predicted). Clinicians and patients manage lung function primarily through efforts to reduce airway infections, increase airway clearance, aid sputum clearance and maintain body weight through good nutrition. The Committee heard from the clinical specialists that approximately 98% of people with cystic fibrosis are registered with cystic fibrosis centres, and that clinicians use the Cystic Fibrosis Trust guidelines as the basis for best standard of care. The Committee heard from the clinical specialists that, as with hypertonic saline, rhDNase is inhaled as a nebulised solution and is an adjunct to physiotherapy, along with inhaled, oral or intravenous antibiotics for Pseudomonas aeruginosa, and that use of rhDNase varies widely across the UK. The Committee concluded that best standard of care for cystic fibrosis was complex and tailored to patient needs, and that rhDNase treatment was considered a component of best standard of care.\nThe Committee considered the place of mannitol within the cystic fibrosis treatment pathway, particularly in relation to the use of hypertonic saline. It noted the therapeutic indication of mannitol as an add-on therapy to best standard of care. The Committee heard from the clinical specialists that, after treatment with rhDNase, a patient would be offered either mannitol or hypertonic saline. The clinical specialists stated that approximately 40% of patients in the UK are treated with hypertonic saline. However, the patient expert highlighted that the unpleasant taste and experience of hypertonic saline can lead to poor adherence and this was confirmed by the clinical specialists. The Committee considered whether mannitol could replace nebulised hypertonic saline, but noted that the decision problem and the marketing authorisation clearly defined mannitol as an add-on therapy, and it would not be expected to replace any component of current treatment. The Committee was aware that both of the trials presented by the manufacturer excluded patients taking hypertonic saline, and therefore that the manufacturer had not provided the Committee with any evidence of effectiveness of mannitol added on to hypertonic saline. At the second meeting, the manufacturer noted that, because mannitol and hypertonic saline have a similar mechanism of action (both are osmotic agents), the manufacturer did not expect that mannitol would be added on to a treatment regime containing hypertonic saline. Also, taking into consideration the treatment pathway survey provided by the manufacturer in response to the ACD, the Committee acknowledged that mannitol was unlikely to be used in most patients, and that mannitol would be used as an add-on therapy to best standard of care, but not as a replacement for hypertonic saline use in people with stable cystic fibrosis. The Committee also noted that the manufacturer in its response to the ACD proposed that mannitol should only be considered in people with cystic fibrosis for whom hypertonic saline is not appropriate.\nThe Committee considered a patient's experience of cystic fibrosis, which involves several treatments, and how patients would use mannitol. The patient expert explained the difficulties in adhering to treatments, and stated that using mannitol with an inhaler would be much easier than using hypertonic saline with a nebuliser and would likely encourage adherence. Again, the Committee was aware that the marketing authorisation for mannitol stipulates that it would add on to, rather than replace, existing therapies. The Committee heard from the patient expert and clinical specialists that the treatment time for mannitol could be cut to 2–3 minutes twice a day with training and practice, whereas nebulised treatments take much longer. The patient expert also described the issues faced by carers, with increased burdens from both assisting with treatment and helping patients to maintain normal lives. The patient expert and clinical specialists stated that current therapies (particularly therapies delivered by nebulisers) are complex to set up and to deliver, and equipment needs careful cleaning, which adds to the treatment burden, as do the difficulties in travelling with nebuliser equipment. The patient expert also highlighted the cost to patients of treatments, which are not fully funded by the NHS. The Committee agreed that there were potential advantages to patients of having a wider choice of treatment options. The Committee concluded that cystic fibrosis and its management had a major impact on the quality of life of patients and their carers, and that mannitol could ease some of this burden because it is a dry powder for inhalation, is associated with fewer unpleasant effects, needs less costly equipment and needs less time to administer than nebulised treatments.\n\n# Clinical effectiveness\nThe Committee noted that the manufacturer's original submission was in line with the anticipated marketing authorisation (treatment of cystic fibrosis in adults aged 18 years and over as an add-on therapy to rhDNase, and in patients ineligible for, intolerant of, or whose condition inadequately responded to, rhDNase), and did not reflect the current approved marketing authorisation (treatment of cystic fibrosis in adults as an add-on therapy to best standard of care). The Committee also noted that the population specified in the scope included children, and included rhDNase and hypertonic saline as comparators. The Committee noted that the group of all people not using rhDNase was a clinically heterogeneous group, and included patients who cannot use rhDNase, and patients who can but do not use rhDNase for reasons not recorded. The Committee heard from the clinical specialists that the use of rhDNase varies geographically within the NHS. The Committee concluded that the analyses carried out for the populations described as people using rhDNase and all people not using rhDNase would reflect the population in the final marketing authorisation.\nThe Committee considered the evidence submitted by the manufacturer on the clinical effectiveness of mannitol. The Committee was concerned that the statistical power of the presented analyses was reduced by having to limit the population to adults, which reduced the population to almost half of the original trial population, as well as by differentiating according to rhDNase use, and then further according to the reasons for not using rhDNase. The Committee was also concerned that a considerable number of initial study participants did not proceed to randomisation. The Committee further noted that the analysis of the subgroups using and not using rhDNase was part of the trial protocol, but that the trials were powered for statistical significance only for the group using rhDNase, and not for the group not using rhDNase. The Committee concluded there were some concerns about the design of the trials and the resulting analyses, particularly with the post-hoc analyses and low statistical power, and that these factors increased the uncertainty in the results, including the possibility that real differences existed that the study did not demonstrate statistically.\nThe Committee heard from the manufacturer that 50 mg mannitol twice daily was used as the placebo in the trials after a request from regulatory authorities. The Committee heard from the manufacturer that it chose this dose from a dose-ranging study. Both the manufacturer and clinical specialists acknowledged that there was likely to be a small therapeutic effect at this dose, as also suggested by the FEV1 increasing from baseline by 52.4 ml in the DPM-CF-302 trial in the control group. The Committee concluded that mannitol would be more effective than reported in the trials, if the placebo had had a clinical effect.\nThe Committee considered the outcomes used in the trials, and how these differed from the outcomes used in clinical practice in adults with cystic fibrosis. The Committee discussed the manufacturer's selection of absolute change in FEV1 in millilitres in the trial and FEV1% predicted in the economic model, and the manufacturer's definition of 'responders' as people whose absolute FEV1 improved by 100 ml or 5% or more, or whose FEV1% predicted improved by 5% points. The Committee heard from clinical specialists that both absolute FEV1 and FEV1% predicted measurements are used in clinical practice, that a change in absolute FEV1 between 75 and 100 ml is clinically meaningful, and that FEV1% predicted is used for children and to compare across different adult patient populations. The clinical specialists explained that the manufacturer's definition of a response did not accurately reflect clinical practice in the UK. If a patient felt better, but did not reach the threshold defining response (for example, their absolute FEV1 increased by only 80 ml), the clinician would be unlikely to recommend stopping treatment. The patient expert concurred, stating that lung function can vary from day to day, and that small changes could make a difference to daily life and activity. The Committee concluded that the FEV1 response outcomes were clinically relevant, but that the definition of 'responders' in the original manufacturer's submission differed from UK practice.\nThe Committee considered whether the 2 trials presented were equivalent, as the eligibility criteria at the lower end of FEV1% differed between the 2 studies. The clinical specialists explained this was because DPM-CF-301 was conducted largely in the UK, and DPM-CF-302 largely in the US, where prophylactic antibiotics and rhDNase are used more frequently than in the UK, and because there are differences in the regulations of the Food and Drug Administration and European Medicines Agency pertaining to the lower limit of FEV1% predicted for inhaled substances. The Committee was concerned about the way in which the 2 trials were blinded, and whether functional unblinding existed. It was also concerned that mannitol may cause rebound bronchoconstriction, but acknowledged that patients had undergone a mannitol tolerance test before entering the trials, and also heard from the clinical specialists that rebound bronchoconstriction did not occur in the trials. Overall, the Committee concluded that the 2 trials presented were equivalent and that it was reasonable to pool the results, but that there were methodological concerns about the analysis of clinical outcomes in the studies, and that there may have been functional unblinding, which would increase uncertainty about the clinical effectiveness of mannitol.\nThe Committee discussed the issue that hypertonic saline was not included as a comparator in the manufacturer's submission, although it was included in the scope and the ERG's indirect comparison (see section 3.37). Being aware that the use of nebulised hypertonic saline was an exclusion criterion in both the DPM-CF-301 and DPM-CF-302 trials, the Committee noted that there was no clinical-effectiveness data for mannitol in people who used hypertonic saline. The Committee heard from the manufacturer and the ERG that there were difficulties in comparing the 2 osmotic agents, in particular because of the heterogeneity in the outcome measures in the clinical trials of the 2 osmotic agents and the lack of definition of the concentration of hypertonic saline solution used in clinical practice in the UK. The Committee noted the Cochrane review of hypertonic saline for cystic fibrosis, and the apparent improvement in pulmonary exacerbations and quality of life compared with isotonic saline, and heard that the clinical specialists considered the review to have been well-performed and valid. The Committee noted that, despite the final marketing authorisation permitting the addition of mannitol to best standard of care, mannitol would be unlikely to be used as an add-on to hypertonic saline because mannitol and hypertonic saline have similar mechanisms of action (see section 4.3). However, because the lack of clinical evidence precluded the use of hypertonic saline as a comparator in the analysis, and because the Committee was not presented with any evidence demonstrating the effectiveness of mannitol in people using hypertonic saline, the Committee concluded that the only possible recommendation is for people for whom other osmotic agents are not considered appropriate. The Committee concluded that adults with cystic fibrosis who cannot take hypertonic saline, for example for reasons of intolerability, represent a population with unmet need who would be able to benefit from the use of mannitol. The Committee further concluded that a clinical trial would be needed to establish the relative effectiveness of mannitol compared with hypertonic saline.\nThe Committee considered the incidence of adverse reactions during the trials, and their effects on people with cystic fibrosis. The Committee heard from the clinical specialists that productive cough is seen as a positive effect whereas irritating cough is seen as negative, but noted that learning to control cough is an important part of managing cystic fibrosis. The patient expert discussed the experience of using current therapies, and how the negative effects (such as unpleasant taste and sensations) affect a person's daily life and increase the burden of treatment. The Committee considered the manufacturer's response to the ACD and noted that mannitol was not more likely to cause haemoptysis than best supportive care. In the Committee's view, adverse reactions were not sufficiently captured by effects on quality of life through the HUI2 measurement in DPM-CF-302, given that a week could elapse between the adverse reaction and reporting, and the bias towards a higher chance of filling in the questionnaire when feeling well, rather than feeling ill. The Committee concluded that the treatment of cystic fibrosis can cause several moderate and severe adverse reactions, and that it can be difficult to establish the effect of adverse reactions on health-related quality of life in a disease as complex as cystic fibrosis.\nThe Committee noted that each trial collected quality-of-life data but that the manufacturer had not submitted EQ-5D data as preferred by NICE. The Committee heard from the clinical specialists and the patient expert that assessing quality of life in people with cystic fibrosis is very difficult because they often describe their quality of life as being equivalent to people without cystic fibrosis or without other chronic conditions. The patient expert explained that she perceived her life as 'normal', and had never known any other health state. The Committee recognised the difficulty in valuing health states in chronic conditions, but that the standard method of using the general population's valuation of descriptions of health-related quality of life to generate utility values was appropriate. The Committee concluded that current measures of quality of life may not accurately capture the consequences of having cystic fibrosis and of its treatments.\nThe Committee considered the relationship between absolute change in FEV1 and pulmonary exacerbations. The Committee heard from the clinical specialists that FEV1 and pulmonary exacerbations have not previously been shown to be directly related. The Committee noted that the average rate of pulmonary exacerbations was lower in people considered 'responders' than in 'non-responders' in DPM-CF-301. The Committee questioned that incidence of pulmonary exacerbations in people not using rhDNase was lower than in people using rhDNase in DPM-CF-301, but it was the other way around in DPM-CF-302, and the manufacturer could not explain this difference. The Committee was aware that the 36.5% relative risk reduction in the rate of exacerbations with mannitol compared with control in people not using rhDNase was not statistically significant, but acknowledged that this could be a result of the post-hoc subgrouping (see section 3.10). On balance, however, the Committee acknowledged that it was plausible that absolute change in FEV1 and pulmonary exacerbations could be related. The Committee concluded that mannitol is clinically effective in improving both lung function (FEV1) and pulmonary exacerbations in people with cystic fibrosis. The Committee further concluded that there are subgroups of people who may experience greater benefit from mannitol, such as people who cannot use rhDNase, but that there is a degree of uncertainty about the magnitude of any increased clinical effectiveness.\n\n# Cost effectiveness\nThe Committee considered the manufacturer's cost-effectiveness analysis, and the ERG's critique and exploratory analyses. It noted that the manufacturer originally used a patient-level simulation model to evaluate the cost-effectiveness of mannitol compared with best standard of care in people using rhDNase and people ineligible for or intolerant of, or whose condition inadequately responded to, rhDNase. The Committee also noted that clinical-effectiveness data presented in the submission were not used directly in the model, instead the manufacturer derived transition parameters from the 2 mannitol trials and from the literature, and incorporated them into the model through regression analysis. In a response to the ACD, the manufacturer provided a revised cost-effectiveness model, addressing some of the Committee's concerns. The Committee noted that the structure of the original model was not a health-state model, but rather was a model of the cystic fibrosis treatment pathway. The Committee was aware of the ERG's concerns about the manufacturer's original assumptions that any improvement in FEV1% predicted would be maintained throughout the lifetime of the patient, and that it would be directly translated into lowered morbidity and mortality rates. The Committee considered that not all relevant UK data were identified by the manufacturer's search strategy in the original submission, and that the manufacturer's response to the ACD addressed these concerns in part. The Committee acknowledged the changes to the model made by the manufacturer in their response to the ACD, but that substantial uncertainty remained about the long-term benefits of using mannitol. The Committee noted that the ICER would increase if the effects of mannitol were only maintained in the short term. The Committee concluded that the cost-effectiveness model was complex and may not adequately reflect the clinical trial data.\nThe Committee considered the way in which the manufacturer had incorporated the clinical-effectiveness data in the model, and was concerned by the limited number of variables incorporated from the trials. It noted that the modelling of treatment effect used FEV1% predicted, and not the trials' primary outcomes of absolute FEV1. The Committee considered the assumptions and variables incorporated into the manufacturer's model, one of which being that mortality depended only on FEV1% predicted, the presence or absence of Burkholderia cepacia infection, age and sex. The Committee was aware that other studies, including one using UK data, demonstrated a wider range of variables associated with mortality in cystic fibrosis than the variables in the BioGrid data used by the manufacturer. The Committee particularly noted that BMI was not included in the manufacturer's mortality calculations, whereas it was a parameter for other variables in the model, and had been identified in registry studies as an independent risk factor for death in cystic fibrosis. In addition, the Committee noted that the hazard ratio associated with Burkholderia cepacia infection was greater in the manufacturer's analysis than in multivariate survival analyses of UK and US registry data. The Committee noted that the manufacturer stated that mannitol did not affect the risk of infection with Burkholderia cepacia complex in the model. The Committee acknowledged that there was little evidence that mannitol would alter other factors associated with mortality, but concluded that the mortality rate in the manufacturer's model may not accurately reflect mortality in cystic fibrosis. The Committee considered that other validated models of cystic fibrosis mortality exist, and that the manufacturer's model was unlikely to accurately represent the cystic fibrosis population in the UK. The Committee concluded that the model underestimated the mortality rate, and that a higher mortality rate would increase the ICER.\nThe Committee expressed concerns about the assumption used in the model related to how change in FEV1% predicted is modelled over time derived from the BioGrid study, but was satisfied with the manufacturer's clarification at the second meeting that FEV1% predicted declined over time in the model, as expected in a cohort of patients with cystic fibrosis. Given that there is a rise in the rate of pulmonary exacerbations with age, the Committee considered it was difficult to interpret with any certainty the evidence provided by the regression model. The Committee was also concerned that the manufacturer did not consider the effect of treatment with mannitol on BMI, even though BMI was a parameter in the model used to estimate FEV1% predicted. The Committee concluded that there was substantial uncertainty in the assumptions surrounding the changes in FEV1% predicted with age and that this led to uncertainty about the applicability of the model to the UK population with cystic fibrosis.\nThe Committee considered the assumption that the difference in FEV1% predicted from treatment with mannitol observed at week 26 would be maintained over the patient's lifetime, and whether this was likely to be seen in clinical practice. The Committee noted that this delay in FEV1 decline would prolong the time before, but possibly not prevent, future lung transplants. The Committee noted that the assumption of a maintained long-term benefit of mannitol would affect the ICER favourably, but that there was substantial uncertainty around this assumption. The Committee noted the sensitivity analyses carried out by the manufacturer and the ERG in which the time horizon was shortened to 5 and 10 years, which could be used as a proxy for a shorter duration of benefit, and that the ICERs were considerably increased with these shorter time horizons. However, it noted the ERG's opinion that a longer time horizon of 50 years may reflect the expected benefit of patients who entered the clinical studies with a mean age around 30 years. The Committee concluded that although there was evidence on the short-term effectiveness of mannitol on FEV1, the long-term effect of mannitol on FEV1 was unknown and that this increased the uncertainty in the ICER.\nThe Committee considered the effect of varying adherence to treatment and of stopping rules on the ICERs, and discussed the ERG's sensitivity analysis and the manufacturer's revised analysis of reduced adherence. The Committee noted that, in the trial, the adherence was 87% based on the date of the last treatment, but the manufacturer had assumed costs reflecting 100% adherence in the model. The Committee therefore concluded that the costs of mannitol were overestimated in the original submission. However, the Committee noted that the sensitivity analyses reported in the manufacturer's response to the ACD lacked face validity because the analyses included reduced costs for mannitol, but no changes to the benefits. The Committee concluded that there is uncertainty around the validity of the assumptions around adherence and whether stopping rules reflect clinical practice, but that an adherence rate as seen in the trial might reduce the base-case ICER.\nThe Committee noted from the manufacturer's comments that the original definition of PDPE, as used in the trials, was different from the definition used in clinical practice, and therefore more clinical exacerbations would be seen in clinical practice. The Committee considered that this could imply that mannitol may be more effective in preventing exacerbations and hospital admissions than assumed in the cost-effectiveness model, which used the trial definition of PDPE. The Committee concluded that, in clinical practice, mannitol could prevent more exacerbations than those within the PDPE definition, which would decrease the ICER.\nThe Committee considered that adverse reactions were not incorporated into the manufacturer's model. The Committee heard from the patient expert and clinical specialists that quality-of-life measurements did not accurately capture the effect of adverse reactions on the quality of life of people with cystic fibrosis. The Committee noted that treatments for cystic fibrosis can increase the incidence of haemoptysis, but that haemoptysis was also associated with exacerbations, which occurred less frequently in people taking mannitol compared with people not taking mannitol. The Committee concluded that the economic model had not incorporated the specific impact of adverse reactions on the health-related quality of life in people with cystic fibrosis and that there was uncertainty about how this would affect the ICER.\nThe Committee considered the generalisability and internal validity of the model. The Committee considered that the relationship between FEV1% predicted and lung transplantation in the model could not be fully explained by the manufacturer or the ERG. The Committee heard from the ERG that the proportion of people with cystic fibrosis alive at 55 years predicted by the model (15%) was greater than that found in the UK cystic fibrosis population. The Committee heard from the ERG that approximately 2% of people with cystic fibrosis are still alive at 50 years, but the clinical specialists questioned the validity of this number from the cystic fibrosis registry data. The Committee noted the comparison of the Australian data with UK registry data provided by the manufacturer in response to the ACD, and the manufacturer's interpretation that this indicated a similar trend in mortality. The Committee noted that there was a difference between the mean FEV1% predicted values in the BioGrid and UK population datasets (see section 3.54). The Committee considered the clinical specialists' and ERG's comments that any improvement in FEV1% predicted would reduce the mortality rate. Based on this, the Committee was not persuaded by the manufacturer's interpretation, and remained concerned that mortality was not modelled in a way that accurately reflected the mortality rate in people with cystic fibrosis in the UK. The Committee noted that, when the relative risk of death for the individual subgroups was used in the model, more QALYs were gained with mannitol in people not using rhDNase than in people using rhDNase. The Committee heard from the manufacturer that this was possibly a chance finding because of the small sample size in the subgroup of people who could not use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. The Committee concluded that there were substantial issues with generalisability and internal validity of the model, and that this would increase the uncertainty around the ICERs.\nThe Committee considered the quality-of-life measurements collected in the 2 trials and those used in the model. The Committee noted that the manufacturer had used the HUI2 utility measure, rather than the EQ-5D measure preferred by NICE. The Committee noted that the multiple comorbidities associated with cystic fibrosis and their large impact on daily life suggested that the baseline utility value of 0.899 was high, and that the revised figure of 0.896 for people not using rhDNase was not substantially different. The Committee was also aware that the model was sensitive to the baseline utility with the ICER increasing as the baseline utility decreased. In the original model, the utility increase in patients with improved respiratory symptoms was greater in the mannitol group than in the control group, whereas the utility decrease in patients without improved symptoms was greater in the control group than in the mannitol group. In response to the ACD, the manufacturer submitted a model where the utility values for the health states were the same, irrespective of treatment. However, the Committee concluded that it was not convinced that the health-related quality of life of the health states in the model had been valued with any certainty, and that this led to increased uncertainty around the calculated ICERs for mannitol compared with best standard of care.\nThe Committee considered the relationship between the outcomes, mortality, and quality of life within the model. The Committee noted the uncertainty around the effect of mannitol on life expectancy given the assumption of lifetime efficacy in the model. The Committee noted that virtually all of the benefit of mannitol was from its modelled extension of life-years gained, with very little benefit resulting from improved health-related quality of life, and that the ERG suggested that a more direct link between lung function and quality-of-life utilities could have produced lower ICERs. The Committee considered whether this was likely to be an accurate reflection of real life, and heard from the patient expert that there were substantial quality-of-life improvements in taking an inhaled treatment such as mannitol. The Committee concluded that there was uncertainty about the accuracy of the quality-of-life data and the projected benefits of mannitol on life expectancy, and as a consequence there was further uncertainty as to the robustness of the modelled ICERs.\nThe Committee noted that the costs presented initially by the manufacturer were treatment specific rather than health-state specific. The Committee agreed that the use of health-state specific costs was more appropriate and acknowledged that the manufacturer had incorporated health-state specific costs in the model provided as part of the manufacturer's response to the ACD. The Committee concluded that the modelling incorporating health-state specific costs was more appropriate than that based on treatment specific costs, but that a model based on lung-function specific costs and utilities would be even more appropriate.\nThe Committee considered the ICERs produced by the manufacturer and the ERG. The Committee noted that the manufacturer's original base-case ICERs were above £40,000 per QALY gained in both people using and people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase. Furthermore, the Committee noted that the ERG's base-case ICERs were £82,500 per QALY gained in people using rhDNase and £29,900 per QALY gained in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, when subgroup specific model inputs were used. The Committee noted that, in response to a request for clarification, the manufacturer's probabilistic ICERs were £27,700 per QALY gained for people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and £54,300 per QALY gained in people using rhDNase, and the respective ERG's estimates were £30,100 per QALY gained for those who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and £53,800 per QALY gained for the rhDNase group. The Committee had not been provided with an ICER for the whole population for which mannitol is licensed, but could conclude from the subgroup data by rhDNase use that mannitol would not represent a cost-effective treatment for the whole population for which it is licensed. Noting that the ICERs for the subgroup of people using rhDNase were between £50,000 and £80,000 per QALY gained, the Committee concluded that mannitol was not cost effective for people using rhDNase, and could not be recommended for this subgroup. The Committee concluded that the ICERs for mannitol in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase were underestimates because mortality in the model was underestimated, and also associated with several uncertainties because of the lack of validity in the model (for example, the duration of the effect long term). Therefore, the Committee concluded that the ICERs for mannitol were likely to be above £30,000 per QALY gained in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, and that mannitol could not be recommended for this subgroup.\nThe Committee was aware of the ICERs provided in the manufacturer's response to the ACD in the subgroup of people not using rhDNase (irrespective of the reason for not using rhDNase). The Committee understood from the ERG's critique that this new ICER in people not using rhDNase was lower than the ICER in the original subgroup of people who cannot use rhDNase. According to the ERG there were several factors that could have led to the lower new ICER for adults not using rhDNase, including the manufacturer having used a bigger difference in cost between mannitol and control, having used exacerbation rates suggested by the ERG, and having included drop-out rates derived from the trials, rather than having assumed that all people whose condition responded to mannitol remained on treatment for their lifetime. However the Committee was also aware that mannitol improved lung function less in the people not using rhDNase than in people who cannot use rhDNase, and therefore found the new ICERs counterintuitive. Importantly, the Committee noted that the subgroup of people not using rhDNase (for unspecified reasons) is clinically not clearly identifiable, and therefore it could not make recommendations for this subgroup.\nThe Committee further explored whether there was a group of adults with cystic fibrosis in whom treatment with mannitol would provide a cost-effective use of NHS resources, taking into consideration the responses received on the ACD. The Committee was aware that the manufacturer had, in its response to the ACD, made a proposition for increased cost effectiveness for mannitol treatment in patients with rapidly declining lung function irrespective of rhDNase use. Furthermore, the Committee noted a statement from the clinical specialists in response to ACD consultation, which identified patients with rapidly declining lung function, despite best standard of care, because those patients would particularly benefit from mannitol, a suggestion that the Committee considered was biologically plausible. The Committee noted that any increase in lung function would be proportionally greater for patients with rapidly declining lung function because they would have more to gain than patients with more stable lung function. The Committee was therefore aware that a group with rapidly declining lung function has higher capacity to benefit from mannitol treatment. The Committee further noted that mannitol appeared to be more clinically effective in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase (see section 4.13). The Committee concluded that there is an unmet clinical need in patients with rapidly declining lung function, particularly if there are no other therapies appropriate to offer the patient.\nThe Committee discussed the cost effectiveness of mannitol in people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, and whose lung function declines rapidly (yearly FEV1% predicted decline of more than 2%). The Committee used, as a starting point for these discussions, the manufacturer's original probabilistic ICER of £27,700 per QALY gained in people who cannot use rhDNase and the ERG's ICER of £30,100 per QALY gained. There were factors that the Committee agreed would increase uncertainty around the ICERs; those that may increase the ICERs include assumptions about mortality and the long-term effect of mannitol on lung function. Factors that may decrease the ICERs include the possibility of higher rates of pulmonary exacerbations in clinical practice, a rate of adherence reflecting clinical practice, establishing if there is a link between lung function and quality-of-life utilities, and estimating more realistic utility values associated with mannitol use. The Committee agreed that, if mannitol treatment was offered only to patients with a rapid decline in lung function, the ICER would most likely be lower because of this group's lower quality-of-life and lung function, and a greater potential to improve. The Committee concluded that the ICER for mannitol in patients for whom hypertonic saline is not considered appropriate (see section 4.10), who cannot use rhDNase, and whose lung function is rapidly declining would be under £30,000 per QALY gained. It also took into account the severity of the disease and the importance of treatment options for people with cystic fibrosis who have few alternative options. The Committee concluded that mannitol should be recommended as an acceptable use of NHS resources as a treatment option for people with cystic fibrosis who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, whose lung function is rapidly declining, and for whom other osmotic agents are considered inappropriate.\nThe Committee discussed whether mannitol should be considered an innovative technology, or if there were any significant and substantial health benefits that were not included in the economic model. It heard from the clinical specialists and the patient expert that the treatment burden is substantially less for an inhaler than for a nebuliser and that mannitol, being a dry powder, represents a step-change in the way cystic fibrosis is managed in the UK. When questioned, the manufacturer stated that the model accurately reflected the utility gain to patients. The Committee concluded that treatment with an inhaler provided practical advantages over treatment with nebulisers, but mannitol as an add-on therapy would not replace the use of nebulisers, and so could not be considered a step-change in treatment.\nThe Committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations. The only potential equality issue identified was whether the inhaler used for mannitol inhalation would present a disproportionate burden on patients with physical disabilities. However, the Committee noted the clinical specialists' and patient expert's view that all available treatments are difficult to administer, and that the use mannitol as an add-on therapy to best standard of care would not increase the treatment burden.\n\n# Summary of Appraisal Committee's key conclusions\nTA266\nAppraisal title: Mannitol dry powder for inhalation for treating cystic fibrosis\nSection\nKey conclusion\nMannitol dry powder for inhalation is recommended as an option for treating cystic fibrosis in adults:\nwho cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and\nwhose lung function is rapidly declining (forced expiratory volume in 1 second decline greater than 2% annually) and\nfor whom other osmotic agents are not considered appropriate.\nThe Committee had not been provided with an ICER for the whole population for which mannitol is licensed. The manufacturer made cases for other subgroups, some based on the anticipated, but later amended wording of the marketing authorisation, for example people using rhDNase or people who cannot use rhDNase. However, the Committee concluded that the ICERs for these subgroups were too high for mannitol to be an appropriate use of NHS resources.\nThe Committee agreed that people who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, and whose lung function declined rapidly (yearly FEV1% predicted decline of more than 2%) have an unmet clinical need, particularly as there are no other therapies available, and an increased capacity to benefit from treatment with mannitol. Although no ICER was specifically presented for this subgroup, the Committee was able to infer from the other evidence that the ICER for mannitol in this subgroup would be under £30,000 per QALY gained.\nCurrent practice\nClinical need of patients, including the availability of alternative treatments\nThe Committee heard from the patient expert and clinical specialists that current treatments are difficult to use and do not encourage adherence. The Committee concluded that cystic fibrosis and its management had a major impact on the quality of life of patients and their carers.\nThe technology\nProposed benefits of the technology\nHow innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?\nThe patient expert explained the difficulties in adhering to current treatments, and felt that using mannitol with an inhaler would be easier than using hypertonic saline with a nebuliser and would be likely to encourage adherence.\nHowever, the Committee concluded that mannitol could not be considered an innovative step-change because it would not replace the use of nebulisers in cystic fibrosis\ntreatments.\nWhat is the position of the treatment in the pathway of care for the condition?\nClinical specialists explained that after treatment with rhDNase, a patient would be offered either mannitol or hypertonic saline. A treatment pathway survey provided in response to the ACD found that mannitol was unlikely to be used in most patients, and that it would be unlikely to replace hypertonic saline in people with stable cystic fibrosis.\nAdverse reactions\nTreatments for cystic fibrosis can increase the incidence of haemoptysis, but haemoptysis is also associated with exacerbations, which occurred less frequently in people taking mannitol compared with people not taking mannitol. The Committee concluded that the treatment of cystic fibrosis can cause a number of moderate and severe adverse reactions, and that it can be difficult to establish the effect of adverse reactions on health-related quality of life.\nEvidence for clinical effectiveness\nAvailability, nature and quality of evidence\nThe evidence of clinical effectiveness was derived from 2 randomised multinational double-blind controlled trials (DPM-CF-301 and DPM-CF-302). The trials were designed to assess the effectiveness of twice-daily mannitol at a dose of 400 mg compared with mannitol at a sub-therapeutic dose of 50 mg in addition to best supportive care with or without rhDNase. The trials had 26-week double-blind phases, followed by an unblinded phase of 26–52 weeks. The inclusion and exclusion criteria for the 2 trials were similar. Dividing the adult-only intention-to-treat population of 341 into users and non-users of rhDNase, and then into different populations of non-users of rhDNase further reduced the statistical power of the analyses.\nRelevance to general clinical practice in the NHS\nThe Committee heard from the clinical specialists that best standard of care for cystic fibrosis has a complex treatment pathway, that approximately 98% of patients with cystic fibrosis are registered with cystic fibrosis centres, and that clinicians use the Cystic Fibrosis Trust guidelines as the basis for best standard of care on an individual basis.\nUncertainties generated by the evidence\nThe Committee noted that there were significant concerns about the post-hoc stratification into subgroups by rhDNase use and lung function. It noted that the analysis was underpowered and the small numbers in these analyses increased uncertainty and reduced the statistical power of the trial results. The Committee noted that hypertonic saline was not presented as a comparator, and that mannitol would be unlikely to replace hypertonic saline in people with stable cystic fibrosis.\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\nThe manufacturer provided data for people using rhDNase, and people who cannot use rhDNAse because of ineligibility, intolerance or inadequate response to rhDNase. The Committee concluded that people who cannot use rhDNase may experience greater benefit from mannitol, but that there is a degree of uncertainty about the magnitude of any increased clinical effectiveness.\nFurthermore, data for people not using rhDNAse (irrespective of the reason) were also provided as part of the manufacturer's response to the ACD. The Committee noted that the subgroup of people not using rhDNase (for unspecified reasons) is clinically not clearly identifiable, and therefore it could not make recommendations for this subgroup.\nThe Committee also considered a subgroup of people with rapidly declining lung function (of greater than 2% per year). The Committee was aware that a group with rapidly declining lung function has higher capacity to benefit from mannitol treatment.\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\nThe Committee concluded that mannitol is clinically effective in improving both lung function (FEV1) and pulmonary exacerbations in people with cystic fibrosis. The Committee further concluded that there are subgroups of people who may experience greater benefit from mannitol, such as people who cannot use rhDNase, but that there is a degree of uncertainty about the magnitude of any increased clinical effectiveness.\nEvidence for cost effectiveness\nAvailability and nature of evidence\nThe manufacturer developed a Markov health-state transition model, taking into account individual patient pathways over a lifetime horizon, and modelling 2 treatment options: treatment with inhaled mannitol and treatment without inhaled mannitol. The manufacturer did include hypertonic saline as a comparator. The manufacturer did not use clinical-effectiveness data from the trials presented in the submission other than to obtain baseline values and some transition parameters; instead, the manufacturer derived transition parameters from the literature and from its own commissioned studies, incorporating them into the model using regression analysis. The Committee noted that the structure of the original model was not a health-state model, but rather was a model of the cystic fibrosis treatment pathway. The Committee acknowledged the changes to the model made by the manufacturer in their response to the ACD, in light of the ERG's concerns. The Committee concluded that the cost-effectiveness model was complex and may not adequately reflect the clinical trial data.\nUncertainties around and plausibility of assumptions and inputs in the economic model\nThe Committee was concerned about the manufacturer's assumptions that any improvement in FEV1 would be maintained throughout the lifetime of the patient, and that it would be directly translated into lower morbidity and mortality rates. It was concerned about the limited number of variables incorporated into the model, and that there were other models of cystic fibrosis that had incorporated a greater variety of variables. The Committee concluded that there was substantial uncertainty surrounding the assumption that FEV1% predicted changed with age and that the use of UK data would have been more appropriate, and that this led to uncertainty about the applicability of the model to the UK population with cystic fibrosis.\nIncorporation of health-related quality-of-life benefits and utility values\nHave any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?\nThe Committee was also aware that the model was sensitive to the baseline utility, with the ICER increasing as the baseline utility decreased. The Committee noted that adverse events and their effect on quality of life were not incorporated into the model. The Committee was concerned by the use of HUI2 data rather than the EQ-5D. The Committee concluded that it was not convinced that the health-related quality-of-life of patients with cystic fibrosis had been valued with any certainty. The Committee noted that virtually all of the benefit of mannitol was from its modelled extension of life years gained, with very little benefit resulting from improved health-related quality of life.\nThe Committee agreed with the manufacturer's statement at the meeting that the model included all potential benefits associated with mannitol treatment, and that no additional health-related benefits had been identified that had not been adequately captured by the economic model.\nAre there specific groups of people for whom the technology is particularly cost effective?\nThe Committee considered the subgroup defined by rapidly declining lung function (greater than 2% per annum) whose condition was unsuitable for treatment with rhDNase. The Committee noted that any increase in lung function would be proportionally greater, and that mannitol was likely to be more clinically effective in this subgroup, which would consequently decrease the ICER.\nWhat are the key drivers of cost effectiveness?\nFactors that would increase the ICERs include alternative assumptions about mortality and the long-term effect of mannitol on lung function. Factors that could decrease the ICERs included the possibility of higher rates of pulmonary exacerbations seen in clinical practice, a rate of compliance reflecting the trials, establishing if there is a link between lung function and quality-of-life utilities, and estimating more realistic utilities associated with mannitol use.\nMost likely cost-effectiveness estimate (given as an ICER)\nThe Committee noted that if mannitol treatment was offered only to patients with a rapid decline in lung function, the ICER would most likely be lower than in the whole population because of this group's lower quality of life and lung function, and a greater potential to improve. The Committee concluded that the ICER for mannitol in patients for whom hypertonic saline is not considered appropriate, who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase, and whose lung function is rapidly declining would be under £30,000 per QALY gained. It also took into account the severity of the disease and the importance of treatment options for people with cystic fibrosis who have few alternative options. The Committee concluded that mannitol should be recommended as an acceptable use of NHS resources as a treatment option in this group.\nAdditional factors taken into account\nPatient access schemes (PPRS)\nNot applicable\nEnd-of-life considerations\nNot applicable\nEqualities considerations and social value judgements\nThe only potential equality issue identified was whether the inhaler used for mannitol inhalation would present a disproportionate burden on patients with physical disabilities. However, the Committee noted the clinical specialists' and patient expert's view that all available treatments are difficult to administer, and that the use mannitol as an add-on therapy to best standard of care would not increase the treatment burden.\n\n# Recommendations for further research\nThe Committee concluded that a clinical trial is needed to establish the relative effectiveness of mannitol compared with hypertonic saline.# Related NICE guidance\nThere is no related guidance for this technology.# Review of guidance\nThe guidance on this technology will be considered for review in October 2015. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.\nAndrew DillonChief ExecutiveNovember 2012# Changes after publication\nFebruary 2014: minor maintenance# About this guidance\nNICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.\nThis guidance was developed using the NICE single technology appraisal process.\nWe have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\nYour responsibility\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\nCopyright\n© National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE."}}},{"rowIdx":93,"cells":{"id":{"kind":"string","value":"ec1de4cfafd8784038ec92328c7180ec7d49fe86"},"source":{"kind":"string","value":"nice"},"text":{"kind":"string","value":"Sofosbuvir for treating chronic hepatitis C\n\n# Guidance\nSofosbuvir is recommended as an option for treating chronic hepatitis C in adults, as specified in table 1.\n\n# Table 1 Sofosbuvir for treating adults with chronic hepatitis C\nSofosbuvir in combination with peginterferon alfa and ribavirin\nSofosbuvir in combination with ribavirin\nGenotype\nTreatment history\nRecommendation\nTreatment history\nRecommendation\nAdults with genotype 1 HCV\nAll\nRecommended\nAll\nNot recommended\nAdults with genotype 2 HCV\nAll\nNot licensed for this population\nTreatment-naive\nOnly recommended for people who are intolerant to or ineligible for interferon\nTreatment-experienced\nRecommended\nAdults with genotype 3 HCV\nTreatment-naive\nOnly recommended for people with cirrhosis\nTreatment-naive\nOnly recommended for people with cirrhosis who are intolerant to or ineligible for interferon\nTreatment-experienced\nRecommended\nTreatment-experienced\nOnly recommended for people with cirrhosis who are intolerant to or ineligible for interferon\nAdults with genotype 4, 5 or 6 HCV\nAll\nOnly recommended for people with cirrhosis\nAll\nNot recommended\nHCV – hepatitis C virus\nTreatment‑naive – the person has not had treatment for chronic hepatitis C\nTreatment‑experienced – the person's hepatitis C has not adequately responded to interferon‑based treatment\nPeople currently receiving treatment initiated within the NHS with sofosbuvir that is not recommended for them by NICE in this guidance should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.# The technology \nSofosbuvir (Sovaldi, Gilead Sciences) is a uridine nucleotide analogue that inhibits hepatitis C virus (HCV) polymerase, preventing viral replication. Sofosbuvir has a UK marketing authorisation for use 'in combination with other medicinal products for treating chronic hepatitis C in adults'. The recommended dose is 1 daily 400 mg tablet, taken orally. It should be used in combination with peginterferon alfa and ribavirin, or ribavirin only, as stated in the summary of product characteristics. Monotherapy with sofosbuvir is not recommended. The average duration of treatment is 12 or 24 weeks depending on the person's HCV genotype and history of previous treatment with interferon. Combination treatment regimens without peginterferon alfa for people with genotype 1, 4, 5 or 6 HCV infection have not been investigated in phase III studies. According to the summary of product characteristics, treatment regimens without peginterferon alfa should be used for people with genotype 1, 4, 5 or 6 infection only if they are intolerant to or ineligible for peginterferon alfa therapy and are in urgent need of treatment. The summary of product characteristics states that, for all genotypes, consideration should be given to extending the duration of therapy from 12 to 24 weeks, especially for people who have 1 or more factors historically associated with lower response rates to interferon‑based therapies. These include people with advanced liver fibrosis or cirrhosis, high baseline viral concentrations, previous unresponsiveness to peginterferon alfa and ribavirin combination therapy, or a single nucleotide polymorphism without 2 copies of the C allele near their IL28B gene (that is, non‑CC genotype IL28B polymorphism); or for people of African and Caribbean family origin.\nThe summary of product characteristics lists the following most common adverse reactions for sofosbuvir plus ribavirin, with or without peginterferon alfa: fatigue, headache, nausea and insomnia. For full details of adverse reactions and contraindications, see the summary of product characteristics.\nThe cost of sofosbuvir is £11,660.98 per 28 tablet pack of 400 mg tablets (excluding VAT, 'British national formulary' May 2014). The cost of a 12 week course of treatment is £34,982.94 and a 24 week course is £69,965.88 (both excluding VAT), not including the cost for ribavirin and peginterferon alfa. Costs may vary in different settings because of negotiated procurement discounts.# The company's submission\nThe Appraisal Committee (section 8) considered evidence submitted by Gilead Sciences and a review of the submissions by the Evidence Review Group (ERG; section 9).\nThe company provided clinical‑effectiveness evidence, identified by systematic review, consisting of 13 studies investigating the effect of sofosbuvir plus ribavirin alone or ribavirin and peginterferon alfa in adults with chronic hepatitis C. These included:\nStudies in people who have not had treatment for hepatitis C virus (HCV) before (described as 'treatment‑naive' in this document) with genotype 1, 4, 5 or 6 HCV:\nphase III open‑label, single arm study (NEUTRINO, n=327)\nphase II randomised controlled trials (ATOMIC, n=332; QUANTUM, n=50; SPARE, genotype 1 only, n=60).\nStudies in people with treatment‑naive HCV or in people who have had treatment before (described as 'treatment‑experienced' in this document) with genotype 2 and 3 HCV:\nphase III randomised controlled trials (FISSION, n=499 treatment‑naive; FUSION, n=201 treatment‑experienced; POSITRON, n=278 treatment‑naive and ‑experienced, people who had treatment before were considered to be intolerant to interferon, ineligible for interferon or unwilling to take it; VALENCE, n=419 treatment‑naive and ‑experienced)\nphase II open‑label, randomised controlled trial (ELECTRON, n=95 treatment‑naive)\nphase II single‑arm open‑label study (LONESTAR‑2, n=47 treatment‑experienced)\nphase II 2‑arm open‑label single cohort study (PROTON, n=25 treatment‑naive).\nphase II open‑label 4 cohort study in people with genotype 1, 2 and 3 HCV and HIV co‑infection (PHOTON‑1, n=223).\nphase II open‑label single‑arm study in people with HCV waiting for a liver transplant (P7977‑2025, n=61).People in the sofosbuvir trials were tested for cirrhosis using Fibrotest (a biomarker test that uses the results of 6 blood serum tests to generate a score correlating to the degree of liver damage) and Fibroscan (a non‑invasive scan allowing the measurement of liver fibrosis based on its elasticity). No liver biopsies were performed at study entry and therefore liver fibrosis according to METAVIR score (which is based on liver biopsy histology) was not available for the sofosbuvir trials.\n\n# Evidence in people with genotype 1, 4, 5 or 6 HCV\n\n## Treatment-naive population\nNEUTRINO compared the efficacy and safety of sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks in people with genotype 1, 4, 5 or 6 treatment‑naive chronic HCV with a historical control. The primary outcome was sustained virological response 12 weeks after the end of treatment. The study did not include sites in the UK. A historical control rate of 60% for sustained virological response was used for peginterferon alfa‑2a and ribavirin, taken from the phase III telaprevir (ADVANCE) and boceprevir (SPRINT‑2) trials. The people in the study had a median age of 54 years (age range 19 to 70 years); 64% were men; 78% had baseline HCV RNA greater than 6 log10 IU/ml (viral load, or the number of virus particles in the blood; a viral load less than 6 log10 IU/ml has been linked to better response to treatment); 17% had cirrhosis; 89% had genotype 1 HCV and 11% had genotype 4, 5 or 6 HCV.\nResults from the NEUTRINO study showed that 12 weeks after the end of treatment with sofosbuvir plus peginterferon alfa and ribavirin, 90% (95% confidence interval 87 to 93%, p<0.001) of people with genotype 1, 4, 5 or 6 treatment‑naive HCV had a sustained virological response. Cirrhosis and non‑CC IL28B polymorphism were both associated with a reduced sustained virological response at 12 weeks: 92% (95% CI 89 to 95%) for people without cirrhosis, 80% (95% CI 67 to 89%) for those with cirrhosis (p=0.0018), and 98% (95% CI 93 to 100%) for people with the IL28B CC genotype polymorphism compared with 87% (95% CI 82 to 91%) for those with the non‑CC IL28B polymorphism (p=0.006). Sustained virological response at 12 weeks was 90% for people with genotype 1 HCV. Overall, the sustained virological response at 12 weeks was 97% for people with genotype 4, 5 or 6 HCV (100% in the 33 people without cirrhosis, and 50% in the 2 people with cirrhosis). No patient had a relapse during treatment. Relapse after virological response at the end of treatment occurred in 28 of 327 people after stopping treatment; 25 completed 12 weeks of treatment and 3 did not complete the treatment course. The company did not provide any information about the family origin of people in the NEUTRINO study.\nATOMIC compared the efficacy and safety of sofosbuvir plus peginterferon alfa and ribavirin in people with genotype 1, 4, 5 or 6 treatment‑naive chronic HCV. The study included 3 treatment arms: 1 arm had sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks, the second arm had the same treatment for 24 weeks, and the third arm had the same treatment for 12 weeks, followed by 12 weeks of sofosbuvir monotherapy (sofosbuvir monotherapy is outside of the marketing authorisation for sofosbuvir, but the results were included by the company for information). The primary outcome was sustained virological response 24 weeks after the end of treatment. Most people had genotype 1 HCV, and no one with genotype 5 HCV was enrolled in the study. Results showed that after treatment with sofosbuvir, sustained virological responses of 96–98% were achieved in each treatment arm. This suggests that for sofosbuvir plus peginterferon alfa and ribavirin treatment there is no increase in sustained virological response when treatment is extended beyond 12 weeks.\nQUANTUM compared the efficacy and safety of sofosbuvir plus ribavirin for 12 weeks with 24 weeks of treatment in people with genotype 1, 4, 5 or 6 treatment‑naive chronic HCV. The primary outcome was sustained virological response 12 weeks after the end of treatment, which was 56% (n=25) for people who had 12 weeks of sofosbuvir plus ribavirin and 52% (n=25) for people who had 24 weeks of sofosbuvir plus ribavirin. Results showed no statistically significant difference between treatment arms.\nSPARE was a 2 part study that investigated the efficacy and safety of sofosbuvir plus ribavirin treatment for 24 weeks in people with genotype 1 treatment‑naive chronic HCV. The first part was a 1 arm open‑label study of the efficacy and safety of sofosbuvir plus ribavirin treatment for 24 weeks. The second part investigated 24 weeks of sofosbuvir plus ribavirin (using the licensed weight‑based dose) compared with sofosbuvir plus a low, unlicensed dose of ribavirin. The primary outcome was sustained virological response 24 weeks after the end of treatment. In part 1 of the study, sustained virological response was achieved in 90% (n=9) of people. In part 2, 24 people in each group (96%) had viral suppression by week 4 of treatment. However after completing treatment, 7 people in the weight‑based ribavirin group and 10 people in the low‑dose ribavirin group had a relapse. The sustained virological response 12 weeks after the end of treatment in the intention‑to‑treat population was 68% (n=25) for people having 24 weeks of sofosbuvir plus weight‑based ribavirin and 48% (n=25) for people having 24 weeks of sofosbuvir plus low‑dose ribavirin. The sustained virological response 24 weeks after the end of treatment was the same as the response 12 weeks after the end of treatment.\n\n## Treatment-experienced population\nThe company did not provide any evidence for the efficacy of sofosbuvir plus ribavirin, or sofosbuvir plus peginterferon alfa and ribavirin in people with genotype 1, 4, 5 or 6 treatment‑experienced chronic HCV.\n\n# Evidence in people with genotype 2 or 3 HCV\n\n## Treatment-naive population\nFISSION compared sofosbuvir plus ribavirin for 12 weeks with peginterferon alfa‑2a plus ribavirin treatment for 24 weeks in people with genotype 2 or 3 treatment‑naive chronic HCV. The primary outcome was sustained virological response 12 weeks after the end of treatment. The non‑inferiority of sofosbuvir plus ribavirin compared with peginterferon alfa‑2a plus ribavirin for sustained virological response at 12 weeks (primary end point) was tested. People in the study were randomised in a 1:1 ratio and stratified by the presence or absence of cirrhosis, HCV genotype (2 or 3) and baseline HCV RNA level (<6 log10 IU/ml or ≥6 log10 IU/ml). The people in the study had a median age of 50 years (range from 19 to 77 years); 66% were men; 57% had baseline HCV RNA levels greater than 6 log10 IU/ml; 20% had cirrhosis; 72% had genotype 3 HCV.\nResults from FISSION showed that at 12 weeks after the end of treatment, sustained virological response was 67% in both treatment groups. Sofosbuvir plus ribavirin was non‑inferior to peginterferon alfa‑2a plus ribavirin for the primary end point. The absolute difference between treatment groups after adjusting for stratification was 0.3% (95% CI −7.5% to 8.0%, non‑inferiority p<0.001). HCV genotype and cirrhosis were associated with differences in sustained virological response (see table 2).\n\n## Table 2 Sustained virological response 12 weeks after the end of treatment from FISSION\nPercentage of people with a sustained virological response 12 weeks after end of treatment (95% CI)\nHCV genotype\nSofosbuvir plus ribavirin\nPeginterferon alfa‑2a plus ribavirin\n% (90 to 100%), (n=70)\n% (66 to 87%), (n=67)\n% (48 to 63%), (n=183)\n% (55 to 70%), (n=176)\n-r 3 without cirrhosis\n% (65 to 78%), (n=206)\n% (67 to 80%), (n=193)\n-r 3 with cirrhosis\n% (33 to 62%), (n=50)\n% (25 to 53%), (n=50)\nwithout cirrhosis\n%*, (n=59)\n%*, (n=54)\nwith cirrhosis\n%*, (n=11)\n%*, (n=13)\nwithout cirrhosis\n%*, (n=145)\n%*, (n=139)\n, with cirrhosis\n%*, (n=38)\n%*, (n=37)\n*Confidence intervals not reported, HCV; hepatitis C virus\nELECTRON was carried out in 2 centres in New Zealand. The study included 8 treatment arms, only 5 of which were used by the company to inform its submission. The treatment arms presented included people with genotype 1, 2 and 3 treatment‑naive chronic HCV who had sofosbuvir plus ribavirin with or without peginterferon alfa‑2a. In 4 of the treatment arms, people with genotype 2 or 3 HCV had sofosbuvir plus ribavirin for 12 weeks and either 0, 4, 8 or 12 weeks of peginterferon alfa‑2a. In another treatment arm, added as a protocol amendment after the 4 previous dose‑ranging treatment arms were completed, people with genotype 2 or 3 HCV had sofosbuvir plus peginterferon alfa‑2a and ribavirin for 8 weeks. Across the 5 study arms that were included in the company's submission, 100% of people with genotype 2 or 3 HCV had a sustained virological response 12 weeks after the end of treatment.\nPROTON was a study in 22 centres in the USA in which people with genotype 1, 2 and 3 treatment‑naive chronic HCV had sofosbuvir plus peginterferon alfa‑2a and ribavirin. The company only presented results from the study arm that included people with genotype 2 or 3 HCV, who had sofosbuvir plus peginterferon alfa‑2a and ribavirin for 12 weeks, because the other study arm was not used to inform its regulatory submission. Results from PROTON showed that sustained virological response 12 weeks after the end of treatment was 92% (no confidence interval reported in company's submission) across both genotypes, and 93% in people with genotype 2 HCV and 90% in people with genotype 3 HCV.\n\n## Treatment-experienced population\nFUSION compared the efficacy and safety of sofosbuvir plus ribavirin for either 12 or 16 weeks in people with genotype 2 or 3 chronic HCV, whose disease had no response to previous HCV treatment (25%), or had lost its initial response during or after previous HCV treatment (75%). The study did not include sites in the UK. The people in the study had a median age of 56 years (range 24 to 70 years); 70% were men; 73% had baseline HCV RNA levels greater than 6 log10 IU/ml; 34% had cirrhosis; 63% had genotype 3 HCV.\nResults from FUSION showed that HCV genotype and cirrhosis were associated with differences in sustained virological response (see table 3).\n\n## Table 3 Sustained virological response 12 weeks after the end of treatment from FUSION\nPercentage of people with a sustained virological response 12 weeks after end of treatment\nHCV genotype\nSofosbuvir plus ribavirin for 12 weeks\nSofosbuvir plus ribavirin for 16 weeks\n-r 3\n% (95%CI 40 to 60%), (n=100)\n% (95% CI 63 to 81%), (n=95)\n%*, (n=36)\n%*, (n=32)\n%*, (n=64)\n%*, (n=63)\nwithout cirrhosis\n%*, (n=26)\n%*, (n=23)\nwith cirrhosis\n%*, (n=10)\n%*, (n=9)\nwithout cirrhosis\n%*, (n=38)\n%*, (n=40)\nwith cirrhosis\n%*, (n=26)\n%*, (n=23)\n*Confidence intervals not reported, HCV; hepatitis C virus\nLONESTAR‑2 evaluated the efficacy and safety of sofosbuvir plus peginterferon alfa‑2a and ribavirin for 12 weeks in people with genotype 2 or 3 chronic HCV, whose disease had no response to previous HCV treatment (15%), or had lost its initial response during or after previous HCV treatment (85%). The study included 1 site in the USA. The people in the study had a median age of 56 years (age range 39 to 72 years); 68% were men; the mean baseline HCV RNA level was 6.2 log10 IU/ml (range from 4.0 to 7.2 log10 IU/ml); 55% had cirrhosis; 51% had genotype 3 HCV.\nResults from LONESTAR‑2 showed that sustained virological response 12 weeks after the end of treatment was 89% (no confidence intervals were reported in the company's submission) in people with genotype 2 or 3 HCV. HCV genotype and cirrhosis were not associated with statistically significant differences in sustained virological response. At 12 weeks after the end of treatment, sustained virological response was 96% and 83% in people with genotype 2 and genotype 3 HCV respectively. In people with genotype 2 HCV without cirrhosis, sustained virological response at 12 weeks after the end of treatment was 100% and in people with cirrhosis it was 93%. In people with genotype 3 HCV, the sustained virological response was 83% for people with and without cirrhosis.\n\n## Treatment-naive or treatment-experienced\nVALENCE was an unblinded study in which all people with genotype 2 HCV had sofosbuvir plus ribavirin for 12 weeks, and those with genotype 3 HCV had sofosbuvir plus ribavirin for 24 weeks. Because of changes made during the study, 11 people with genotype 3 HCV had a 12 week course of therapy. As a result of emerging data showing that people with genotype 3 HCV had higher sustained virological responses when they were treated for longer, treatment for all people with genotype 3 in the study was extended to 24 weeks and the goals of the study were redefined to be descriptive and not include hypothesis testing. People in the study had a median age of 51 years (range 19 to 74 years); 60% were men; the mean baseline HCV RNA level was 6.4 log10 IU/ml; 21% had cirrhosis; 78% had genotype 3 HCV. In around 65% of people with treatment‑experienced HCV, initial response was lost during or after previous treatment, 30% had no response to interferon‑based treatment, and 5% were intolerant to interferon.\nResults from VALENCE showed that sustained virological response 12 weeks after the end of treatment for people with genotype 2 HCV having sofosbuvir plus ribavirin for 12 weeks was 93% (no confidence intervals were reported in company's submission). In people with genotype 3 HCV who were treated for 24 weeks, the sustained virological response 12 weeks after the end of treatment was 84% overall, 93% in people who had never been treated and 77% in people who had been previously treated (no confidence intervals for this study were reported in the company's submission).\n\n## Population for whom interferon treatment was unsuitable (treatment-naive and treatment-experienced)\nPOSITRON evaluated the efficacy and safety of sofosbuvir plus ribavirin compared with placebo for 12 weeks in people with genotype 2 or 3 HCV. People in the study had previously discontinued interferon therapy owing to unacceptable adverse events (the company referred to this group as interferon intolerant), or had a concurrent medical condition preventing therapy with an interferon‑containing regimen (the company referred to this group as interferon ineligible), or were unwilling to have interferon treatment. Similar proportions of people with genotype 2 and 3 HCV were enrolled (51% and 49% respectively) in the study. People were randomised in a 3:1 ratio to receive sofosbuvir plus ribavirin or placebo, and were stratified (grouped) by the presence or absence of cirrhosis. The difference in sustained virological response 12 weeks after the end of treatment was assessed for superiority, which was demonstrated if the p‑value was less than 0.05. People treated in the study had a median age of 54 years (range 21 to 75 years); 54% were men; 70% had baseline HCV RNA levels greater than 6 log10 IU/ml; 16% had cirrhosis. The proportions of people who were intolerant to interferon, ineligible for interferon, or unwilling to have it were 9%, 44%, and 47% respectively. Most people had not had previous treatment for chronic hepatitis C (81.3%).\nResults from POSITRON showed that HCV genotype and cirrhosis were associated with differences in sustained virological response in people treated with sofosbuvir plus ribavirin (see table 4). The difference in sustained virological response between the sofosbuvir plus ribavirin and the placebo group was statistically significant (p<0.001) for people with genotype 2 or 3 chronic HCV.\n\n## Table 4 Sustained virological response 12 weeks after the end of treatment from POSITRON\nPercentage of people with a sustained virological response 12 weeks after end of treatment\nHCV genotype\nSofosbuvir plus ribavirin for 12 weeks\nPlacebo\n-r 3\n% (95%CI 72 to 83%), (n=207)\n%, (n=71)\n%*, (n=109)\n%*, (n=98)\nwithout cirrhosis\n%*, (n=92)\nwith cirrhosis\n%*, (n=17)\nwithout cirrhosis\n%*, (n=84)\nwith cirrhosis\n%- (n=14)\n*Confidence intervals not reported, HCV; hepatitis C virus\n\n# People with HIV and HCV co-infection\nThe safety and efficacy of 12 or 24 weeks of treatment with sofosbuvir plus ribavirin in people with genotype 1, 2 or 3 chronic hepatitis C who were co‑infected with HIV was evaluated in an open‑label clinical study (PHOTON‑1). People in the study had genotype 2 or 3 treatment‑naive or treatment‑experienced HCV or genotype 1 treatment‑naive HCV. People with genotype 2 or 3 treatment‑naive HCV had sofosbuvir plus ribavirin for 12 weeks. People with genotype 2 or 3 treatment‑experienced HCV and people with genotype 1 treatment‑naive HCV had sofosbuvir plus ribavirin for 24 weeks. Participants were either not on antiretroviral therapy with a CD4+ cell count above 500 cells/mm3 or had virologically suppressed HIV‑1 with a CD4+ cell count above 200 cells/mm3. At the time of enrolment, 95% of participants had antiretroviral therapy. Preliminary sustained virological response at 12 weeks was available for 210 people.\nResults from PHOTON‑1 showed that treatment with sofosbuvir plus ribavirin for 12 weeks in people with genotype 1, 2 or 3 HCV and HIV co‑infection and 24 weeks in people with genotype 1, 2 or 3 HCV and HIV co‑infection resulted in sustained virological response at 12 weeks after treatment irrespective of HCV genotype (≥93%; interim analysis). Similar safety and tolerability profiles were reported in people with HIV and HCV co‑infection and in people with HCV only.\n\n# People awaiting liver transplant\nAn open‑label clinical study (P7977‑2025) was carried out in people with chronic hepatitis C awaiting a liver transplant. It evaluated the safety and efficacy of sofosbuvir plus ribavirin administered before transplant to prevent post‑transplant HCV reinfection. The primary end point of the study was post‑transplant virological response (HCV RNA undetectable at 12 weeks after transplant). People with HCV regardless of genotype, with hepatocellular carcinoma suitable for liver transplant, had 400 mg sofosbuvir and 1000–1200 mg ribavirin daily for a maximum of 24 weeks. This was subsequently amended to 48 weeks or until the time of liver transplant, whichever was first. An interim analysis of results for 61 people who had sofosbuvir and ribavirin, most of whom had genotype 1 HCV, showed that 44 had a liver transplant up to 48 weeks after treatment with sofosbuvir and ribavirin and 41 had no detectable HCV RNA at the time of their transplant. Results suggested that treatment with sofosbuvir and ribavirin prevented HCV recurrence in 64% of people compared with a 100% historical risk of reinfection without prophylaxis. During treatment, HCV RNA suppression in people with well‑compensated cirrhosis awaiting a liver transplant for hepatocellular carcinoma was rapid and similar to that seen in other patient populations treated with sofosbuvir regimens.\n\n# Adverse effects of treatment\nThe company presented data on adverse events for NEUTRINO, FISSION, FUSION, POSITRON and VALENCE. The most common adverse events among people receiving sofosbuvir and ribavirin therapy (with or without peginterferon alfa) were fatigue, headache, anaemia, nausea, insomnia, irritability, rash, pruritis, myalgia, decreased appetite, influenza‑like illness, chills, pyrexia, and neutropenia. Of these events, fatigue and headache were usually the most frequent, affecting more than 40% of the people in some studies.\n\n# Health-related quality of life\nThe company assessed health‑related quality of life during the phase II and III trials using the Chronic Liver Disease Questionnaire – Hepatitis C (CLDQ‑HCV), the Functional Assessment of Chronic Illness Therapy‑Fatigue measurement system (FACIT‑F), the Work Productivity and ActivityImpairment questionnaire (WPAI), or the Short Form‑36 items survey (SF‑36). People in the phase III trials were not aware of their sustained virological response when completing the quality‑of‑life questionnaires. The results from NEUTRINO showed that there were differences in health‑related quality of life scores between baseline and the end‑of‑treatment and that scores returned to baseline values by the post‑treatment week 12 visit. The results from the FISSION study indicated that health‑related quality of life during treatment in people who had peginterferon alfa‑2a plus ribavirin was statistically significantly lower than for people in the sofosbuvir plus ribavirin arm. No difference was seen between the arms 12 weeks after the end of each treatment. The CLDQ‑HCV results from FUSION indicated that health‑related quality of life scores did not decrease significantly in either treatment group and there were no statistically significant differences in overall scores between the groups. The health‑related quality of life data obtained from POSITRON showed decreases (worsening) in all SF‑36 scales and the Mental Component and Physical Component scores in both treatment groups during treatment (baseline through to week 12). In the sofosbuvir plus ribavirin group the differences were statistically significant (p<0.001) from baseline in the Physical Function scale, Role Physical, Vitality, Social Functioning, Role Emotional, and Mental Health scales; however, there were no statistically significant differences from placebo at any time point.\n\n# Mixed treatment comparison\nThe company carried out a mixed treatment comparison to explore the comparative data for sofosbuvir and other relevant comparators. Because of limited data, a mixed treatment comparison network could not be formed for all the relevant populations in the decision problem and the comparison was done only for people with genotype 1, 2 or 3 treatment‑naive HCV for whom interferon therapy was suitable. In addition, the company's economic model required that efficacy data were split by cirrhosis status and these data were not available for all trials. In people with genotype 1 HCV, a network including sofosbuvir was possible only by linking 2 small phase II trials (ATOMIC and PROTON) which included only people without cirrhosis. In people with genotype 2 or 3 HCV, the mixed treatment comparison results were based on people with and without cirrhosis combined. The results of the mixed treatment comparison showed that for people with genotype 1 treatment‑naive HCV regardless of cirrhosis status, 84.9% of those who had sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks had a sustained virological response at 12 weeks after treatment, compared with 46.2% of people who had peginterferon alfa and ribavirin for 48 weeks, 76.5% of people who had telaprevir plus peginterferon alfa and ribavirin and 69.7% of people who had boceprevir plus peginterferon alfa and ribavirin. For people with genotype 2 treatment‑naive HCV without cirrhosis, 98.6% of those who had sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks had a sustained virological response at 12 weeks after treatment, compared with 85.6% of people who had peginterferon alfa and ribavirin for 24 weeks. For people with genotype 2 treatment‑naive HCV with cirrhosis, sustained virological response was achieved in 97.5% of people who had sofosbuvir and ribavirin for 12 weeks, and in 67.5% of those who had peginterferon alfa and ribavirin for 24 weeks. For people with genotype 3 treatment‑naive HCV without cirrhosis for whom interferon therapy was suitable, 62% of those who had sofosbuvir plus ribavirin for 12 weeks had a sustained virological response at 12 weeks after treatment, compared with 68.3% of people who had peginterferon alfa and ribavirin for 24 weeks. For people with genotype 3 treatment‑naive HCV with cirrhosis who had sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa and ribavirin for 24 weeks, the sustained virological response was similar (47.8% and 42.8% respectively) between the 2 treatment groups. The company highlighted several limitations to its mixed treatment comparison including the fact that the 12‑week sofosbuvir plus ribavirin regimen used to treat genotype 3 HCV is not licensed. Therefore, the company stated that the results of the mixed treatment comparison could not be considered robust.\n\n# Evidence Review Group comments\nThe ERG reviewed the clinical evidence in the company's submission. It considered that the company's interpretation of the clinical evidence was overall justified and unbiased. However, the ERG cautioned that most of the evidence provided did not directly address the decision problem, because of the lack of head‑to‑head studies against current standard of care comparators. In addition, it highlighted that no studies were included that examined the efficacy of sofosbuvir within its marketing authorisation for people with genotype 1 treatment‑experienced HCV. The ERG also noted that some of the evidence from VALENCE supporting the treatment regimens licensed for use in people with genotype 3 HCV should be interpreted with caution because randomisation was broken during the study, and some people were switched from 12 to 24 weeks of treatment with sofosbuvir plus ribavirin.\nThe ERG noted that the company only included adverse events from the 5 phase III studies (NEUTRINO, FISSION, FUSION, POSITRON and VALENCE). However, the ERG confirmed that the adverse events in the phase II studies were similar to those in the phase III studies. Overall, the ERG was satisfied that the evidence showed that treatment with sofosbuvir‑based regimens was generally well tolerated and led to fewer adverse events than treatment with peginterferon alfa and ribavirin.\n\n# Cost effectiveness\nThe company identified 112 cost‑effectiveness studies of chronic hepatitis C treatments. No studies were identified that compared sofosbuvir with alternative treatments.\nTo assess the cost effectiveness of sofosbuvir the company submitted a multi‑state Markov model, which compared sofosbuvir plus ribavirin and sofosbuvir plus peginterferon alfa and ribavirin with the comparators defined in the decision problem (that is, boceprevir or telaprevir plus peginterferon alfa and ribavirin for people with genotype 1 HCV, and peginterferon alfa and ribavirin or placebo for people with other HCV genotypes). The structure of the model was based on published health economic models, but was amended by the company to reflect the data available from its pivotal clinical trials and only distinguished between people with and without cirrhosis. The company used patient characteristics from the HCV UK research database to inform the population entering the model, including mean age at start of treatment, disease severity distribution and weight. The model had a total of 9 health states according to disease stage and treatment response. People entered the model in either the non‑cirrhotic or compensated cirrhosis stages of disease. People who had antiviral treatment could move into the non‑cirrhotic or sustained virological response cirrhotic health states. Those who did not clear the virus after treatment remained in their respective health states, or progressed to more severe stages of chronic HCV. All patients in the decompensated cirrhosis health state were assumed to be candidates for liver transplant. The model assumed that people who have a sustained virological response will not progress to more severe health states during or after therapy. Reversion to less severe health states was not permitted if treatment was unsuccessful.\nThe company applied age‑specific general population mortality rates to each health state in the model. The same model structure was used for all patients irrespective of HCV genotype or treatment experience. For the first 2 years a 3‑month cycle was used in the model, then the remaining cycles each lasted 1 year. A half‑cycle correction was applied, which is consistent with previous hepatitis C appraisals. An NHS and personal and social services perspective was taken and a lifetime horizon was used, with costs and outcomes discounted at 3.5%.\nData from clinical trials were used to inform model inputs for treatment effects, health‑related quality of life and adverse events. Treatment effect data were based on the sustained virological responses taken from the sofosbuvir clinical trials. If data for comparators were not available in these trials, they were taken from other published studies identified by the company. The company collected quality‑of‑life scores at baseline, week 12 during treatment, and at 4, 12 and 24 weeks after treatment. The SF‑36 quality of life data were converted to SF‑6D utility data and used in the company's base case. The company also converted SF‑36 data to the EQ‑5D and incorporated these in a deterministic sensitivity analysis. Adverse event rates were obtained from the sofosbuvir clinical trials and published studies. The company incorporated the rates of grade 3 and 4 pruritus, diarrhoea and nausea, vomiting, rash, anaemia, thrombocytopenia, neutropenia, and depression from the trials into the model so that drug acquisition costs could be included for interventions associated with managing these adverse events.\nThe company used transition probabilities for disease progression from 2 published UK health technology assessments and 1 UK study: Hartwell et al. (2011), Shepherd et al. (2007), and Grishchenko et al. (2009), which used estimates from the Trent database (a large sample of people with HCV who attended only non‑tertiary centres in the UK).\nUtility values estimated from the sofosbuvir clinical studies were not used to inform the model. Instead, the company used utility values from previous technology appraisals for hepatitis C treatments that were based on the UK trial of mild chronic hepatitis C by Wright et al. (2006). The company calculated treatment‑related utilities by applying treatment‑related utility decrements to the baseline utility estimates.\nThe company compared sofosbuvir plus ribavirin (with or without peginterferon alfa), telaprevir plus peginterferon alfa and ribavirin, boceprevir plus peginterferon alfa and ribavirin, peginterferon alfa plus ribavirin, and best supportive care. Sofosbuvir, telaprevir, boceprevir, peginterferon alfa‑2a and ribavirin were used in the model according to their marketing authorisations. The company applied no stopping rules, lead‑in phase, or option for sofosbuvir retreatment, in line with the sofosbuvir clinical trials.\nThe company used costs in the model that reflected the UK NHS perspective, comprising treatment‑related costs (drug acquisition and patient monitoring), health‑state costs and adverse event costs. Drug costs were based on the list price in the BNF (June 2013). Costs for drugs used to treat adverse events in the model were taken from the BNF. The company used the BNF price of ribavirin (Copegus 400 mg, 56 tablet packs) at a cost of £246.65 in the model. Costs for the health states in the model were identified using published sources taken from the resource and costs systematic review done by the company. The costs for the non‑cirrhotic health state were based on a calculation of the costs associated with mild and moderate cirrhosis (Wright et al.) using an assumed 77%: 23% split between mild and moderate cirrhosis. Costs were inflated to 2011/12 prices (using the Hospital and Community Health Service pay and prices index).\nMonitoring costs included resource unit costs of outpatient appointments, inpatient care, tests and investigations (virology, pathology, haematology, immunology, radiology) and procedures (liver biopsy). The source for monitoring costs was the National Schedule of Reference Costs, published studies or expert opinion.\n\n# Results\nThe company presented base‑case analyses for sofosbuvir plus ribavirin with or without peginterferon alfa compared with current standard of care, based on HCV genotype, interferon eligibility and treatment history. The company's results show that sofosbuvir treatment regimens increased the cost of treatment, but were associated with more quality‑adjusted life years (QALYs) gained, a greater probability of sustained virological response (cure), and a reduction in end‑stage liver disease and death.\n\n## Genotype 1\nFor people with genotype 1 treatment‑naive HCV for whom interferon therapy was suitable, the company's base‑case analysis showed that the incremental cost‑effectiveness ratio (ICER) for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks was £14,930 per QALY gained (incremental cost £19,129; incremental QALYs 1.3). Boceprevir plus peginterferon alfa and ribavirin was dominated (that is, sofosbuvir plus peginterferon alfa and ribavirin was less expensive and more effective) and telaprevir plus peginterferon alfa and ribavirin was extendedly dominated (that is, its ICER is higher than that of the next, more effective option when compared with a common baseline). For people with genotype 1 treatment‑naive HCV for whom interferon therapy was not suitable, the company's base‑case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £49,249 per QALY gained (incremental cost £63,903; incremental QALYs 1.3).\nThe company did not do an economic analysis for genotype 1 treatment‑experienced HCV because there was no clinical evidence available to populate the economic model for this population. However, an economic analysis for genotype 1 treatment‑experienced HCV was later provided by the company (see section 3.69).\n\n## Genotype 2\nIn people with genotype 2 treatment‑naive HCV for whom interferon therapy was suitable, the company's base‑case ICER for sofosbuvir plus ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 24 weeks was £46,324 per QALY gained (incremental cost £27,779; incremental QALYs 0.6). In people with genotype 2 treatment‑naive HCV for whom interferon therapy was not suitable, the company's base‑case ICER for sofosbuvir plus ribavirin for 12 weeks compared with no treatment was £8154 per QALY gained (incremental cost £20,051; incremental QALYs 2.5).\nIn people with genotype 2 treatment‑experienced HCV for whom interferon therapy was suitable, the company's base‑case ICER for sofosbuvir plus ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks was £9274 per QALY gained (incremental cost £21,498; incremental QALYs 2.3). In people with genotype 2 treatment‑experienced HCV for whom interferon therapy was not suitable, the company's base‑case ICER for sofosbuvir and ribavirin treatment for 12 weeks compared with no treatment was £8591 per QALY gained (incremental cost £20,697; incremental QALYs 2.4).\n\n## Genotype 3\nIn people with genotype 3 treatment‑naive HCV for whom interferon therapy was suitable, the company's base‑case ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 24 weeks was £20,613 per QALY gained (incremental cost £24,970; incremental QALYs 1.2). In people with genotype 3 treatment‑naive HCV for whom interferon therapy was not suitable, the company's base‑case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £21,478 per QALY gained (incremental cost £55,137; incremental QALYs 2.6).\nIn people with genotype 3 treatment‑experienced HCV for whom interferon therapy was suitable, the company's base‑case ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks was £8557 per QALY gained (incremental cost £19,634; incremental QALYs 2.3). In people with genotype 3 treatment‑experienced HCV for whom interferon therapy was not suitable, the company's base‑case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £28,569 per QALY gained (incremental cost £58,828; incremental QALYs 2.1).\n\n## Genotypes 4, 5 or 6\nIn people with genotype 4, 5 or 6 treatment‑naive HCV for whom interferon therapy was suitable, the company's original base‑case ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks was £26,797 per QALY gained (incremental cost £23,942; incremental QALYs 0.9). In sensitivity analyses, the sustained virological response for peginterferon alfa plus ribavirin for 48 weeks (which varied between 26.6% and 73.4%) had a large impact on the cost‑effectiveness results.\nThe company tested the robustness of the model using deterministic sensitivity analyses. Results showed that the ICERs were most sensitive to changes in the discount rate (varied between 0% and 6% for costs and outcomes simultaneously) and the utility increment after achieving a sustained virological response. The company concluded that the results of the deterministic sensitivity analyses showed that the ICERs for sofosbuvir remained below £20,000 per QALY gained in the following subgroups:\npeople with genotype 2 treatment‑naive and treatment‑experienced HCV, for whom interferon treatment is unsuitable, compared with no treatment\npeople with genotype 2 and 3 treatment‑experienced HCV, for whom interferon therapy is suitable, compared with no treatment.The results of the deterministic sensitivity analyses showed that the ICERs for sofosbuvir were between £20,000 and £30,000 per QALY gained in the following subgroups:\npeople with genotype 1 treatment‑naive HCV, for whom interferon therapy is suitable, compared with peginterferon alfa and ribavirin and boceprevir plus peginterferon alfa and ribavirin\npeople with genotype 2 treatment‑experienced HCV, for whom interferon therapy is suitable, compared with peginterferon alfa and ribavirin\npeople with genotype 3 treatment‑experienced HCV, for whom interferon therapy is suitable, compared with peginterferon alfa and ribavirin.The results of the deterministic sensitivity analyses showed that the ICERs for sofosbuvir were above £30,000 per QALY gained in the following subgroups:\npeople with genotype 1 treatment‑naive HCV, for whom interferon therapy is suitable, compared with telaprevir plus peginterferon alfa and ribavirin\npeople with genotype 3 treatment‑naive HCV, for whom interferon is unsuitable, compared with no treatment\npeople with genotype 3 treatment‑naive HCV, for whom interferon therapy is suitable, compared with peginterferon alfa and ribavirin.\nThe company also carried out probabilistic sensitivity analyses to explore parameter uncertainty. Although it did not draw any specific conclusions from the analyses, results suggested that sofosbuvir had less than a 50% probability of being cost effective in 6 of the base‑case comparisons (if the maximum acceptable ICER was £20,000 per QALY gained) and greater than a 50% probability of being cost effective in 9 of the base‑case comparisons (if the maximum acceptable ICER was £30,000 per QALY gained).\nDuring clarification, the company explored the effect of including a transition probability from Cardoso et al. (2010) (0.005; 95% CI 0.013 to 0.002) from the sustained virological response cirrhotic health state to the hepatocellular carcinoma health state in the economic model, and varied the probability in line with the upper and lower limits of the 95% confidence interval (see section 3.52). The ICERs from the company's exploratory analyses were slightly higher than those estimated in the company's base case (ranging from £7507 per QALY gained to £54,957 per QALY gained ).\n\n## HCV and HIV co-infected populations\nThe company provided a separate economic analysis for people co‑infected with HIV and HCV. In people with HIV and genotype 1 treatment‑naive HCV for whom interferon therapy is suitable, the company's base‑case ICER for sofosbuvir plus ribavirin treatment for 24 weeks compared with no treatment was £28,504 per QALY gained, or £43,836 per QALY gained compared with peginterferon alfa‑2a and ribavirin treatment for 48 weeks. The company's base‑case ICER for sofosbuvir plus ribavirin for 12 weeks compared with peginterferon alfa 2a and ribavirin treatment for 48 weeks in people with genotype 2 treatment‑naive HCV and HIV‑co‑infection was £55,867 per QALY gained. The company's base‑case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment in people with genotype 2 treatment‑experienced HCV and HIV co‑infection was £10,572 per QALY gained, or £128,248 per QALY gained compared with peginterferon alfa‑2a and ribavirin treatment for 48 weeks. For people with genotype 3 treatment‑naive HCV and HIV co‑infection, 12 weeks of sofosbuvir plus ribavirin dominated treatment with peginterferon alfa and ribavirin. The ICERs for 24 weeks of sofosbuvir plus ribavirin were £10,646 per QALY gained compared with no treatment and £90,822 per QALY gained compared with peginterferon alfa‑2a and ribavirin for 48 weeks in people with genotype 3 treatment‑experienced HCV and HIV co‑infection. The company did not provide an economic analysis for people co‑infected with HIV and genotype 4, 5 or 6 HCV.\n\n# Evidence Review Group comments\nThe ERG reviewed the company's model and economic systematic review. The ERG considered that the company's methods of economic evaluation and the model produced were acceptable. It validated the company's model by comparing the total costs and QALYs predicted by the model for the treatment‑naive interferon‑eligible genotype 1 HCV population with the corresponding figures for treatment with peginterferon alfa plus ribavirin with and without boceprevir or telaprevir obtained from the previous NICE technology appraisals for boceprevir for the treatment of genotype 1 chronic hepatitis C and telaprevir for the treatment of genotype 1 chronic hepatitis C. The ERG found that the company's model for sofosbuvir was broadly consistent with previous models considered in NICE technology appraisals for hepatitis C, in terms of total costs and QALYs assumed for peginterferon alfa and ribavirin, and for telaprevir. However, the ERG noted that there was a discrepancy between models in the total costs estimated for boceprevir, but it was not able to account for the differences without reviewing the data used in the boceprevir submission. The ERG also considered that the company's economic model captured most of the important aspects of the disease pathway, but noted that it did not include a transition from the sustained virological response cirrhotic health state to the hepatocellular carcinoma health state, which had been previously included in other hepatitis C models. Despite this omission from the company's model, the ERG showed that it did not affect the base‑case ICERs substantially. The ERG considered that the company's model extrapolated intermediate outcomes to final outcomes in a consistent way, drawing on standard sources from the literature.\nThe ERG noted that the transition probabilities used by the company in its economic model for the HCV and HIV co‑infected population from the non‑cirrhotic to compensated cirrhosis health states were higher than those assumed for the mono‑infected population. The ERG further noted that people with HCV and HIV co‑infection are likely to have a higher mortality than the population with HCV only, regardless of sustained virological response, and this was not taken into account in the company's model. The ERG noted that a study by Van Der Helm et al. (2013) concluded that the effects of HCV treatment on HIV progression needed to be evaluated further. Therefore, in the ERG's opinion, the evidence needed to accurately evaluate the cost effectiveness of sofosbuvir in the HCV and HIV co‑infected population was not currently available.\n\n# Additional exploratory ERG analyses\nThe ERG carried out several exploratory analyses, which included:\nadding a transition probability from the sustained virological response cirrhotic health state to the hepatocellular carcinoma health state and exploring the effect of using different transition probabilities between these 2 health states\nassessing the effect on the ICERs of variations to all‑cause mortality probabilities\nevaluating the effect of changing the average age of entry into the model\nusing a range of alternative sustained virological response estimates from studies of comparator treatments\nassessing the effect of an alternative distribution of people with cirrhosis\nexploring the effect of the number of people having 24 weeks of sofosbuvir compared with those having 12 weeks of sofosbuvir\nassessing the effect of using alternative utility increments after sustained virological response.\nThe ERG heard from its clinical advisers that a transition from the sustained virological response cirrhotic health state to the hepatocellular carcinoma health state should be included in models for chronic hepatitis C to reflect the clinical course of the disease. The ERG noted that this transition was not included in the company's economic model. In addition, the ERG was unable to calculate the transition probability between these 2 health states used by the company (0.005) in its response to clarification based on the study by Cardoso et al. (see section 3.47). The ERG recalculated the transition probability using the Cardoso et al. study, to produce a value of 0.0123 (95% CI 0.028 to 0.0218). The effect of including this value (and also the upper and lower confidence interval values) was explored by the ERG in a sensitivity analysis that produced ICERs ranging from £7593 per QALY gained to £60,887 per QALY gained ).\nThe ERG noted that the company used the simple average of mortality from men and women to calculate the age‑specific mortality used in the model. The ERG commented that more men are treated for HCV in clinical practice in England, therefore a weighted average should have been used. During clarification, the company re‑ran their economic model with weighted average mortality probabilities, but did not indicate what weights were used to obtain its results. The ERG carried out an exploratory analysis using a weighting of 61% men and 39% women as used in Wright et al. The ICERs from the ERG's exploratory analyses were slightly higher than those estimated in the company's base case (ranging from £7453 per QALY gained to £50,083 per QALY gained ).\nThe ERG noted that the company's model used an efficacy estimate drawn from a single source when multiple efficacy estimates were available for the same treatment and indication. NICE asked the ERG to carry out further exploratory analyses to inform the Committee's understanding of the effect on the company's ICERs of using a range of alternative sustained virological response estimates from studies of comparator treatments. For people with genotype 1 treatment‑naive HCV, the ERG used alternative estimates of sustained virological response for boceprevir plus peginterferon alfa‑2b and ribavirin from the SPRINT‑2 study, in line with estimates used in the NICE technology appraisal of boceprevir (that is, 68.2% for people with no cirrhosis and 41.7% for people with cirrhosis, compared with the company's base‑case values of 64.1% for people with no cirrhosis and 55.0% for people with cirrhosis). Applying the alternative sustained virological response estimates for boceprevir gave a lower ICER than the company's base case (the ICER was not reported by the ERG in its additional analyses).\nThe ERG also used alternative sustained virological response estimates for people with genotype 3 treatment‑naive HCV, who are eligible for interferon. First, the ERG modelled the effect of an alternative sustained virological response of 90.7% for sofosbuvir plus peginterferon alfa‑2a and ribavirin. This response was at the lower end of the 95% confidence interval for the population with no cirrhosis from the sofosbuvir trials (an estimate of 97.4% was used in the company's base case, an average of the sustained virological response from ELECTRON and PROTON). The resulting ICER for sofosbuvir plus peginterferon alfa‑2a and ribavirin compared with peginterferon alfa‑2a and ribavirin for this subgroup was £23,772 per QALY gained (compared with the company's base‑case ICER of £20,613 per QALY gained). The ERG also explored the effect of an alternative sustained virological response of 92.3% for sofosbuvir plus peginterferon alfa‑2a and ribavirin in people with genotype 3 treatment‑naive HCV and cirrhosis. Applying this alternative response lowered the ICER to £18,187 per QALY gained.\nThe ERG also explored the effect of alternative assumptions about the natural history of chronic hepatitis C infection on the company's ICERs. In particular, it investigated the effect of assuming an alternative distribution of cirrhosis. The ERG used a distribution for new and existing cirrhosis obtained from Hartwell et al. (2011) based on data from a London teaching hospital where 32% of existing patients with HCV and 10% of new patients with HCV had cirrhosis. The results of the exploratory analysis suggested that using this distribution increased the company's base‑case ICERs for people with treatment‑naive HCV and reduced the ICERs for people with treatment‑experienced HCV across all genotypes. In people with genotype 3 treatment‑naive HCV for whom interferon therapy was suitable, the ICER for sofosbuvir plus peginterferon alfa‑2a and ribavirin (12 weeks) compared with peginterferon alfa and ribavirin (24 weeks) increased from £20,613 per QALY gained in the company's base case to £30,175 per QALY gained. The ICERs for treatment for people with genotype 1 treatment‑naive HCV remained above £30,000 per QALY gained (irrespective of interferon eligibility). Results for all other subgroups remained below £30,000 per QALY gained.\nThe ERG explored the effect of using a lower transition probability from the non‑cirrhotic health state to the compensated cirrhosis health state, at age 40 years in the company's model. The resulting ICERs increased across all subgroups and were higher than those estimated in the company's base case (ranging from £9458 per QALY gained to £61,077 per QALY gained ).\nThe ERG explored the effect on the company's base‑case ICERs of varying the percentage of people having 24 weeks of sofosbuvir treatment compared with those having 12 weeks of treatment. The 3 subgroups who might have 12 or 24 weeks of sofosbuvir treatment according to the marketing authorisation are people with:\ngenotype 1 HCV, having sofosbuvir plus peginterferon alfa and ribavirin\ngenotype 2 HCV, having sofosbuvir and ribavirin\ngenotype 3 HCV, having sofosbuvir plus peginterferon alfa and ribavirin. The ERG's clinical advisers differed in their opinions about how long these groups would have treatment. One clinical expert stated that it would be unlikely that more than 1–2% of people would be considered better off with longer therapy and that this group are identified in the summary of product characteristics as needing consideration for longer treatment periods. Another clinical expert stated that at least 20% of people might need 24 weeks of therapy, especially those who are intolerant to interferon or have severe cirrhosis.\nThe ERG pointed out that the company's economic model allows for a 12 week regimen of sofosbuvir plus peginterferon alfa and ribavirin for people with genotype 1 treatment‑naive HCV for whom interferon therapy is suitable and a 12 week regimen of sofosbuvir and ribavirin for people with genotype 2 treatment‑naive HCV (regardless of interferon eligibility). The economic model did allow for a 24 week regimen of sofosbuvir and ribavirin for various genotype 3 HCV subgroups. The ERG therefore compared sofosbuvir plus ribavirin for 24 weeks with either peginterferon alfa and ribavirin treatment for 24 weeks in people with genotype 3 treatment‑naive HCV and either no treatment or 48 weeks of peginterferon alfa and ribavirin treatment for people with genotype 3 treatment‑experienced HCV. The resulting ICERs were more than double the company's base‑case results (which assumed that these patient groups only have 12 weeks of sofosbuvir and ribavirin).\nThe ERG carried out sensitivity analyses to evaluate the effect of changing the average age of entry into the model. The resulting ICERs generally decreased when a lower average age of 35 years was selected for entry into the model, and were higher when the average age selected was 55 years. The lowest ICERs ranged from £6717 per QALY gained (using 35 years) to £9170 per QALY gained (using 55 years) for sofosbuvir compared with boceprevir plus peginterferon alfa and ribavirin in people with genotype 1 treatment‑naive HCV, for whom interferon therapy is suitable. The highest ICERs ranged from £47,254 per QALY gained (using 35 years) to £60,976 per QALY gained (using 55 years) for sofosbuvir compared with 24 weeks of peginterferon alfa‑2a and ribavirin treatment in people with genotype 2 treatment‑naive HCV, for whom interferon therapy is suitable.\nThe ERG also carried out sensitivity analyses to explore the effect on the company's ICERs of using different utility increments (0 and 0.04 , compared with the company's estimate of 0.05) after sustained virological response. The resulting ICERs in the ERG's sensitivity analysis were consistently higher than the company's base‑case results. When using a utility increment of 0.04, the ICERs ranged from £7899 per QALY gained for sofosbuvir plus peginterferon alfa and ribavirin compared with boceprevir plus peginterferon alfa and ribavirin in people with genotype 1 treatment‑naive HCV, for whom interferon therapy is suitable, to £53,793 per QALY gained for sofosbuvir plus peginterferon alfa and ribavirin compared with no treatment in people with genotype 1 treatment‑naive HCV, for whom interferon treatment is unsuitable. When using a utility increment of 0, the ICERs ranged from £12,732 per QALY gained for sofosbuvir plus peginterferon alfa and ribavirin compared with boceprevir plus peginterferon alfa and ribavirin in people with genotype 1 treatment‑naive HCV, for whom interferon therapy is suitable, to £92,795 per QALY gained for sofosbuvir plus peginterferon alfa and ribavirin compared with no treatment in people with genotype 1 treatment‑naive HCV, for whom interferon treatment is unsuitable.\nThe ERG also explored the effect on the company's base‑case ICERs when alternative estimates of sustained virological response for peginterferon alfa plus ribavirin to those used by the company (from McHutchison et al. 2009) were applied, for people with genotype 1 treatment‑naive HCV for whom interferon therapy is suitable. The ERG used estimates from Roberts et al. (2009), which reported a sustained virological response of 51% for people without cirrhosis and 6% for people with cirrhosis, and estimates from Hadziyannis et al. (2004), which were 56% and 38% respectively. Using the estimates from Roberts et al. the company's ICER for sofosbuvir plus peginterferon alfa and ribavirin compared with peginterferon alfa and ribavirin increased to £18,209 per QALY gained. Similarly, the base‑case ICER increased to £21,848 per QALY gained for the same comparison when estimates from Hadziyannis et al. were used.\nThe ERG also carried out a scenario analysis that considered the combined impact on the company's ICERs of including a transition from the sustained virological response cirrhotic health state to the hepatocellular carcinoma health state, alternative utility increments after a sustained virological response, and an alternative estimate of efficacy for peginterferon alfa and ribavirin in the population with genotype 1 treatment‑naive HCV who are eligible for interferon (using values described in sections 3.52, 3.61 and 3.62). The ICERs from the ERG's exploratory analyses were higher than those estimated in the company's base case (ranging from £9415 per QALY gained to £109,526 per QALY gained ).\n\n## Additional analyses for genotypes 1 and 3 HCV\nDuring consultation the Committee asked that the company provide additional evidence, which the Committee believed would permit it to come to a better informed conclusion. Specifically, the Committee requested that the company carry out several exploratory analyses for sofosbuvir plus ribavirin, with or without peginterferon alfa, compared with peginterferon alfa and ribavirin in people with genotype 1 and genotype 3 chronic hepatitis C, because these genotypes represent 89% of HCV infections in England. This included revised cost‑effectiveness analyses presented separately for people with and without cirrhosis, with and without HIV‑co‑infection, and by treatment history. The Committee asked that the analyses should incorporate:\nthe transition from the sustained virological response cirrhotic health state to the hepatocellular carcinoma health state, using the transition probability estimates from Cardoso et al.\nalternative sustained virological response estimates for peginterferon alfa and ribavirin (for example from Hadziyannis et al.)\nalternative utility increments after sustained virological response (for example SF‑36 values from the trials collected at 24 weeks post‑treatment, and Vera‑Llonch et al.) and\nalternative costs for ribavirin (for example, the cost of generic ribavirin as calculated by the Commercial Medicines Unit Electronic Market Information Tool) in the model. The Committee also asked that sensitivity analyses, including the Committee's assumptions, should be explored:\nassuming that up to 100% of people with genotype 3 HCV have sofosbuvir plus ribavirin for 24 weeks\nassuming that an increased proportion of people for whom interferon therapy is suitable may be unwilling to have interferon treatment and therefore have sofosbuvir plus ribavirin for 24 weeks\nvarying the age of entry into the model from 35 and 55 years\nvarying all‑cause mortality by assuming the population entering the model comprises 61% men and 39% women, in line with estimates from Wright et al.\nThe company provided the additional analyses requested, although the revised base‑case assumptions were slightly different to those requested by the Committee. The company justified each change to the revised base‑case assumptions, which included a transition from the sustained virological response cirrhotic health state and the non‑sustained virological response cirrhotic health state to the hepatocellular carcinoma health state, using the transition probability estimates from Cardoso et al. (2010); alternative utility increments from Vera‑Llonch et al., alternative costs for ribavirin and all‑cause mortality assuming the population entering the model comprises 61% men and 39% women, in line with estimates from Wright et al. The company chose to use the sustained virological response rates for peginterferon alfa and ribavirin from McHutchison et al. for its revised base case, and provided a sensitivity analysis incorporating the sustained virological response rates from Hadziyannis et al. (see section 3.74).\nThe company presented ICERs to the Committee for subgroups stratified by genotype, treatment history, interferon eligibility and cirrhosis status. The company provided the Committee with a 'global' ICER based on all patients mono‑infected with HCV for genotypes 1 to 6, which was £16,199 per QALY gained. The company also provided the Committee with 'global' ICERs by genotype, weighted by treatment history and cirrhosis status, which ranged from £10,753 per QALY gained in people with genotype 1 HCV to £31,361 per QALY gained in people with genotype 2 HCV.\n\n## Genotype 1\nFor people with treatment‑naive genotype 1HCV, for whom interferon therapy is suitable, the company's revised base‑case analysis showed that the ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks was £17,476 per QALY gained. The ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with boceprevir plus peginterferon alfa and ribavirin was £10,335 per QALY gained and £15,396 per QALY gained compared with telaprevir plus peginterferon alfa and ribavirin. For people with genotype 1 treatment‑naive HCV, for whom interferon therapy is not suitable, the company's base‑case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £47,611 per QALY gained.\nWhen stratified by the presence or absence of cirrhosis, the company's revised base‑case analysis showed that the ICER for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks in people with treatment‑naive HCV who are eligible for interferon was £25,237 per QALY gained for people without cirrhosis, and £5352 for people with cirrhosis. The stratified ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with boceprevir plus peginterferon alfa and ribavirin was £14,280 per QALY gained for people without cirrhosis and £2819 per QALY gained for people with cirrhosis. The stratified ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with telaprevir plus peginterferon alfa and ribavirin was £22,304 per QALY gained for people without cirrhosis and £4253 per QALY gained for people with cirrhosis. For people with genotype 1 treatment‑naive HCV for whom interferon therapy is not suitable, the company's base‑case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment, stratified by cirrhosis status, was £51,478 per QALY gained for people without cirrhosis and £35,754 per QALY gained for people with cirrhosis.\nBecause of the lack of clinical trial evidence in people with genotype 1 treatment‑experienced HCV, the company provided the Committee with an estimated cost‑effectiveness calculation for this subgroup. The company explained that historically, approximately 50% of people with genotype 1 treatment‑naive HCV had disease that responded to treatment with peginterferon alfa and ribavirin, but in the interim analysis provided to the US Food and Drug Administration (FDA), 89% of people with genotype 1 treatment‑naive HCV in NEUTRINO had disease that responded to sofosbuvir plus peginterferon alfa and ribavirin. The FDA accepted that the higher rate of overall sustained virological response seen in NEUTRINO was likely driven by those patients who were virus‑free 12 weeks after the end of treatment, but who would not have had this response if treated with peginterferon alfa and ribavirin alone. Assuming that people who would have had a sustained virological response with peginterferon alfa and ribavirin alone had a sustained virological response with sofosbuvir plus peginterferon alfa and ribavirin, the FDA assumed that the increase in sustained virological response from 50% to 89% represented the efficacy of sofosbuvir plus peginterferon alfa and ribavirin. The FDA calculated that given the high sustained virological responses in NEUTRINO, an approximate sustained virological response was 78% for people with treatment‑experienced genotype 1 HCV. Additionally, the company presented interim evidence from Pol et al. (2013), a study of the efficacy of sofosbuvir in people with genotype 1 treatment‑experienced HCV, which suggested that sustained virological responses in this group were 74% after treatment with sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks. Using the estimated sustained virological response of 78% calculated by the FDA, the company's ICER for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa and ribavirin alone for 48 weeks was £12,641 per QALY gained. The company's ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with boceprevir plus peginterferon alfa and ribavirin was £683 per QALY gained and £8203 per QALY gained when compared with telaprevir plus peginterferon alfa and ribavirin in people with genotype 1 treatment‑experienced HCV.\n\n## Genotype 3\nIn people with genotype 3 treatment‑naive HCV for whom interferon therapy is suitable, the company's revised base‑case ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 24 weeks was £21,860 per QALY gained. In people with genotype 3 treatment‑naive HCV for whom interferon therapy is unsuitable, the company's base‑case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £21,049 per QALY gained.\nIn people with genotype 3 treatment‑experienced HCV for whom interferon therapy is suitable, the company's base‑case ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks was £13,883 per QALY gained. In people with genotype 3 treatment‑experienced HCV, for whom interferon therapy is unsuitable, the company's base‑case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £27,483 per QALY gained.\nWhen stratified by the absence or presence of cirrhosis, in people with genotype 3 treatment‑naive HCV for whom interferon therapy is suitable, the company's revised base‑case ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 24 weeks was £40,623 per QALY gained for people without cirrhosis and £6556 per QALY gained for people with cirrhosis. In people with genotype 3 treatment‑naive HCV for whom interferon therapy is unsuitable, the company's revised base‑case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £28,044 per QALY gained in people with no cirrhosis, and £10,505 per QALY gained in people with cirrhosis. In people with treatment‑experienced genotype 3 HCV for whom interferon therapy is suitable, the company's revised base‑case ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks was £18,592 per QALY gained in people without cirrhosis and £6260 per QALY gained in people with cirrhosis. In people with genotype 3 treatment‑experienced HCV for whom interferon therapy is unsuitable, the company's revised base‑case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £31,416 per QALY gained in people without cirrhosis and £19,179 per QALY gained in people with cirrhosis.\n\n## HCV and HIV co-infected populations\nThe company provided a separate economic analysis for people co‑infected with HIV and HCV. The company reported results from the 1910 study (Rodriguez‑Torres et al. ), which included (F0‑F3) patients with HCV and HIV co‑infection and no cirrhosis. The sustained virological response of 90% seen in the 1910 study was also seen in people with HCV mono‑infection and no cirrhosis in NEUTRINO, which suggested that similar response rates are seen in people with genotype 1 HCV having sofosbuvir plus peginterferon and ribavirin for 12 weeks, regardless of HCV and HIV co‑infection status. The company presented revised base‑case ICERs in people co‑infected with HIV and genotype 1 or 3 HCV, which ranged from £10,376 per QALY gained in people with genotype 3 treatment‑experienced HCV and HIV having sofosbuvir and ribavirin for 24 weeks compared with no treatment, to £27,059 per QALY gained in people with genotype 1 treatment‑naive HCV having sofosbuvir and ribavirin for 24 weeks compared with no treatment.\n\n## Additional sensitivity analyses\nThe Committee asked that the revised base case include the sustained virological responses from Hadziyannis et al. rather than from McHutchison et al. for peginterferon alfa and ribavirin in people with genotype 1 treatment‑naive HCV. The company expressed concern about this approach because the sustained virological response in Hadziyannis et al. assumed that a METAVIR score from F0 to F2 represented people without cirrhosis and a score from F3 to F4 represented people with cirrhosis, whereas in NEUTRINO, METAVIR scores of F4 for cirrhosis and F0‑F3 for non‑cirrhosis were defined. The company also commented that people in the McHutchison et al. study were more representative of people in the NEUTRINO study. Therefore, the company used the sustained virological responses from McHutchison et al. in its revised base‑case analysis. However, it provided the Committee with the results of a scenario analysis in which it used the sustained virological responses for peginterferon alfa and ribavirin from Hadziyannis et al., which suggested that for people with genotype 1 treatment‑naive HCV, the ICER for sofosbuvir plus peginterferon alfa and ribavirin compared with peginterferon alfa and ribavirin alone was £25,014 per QALY gained, whereas its revised base‑case ICER using the sustained virological responses for peginterferon alfa and ribavirin from McHutchison et al. was £17,476 per QALY gained.\nThe company presented a scenario analysis assuming that 100% of people with genotype 3 HCV for whom interferon therapy is suitable would have 24 weeks of sofosbuvir and ribavirin. In people with genotype 3 treatment‑naive HCV for whom interferon therapy is suitable, assuming that 100% of people would have 24 weeks of sofosbuvir and ribavirin treatment compared with 24 weeks of peginterferon alfa and ribavirin treatment, the ICER was £46,956 per QALY gained. In people with genotype 3 treatment‑experienced HCV for whom interferon therapy is suitable, assuming that 100% of people would have 24 weeks of sofosbuvir and ribavirin treatment compared with 48 weeks of peginterferon alfa and ribavirin treatment, the ICER was £48,306 per QALY gained. The company also presented the results of a scenario analysis using the upper (20%) and lower (2%) proportion of people with genotype 3 HCV for whom interferon therapy is suitable and who were expected to have sofosbuvir and ribavirin for 24 weeks as suggested by the ERG's clinical advisers. In people with genotype 3 treatment‑naive HCV for whom interferon therapy is suitable, assuming that 2% of people would have 24 weeks of sofosbuvir and ribavirin treatment compared with 24 weeks of peginterferon alfa and ribavirin treatment, the ICER was £22,385 per QALY gained, and £27,062 per QALY gained when 20% was used. In people with genotype 3 treatment‑experienced HCV for whom interferon therapy is suitable, assuming that 2% of people would have 24 weeks of sofosbuvir and ribavirin treatment compared with 24 weeks of peginterferon alfa and ribavirin treatment, the ICER was £14,467 per QALY gained and £19,890 per QALY gained when 20% was used.\nThe ERG reviewed the company's additional evidence. The ERG noted that the company had used most of the Committee's preferred base‑case assumptions (see section 3.64). It further noted that the company did not provide a sensitivity analysis exploring the impact on the ICER of using utility data collected in the clinical trials. The ERG carried out an exploratory analysis in which it used all of the Committee's preferred assumptions to calculate the ICERs for treatment for people with genotype 1 and 3 HCV and also carried out the exploratory scenario analyses requested by the Committee (see section 3.64). The ERG's exploratory analyses resulted in an ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks of £30,993 per QALY gained for people with treatment‑naive genotype 1 HCV, for whom interferon therapy is suitable. The ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with boceprevir plus peginterferon alfa and ribavirin was £12,172 per QALY gained and £18,704 per QALY gained compared with telaprevir plus peginterferon alfa and ribavirin. For people with genotype 1 treatment‑naive HCV, for whom interferon therapy is unsuitable, the base‑case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £58,113 per QALY gained.\nThe ERG stratified the exploratory ICERs by the presence or absence of cirrhosis. The ICER for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks was £38,460 per QALY gained for people without cirrhosis, and £12,891 for people with cirrhosis. The ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with boceprevir plus peginterferon alfa and ribavirin was £15,653 per QALY gained for people without cirrhosis and £2274 per QALY gained for people with cirrhosis. The ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with telaprevir plus peginterferon alfa and ribavirin was £24,509 per QALY gained for people without cirrhosis and £4680 per QALY gained for people with cirrhosis compared with telaprevir plus peginterferon alfa and ribavirin. For people with genotype 1 treatment‑naive HCV for whom interferon therapy is unsuitable, the base‑case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £58,118 per QALY gained for people without cirrhosis and £58,093 per QALY gained for people with cirrhosis.\nIn people for whom interferon therapy is suitable, with genotype 3 treatment‑naive HCV, the ERG's exploratory analyses resulted in an ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 24 weeks of £28,666 per QALY gained. In people with genotype 3 treatment‑naive HCV for whom interferon therapy is unsuitable, the base‑case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £26,611 per QALY gained. In people with genotype 3 treatment‑experienced HCV for whom interferon therapy is suitable, the ERG's exploratory analyses showed that the ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks was £16,979 per QALY gained. In people with genotype 3 treatment‑experienced HCV, for whom interferon therapy is unsuitable, the company's base‑case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £34,261 per QALY gained.\nWhen stratified by the presence or absence of cirrhosis, in people with genotype 3 treatment‑naive HCV for whom interferon therapy is suitable, the ERG's exploratory analyses resulted in an ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 24 weeks that was £46,036 per QALY gained for people without cirrhosis and £8318 per QALY gained for people with cirrhosis. In people with genotype 3 treatment‑naive HCV for whom interferon therapy is suitable, the ERG's exploratory analyses showed that the ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £31,851 per QALY gained in people with no cirrhosis, and £15,133 per QALY gained in people with cirrhosis. In people with treatment‑experienced genotype 3 HCV for whom interferon therapy is suitable, the ERG's exploratory analyses showed that the ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks was £20,694 per QALY gained in people without cirrhosis and £8093 per QALY gained in people with cirrhosis. In people with genotype 3 treatment‑experienced HCV for whom interferon therapy is unsuitable, the ERG's exploratory analyses showed that the ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment was £35,744 per QALY gained in people without cirrhosis and £29,704 per QALY gained in people with cirrhosis.\n\n## Additional analyses in genotype 4, 5 and 6 HCV\nDuring consultation several consultees, including the company, asked that the Committee reconsider the clinical and cost‑effectiveness evidence for people with genotype 4 HCV. The consultees indicated that people with genotype 4 HCV represent a group with a particularly high unmet need and minority ethnic groups represent a higher proportion of people who have genotype 4 HCV in the UK. Whereas genotype 4 HCV accounts for 5% of all HCV genotypes in the UK (but is more prevalent in the Middle East and Africa), the prevalence of genotype 4 in the UK is increasing because of migration, HIV co‑infection and intravenous drug use. Additionally, a consultee stated that the proportion of people with genotype 4 HCV who have haemophilia is higher than in other genotypes because of infection with blood products imported from abroad.\nIn order to fully explore the potential equality issues raised during consultation, additional evidence was requested from the company, which included HCV prevalence data by genotype and family origin, HIV co‑infection and haemophilia in the UK. The company provided NICE with evidence from a HCV genotype surveillance report commissioned by the company to be produced by Public Health England, which showed the proportion of people with genotype 1 or 3 HCV who were of white or white British family origin was 81% and 72% respectively, whereas minority ethnic groups represented 8% and 18% respectively. The proportion of people with genotypes 4, 5 and 6 HCV who were of white or white British family origin was 44%, 53% and 19%, respectively, whereas minority ethnic groups represented 39%, 28% and 74%, respectively (see table 5).\n\n## Table 5 Genotype by family origin\nHCV genotype\nWhite or white British (%)\nAsian or Asian British (%)\nBlack or black British (%)\nOther or mixed origin (%)\nUnknown (%)\nNon‑1\nDual\nHCV, hepatitis C virus\nThe company also provided genotype distribution data from the 2012 United Kingdom Haemophilia Centre Doctors' Organisation look‑back exercise, which reported a prevalence of 3% and 1% of HCV genotypes 4 and 5 respectively among UK HCV‑infected people with haemophilia. The proportion of people with haemophilia with genotypes 1, 2 and 3 HCV is 96%. Additionally, the company presented commercial‑in‑confidence evidence that a disproportionate number of people with HIV co‑infection have genotype 4 HCV compared with people without HIV co‑infection.\nThe Committee requested that the company submit a literature review of a range of sustained virological responses for peginterferon alfa and ribavirin to address uncertainty in the sustained virological responses in the comparator arm of the economic model. The company identified 7 studies reporting efficacy data for patients with genotype 4, 5 or 6 HCV in its systematic literature review. The company excluded all studies that recruited solely from Egypt, Africa, Asia or the Middle East because of documented differences in baseline characteristics and response to treatment. According to the company, only Manns et al. (2001) and Lindsay et al. (2001) provided combined data on genotypes 4, 5 and 6 HCV. Of these studies, Manns et al. included more patients (n=16) compared with Lindsay et al. (n=8). The company supported the use of Manns et al. with unpublished data from Imperial College London, which provides treatment for the largest numbers of people with genotype 4 HCV in England, suggesting that the sustained virological response of 50% from Manns et al. in people without cirrhosis was similar to the rate observed at Imperial College (49.5% in patients with genotype 4 having peginterferon alfa and ribavirin for 48 weeks). The company also calculated the sustained virological response for people with genotype 4, 5 or 6 HCV with cirrhosis to be 38.6% based on the relative difference in sustained virological response between people without cirrhosis and people with cirrhosis in the studies in genotype 1, 2 and 3 HCV.\nThe ERG did not agree that only studies that included combined genotypes 4, 5 and 6 HCV should be analysed, because this approach excluded some trials of genotype 4 HCV that have larger sample sizes. The ERG did its own rapid systematic literature review that identified 17 studies with sample sizes of 10 or more people with genotype 4 HCV. Ten of the studies took place in the Middle East (particularly Egypt) and 7 were from Europe (3 were randomised controlled studies, 4 were non‑randomised studies). The ERG calculated the overall weighted mean sustained virological response for the 4 well‑reported Middle Eastern studies out of the 10 and the 3 randomised controlled studies from the 7 European studies separately, resulting in a sustained virological response of 65.6% and 55.7%, respectively. When all 17 studies were combined with Manns et al. and Lindsay et al., the resulting weighted sustained virological response was 54.8%. The ERG's clinical advisers provided comment on the relevance of the Middle Eastern studies to NHS practice, stating that there is a significant difference between patients of Egyptian family origin in Europe and those in Egypt, because the average age and number of comorbidities is higher in most European studies, which translates into a reduced response rate.\nThe Committee also asked the company to provide a revised base‑case ICER for sofosbuvir plus peginterferon alfa and ribavirin treatment for 12 weeks compared with peginterferon alfa and ribavirin treatment for 48 weeks for people with genotype 4, 5 or 6 treatment‑naive HCV, using the Committee's preferred assumptions, which were using:\nthe Cardoso et al. transition probabilities from the sustained virological response with cirrhosis health state and the cirrhosis health state without a sustained virological response to the hepatocellular carcinoma health state\nthe utility increment after a sustained virological response from Vera‑Llonch et al. and\na men:women distribution ratio from Wright et al. The Committee also requested that the company show the impact of alternative sustained virological responses for peginterferon alfa and ribavirin alone for 48 weeks from the systematic review of published sources included in its initial submission to the Committee, together with a rationale for the preference of Manns et al. in the revised base‑case model over other sources.\nThe company used the sustained virological responses observed in NEUTRINO for the sofosbuvir plus peginterferon alfa and ribavirin arm of the model. The revised base‑case ICER for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa and ribavirin for 48 weeks (using the sustained virological response of 50% for peginterferon alfa and ribavirin from Manns et al.) increased from £26,797 per QALY gained in the original model to £27,505 per QALY gained in the revised base‑case model. The company had identified 7 studies, which included peginterferon alfa and ribavirin for 48 weeks in a treatment arm with sustained virological responses ranging from 33% (Zeuzem et al. 2005) to 77% (Fried et al. 2002). These sustained virological responses were not stratified by cirrhosis status, therefore the company applied the same sustained virological response for people without cirrhosis as for people with cirrhosis in the model. Sustained virological responses for sofosbuvir plus peginterferon alfa and ribavirin from the NEUTRINO study were stratified by cirrhosis status (100% for people without cirrhosis and 50% for people with cirrhosis). The resulting ICERs for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa and ribavirin for 48 weeks using the sustained virological response from Zeuzem et al. (33%) was £19,148 per QALY gained, and £244,387 per QALY gained when Fried et al. (77%) was used. The company also calculated the ICER for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa and ribavirin for 48 weeks using the sustained virological response of 97% for the combined cohort of people with and without cirrhosis in NEUTRINO. The resulting ICER was £47,394 per QALY gained.\nThe company provided a sensitivity analysis that used the transition probability from the compensated cirrhosis without a sustained virological response health state to hepatocellular carcinoma from Fattovich et al. (1997) rather than Cardoso et al., which increased the ICERs from £27,505 to £31,713 per QALY gained in the revised base case. When the sustained virological response for peginterferon alfa and ribavirin for 48 weeks from Zeuzem et al. and Fried et al. were used, the ICERs were £22,096 and £151,837 per QALY gained, respectively.\nThe ERG used the same revised base‑case assumptions as the company and applied the weighted sustained virological response from the 17 studies it identified, which resulted in a ICER of £37,820 per QALY gained and increased to £40,761 per QALY gained when the transition probability from Fattovich et al. was used for the transition from compensated cirrhosis without a sustained virological response to hepatocellular carcinoma. When the ERG used the weighted sustained virological response from the 10 Middle Eastern studies, the ICER for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa and ribavirin for 48 weeks was £69,181 per QALY gained, whereas the ICER using the 7 European studies in people with genotype 4 HCV only was £40,664 per QALY gained, and £39,109 per QALY gained when the 7 European studies were supplemented with the results from Manns et al. and Lindsay et al.\nFull details of all the evidence are in the committee papers.# Consideration of the evidence\nThe Appraisal Committee reviewed the data available on the clinical and cost effectiveness of sofosbuvir, having considered evidence on the nature of chronic hepatitis C and the value placed on the benefits of sofosbuvir by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.\nThe Committee heard from the clinical experts that chronic hepatitis C is often clinically asymptomatic, and that it is estimated to be undiagnosed in approximately 50% of people with the condition in England. However, when the condition progresses and cirrhosis occurs, it has a significant daily effect on the person with the virus and their carers. The Committee acknowledged the concerns of the patient experts that there is a stigma attached to having chronic hepatitis C, because of its link to injectable drug use. In addition, there is a reluctance to treat chronic hepatitis C in people who use injectable drugs, partly because of mistaken beliefs that they do not adhere to treatment and often become re‑infected. The Committee heard from the patient experts that the availability of sofosbuvir and other new treatments that are expected to become available over the next 5 years will encourage more people with chronic hepatitis C to seek diagnosis and treatment. In addition, people who use injectable drugs whose chronic hepatitis C is successfully treated may go on to address their drug use, leading to broader societal benefits that are not captured in the company's evidence submission. The Committee recognised the effect of chronic hepatitis C on the lives of people with the virus. It concluded that treatments that give a sustained virological response (which is considered equivalent to a cure), and that consequently help reduce the rate of HCV transmission and the stigma associated with having chronic hepatitis C, are of significant importance.\nThe Committee discussed the clinical management of chronic hepatitis C in adults. It heard from the clinical experts that different treatment options can have varied results, depending on the person's HCV genotype, level of liver damage, comorbidities and previous treatment history. For people with genotype 1 chronic hepatitis C, the Committee heard that boceprevir plus peginterferon alfa and ribavirin or telaprevir plus peginterferon alfa and ribavirin (see the NICE technology appraisal guidance on boceprevir for the treatment of genotype 1 chronic hepatitis C and telaprevir for the treatment of genotype 1 chronic hepatitis C) are commonly used, and that for people with genotypes 2 to 6 HCV, peginterferon alfa plus ribavirin or watchful waiting (closely monitoring the condition but not giving any treatment) are currently the main treatment options. The clinical experts highlighted that interferon‑based treatment can be associated with side effects such as chronic fatigue, neuropsychological effects and flu‑like symptoms, which can be a barrier to people wanting to start treatment, or taking their treatment for the recommended duration. The Committee also heard from the patient experts that interferon‑based treatment may cause chronic side effects, such as autoimmune responses and thyroid problems, which need additional long‑term management and therefore pose another barrier to people starting and completing treatment. The Committee acknowledged that the marketing authorisation for sofosbuvir offers people the option to have shortened courses of peginterferon alfa and ribavirin, or in some circumstances to have treatment without peginterferon alfa, thereby reducing potential adverse effects associated with interferon‑based therapy. The Committee agreed with the clinical experts and patient experts that the option to have a shortened course of interferon‑based therapy with sofosbuvir, or the possibility of sofosbuvir being used without peginterferon alfa in some circumstances, would make it a valuable treatment option for people with chronic hepatitis C.\nThe Committee acknowledged that the marketing authorisation in the UK for sofosbuvir licenses it to be used in adults with chronic hepatitis C in all genotypes. It heard from the clinical experts that in England, most people with chronic hepatitis C have genotypes 1 or 3 HCV (46% and 43% respectively), with genotype 1 HCV being associated with a poor response to antiviral therapy and an increased rate of progression to severe chronic liver disease. The Committee noted that the marketing authorisation also allows sofosbuvir to be used in people who have or have not had previous treatment for chronic hepatitis C. The Committee also noted that the marketing authorisation allows sofosbuvir in combination with ribavirin to be used in people with genotypes 1, 4, 5 or 6 HCV who could be considered interferon intolerant or ineligible and who are in urgent need of treatment. It heard from company representatives that people would be considered interferon intolerant or ineligible if interferon treatment was contraindicated (as described in the summary of product characteristics for peginterferon) or in people whose disease did not have an adequate response to previous interferon treatment. The Committee asked the clinicians and commissioners for a definition of who would be considered interferon intolerant or ineligible, but did not receive a clear response. The Committee heard from the clinical experts that sofosbuvir is an important new treatment that will address an unmet need, particularly in people who have previously been treated but did not have a sustained virological response, in people whose condition has relapsed, or in people who have become re‑infected after treatment. The Committee was aware that the marketing authorisation specifies that sofosbuvir treatment should be 'initiated and monitored by a physician experienced in the management of patients with chronic hepatitis C'. It agreed with comments received during consultation that treatment should be focused in specialist centres and that treatment decisions, such as determining whether someone is interferon intolerant or ineligible for interferon treatment, should be made preferably by a multidisciplinary team. The Committee concluded that most people with chronic hepatitis C are likely to have at least some benefit from adding sofosbuvir to their treatment regimen and that the condition should be treated in an appropriate setting, as specified in the sofosbuvir marketing authorisation.\n\n# Clinical effectiveness\nThe Committee considered the clinical effectiveness of sofosbuvir plus ribavirin, with or without peginterferon alfa, for people with genotypes 1 to 6 chronic hepatitis C. It noted the concerns of the Evidence Review Group (ERG) that because of the lack of head‑to‑head studies comparing sofosbuvir with current standard of care treatments, most of the evidence provided by the company did not directly address the decision problem. The Committee acknowledged that the company was able to provide evidence from only 1 head‑to‑head trial (FISSION, in people with genotype 2 or 3 treatment‑naive HCV, for whom interferon therapy is suitable; see sections 3.8–3.9) that was consistent with the decision problem. The Committee was aware that the direct comparison with standard of care treatment was further limited to people with genotype 2 HCV only because the marketing authorisation recommends 24 weeks of sofosbuvir and ribavirin treatment for people with genotype 3 HCV, but people with genotype 3 HCV in the FISSION study had 12 weeks of sofosbuvir and ribavirin. In addition, the Committee expressed concern about the robustness of the estimates of the clinical effectiveness of sofosbuvir across the different subgroups for whom it is licensed when stratified (grouped) by treatment history, presence or absence of cirrhosis, and interferon eligibility, given that most trials were single‑arm and open‑label with historical controls that only included relatively small patient numbers and provided short‑term data. The Committee heard from the clinical experts that the current standard of care has been used for many years in the UK, and has been supported by numerous trials; therefore it was not unreasonable to use historical controls. The clinical experts also commented that hepatitis C trials are often open label because some people realise they are taking an interferon‑based regimen, potentially making blinding difficult. The Committee was aware that the number of people with cirrhosis in the clinical trials was relatively small, although it reflected the proportion of people with cirrhosis seen in clinical practice, and the exclusion criteria meant that people who use injectable drugs were not included in any studies. The Committee acknowledged the limitations of carrying out trials for hepatitis C, and concluded that there was considerable uncertainty surrounding the evidence base presented by the company. Therefore the true magnitude of the effect of sofosbuvir in each subgroup could not be robustly estimated.\nThe Committee acknowledged that in the NEUTRINO trial, people with genotype 1 (89% of people in the trial), 4, 5 or 6 treatment‑naive HCV who had sofosbuvir plus peginterferon alfa and ribavirin had a high sustained virological response (91%) 12 weeks after treatment compared with the historical control of 60% that was presented by the company. The Committee concluded that sofosbuvir plus peginterferon alfa and ribavirin was clinically more effective than peginterferon alfa and ribavirin alone in inducing a sustained virological response in people with treatment‑naive genotype 1, 4, 5 or 6 HCV.\nThe Committee considered the clinical effectiveness of sofosbuvir plus peginterferon alfa and ribavirin in people with treatment‑experienced genotype 1, 4, 5 or 6 HCV. No trial data were available on the clinical effectiveness of sofosbuvir in people with these genotypes who had previously had treatment for HCV. The Committee heard from the clinical experts that there was no reason to expect a different response in treatment‑experienced HCV than in treatment‑naive HCV. The Committee also heard from clinical experts that it was unlikely that further studies of sofosbuvir plus peginterferon alfa and ribavirin in people with treatment‑experienced HCV would be started because new interferon‑free regimens are rapidly replacing older interferon‑based regimens. The Committee was aware of the evidence from the company that the US Food and Drug Administration had accepted that the increase in sustained virological response in people with genotype 1 treatment‑naive HCV from 50% to 89% in NEUTRINO (subsequently recalculated as 91%) represented an efficacy of 78% for sofosbuvir plus peginterferon alfa and ribavirin in those people who would not have a sustained virological response with peginterferon alfa and ribavirin alone (see section 3.69). The Committee also considered interim results from an ongoing open‑label, single‑arm study by Pol et al. (2013) on the efficacy of sofosbuvir plus peginterferon alfa and ribavirin in people with genotype 1 treatment‑experienced HCV, which the company provided during consultation. These interim data suggested that 74% of patients who did not previously have a sustained virological response with peginterferon alfa plus ribavirin plus another direct‑acting antiviral (ledipasvir or tegobuvir) had a sustained virological response 12 weeks after treatment with sofosbuvir plus peginterferon alfa and ribavirin. The Committee also considered that in the small numbers of people with genotype 4, 5 or 6 HCV in the NEUTRINO study (in people with treatment‑naive genotype 1, 4, 5 and 6 HCV), the sustained virological responses 12 weeks after sofosbuvir treatment were approximately 97%, which was similar to those in people with genotype 1 HCV (see section 3.3). The Committee concluded that although there was uncertainty about the robustness of the evidence base in people with HCV genotype 1, 4, 5 or 6 who have had HCV treatment before, there was sufficient evidence for the Committee to make a recommendation on the use of sofosbuvir in people with genotype 1, 4, 5 or 6 treatment‑experienced HCV.\nThe Committee discussed the design of the clinical trials for sofosbuvir plus ribavirin in people with genotype 2 and 3 HCV. It noted that the main evidence came from 4 trials (FISSION, , FUSION, , POSITRON and VALENCE . The Committee acknowledged that FISSION was the only trial with an active comparator (peginterferon alfa‑2a and ribavirin treatment for 24 weeks) but noted that it was an open‑label study, which was susceptible to the introduction of selection bias and that when broken down by genotype, treatment history, interferon eligibility and cirrhosis status, the results were based on small patient numbers. The Committee was also aware that sustained virological response in the combined study population (FISSION) was 67% in both the sofosbuvir plus ribavirin 12 week treatment arm and in the peginterferon alfa‑2a and ribavirin 24 week treatment arm. The Committee noted that when stratified by genotype, people with genotype 2 HCV had a higher sustained virological response with 12 weeks of sofosbuvir plus ribavirin (97%) than people having peginterferon alfa and ribavirin alone (78%). The Committee noted that people with genotype 3 HCV having 12 weeks of sofosbuvir plus ribavirin had a lower sustained virological response rate 12 weeks after treatment (56%) than people receiving peginterferon alfa and ribavirin alone for 24 weeks (63%). The Committee was aware that all 4 trials in people with genotype 2 and 3 HCV had small patient numbers in each stratified subgroup (by genotype, treatment history, interferon eligibility and cirrhosis) and different designs, and concluded that these factors introduced uncertainty around the clinical effectiveness of sofosbuvir. On balance, the Committee concluded that sofosbuvir plus ribavirin was clinically more effective than peginterferon alfa and ribavirin alone in inducing a sustained virological response at 12 weeks after treatment in people with genotype 2 HCV.\nThe Committee further considered the results of the VALENCE study, which showed that longer treatment with sofosbuvir plus ribavirin was needed for people with genotype 3 treatment‑naive HCV (24 weeks rather than 12 weeks) to obtain a comparable sustained virological response at 12 weeks after treatment to that seen in people with genotype 2 HCV (data not reported here; academic‑in‑confidence). This was also supported by the results of FISSION, which showed that the sustained virological response for 12 weeks treatment with sofosbuvir and ribavirin in people with genotype 3 HCV was consistently lower than that seen in people with genotype 3 HCV who had peginterferon alfa‑2a and ribavirin for 24 weeks (see section 3.9). The Committee also discussed the clinical effectiveness of sofosbuvir in people with genotype 2 and 3 treatment‑experienced HCV, noting that the evidence for this subgroup came from FUSION (which compared sofosbuvir plus ribavirin for 12 weeks with sofosbuvir and ribavirin for 16 weeks), and from subpopulations in VALENCE. The Committee noted that sustained virological response was consistently higher for people with genotype 2 HCV (86% and 94% in the 12 week and 16 week treatment groups in FUSION; 93% after 12 weeks treatment in VALENCE) than for people with genotype 3 HCV, who needed longer treatment with sofosbuvir and ribavirin (16 weeks and 24 weeks) for a similar response to be shown. The Committee noted that in the studies people with cirrhosis also generally had a lower response than those without cirrhosis (irrespective of genotype). The Committee considered that treatment with sofosbuvir plus ribavirin was likely to lead to a better sustained virological response in people with genotype 3 HCV compared with the current standard of care (24 weeks of peginterferon alfa and ribavirin treatment), but only when sofosbuvir plus ribavirin treatment was extended to 24 weeks. The Committee concluded that taking into account the limitations of the trial designs and the use of historical controls there was considerable uncertainty around the true magnitude of benefit of sofosbuvir plus ribavirin compared with peginterferon alfa and ribavirin for 24 weeks in people with genotype 3 HCV.\nThe Committee considered the available evidence for sofosbuvir plus peginterferon alfa and ribavirin in people with genotype 3 HCV. The Committee was aware that the European public assessment report for sofosbuvir stated that because peginterferon alfa and ribavirin alone had a higher historical efficacy in people with genotype 3 HCV than in people with genotype 1 HCV, it could be inferred that a similar improvement in efficacy seen in people with genotype 1 HCV would be expected in people with genotype 3 HCV when sofosbuvir was added to peginterferon alfa and ribavirin. This was supported by the relevant results from PROTON and ELECTRON, which showed that the sustained virological responses 12 weeks after the end of treatment were 90% and 100%, respectively in people with genotype 3 HCV. The Committee was aware that these results were from open‑label studies in small numbers of people, and that there was considerable uncertainty around the true magnitude of benefit of sofosbuvir plus peginterferon alfa and ribavirin in people with genotype 3 HCV. On balance, however, the Committee concluded that 12 weeks of sofosbuvir plus peginterferon alfa and ribavirin was clinically more effective than peginterferon alfa and ribavirin alone for 24 weeks in inducing a sustained virological response in people with genotype 3 treatment‑naive HCV.\nThe Committee considered the available evidence for sofosbuvir plus ribavirin in people co‑infected with chronic hepatitis C and HIV. It noted that the interim analysis presented in the company's original submission and the regulatory submission was from an ongoing open‑label study with sofosbuvir and ribavirin (PHOTON‑1), which included people with genotype 1, 2 or 3 HCV and HIV who had not had treatment for hepatitis C, and people with genotype 2 or 3 HCV and HIV who had been treated before. The Committee subsequently considered the evidence provided by the company during consultation from the 1910 study (Rodriguez‑Torres et al. ), which compared sofosbuvir plus peginterferon alfa and ribavirin treatment with peginterferon alfa and ribavirin alone in people with genotype 1 HCV and HIV. The Committee was aware that the interim results of both studies suggested that sustained virological responses in people with HCV and HIV‑co‑infection were similar to those seen in people with HCV mono‑infection. The Committee understood that the summary of product characteristics states that people with HCV and HIV co‑infection should have the same sofosbuvir treatment schedule as people with HCV mono‑infection, and concluded that this was appropriate.\nThe Committee considered the adverse reactions associated with sofosbuvir plus ribavirin with and without peginterferon alfa. It noted that the adverse events reported in the main sofosbuvir clinical studies (NEUTRINO, FISSION, FUSION, POSITRON and VALENCE) were generally consistent with those reported in other studies for hepatitis C treatments. It heard from the clinical experts that sofosbuvir is considered to have a better safety profile than peginterferon alfa and ribavirin, and most adverse events reported in the trials were likely to be related to treatment with peginterferon alfa and ribavirin rather than sofosbuvir. The Committee concluded that the adverse reactions associated with sofosbuvir plus ribavirin with or without peginterferon alfa were generally tolerable and that sofosbuvir was not likely to cause additional adverse reactions compared with existing treatment regimens.\nThe Committee discussed the company's mixed treatment comparison. It heard from the company that a network could not be formed for all the relevant populations and a comparison could be performed only for genotypes 1, 2 and 3 treatment‑naive HCV because of data limitations. Therefore, results from the mixed treatment comparison were not used to inform the economic model. The Committee noted that instead, the company adopted what they described as a conservative approach and used trial data that reported the highest sustained virological response for the comparators, including naive comparisons with boceprevir and telaprevir plus peginterferon alfa and ribavirin for people with genotype 1 HCV. The Committee agreed with the ERG's view that the company's mixed treatment comparison was not robust. Therefore the Committee concluded that it was reasonable for the company not to use the mixed treatment comparison to inform its cost‑effectiveness analyses.\n\n# Cost effectiveness\nThe Committee considered the company's original economic model provided in the company's submission, the assumptions underlying the values of the parameters, and the critique and exploratory analyses carried out by the ERG. The Committee also considered the revised base‑case model submitted by the company in response to the additional analyses requested by the Committee. The Committee noted that the company's model structure differed slightly from that used in previous technology appraisals for hepatitis C, in that people with mild and moderate chronic hepatitis C were considered collectively as a population without cirrhosis, and therefore the model distinguished only between people with and without cirrhosis. The Committee heard from the clinical experts that this approach was reasonable and consistent with how people are currently diagnosed in clinical practice. It heard from the clinical experts that previously, people had invasive liver biopsies and as a result their disease was classified as mild, moderate or severe. However, current practice involves the use of less invasive diagnostic tests that do not differentiate between mild and moderate disease and can distinguish only between cirrhosis and non‑cirrhosis. The Committee also noted that the company's model incorporated the assumption that all people who had cirrhosis were candidates for liver transplant, and that pre‑transplant patients were therefore included in the modelling presented. The Committee concluded the approach taken by the company was appropriate.\nThe Committee acknowledged that the ICERs from the company's original economic model were for treatment for a combined cohort of people with and without cirrhosis (hereafter referred to as the 'combined cohort'). The Committee heard from clinical experts that it was standard clinical practice for people with and without cirrhosis to be considered as separate subgroups, because cirrhosis affects a person's likelihood of a sustained virological response. The Committee considered individual ICERs presented by the company for each genotype by treatment history, interferon eligibility and cirrhosis status (where available) and noted that the ICERs were consistently much lower in the subgroups of people with cirrhosis than in the subgroups of people without cirrhosis. The Committee also noted that patient numbers underpinning the clinical evidence used in the economic model were very small for the groups of people with cirrhosis, and that the sustained virological responses were in some cases as high as in people without cirrhosis. The Committee heard from clinical experts that sustained virological responses were historically lower in people with cirrhosis across all HCV genotypes than in people without cirrhosis. In addition, the Committee was aware that the summary of product characteristics states that consideration should be given to extending sofosbuvir treatment from 12 to 24 weeks in people who have 1 or more factors historically associated with lower response rates to interferon‑based therapies and that 1 of the factors listed is cirrhosis. The Committee considered that the high sustained virological responses that were generated from the small numbers of patients in the subgroup of people with cirrhosis (which resulted in very low ICERs) in each stratified subgroup should be interpreted with caution. The Committee noted that the ICERs from the combined cohort appeared artificially low, considering that most of the group would not have cirrhosis. The Committee concluded that the consideration of the cost effectiveness of sofosbuvir for each genotype should take into consideration both the combined cohort ICER and also the estimated ICERs for treatment in people with and without cirrhosis.\nThe Committee acknowledged that, in response to consultation, the company presented a revised base‑case model for HCV genotypes 1, 3, 4, 5 and 6 that incorporated most of its preferred assumptions (see section 3.64). The company explained and justified deviations from the Committee's preferred assumptions, which were included in the revised model.\nThe Committee noted that the revised model included a transition probability from the sustained virological response cirrhotic health state to the hepatocellular carcinoma health state (0.0128) using data from Cardoso et al. as requested by the Committee. In addition, the company also updated the transition probability from the health state for people with cirrhosis who have not had a sustained virological response to the hepatocellular carcinoma health state (0.0631; also from Cardoso et al.) rather than using the transition probability estimate (0.014) from Fattovich et al. (1997) that was used in the original model. The Committee heard from the clinical experts that using both transition probabilities from the Cardoso et al. study also had face validity because it would allow the modelling of a relative reduction in the probability that a patient would progress to hepatocellular carcinoma after having a sustained virological response. The Committee also heard from the clinical experts that the Cardoso et al. evidence that a person with cirrhosis who has a sustained virological response is 4 to 5 times less likely to later have hepatocellular carcinoma is consistent with the progression to hepatocellular carcinoma seen in clinical practice. The Committee noted that the Cardoso et al. transition probabilities were based on a population whose baseline characteristics were closer to the population seen in clinical practice in England. However, the Committee also heard from clinical experts that exploring alternative sources for transition probabilities, such as Fattovich et al. was appropriate. The Committee concluded that although there is significant uncertainty about the absolute reduction in the probability of progression to hepatocellular carcinoma between the sustained virological response with cirrhosis health state and the health state of cirrhosis without a sustained virological response, Cardoso et al. was an acceptable source for transition probabilities for the company's revised base‑case model. However, the Committee also concluded that it was plausible that the transition probability for people without a sustained virological response may lie somewhere between the Cardoso et al. and Fattovich et al. estimates.\nThe Committee considered the impact of using alternative sustained virological responses for peginterferon alfa and ribavirin in genotype 1 HCV on the results from the revised economic model. The Committee noted that the company preferred the sustained virological responses for peginterferon alfa and ribavirin treatment in people with genotype 1 HCV from McHutchison et al. because it was a larger study and the baseline characteristics of patients were better matched to the patients in the pivotal NEUTRINO trial. It also noted that the ERG considered the estimates from Hadziyannis et al. (2004) to be more relevant because they were most generalisable to patients with HCV in England. This was because the study included people with the genotypes most relevant to the UK population, that is, genotypes 1 and 3 HCV. The Committee heard from the clinical experts that there is a wide variation in sustained virological response in clinical practice and that the baseline characteristics of patients included in each study differed. This had an impact on the absolute sustained virological responses in these studies. The clinical experts noted that it was important to consider a range of alternative sustained virological responses from the evidence base rather than arbitrarily choosing a single rate from a particular study. The Committee noted that the sensitivity analyses subsequently presented by the company showed that the ICERs for sofosbuvir plus peginterferon alfa and ribavirin compared with peginterferon alfa and ribavirin alone in people with genotype 1 treatment‑naive HCV were £25,000 per QALY gained using the estimates from Hadziyannis et al. compared with £17,500 per QALY gained using the estimates from McHutchison et al. On balance, the Committee concluded that the sustained virological responses from McHutchison et al. were an acceptable source for including in its base‑case model, but noted that the sustained virological responses could lie between those provided by the McHutchison and Hadziyannis data sets.\nThe Committee considered the cost of ribavirin used in the company's model. The Committee noted that the company used the cost of ribavirin from the BNF (June 2013) in the original model (Copegus; £246.65) and asked that the company explore the impact of using the price of generic ribavirin paid by the NHS (£42.05 based on the Department of Health Commercial Medicines Unit Electronic market information tool) which is available nationally through contracts negotiated by the NHS Commercial Medicines Unit. In response to consultation the company included the generic cost of ribavirin in its revised base‑case analysis, but noted that the Medicines and Healthcare products Regulatory Agency stated that generic ribavirin should only be used in combination with interferon alfa‑2b, which only has 3% of the market share in the UK. The Committee concluded that the generic cost of ribavirin had a small effect on the ICER as demonstrated by the ERG analysis, but that sensitivity analyses around the generic costs of comparator treatment were appropriate.\nThe Committee discussed the utility values used in the company's model. It acknowledged that health‑related quality of life was largely assessed in the clinical trials for sofosbuvir using the SF‑36 questionnaire and that none of the clinical trials collected data using the EQ‑5D quality‑of‑life measure. The Committee understood that the company obtained SF‑36 health‑related quality‑of‑life data at various time points, including 24 weeks after the end of treatment in some trials. The Committee appreciated that the company tried to be pragmatic in its approach to modelling the effects of treatment by applying a utility increment of 0.05 (from Wright et al.) after sustained virological response in the company's base‑case analysis. However, it asked that the company present a revised base‑case model that explored the use of different utility estimates including more up‑to‑date estimates from the literature such as Vera‑Llonch et al. (2013) and estimates from the pivotal clinical trials. The Committee noted that the company stated it was unable to incorporate the estimates from the pivotal clinical trials because the data were not available, but provided a revised base‑case model incorporating an alternative utility increment (0.041; Vera‑Llonch et al.) after a sustained virological response. The Committee noted that using this utility increment increased the company's base‑case ICERs slightly. The Committee concluded that although alternative utility estimates from the pivotal studies would have been preferred, using the utility increment from Vera‑Llonch et al. in its revised base case was acceptable.\nThe Committee discussed the discount rate used in the company's model and considered whether this appraisal met the criteria for using a non‑reference case discount rate for costs and health benefits that can be applied in situations when treatment restores people who would otherwise die or have a very severely impaired life to full or near full health, and when this is sustained over a very long period (normally at least 30 years), as described in NICE's guide to the methods of technology appraisal. The Committee noted that the company's base‑case analysis used a discount rate of 3.5% for costs and health benefits in line with the NICE reference case and that the deterministic sensitivity analysis presented by the company suggested that the ICERs were particularly sensitive to the discount rate used. The Committee heard from the clinical experts that a person who does not have cirrhosis and has a sustained virological response could be considered cured. However, the Committee was aware that no data are available beyond the follow‑up period from the trials; therefore evidence supporting the long‑term durability of a sustained virological response is lacking. The Committee also noted that people with cirrhosis who experience a sustained virological response would not have their health fully restored. Therefore, the Committee concluded that sofosbuvir did not meet the criteria for using non‑reference case discount rates, and agreed that the company's approach to using the standard discount rate of 3.5% was appropriate.\nThe Committee considered whether the cost effectiveness of sofosbuvir for treating hepatitis C was better assessed for the population as a whole (that is, using the 'global' ICERs presented by the company in response to consultation, which are weighted by genotype, treatment history and the presence or absence or cirrhosis, see section 3.66) or separately for each genotype. The Committee was unconvinced by the global ICER approach put forward by the company because the evidence from the clinical experts suggested that in clinical practice treatment is stratified by genotype, treatment history and other characteristics, including cirrhosis status. This is because the capacity to benefit from treatment for chronic hepatitis C differs depending on the patient's characteristics. The Committee therefore concluded that it was more appropriate to consider the clinical and cost effectiveness for each relevant subgroup of patients separately in the company's base‑case analyses.\n\n# Genotype 1\n\n## Treatment-naive, interferon eligible\nThe Committee considered the cost effectiveness of sofosbuvir plus peginterferon alfa and ribavirin for people with genotype 1 treatment‑naive HCV who are eligible for interferon treatment. The Committee noted that the ICER for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa and ribavirin alone for 48 weeks was less than £17,500 per QALY gained. The Committee noted that the ICERs for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with response‑guided treatment with boceprevir plus peginterferon alfa and ribavirin and telaprevir plus peginterferon alfa and ribavirin were £10,300 and £15,400 per QALY gained, respectively. The Committee noted that when stratified by the presence or absence of cirrhosis, the ICERs for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa and ribavirin for 48 weeks were £5400 and £25,200 per QALY gained, respectively. The ICERs for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with boceprevir plus peginterferon alfa, when stratified by the presence or absence of cirrhosis, were £2800 and £14,300 per QALY gained, respectively. The ICERs for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with telaprevir plus peginterferon alfa, when stratified by the presence or absence of cirrhosis, were £4200 and £22,300 per QALY gained, respectively. The Committee also considered the ERG's exploratory analyses (see section 3.76). The ERG's resulting ICER for the combined cohort for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa and ribavirin alone for 48 weeks was just over £30,000 per QALY gained. The Committee believed that this ICER represented the upper limit of what could be considered to be plausible, but that the ICERs for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with response‑guided boceprevir and telaprevir plus peginterferon alfa and ribavirin treatment, which are the standard of care in the NHS, were £12,200 and £18,700 per QALY gained. The Committee concluded that sofosbuvir plus peginterferon alfa and ribavirin was cost effective for people with treatment‑naive genotype 1 HCV.\n\n## Treatment-experienced, interferon eligible\nThe Committee considered the cost effectiveness of sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with standard of care in people with genotype 1 treatment‑experienced HCV for whom interferon is suitable. The Committee acknowledged the uncertainty in the ICER for the population who have treatment‑experienced HCV in the light of the lack of clinical evidence, but noted that there are very few treatment options for these patients, who have a high unmet need. The Committee noted that the estimate of sustained virological response in the treatment‑experienced population provided by the company was accepted by the European Medicines Agency and clinical experts. The Committee noted that the ICERs for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa and ribavirin for 48 weeks (£12,600 per QALY gained), boceprevir plus peginterferon alfa and ribavirin (£700 per QALY gained), and telaprevir plus peginterferon alfa and ribavirin (£8200 per QALY gained) for the combined cohort of people with and without cirrhosis could be considered cost effective although ICERs stratified by cirrhosis status were not available. The Committee considered that if the relative proportion of people with and without cirrhosis was similar to that observed in the group with treatment‑naive HCV, then it would be likely that the stratified ICERs for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa and ribavirin alone for 48 weeks would be cost effective for people with and without cirrhosis even when taking into account the assumptions in the ERG's exploratory analyses, which would increase the ICERs further. The Committee also noted that the stratified ICERs for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with response‑guided boceprevir and telaprevir plus peginterferon alfa and ribavirin treatment would be even lower for these groups, and that these 2 treatment regimens are the standard of care in the NHS. The Committee concluded that sofosbuvir plus peginterferon alfa and ribavirin is a cost‑effective treatment option for people with genotype 1 treatment‑experienced HCV who are eligible for interferon treatment.\n\n## Treatment-naive, interferon ineligible\nThe Committee considered the cost effectiveness of sofosbuvir plus ribavirin for 24 weeks compared with standard of care (no treatment) in people with genotype 1 treatment‑naive HCV for whom interferon is unsuitable. It noted that the ICER for sofosbuvir and ribavirin compared with no treatment for this population was £47,600 per QALY gained. In response to consultation, the company stated that although it is necessary to have options for this subgroup of patients for whom interferon treatment is unsuitable and who have a high unmet need, it is anticipated that the number of people in this group having 24 weeks of sofosbuvir plus ribavirin would be extremely low. The Committee also heard from the company that it was not expecting people with genotype 1 HCV who are interferon eligible to be given the option of the 24 week interferon‑free sofosbuvir regimen. The Committee concluded that although the number of people with genotype 1 treatment‑naive HCV for whom interferon is unsuitable is potentially small, the high ICER for sofosbuvir plus ribavirin alone compared with no treatment for this population does not represent a cost‑effective use of NHS resources and could not be recommended.\n\n## Treatment-experienced, intolerant to or ineligible for interferon treatment\nThe Committee considered the lack of evidence for sofosbuvir plus ribavirin for 24 weeks compared with the standard of care (no treatment) in the subgroup of people with genotype 1 treatment‑experienced HCV who are intolerant to or ineligible for interferon treatment. However, considering the Committee had accepted the ICERs generated using the sustained virological responses recognised by the US Food and Drug Administration (FDA) for the genotype 1 treatment‑experienced HCV population who are eligible for interferon, the Committee took a pragmatic view on how to establish an estimated ICER for this population. The starting point for the Committee was the ICER of £47,600 per QALY gained (that is the ICER for people with genotype 1 treatment‑naive HCV, for whom interferon is unsuitable). Assuming that the relative difference between the ICERs in the treatment‑naive and treatment‑experienced HCV groups seen in other genotypes also applies to genotype 1 HCV, the Committee would expect that the ICERs for the genotype 1 treatment‑experienced HCV group would likely be slightly lower than the ICER for people in the genotype 1 treatment‑naive HCV group. When stratified by the presence or absence of cirrhosis, the ICERs would be likely to increase in the subgroup without cirrhosis and decrease in the subgroup with cirrhosis, in a similar proportion to that seen in the subgroup of people with treatment‑naive genotype 1 HCV for whom interferon is unsuitable. However, the ICERs would still remain high. The Committee noted that if the assumptions used in the ERG's exploratory analyses were applied, the ICERs would increase in the combined cohort as well as in the subgroups with and without cirrhosis. The Committee was aware that people with genotype 1 treatment‑experienced HCV for whom interferon is unsuitable are a group with a high unmet need. However, the Committee concluded that based on the very uncertain evidence presented and the high ICERs, treatment with sofosbuvir plus ribavirin for 24 weeks does not represent a cost‑effective use of NHS resources for people with genotype 1 treatment‑experienced HCV who are intolerant to or ineligible for interferon treatment and therefore could not be recommended in this group.\n\n# Genotype 2\nThe Committee considered the cost effectiveness of sofosbuvir plus ribavirin compared with peginterferon alfa and ribavirin for 24 weeks in people with genotype 2 HCV who are eligible for interferon treatment, or no treatment in people who are intolerant or ineligible for treatment with interferon. The Committee noted that sofosbuvir plus peginterferon alfa and ribavirin does not have a marketing authorisation for treating genotype 2 HCV. The Committee noted that the ICER from the company's original base‑case model for sofosbuvir and ribavirin compared with peginterferon alfa and ribavirin alone was approximately £46,300 per QALY gained in people who are eligible for treatment with interferon and who have treatment‑naive HCV, and £12,500 per QALY gained in people who have treatment‑experienced HCV and are eligible for treatment with interferon. The ICER for sofosbuvir and ribavirin compared with no treatment for people who are intolerant to or ineligible for interferon was £8200 per QALY gained for people with treatment‑naive HCV, and £8600 per QALY gained for people with treatment‑experienced HCV. The Committee concluded that sofosbuvir plus ribavirin was not a cost‑effective use of NHS resources in adults with genotype 2 treatment‑naive HCV who are eligible for treatment with interferon. However, the Committee concluded that sofosbuvir plus ribavirin was a cost‑effective use of NHS resources for adults with genotype 2 HCV who are eligible for treatment with interferon and who have had treatment for HCV, and for adults with genotype 2 HCV who are intolerant or ineligible for interferon treatment, regardless of their treatment history.\n\n# Genotype 3\n\n## Treatment-naive, interferon eligible\nThe Committee considered the cost effectiveness of sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa and ribavirin for 48 weeks in people with genotype 3 treatment‑naive HCV who are eligible for treatment with interferon. The Committee noted from the company's revised base case that the combined cohort ICER (with and without cirrhosis) for sofosbuvir plus peginterferon alfa and ribavirin compared with peginterferon alfa and ribavirin alone for this population was approximately £21,900 per QALY gained. The Committee noted that when stratified by cirrhosis status, the ICER for people with treatment‑naive HCV without cirrhosis who are eligible for treatment with interferon was approximately £40,600 per QALY gained, whereas the ICER for people with cirrhosis was approximately £6600 per QALY gained. The Committee noted that the ICERs for the subgroups of patients with or without cirrhosis were highly uncertain due to the small patient numbers included in the studies. The Committee noted that the effect of using the combined cohort analysis, which includes a larger subgroup without cirrhosis and a small subgroup with cirrhosis, resulted in a combined cohort ICER that was artificially low (£21,900 per QALY gained). The Committee considered that despite this uncertainty there was more confidence around the ICER for the subgroup with cirrhosis because the treatment remained cost effective despite using a variety of assumptions including those suggested by the ERG in its exploratory analyses. The Committee also acknowledged that people with cirrhosis are in greater need of treatment than those without cirrhosis. Therefore, the Committee concluded that sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks could be considered a cost‑effective use of NHS resources in people with genotype 3 treatment‑naive HCV who are eligible for interferon treatment and who have cirrhosis, but it was not a cost‑effective use of NHS resources in people who do not have cirrhosis.\nThe Committee noted that the marketing authorisation for sofosbuvir allows 24 weeks dual therapy with sofosbuvir plus ribavirin as an alternative to 12 weeks with sofosbuvir plus peginterferon alfa and ribavirin for people with genotype 3 HCV who are eligible for treatment with interferon. The Committee considered the exploratory analyses carried out by the company, modelling the effect on the revised base‑case ICERs of varying the proportion of people with genotype 3 HCV receiving sofosbuvir plus ribavirin for 24 weeks in people eligible for treatment with interferon (see section 3.75). The Committee noted that the scenario analysis presented by the company, in which 100% of people with treatment‑naive genotype 3 HCV received sofosbuvir plus ribavirin for 24 weeks compared with peginterferon plus ribavirin for 24 weeks, resulted in an ICER of £47,000 per QALY gained. The ICER for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks treatment compared with peginterferon and ribavirin treatment for 24 weeks increased from approximately £21,900 per QALY gained to approximately £22,400 and £27,100 per QALY gained when it was assumed that 2% and 20% had sofosbuvir and ribavirin for 24 weeks treatment in the population with treatment‑naive HCV who are eligible for interferon. The Committee noted that when stratified by cirrhosis status, the revised base‑case ICER for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks treatment compared with peginterferon and ribavirin treatment for 24 weeks increased in the subgroup without cirrhosis to £41,700 and £51,300 per QALY gained when it was assumed that 2% and 20% had sofosbuvir and ribavirin in the treatment‑naive population. In the subgroup with cirrhosis, the ICER increased to £6800 and £8400 per QALY gained using the same assumptions. The Committee concluded that the duration of treatment with sofosbuvir had a considerable effect on the ICERs in people with genotype 3 HCV, although it heard from the company, clinical experts and commissioners that sofosbuvir and ribavirin treatment for 24 weeks would only be appropriate for people ineligible for interferon therapy.\n\n## Treatment-experienced, interferon eligible\nThe Committee considered the cost effectiveness of sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa and ribavirin for 48 weeks in people with genotype 3 treatment‑experienced HCV who are eligible for treatment with interferon. The Committee noted that the company's revised base‑case ICER for the combined cohort was £13,900 per QALY gained. When stratified by cirrhosis status, the ICER for people without cirrhosis was £18,600 per QALY gained, whereas the ICER for people with cirrhosis was £6300 per QALY gained. The Committee was aware that these ICERs were also uncertain, due to small patient numbers included in the studies, and that sustained virological responses were identical for people in the subgroups with and without cirrhosis, which is clinically unlikely due to the poorer sustained virological responses usually seen in people with cirrhosis. The Committee was willing to accept this uncertainty because the ICERs were within the range it could consider a technology might be cost‑effective in the group without cirrhosis and even lower in the group with cirrhosis. The ICERs remained in this range when the ERG's exploratory assumptions were used. The Committee acknowledged that this subgroup also has no further treatment options and can be considered to have a high unmet need. The Committee therefore concluded that sofosbuvir plus peginterferon alfa and ribavirin was a cost‑effective use of NHS resources in people with genotype 3 treatment‑experienced HCV who were eligible for interferon treatment.\nAs with the treatment‑naive, interferon‑eligible group with genotype 3 HCV, the Committee considered the exploratory analyses carried out by the company that modelled the effect on the revised base‑case ICERs of increasing the proportion of people with treatment‑experienced genotype 3 HCV receiving sofosbuvir plus ribavirin for 24 weeks (see section 3.75). The ICER for sofosbuvir plus ribavirin for 24 weeks compared with peginterferon plus ribavirin for 48 weeks in people with treatment‑experienced genotype 3 HCV who are eligible for interferon treatment increased to £48,300 per QALY gained. The ICER for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa and ribavirin for 48 weeks also increased for the population for whom interferon therapy is suitable and who had treatment‑experienced HCV, from approximately £13,900 per QALY gained to approximately £14,500 and £19,900 per QALY gained when it was assumed that 2% and 20% had sofosbuvir and ribavirin. The Committee concluded that the duration of treatment with sofosbuvir had a considerable effect on the ICERs in people with genotype 3 HCV, and it agreed with the company, clinical experts and commissioners that sofosbuvir and ribavirin treatment for 24 weeks would only be appropriate for people ineligible for interferon therapy.\n\n## Treatment-naive, interferon ineligible\nThe Committee considered the cost effectiveness of sofosbuvir and ribavirin for 24 weeks compared with no treatment in people with genotype 3 treatment‑naive HCV who are ineligible for treatment with interferon. The Committee noted that the company's revised base‑case ICER for this population was £21,000 per QALY gained, which was calculated based on sustained virological responses seen in VALENCE. The Committee noted that the VALENCE study was unblinded when treatment was extended for all people with genotype 3 HCV. Therefore it was of poor quality and open to potential bias. The Committee noted that when the population was stratified by cirrhosis status, the ICER for sofosbuvir plus ribavirin was £28,000 per QALY gained for people without cirrhosis (which increased to £32,000 per QALY gained using the ERG assumptions) and £10,500 per QALY gained for people with cirrhosis. The Committee concluded that given the uncertainty around the ICER in the group without cirrhosis and the possibility that the ICER may be over £32,000 per QALY gained, it could not recommend sofosbuvir plus ribavirin treatment in people with genotype 3 treatment‑naive HCV without cirrhosis who are ineligible for interferon treatment. Because the ICER in the subgroup of people with cirrhosis remained low (£15,100 per QALY gained), even when using the ERG's exploratory assumptions, the Committee concluded that sofosbuvir plus ribavirin is cost effective for people with genotype 3 treatment‑naive HCV who have cirrhosis.\n\n## Treatment-experienced, interferon ineligible\nThe Committee considered the cost effectiveness of sofosbuvir and ribavirin for 24 weeks compared with no treatment in people with treatment‑experienced genotype 3 HCV who are intolerant to or ineligible for treatment with interferon. The Committee considered that this group would represent a very small number of patients in the NHS. The Committee considered the company's revised base‑case ICER of approximately £27,500 per QALY gained for the combined cohort of people with and without cirrhosis. The Committee noted that this ICER was also based on the sustained virological response rates observed in VALENCE, a study that the Committee considered to be of low quality and open to potential bias (see sections 3.16 and 4.32). When the ICERs were stratified by cirrhosis status, the company's revised base‑case ICER for the subgroup without cirrhosis was £31,400 per QALY gained (£35,000 per QALY gained using the assumptions from the ERG exploratory analyses). Due to the uncertainty around the ICER and the possibility that the ICER was over £35,000 per QALY gained, the Committee concluded that sofosbuvir plus ribavirin was not a cost‑effective use of NHS resources in people with treatment‑experienced genotype 3 HCV without cirrhosis who are intolerant to or ineligible for interferon treatment. The Committee noted that the company's revised base‑case ICER for sofosbuvir plus ribavirin for 24 weeks compared with no treatment for people with cirrhosis was £19,200 per QALY gained (£29,700 per QALY gained when using the assumptions from the ERG exploratory analyses). The Committee considered the high unmet need of this subgroup for whom there are currently no other licensed treatment options. The Committee recognised the uncertainty in the evidence base for people with treatment‑experienced genotype 3 HCV who have cirrhosis and are intolerant to or ineligible for interferon. However, on balance, it concluded that it would be consistent with its other recommendations for people with genotype 3 HCV to recommend sofosbuvir plus ribavirin for 24 weeks for people with cirrhosis and that this could be considered a cost‑effective use of NHS resources, because the true ICER was likely to be between the company's revised base case and the ERG's exploratory estimates.\n\n# Genotypes 4, 5 and 6\n\n## Treatment-naive, interferon eligible\nThe Committee considered the company's original base‑case ICER for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa and ribavirin for 48 weeks of approximately £26,800 per QALY gained in people with genotype 4, 5 or 6 treatment‑naive HCV, for whom interferon is suitable. The Committee noted that the ICER was based on a naive comparison of the sustained virological responses 12 weeks after the end of treatment for sofosbuvir plus peginterferon alfa‑2a and ribavirin observed in NEUTRINO and the sustained virological responses 24 weeks after the end of treatment with peginterferon alfa‑2b and ribavirin observed in Manns et al. (2001). The Committee heard from clinical experts and the company that peginterferon alfa 2a and peginterferon alfa‑2b were assumed to be equally efficacious and that sustained virological response 24 weeks after the end of treatment was essentially equivalent to sustained virological response 12 weeks after the end of treatment. The Committee noted that of the 35 people with genotype 4, 5 or 6 in the NEUTRINO study, 100% of the 33 people without cirrhosis achieved a sustained virological response compared with 50% of the 2 people with cirrhosis. However in Manns et al., the subgroup without cirrhosis had a sustained virological response of 50% (as calculated by the company, based on the relative difference in sustained virological response between people without cirrhosis and people with cirrhosis in the studies in genotype 1, 2 and 3 HCV) and the subgroup with cirrhosis had a sustained virological response of 38.6%. The Committee noted that the difference in sustained virological responses between the sofosbuvir plus peginterferon alfa and ribavirin arm and the peginterferon alfa plus ribavirin alone arm of the model was a key driver of the ICER.\nDuring consultation, the company presented the Committee with additional analyses for people with genotype 4, 5 or 6 HCV, which included alternative sustained virological responses for peginterferon alfa plus ribavirin from studies identified in a systematic review of studies in genotypes 4, 5 and 6 HCV and the impact of using different sustained virological responses on the ICER. The Committee noted that the studies were exclusively European (because the company considered the patient characteristics to be more relevant to patients in the UK) whereas the ERG had considered studies from the Middle East and Egypt to be an important source of data because these studies included larger numbers of patients. The Committee noted that the sustained virological responses for peginterferon alfa plus ribavirin in the European studies ranged from 33% (Zeuzem et al. ) to 77% (Fried et al. ), which spanned the range of sustained virological responses seen in the studies identified by the ERG. The Committee considered the revised base‑case ICER of £27,500 per QALY gained presented by the company for sofosbuvir plus peginterferon alfa and ribavirin compared with peginterferon alfa and ribavirin (using the sustained virological responses from Manns et al. for the latter) in people with genotype 4, 5 or 6 HCV. The Committee noted that the company varied the sustained virological response for peginterferon alfa and ribavirin using Zeuzem et al. and Fried et al. but noted that sustained virological responses were not available by cirrhosis status. Therefore the company applied the same sustained virological response for people with and without cirrhosis. The ICERs for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa plus ribavirin for 48 weeks using Zeuzem et al. and Fried et al. were £19,148 and £244,387 per QALY gained, respectively. The Committee considered that a sustained virological response of 77% for 48 weeks of treatment with peginterferon alfa and ribavirin was improbable. The Committee considered the ERG's exploratory analyses, in which the sustained virological responses in the peginterferon alfa and ribavirin arm were based on a weighted average of the responses reported in the individual studies. The ERG used a sustained virological response of 54.8% from the European studies (which included the studies by Manns et al. and Lindsay et al.) which led to an ICER of approximately £39,100 per QALY gained. The Committee considered this to be the most relevant ICER because it was based on studies with populations that were most similar to patients in England and was generated using the Committee's preferred assumptions (see section 4.15). The Committee noted that the sustained virological responses for peginterferon alfa plus ribavirin for 48 weeks in people with genotype 4, 5 or 6 HCV were higher than those reported for people with genotype 1 HCV, providing indirect evidence that people with genotype 4 HCV are not more difficult to treat. The Committee concluded that the ICER of £39,100 per QALY gained for sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks compared with peginterferon alfa plus ribavirin for 48 weeks using the ERG's calculated sustained virological response was the most plausible, although there remained considerable uncertainty about the ICER, because of the small number of people included in the NEUTRINO study.\nThe Committee considered comments received during consultation that recommending sofosbuvir plus peginterferon alfa and ribavirin only for a proportion of people with genotype 1, 2 or 3 HCV, but not for anyone with genotype 4, 5 or 6 HCV could potentially be interpreted as indirect discrimination. It heard from consultees that this was because a larger proportion of minority ethnic groups, people with HIV co‑infection and haemophilia are represented in the genotype 4, 5 and 6 HCV population. In light of NICE's legal obligation to promote equality, the Committee considered the additional evidence provided by the company that included family origin by HCV genotype, and the prevalence of HIV and HCV co‑infection and HCV infection in people with haemophilia. The Committee noted that the family origin evidence was self‑reported (and could therefore not be verified), and used broad categories. The Committee therefore considered this evidence to be uncertain, although it noted the anecdotal evidence provided by other consultees that minority ethnic groups are more highly represented in the genotype 4, 5 and 6 HCV population. The Committee considered the commercial‑in‑confidence evidence presented by the company about the genotype distribution of HCV in people with HCV and HIV co‑infection and agreed that a disproportionate number of people had genotype 4 HCV and HIV co‑infection compared with the overall population of people with HCV in England. The Committee noted that the evidence presented by the company suggested that 96% of people with haemophilia and HCV had genotype 1, 2 or 3 HCV, and 4% had genotype 4 or 5 because no patients were identified with genotype 6 HCV and haemophilia. The Committee noted that the distribution of HCV genotypes in people with haemophilia presented by the company was actually similar to the overall population of people with HCV in England. The Committee concluded that there did not appear to be a disproportionate percentage of people with haemophilia who had genotype 4 HCV in England. The Committee noted that the ICERs for sofosbuvir for people with genotype 4, 5 or 6 HCV for the combined cohort (people with and without cirrhosis) were very high. However, it agreed that, in the light of evidence on the higher representation of minority ethnic groups and HIV co‑infection in these genotypes, further consideration should be given to whether anything could be done to remove or reduce the disproportionate impact for the protected groups.\nThe Committee noted that unlike genotype 1 HCV, people with genotype 4, 5 or 6 HCV currently only have peginterferon alfa and ribavirin for 48 weeks as a treatment option. The Committee considered that the people with the highest unmet need within this population are those with cirrhosis, because their disease is less likely to respond to treatment with peginterferon alfa and ribavirin for 48 weeks. Although the sustained virological response seen in people with genotype 4, 5 or 6 HCV with cirrhosis was 50% in NEUTRINO, the Committee noted that this was based on 2 patients; 1 who had a sustained virological response and 1 who did not. As with some of the other genotypes, the Committee used a pragmatic approach in estimating an ICER for sofosbuvir for the group of people with genotype 4, 5 or 6 with cirrhosis. Using the starting point for the ICER (calculated by the ERG) as £39,100 per QALY gained, the Committee considered whether the ICER for genotypes 4, 5 and 6 responded in a similar manner as for other genotypes, that is, whether it would be significantly lower for treatment in people with cirrhosis than in people without cirrhosis. The Committee considered that it is plausible that the ICER for treatment in people with genotypes 4, 5 or 6 treatment‑naive HCV with cirrhosis could be within the range that is normally accepted as being cost effective, that is between £20,000 and £30,000 per QALY gained, and that the ICER for treatment in people with genotypes 4, 5 or 6 treatment‑naive HCV without cirrhosis is likely to be greatly in excess of the £39,100 per QALY gained estimated by the ERG for the combined cohort. Therefore, taking into consideration the potential equality issues raised about genotypes 4, 5 and 6 HCV, the high unmet need and the lack of treatment options for people with cirrhosis, the Committee considered it was reasonable to conclude that sofosbuvir plus peginterferon alfa and ribavirin for treating people with genotype 4, 5 or 6 treatment‑naive HCV who have cirrhosis was a cost‑effective use of NHS resources.\n\n## Treatment-experienced, interferon eligible\nThe Committee considered cost‑effectiveness evidence presented for people with genotypes 4, 5 or 6 treatment‑experienced HCV, for whom interferon is suitable. The Committee noted that the company did not provide an ICER for treatment in this group and that an estimate for this ICER could only be based on the ICER in people who are eligible for interferon who have not had treatment before. The Committee acknowledged that there is even more uncertainty in the ICER for treatment in the population who have treatment‑experienced HCV in the light of the lack of clinical evidence, but noted that there are very few treatment options for these patients, who have an even higher unmet need than people who have never been treated before. Considering the uncertainty in the evidence, but also taking into consideration the potential equality issues raised for people with genotype 4, 5 or 6 HCV, the Committee took a pragmatic view on how to establish an estimated ICER for this population. The Committee noted that sofosbuvir plus peginterferon alfa and ribavirin was recommended for genotype 1 treatment‑experienced HCV on the basis of unmet need and approval from the FDA based on a sustained virological response that was calculated from the population who had not had treatment before. Therefore, the Committee concluded that a similar approach could be used for people with genotype 4, 5 and 6 treatment‑experienced HCV. Although sustained virological responses are typically lower in the treatment‑experienced populations, the costs associated with disease progression and a comparison with no treatment mean that the ICERs for sofosbuvir in treatment‑experienced people are consistently lower than the ICERs for sofosbuvir in people who have not had treatment. Using the starting point for the ICER (calculated by the ERG) as £39,100 per QALY gained for people with genotype 4, 5 or 6 treatment‑naive HCV, the Committee considered that it was plausible that the ICER in genotypes 4, 5 or 6 treatment‑experienced HCV with cirrhosis could also be within the range that is normally accepted as being cost effective, that is between £20,000 and £30,000 per QALY gained. The Committee concluded that for all these reasons, sofosbuvir plus peginterferon alfa and ribavirin for treating people with genotype 4, 5 or 6 treatment‑experienced HCV who have cirrhosis could be considered a cost‑effective use of NHS resources.\n\n## Interferon unsuitable\nThe Committee considered the group of people with genotype 4, 5 or 6 HCV, for whom interferon therapy is unsuitable. The Committee noted that the company did not provide an ICER for sofosbuvir plus ribavirin in this population. The starting point for the Committee was the only cost‑effectiveness evidence provided for this population, namely the ICER of £39,100 per QALY gained for people with genotype 4, 5 or 6 HCV, for whom interferon therapy is suitable. The Committee noted that the ICER for sofosbuvir plus ribavirin compared with no treatment in people with treatment‑naive genotype 1 HCV who were not eligible for interferon was more than double the ICER for sofosbuvir plus peginterferon and ribavirin compared with peginterferon and ribavirin in people who were interferon eligible. The Committee anticipated that the ICERs for sofosbuvir plus ribavirin in people with genotype 4, 5 or 6 HCV, for whom interferon therapy is unsuitable, would increase significantly due to the fact that treatment would be offered for 24 weeks instead of 12 weeks and this was likely to increase further using the ERG's exploratory assumptions. The Committee considered that, based on the lack of evidence provided for these genotypes, it was necessary to make a value judgment. Although people with genotype 4, 5 or 6 HCV represent a small proportion of the total HCV population in England, it is still an important group with a high unmet need. The Committee reflected on the quality of evidence and the level of uncertainty, in addition to the very high costs associated with sofosbuvir plus ribavirin treatment for 24 weeks. The Committee concluded that treatment with sofosbuvir plus ribavirin for 24 weeks was not a cost‑effective use of NHS resources and could not be recommended for adults with genotype 4, 5 or 6 HCV, for whom interferon therapy is not suitable.\nThe Committee noted the company presented separate economic analyses for people co‑infected with HCV and HIV based on interim results from the PHOTON‑1 study and the 1910 study. The Committee was aware the PHOTON‑1 study provided results for people with genotypes 1, 2 or 3 HCV treated for 12 or 24 weeks with sofosbuvir and ribavirin and the 1910 study provided results for people with genotypes 1 or 3 HCV treated with sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks. The Committee was aware that, other than incorporating higher transition probabilities from the non‑cirrhotic to the compensated cirrhosis state, the modelling did not differ for the mono‑infected and co‑infected populations. The Committee noted the ERG comment that there were differences in patient characteristics and outcomes that were not taken into account in the company's model. On balance, the Committee concluded that, based on the evidence presented and considered for this population, it was reasonable to include the group of people co‑infected with HCV and HIV in the recommendations for the mono‑infected group. However, the Committee agreed with the ERG that there were legitimate concerns about the modelling for the HIV and HCV co‑infected group, and that future economic analyses should be presented separately for this population.\nThe Committee considered the concern expressed in comments received during consultation that some inexperienced clinicians may want to offer sofosbuvir and ribavirin for 24 weeks to people with genotypes 1, 4, 5 or 6 HCV who are interferon eligible in order to avoid the possible adverse effects associated with interferon treatment. The Committee heard from the company that the sustained virological responses with sofosbuvir plus peginterferon alfa and ribavirin in these genotypes are superior to those achieved using sofosbuvir and ribavirin alone. It also heard from company representatives that sofosbuvir plus ribavirin alone was only licensed for people in urgent need of care with genotype 1, 4, 5 or 6 HCV in whom interferon was contraindicated (as described in the summary of product characteristics) or whose disease did not have an adequate response to interferon treatment. The company representatives agreed that sofosbuvir and ribavirin would be regarded as a second‑line option and the decision to use dual therapy should only be made by clinicians experienced in treating hepatitis C, preferably after discussion by a multidisciplinary team. However, the Committee concluded that the concerns expressed during consultation were no longer relevant in light of the Committee's decision that sofosbuvir, in combination with ribavirin, should not be recommended for treating adults with genotype 1, 4, 5 or 6 chronic hepatitis C who are interferon intolerant or ineligible (see sections 1.1 and 4.25, 4.26 and 4.39).\nThe Committee noted a comment received from a member of the public during the second consultation stating that it was potentially more cost effective to treat hepatitis C in people with haemophilia than people without haemophilia due to the large expense associated with treating haemophilia and the additional expenses due to monitoring liver damage in that group. The Committee noted that the clinical trials excluded patients with haemophilia and no clinical evidence or cost‑effectiveness analysis had been presented specifically for people with haemophilia and HCV. Therefore the Committee concluded that no evidence‑based decision or modelling would be possible, and therefore no separate recommendation could be made specifically for this patient group.\nThe Committee discussed comments from the patient experts indicating that in practice the availability of treatment for people with chronic hepatitis C who use injectable drugs was limited, which could represent a potential equality consideration. The Committee heard from the clinical experts that treatment for these people is considered on an individual basis because of concerns about safety and treatment adherence, but that clinicians would like to offer sofosbuvir to people using injectable drugs, taking into account any precautions in the summary of product characteristics. The Committee acknowledged that access to treatment for this patient group was an issue related to implementation and could not be addressed through technology appraisal recommendations. However, the Committee concluded that although people who use injectable drugs were not represented in the pivotal clinical trials for sofosbuvir, based on the current evidence available, there was no reason to deny them access to treatment; therefore any recommendations on the use of sofosbuvir would be irrespective of injectable drug use.\nThe Committee discussed whether sofosbuvir could be considered an innovative treatment, providing a step change in the treatment of chronic hepatitis C. The Committee agreed that sofosbuvir offers the possibility of shortened interferon‑based treatment regimens, or treatment without interferon therapy in some circumstances, which is particularly important and a major development in the current clinical management of chronic hepatitis C. The Committee therefore accepted that sofosbuvir is a valuable new therapy for treating chronic hepatitis C. The Committee agreed with the clinical experts and patient experts that there were other benefits to patients (such as relief of loss of cognitive ability in people with HCV) and public health benefits (such as reduced transmission of HCV) that were not captured in the QALY calculation and that, if taken into account, would decrease the ICERs.\nDuring consultation, although a number of consultees noted the urgent need for guidance on the use of sofosbuvir, a comment was also received from NHS England, who is currently responsible for the commissioning of hepatitis C treatment, that it would not be possible to implement the recommendations in this guidance within 3 months. The Committee were in agreement that there may be increased demand for treatment following positive recommendations, but were not presented with evidence on the likely magnitude of this and considered that some patients may prefer to wait for NICE guidance on other interferon‑free treatments for chronic hepatitis C before they seek treatment. The Committee highlighted that it would be reasonable for NICE to reflect on whether the standard 3‑month implementation period is appropriate. The Committee noted that consultees were interested in the relative cost effectiveness of sofosbuvir compared with other agents in guidance development (although this did not fall within the scope of this appraisal). It therefore concluded that a 1 year review date for the guidance would be appropriate.\n\n# Summary of Appraisal Committee's key conclusions\nTA330\nAppraisal title: Sofosbuvir for treating chronic hepatitis C\nSection\nKey conclusions\nGenotype 1\nThe Committee considered sofosbuvir plus ribavirin with or without peginterferon alpha to be clinically effective in people with genotype 1 treatment‑naive and experienced HCV. The Committee considered treatment with sofosbuvir plus peginterferon alfa and ribavirin compared with peginterferon alfa and ribavirin in people who were eligible for interferon treatment to be cost effective regardless of previous treatment (with an ICER of approximately £17,500 per QALY gained in treatment‑naive patients).The Committee also considered sofosbuvir plus peginterferon alfa and ribavirin to be cost effective compared with boceprevir plus peginterferon and ribavirin, and telaprevir in combination with peginterferon alfa and ribavirin (ICERs of approximately £10,300 and £15,400 per QALY gained respectively). The Committee considered sofosbuvir plus peginterferon alfa and ribavirin to be cost effective in people with treatment‑experienced HCV compared with peginterferon and ribavirin, boceprevir and ribavirin, and telaprevir and ribavirin with ICERs of approximately £12,600, £700 and £8200 per QALY gained respectively.\nSofosbuvir plus ribavirin was not recommended in people for whom interferon was unsuitable (regardless of previous treatment) because of the high ICER compared with standard care (no treatment), which was in excess of £47,600 per QALY gained in the combined population of people with and without cirrhosis.\nGenotype 2\nThe Committee considered sofosbuvir plus ribavirin to be clinically more effective than peginterferon alfa and ribavirin in people with genotype 2 HCV who were eligible for treatment with peginterferon alfa. Sofosbuvir plus ribavirin was not recommended in the group with treatment‑naive HCV because of the high ICER of £46,300 per QALY gained, but was recommended in people with treatment‑experienced HCV because of the ICER of £12,500 per QALY gained.\nThe Committee considered sofosbuvir plus ribavirin to be clinically effective and cost effective compared with no treatment in people for whom treatment with interferon was unsuitable regardless of treatment experience (with ICERs of approximately £8200 and £8600 per QALY gained respectively).\nGenotype 3\nThe Committee considered the extended treatment duration (24 weeks) of sofosbuvir plus with ribavirin to be clinically effective compared with peginterferon alfa and ribavirin. The Committee considered sofosbuvir plus peginterferon alfa and ribavirin to be cost effective in people with treatment‑naive HCV with cirrhosis (with an ICER of approximately £6600 per QALY gained) but not in people with treatment‑naive HCV without cirrhosis (with a high ICER of approximately £40,600 per QALY gained). Treatment was also recommended in people with treatment‑experienced HCV regardless of cirrhosis status with ICERs of below approximately £19,000 per QALY gained.\nThe Committee considered the cost effectiveness of sofosbuvir plus ribavirin to be acceptable in people with cirrhosis who were not eligible for peginterferon alfa regardless of previous treatment. The ICERs for sofosbuvir plus ribavirin were approximately £10,500 per QALY gained for treatment‑naive HCV and approximately £19,200 per QALY gained for treatment‑experienced HCV. The Committee did not consider sofosbuvir plus ribavirin to be cost effective in people without cirrhosis, with ICERs of approximately £28,000 and £31,400 per QALY gained in treatment‑naive and experienced patients respectively.\nGenotypes 4, 5 and 6\nThe Committee considered sofosbuvir plus ribavirin with or without peginterferon alfa to be clinically effective compared with peginterferon alfa and ribavirin in people with treatment‑naive and experienced HCV genotypes 4, 5 and 6.\nThe Committee did not consider sofosbuvir plus peginterferon alfa and ribavirin to be cost effective in people with genotype 4, 5 or 6 HCV without cirrhosis. The Committee noted that the ICER for sofosbuvir plus peginterferon alfa and ribavirin compared with peginterferon and ribavirin in the combined cohort of people with treatment‑naive genotype 4, 5 or 6 HCV was £39,100 per QALY gained. The Committee considered this to be the most relevant ICER because it was based on studies with populations that were most similar to patients in England and was generated using the Committee's preferred assumptions. The Committee considered that ICERs in the population with cirrhosis are consistently lower than in people without cirrhosis and that considering the high unmet need in the population of people with genotype 4, 5 and 6 with cirrhosis, the Committee could consider sofosbuvir plus peginterferon alpha and ribavirin to be cost effective in the treatment‑naive or experienced populations with ICERs that could be between £20,000 and £30,000 per QALY gained. In addition the Committee did not consider sofosbuvir plus ribavirin in people who were not eligible for interferon to be cost effective given the high degree of uncertainty.\nCurrent practice\nClinical need of patients, including the availability of alternative treatments\nThe Committee recognised the effect of chronic hepatitis C on the lives of people with the virus. It concluded that treatments that give a sustained virological response, and that consequently help reduce the rate of HCV transmission and the stigma associated with having chronic hepatitis C, are of significant importance.\nThe Committee was aware of the adverse effects of interferon‑based treatments. The Committee noted that the marketing authorisation for sofosbuvir offers people the option to receive shortened courses of peginterferon alfa and ribavirin, or in some circumstances to have treatment without peginterferon alfa, thereby reducing potential adverse effects with interferon‑based therapy.\nThe technology\nProposed benefits of the technology\nHow innovative is the technology in its potential to make a significant and substantial impact on health‑related benefits?\nThe Committee acknowledged that the marketing authorisation for sofosbuvir offers people the option to receive shortened courses of peginterferon alfa and ribavirin, or in some circumstances to have treatment without peginterferon alfa, thereby reducing potential adverse effects with interferon‑based therapy.\nClinical experts considered sofosbuvir to be an important new treatment which will address an unmet need, particularly in people who have previously been treated but did not have a sustained virological response, in people whose condition has relapsed, or in people who have become re‑infected after treatment. The Committee heard from the patient experts that the availability of sofosbuvir will encourage more people with hepatitis C to seek diagnosis and treatment.\nThe Committee accepted that sofosbuvir is a valuable new therapy. It agreed that there were other benefits (such as relief of loss of cognitive ability in people with HCV) and public health benefits (such as reduced transmission of HCV) that were not captured in the QALY calculation and that, if taken into account, would decrease the ICERs.\nWhat is the position of the treatment in the pathway of care for the condition?\nThe Committee concluded that most people with chronic hepatitis C are likely to have at least some benefit from adding sofosbuvir to their treatment regimen.\nAdverse reactions\nThe Committee concluded that the adverse reactions associated with sofosbuvir plus ribavirin with or without peginterferon alfa were generally tolerable and that sofosbuvir was not likely to cause additional adverse reactions compared with existing treatment regimens.\nEvidence for clinical effectiveness\nAvailability, nature and quality of evidence\nThe Committee acknowledged the limitations of carrying out trials for hepatitis C, and concluded that there was considerable uncertainty surrounding the evidence base presented by the company. Therefore the true magnitude of the effect of sofosbuvir in each subgroup could not be robustly estimated.\nThe Committee concluded that although there was uncertainty about the robustness of the evidence base in people with HCV genotype 1, 4, 5 and 6 who have had HCV treatment before, there was sufficient evidence for the Committee to make a recommendation on the use of sofosbuvir in people with genotype 1, 4, 5 or 6 treatment‑experienced HCV.\nThe Committee noted that the company provided evidence from only 1 head‑to‑head trial (FISSION, in people eligible for interferon with treatment‑naive genotype 2 or 3 HCV) that was consistent with the decision problem.\nThere were limited data for the subgroups with HCV and HIV co‑infection. However, interim results from 2 studies (PHOTON‑1 and 1910) suggested that the efficacy of sofosbuvir plus standard of care is similar to that reported for people with chronic hepatitis C mono‑infection.\nRelevance to general clinical practice in the NHS\nThe Committee was aware that the inclusion criteria for the sofosbuvir trials were broader than for earlier trials in hepatitis C; therefore there was good reason to expect that the people in the trials reflected those who are currently being treated in UK clinical practice.\nUncertainties generated by the evidence\nThe Committee acknowledged the limitations of carrying out trials for hepatitis C, and concluded that there was considerable uncertainty surrounding the evidence base presented by the company. Therefore the true magnitude of the effect of sofosbuvir in each subgroup could not be robustly estimated.\nThe Committee was aware that all 4 trials in people with genotype 2 and 3 HCV had small patient numbers and different designs, and concluded that these factors introduced uncertainty around the clinical effectiveness of sofosbuvir.\nThe Committee concluded that, due to the design of the trials in people with genotype 2 and 3 HCV and the use of historical controls there was uncertainty relating to the true magnitude of benefit of sofosbuvir‑containing regimens compared with standard of care therapies.\nAre there any clinically relevant subgroups for which there is evidence of differential effectiveness?\nThe Committee acknowledged that people with cirrhosis also generally had a lower response than those without cirrhosis (irrespective of genotype). The Committee considered that treatment with sofosbuvir plus ribavirin was likely to lead to a better sustained virological response in people with genotype 3 HCV compared with the current standard of care (24 weeks of peginterferon alfa and ribavirin treatment), but only when sofosbuvir plus ribavirin treatment was extended to 24 weeks. The Committee concluded that, taking into account the limitations of the trial designs and the use of historical controls, there was considerable uncertainty around the true magnitude of benefit of sofosbuvir treatment regimens compared with the standard of care.\nEstimate of the size of the clinical effectiveness including strength of supporting evidence\nThe Committee acknowledged that in the NEUTRINO trial, people with genotype 1 (89% of people in the trial), 4, 5 or 6 treatment‑naive HCV who had sofosbuvir plus peginterferon alfa and ribavirin had a high sustained virological response (91%) 12 weeks after treatment compared with the historical control of 60% that was presented by the company.\nThe Committee noted that sustained virological response was consistently higher for people with genotype 2 HCV (86% and 94% in the 12 week and 16 week treatment groups in FUSION; 93% after 12 weeks treatment in VALENCE) than for people with genotype 3 HCV, who needed longer treatment with sofosbuvir and ribavirin (16 weeks and 24 weeks) for a similar response to be shown.\nThe Committee agreed with the company and ERG's view that the mixed treatment comparison carried out by the company was not robust. Therefore it was reasonable for the company not to use it to inform its cost‑effectiveness analyses.\nEvidence for cost effectiveness\nAvailability and nature of evidence\nThe Committee noted that the company's model structure differed slightly from that used in previous technology appraisals for hepatitis C, in that people with mild and moderate chronic hepatitis C were considered collectively as a population without cirrhosis, and therefore the model distinguished only between people with and without cirrhosis.\nThe Committee acknowledged that, in response to consultation, the company presented a revised base‑case model for HCV genotypes 1, 3, 4, 5 and 6 that incorporated most of the Committee's preferred assumptions.\nUncertainties around and plausibility of assumptions and inputs in the economic model\nThe Committee concluded that although there is significant uncertainty about the absolute reduction in the probability of progression to hepatocellular carcinoma, it considered the Cardoso et.al. estimates to be acceptable. However the Committee also concluded that it was plausible that the transition probability for people without a sustained virological response may lie somewhere between the Cardoso et al. and Fattovich et al. estimates.\nThe Committee considered the use of alternative sustained virological responses for peginterferon alfa and ribavirin based on the results from the revised economic model. The clinical experts noted the heterogeneity of sustained virological response in clinical practice and noted that it was important to consider a range of alternative sustained virological responses from the evidence base rather than arbitrarily choosing a single rate from a particular study. On balance, the Committee concluded that the sustained virological responses from McHutchison et al. were an acceptable source for inclusion in its base‑case model, but noted that the sustained virological responses could lie between those provided by the McHutchison and Hadziyannis data sets.\nThe Committee considered the use of different utility values in the economic model, from literature and the clinical trials. The Committee concluded that although alternative utility estimates from the pivotal studies would have been preferred, using the utility increment from Vera‑Llonch et al. in its revised base case was acceptable.\nIncorporation of health‑related quality‑of‑life benefits and utility values\nHave any potential significant and substantial health‑related benefits been identified that were not included in the economic model, and how have they been considered?\nThe Committee understood that the company obtained SF‑36 health‑related quality of life data at various time points, including 24 weeks after the end of treatment for some trials. The Committee was aware the company had instead applied a utility increment of 0.05 after sustained virological response in the company's base‑case analysis from Wright et al. (2006), and presented a revised model exploring the impact of the Vera‑Llonch et al. (2013) estimates as requested by the Committee.\nThe Committee appreciated that the company tried to be pragmatic in its approach to modelling the effects of treatment, but considered that alternative utility estimates (which were requested by the Committee but not presented) from the pivotal studies to calculate the utility increment after a sustained virological response would have been preferred.\nThe Committee agreed that the possibility of shortened interferon‑based treatment regimens, or treatment without interferon therapy in some circumstances, that sofosbuvir offers is particularly important and a major development in the current clinical management of chronic hepatitis C.\nThe Committee concluded that sofosbuvir did not meet the criteria for differential discounting of health benefits, and agreed that the company's approach to using the standard discount rate of 3.5% was appropriate.\nThe Committee agreed that there were other benefits (such as relief of loss of cognitive ability in people with HCV) and public health benefits (such as reduced onward transmission of HCV) that were not captured in the QALY calculation and that, if taken into account, would decrease the ICERs.\nAre there specific groups of people for whom the technology is particularly cost effective?\nThe Committee concluded that sofosbuvir plus peginterferon alfa and ribavirin is cost effective in the following groups:\nPeople with genotype 1 HCV eligible for treatment with interferon regardless of treatment history.\nPeople with genotype 3 HCV with cirrhosis who have not been treated before.\nPeople with genotype 3 HCV who have been treated before (with or without cirrhosis).\nPeople with genotype 4, 5 and 6 HCV with cirrhosis (regardless of previous treatment experience).\nThe Committee concluded that sofosbuvir plus ribavirin is cost effective in the following groups:\nPeople with genotype 2 HCV who have not been previously treated, for whom interferon is unsuitable.\nPeople with genotype 2 HCV who have been treated before (regardless of interferon eligibility).\nPeople with genotype 3 HCV for whom interferon is unsuitable who have cirrhosis (regardless of treatment history).\nWhat are the key drivers of cost effectiveness?\nThe Committee concluded that the duration of treatment with sofosbuvir had a considerable effect on the ICERs in people with genotype 3 HCV.\nMost likely cost‑effectiveness estimate (given as an ICER)\nRefer to the key conclusions above.\nAdditional factors taken into account\nPatient access schemes (PPRS)\nNot applicable\nEnd‑of‑life considerations\nNot applicable\nEqualities considerations and social value judgements\nThe Committee heard from the clinical experts that treatment for people with chronic hepatitis C who use injectable drugs is considered on an individual basis because of concerns about safety and treatment adherence, but that clinicians would like to offer sofosbuvir to people using injectable drugs, taking into account any precautions in the summary of product characteristics. The Committee concluded that although people who use injectable drugs were not represented in the pivotal clinical trials for sofosbuvir, based on the current evidence available, there was no reason to deny them access to treatment; therefore any recommendations on the use of sofosbuvir would be irrespective of injectable drug use.\nThe Committee considered comments received during consultation which highlighted a potential equality issue from not recommending sofosbuvir for genotypes 4, 5 and 6 stating that there was a higher prevalence of ethnic minorities, people with haemophilia and HIV co‑infection particularly in people with genotype 4. After considering these comments, further evidence was considered necessary to address this potential indirect discrimination in the recommendations. Additional evidence was requested from the company for genotypes 4, 5 and 6 and considered by the Committee. The Committee also received a comment stating that it was potentially more cost effective to treat hepatitis C in people with haemophilia than people without haemophilia due to the expense associated with treating haemophilia and the additional expenses due to monitoring liver damage in people with haemophilia. No clinical evidence or cost‑effectiveness analysis was presented to the Committee specifically for people with haemophilia and HCV. The clinical trials excluded patients with haemophilia, so no evidence‑based decision or modelling would be possible for this patient group. However, the Committee agreed that, in the light of evidence on the higher representation of minority ethnic groups and HIV co‑infection in these genotypes, further consideration should be given to whether anything could be done to remove or reduce the disproportionate impact by the protected groups. Taking into consideration the potential equality issues raised about genotypes 4, 5 and 6 HCV, the high unmet need and the lack of treatment options for people with cirrhosis, the Committee considered it was reasonable to conclude that sofosbuvir plus peginterferon alfa and ribavirin for treating people with genotype 4, 5 or 6 treatment‑naive HCV who have cirrhosis was a cost‑effective use of NHS resources.\nPatient groups for haemophilia were included in the stakeholder matrix for this appraisal and were invited to participate; none chose to participate in the appraisal.\n, 4.41, 4.42, 4.44# Recommendations for further research\nThe Committee heard from the NHS commissioning expert that NHS England is intending to collect clinical data from people treated with the new generation of HCV treatments. The Committee agreed that such efforts should be supported so that clinical data collected in routine clinical practice can be used in any review of guidance on these treatments. It recommended that clinical data, including genotype and sustained virological response at 12 weeks, is collected for all people treated with sofosbuvir in the NHS.# Review of guidance\nNew treatments for chronic hepatitis C are awaiting marketing authorisation. According to clinical experts the approach to treating hepatitis C is likely to change rapidly next year because of the new technologies becoming available. The guidance on this technology will be considered for review within 1 year of publication, when other published guidance for hepatitis C is also reviewed. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators. Andrew Dillon Chief ExecutiveFebruary 2015# About this guidance\nNICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS.\nThis guidance was developed using the NICE single technology appraisal process.\nIt has been incorporated into the NICE pathway on liver conditions along with other related guidance and products.\nWe have produced information for the public explaining this guidance. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.\nNICE produces guidance, standards and information on commissioning and providing high‑quality healthcare, social care, and public health services. We have agreements to provide certain NICE services to Wales, Scotland and Northern Ireland. Decisions on how NICE guidance and other products apply in those countries are made by ministers in the Welsh government, Scottish government, and Northern Ireland Executive. NICE guidance or other products may include references to organisations or people responsible for commissioning or providing care that may be relevant only to England.\nYour responsibility\nThis guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.\nImplementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity and foster good relations. Nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.\nCopyright\n© National Institute for Health and Care Excellence 2015. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not‑for‑profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.\nISBN 978-1-4731-1009-0"}}},{"rowIdx":94,"cells":{"id":{"kind":"string","value":"5c8f362ae74d53be86095ea31ca56c71d7d429a1"},"source":{"kind":"string","value":"cdc"},"text":{"kind":"string","value":"This report is a revision o f the General Recomm endations on Im m unization a?id updates the 2 0 0 6 statement by the Advisory Committee on Im m unization Practices (ACIP) (CDC. General recommendations on im m unization: recommendations o f the Advisory Committee on Im m unization Practices , M M W R 2006;55, M M W R 1991;40); the assessment a n d feedback strategy to increase vaccination rates (CDC. Recommendations o f the Advisory Committee on Im m unization Practices: programmatic strategies to increase vaccination rates-assessment a nd feedback o f provider-based vaccination coverage information.#\nC D C , our planners, and our content experts wish to disclose that they have no financial interests or other relationships w ith the manufacturers o f commercial products, sup pliers o f commercial services, or commercial supporters. This report w ill not include any discussion o f the unlabeled use o f a product or a product under investigational use w ith the exception o f the follow ing situations:\n1. The nonsimultaneous administration o f yellow fever (YF) vaccine and inactivated vaccines. A tla n ta , G A 3 0 3 3 3 . Telephone: 4 0 4 -6 3 9 -1 9 5 8 ; Fax: 4 0 4 -6 3 9 -8 8 2 8 ; E -m a il: aok2@ cdc.gov.\nT h e guidance in this report will help vaccination provid ers to assess vaccine benefits and risks, use reco m m ended ad m inistratio n and storage practices, u n d erstan d the m ost effective strategies for ensuring that vaccination coverage in the p o pulatio n rem ains high, and com m unicate the im portance o f vaccination to reduce the effects o f vaccine-preventable disease. T hese recom m endations are in ten d ed for use in the U nited States; vaccine availability, use, and epidem iologic cir cum stances m ight differ in o th er countries and m ight w arrant different recom m endations.\n\n# M ethods\nT h e Advisory C om m ittee on Im m unization Practices (ACIP) General Recom mendations W ork G roup (GRW G) revises the General Recommendations on Im m unization every 3 to 5 years. Relevant topics are those identified by A C IP as topics that relate to all vaccines, including tim ing and spacing o f doses, vaccine administration, and vaccine storage and handling. N ew topics often are added w hen A C IP decides that previous A C IP state ments on general issues such as com bination vaccines, adolescent vaccination, or adult vaccination should be revised and combined with the General Recommendations on Immunization.\nT h e recom m endations in this rep o rt are based n o t only on available scientific evidence b u t also o n expertise th a t comes directly from a diverse group o f health-care providers and public h ealth officials. G R W G includes professionals from academ ic m ed icin e (pediatrics, fam ily practice, and pharm acy); international (C anada), federal, and state public health professionals; and a m em ber from the nongovernm ental Im m unization A ction C oalition. G R W G , w hich m et m onthly beginning June 2007, form ed subgroups o n the basis o f in ter est in topics such tim in g and spacing, vaccine adm inistration, and storage and handling. T hese subgroups also m et m onthly, conducted literature reviews, and co n trib u ted expert opinion on the need for revisions to specific language. In O ctober 2008, G R W G consulted A C IP to determ ine the best m echanism for approving the resulting docum ent. A C IP concluded that the docum ent could be approved and finalized increm entally w ith a final vote on the entire docum ent.\nRevisions to the following sections were approved through con sensus vote in O ctober 2008 (i.e., were approved as a part o f the entire docum ent and not through separate votes on each section): l)T im in g and Spacing oflm munobiologics; 2) Contraindications and Precautions; 3) Preventing and M anaging Adverse Reactions; 4) Reporting Vaccine Adverse Events; 5) the N ational Vaccine Injury Com pensation Program; and 6) Vaccine Administration. In February 2009, revisions were made to Storage and H andling o f Immunobiologies, and A C IP approved the section. In June 2009, A CIP voted to incorporate the contents of a 1999 ACIP statem ent on com bination vaccines. T he statem ent was revised by G RW G and the A C IP C om bination Vaccines W ork Group. A C IP also approved m inor changes to the section on Special Situations and the section on Vaccination Records. In O ctober 2009, ACIP voted to revise the entire General Recommendations on Immunization, which incorporated ACIP recommendations on adolescent vaccination (1996) and adult vaccination (1991) into the section on Vaccination Programs. Three votes were taken to approve various sections o f the docum ent, and one vote was taken to approve the entire docum ent. At this final meeting, ACIP also discussed concerns about the lack o f evidence that supports use o f antipyretics before or at the time o f vaccination for the prevention o f fever.\n\n# Tim ing and Spacing of Im m unobiologies\n\n# General Principles for Vaccine Scheduling\nO ptim al response to a vaccine depends on m ultiple factors, including the type o f vaccine, age o f the recipient, and im m une status o f the recipient. R ecom m endations for the age at w hich vaccines are adm inistered are influenced by age-specific risks for disease, age-specific risks for com plications, age-specific responses to vaccination, and potential interference w ith the im m une response by passively transferred m aternal antibodies. Vaccines are recom m ended for m em bers o f the youngest age group at risk for experiencing the disease for w hich efficacy and safety have been dem onstrated.\nC ertain products, including inactivated vaccines, toxoids, recombinant subunit vaccines, polysaccharide conjugate vaccines, and live vaccines, require >2 doses to elicit an adequate antibody response. Tetanus and diphtheria toxoids require booster doses to m aintain protective antibody concentrations. Unconjugated polysaccharide vaccines do not induce T-cell memory, and addi tional doses (although they elicit the same or a lower antibody concentration) might increase the level o f protection. Conjugation w ith a protein carrier improves the effectiveness o f polysaccharide vaccines by inducing T-lymphocyte-dependent im m unologic function. M any vaccines th at stim ulate b o th cell-m ediated im m unity and neutralizing antibodies (e.g., live, attenuated virus vaccines) usually can induce prolonged immunity, even if antibody titers decline over time (7). Subsequent exposure to such viruses usually results in a rapid anamnestic antibody response w ithout viremia.\nA pproxim ately 9 0 % -95% o f recipients o f a single dose o f certain live vaccines adm inistered by injection at the recom m ended age (i.e., measles, rubella, and yellow fever vaccines) develop protective antibodies, generally w ith in 14 days o f the dose. For varicella and m um ps vaccines, 8 0% -85% o f vaccinees are protected after a single dose. However, because a lim ited p roportion (5% -15% ) o f measles, m um ps, and rubella (M M R ) or varicella vaccinees fail to respond to 1 dose, a sec ond dose is recom m ended to provide another o p p o rtu n ity to develop im m u n ity (2). O f those w ho do n o t respond to the first dose o f M M R or varicella vaccine, 9 7 % -99% respond to a second dose (3,4).\nT h e Recommended Im m unization Schedules fo r Persons Aged 0 Through 18 Years and the Recommended A d u lt Im m unization Schedule are revised annually. Physicians and oth er health-care providers should ensure th at they are following the m ost upto-date schedules, w hich are available from C D C at h ttp :// www.cdc.gov/vaccines.\n\n# Spacing of Multiple Doses of the Same Antigen\nV accination providers should adhere as closely as possible to recom m ended vaccination schedules (Table 1). A dm inistration at recom m ended ages and in accordance w ith recom m ended intervals betw een doses o f m ultidose antigens provide optim al protection.\nA dm inistration o f doses o f a m ultidose vaccine using inter vals th at are shorter th an recom m ended m ight be necessary in certain circum stances, such as im pending international travel or w hen a person is behind schedule on vaccinations but needs rapid protection. In these situations, an accelerated schedule can be im plem ented using intervals betw een doses that are shorter than intervals recom m ended for rou tin e vaccination.\nT h e accelerated or m in im u m intervals and ages for schedul ing catch-up vaccinations are available at w w .cdc.gov/ vaccines. Vaccine doses should not be adm inistered at intervals less than these m in im u m intervals or at an age th at is younger th an the m in im u m age.- - D u rin g measles outbreaks, i f cases are occurring among infants aged 5 days earlier than the m inim um interval or age should n o t be counted as valid doses and should be repeated as age appropriate. T h e repeat dose should be spaced after the invalid dose by the recom m ended m inim um interval (Table 1). For example, if the first and second doses o f Haemophilus influenzae type b (H ib) were adm inistered only 14 days apart, the second dose w ould be invalid and need to be repeated because the m in im u m interval from dose 1 to dose 2 is 4 weeks. T h e repeat dose should be adm inistered >4 weeks after the invalid dose (in this case, the second). T h e repeat dose is counted as the valid second dose.\nIf the first dose in a series is given >5 days before the recom m ended m in im u m age, the dose should be repeated on or after the date w hen the child reaches at least the m in im u m age. If the vaccine is a live vaccine, ensuring that a m in im u m interval o f 28 days has elapsed from the invalid dose is recom m ended. For example, if the first dose o f varicella vaccine were inadver tently adm inistered at age 10 m onths, the repeat dose w ould be adm inistered no earlier than the child's first birthday (the m in im u m age for the first dose). I f the first dose o f varicella vaccine were adm inistered at age 11 m onths and 2 weeks, the repeat dose should be adm inistered no earlier than 4 weeks thereafter, w hich w ould occur after the first birthday.\nC ertain vaccines (e.g., adult tetanus and d iphtheria toxoids , pediatric diphtheria and tetanus toxoids ; and teta nus toxoid) produce increased rates o f local or systemic reac tions in certain recipients w hen adm inistered m ore frequently than recom m ended (6,/) . Careful record keeping, m aintenance In certain situations, local o r state requirem ents m ig h t m andate th a t doses o f selected vaccines be adm inistered o n o r after specific ages. F or example, a school e n try re quirem ent m ig h t n o t accept a dose o f M M R o r varicella vaccine ad m inistered before the c h ild 's firs t birthday. A C IP recommends th a t physicians and other health-care providers co m p ly w ith local o r state vaccination require m ents w hen scheduling and a d m inistering vaccines.\n-f patient histories, use o f im m u n izatio n inform ation systems (IISs), and adherence to recom m ended schedules can decrease the incidence o f such reactions w ith o u t adversely affecting im m u n ity\n\n# Sim ultaneous Administration\nS im u lta n e o u s a d m in is tra tio n o f vaccines is d efin ed as adm inistering m ore th an one vaccine on the same clinic day, at different anatom ic sites, and n o t com bined in the same syringe. Experim ental evidence and extensive clinical experi ence provide the scientific basis for adm inistering vaccines sim ultaneously Sim ultaneously adm inistering all vaccines for w hich a person is eligible at the tim e o f a visit increases the probability th a t a child, adolescent, or adult will be vaccinated fully by the appropriate age (8). A stu d y conducted during a measles outbreak dem onstrated th at approxim ately one third o f measles cases am o n g unvaccinated b u t vaccine-eligible preschool children m ight have been prevented if M M R had been adm inistered at the same visit w hen another vaccine was adm inistered (9). Sim ultaneous adm inistration also is criti cal w hen preparing for foreign travel and w hen a health-care provider is u ncertain th at a p atien t will retu rn for additional doses o f vaccine. W ith som e exceptions, sim ultaneously adm inistering the m ost w idely used live and inactivated vaccines has produced seroconversion rates and rates for adverse reactions sim ilar to those observed w hen the vaccines are adm inistered separately {10-13). R outine adm in istratio n o f all age-appropriate doses o f vaccines sim ultaneously is recom m ended for children for w hom no specific contraindications exist at the tim e o f the visit. M M R and varicella vaccine can be adm inistered sim ul taneously. Live, atten u ated influenza vaccine (LAIV) does n o t interfere w ith the im m u n e response to M M R or varicella vaccines adm inistered at the sam e visit. N o data exist about the im m u n o g e n ic ity o f oral T y21a ty p h o id vaccine w hen ad m inistered concurrently or w ith in 30 days o f live virus vac cines. In the absence o f such data, if typhoid vaccination is w arranted, adm inistration should n o t be delayed because o f recent adm inistration o f live, attenuated virus vaccines (14). Sim ultaneous ad m inistration of pneum ococcal polysaccharide vaccine (PPSV) and inactivated influenza vaccine elicits a satis factory antib o d y response w ith o u t increasing the incidence or severity o f adverse reactions (75). Sim ultaneous adm inistration o f PPSV and inactivated influenza vaccine is recom m ended for all persons for w h o m b o th vaccines are indicated. Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) and trivalent inactivated influenza vaccine (TIV) can be adm in istered sim ultaneously (76). H epatitis B vaccine adm inistered w ith yellow fever vaccine is as safe and im m unogenic as w hen these vaccines are adm inistered separately (77). Measles and yellow fever vaccines have been adm inistered safely at the same visit and w ith o u t reduction o f im m unogenicity o f either o f the com ponents (18,19).\nD epending on w hich vaccines are adm inistered during the first year o f life, a child m ight receive up to nine injections at the 12-through 1 5 -m o n th visit (M M R , varicella, H ib, pneum ococcal conjugate vaccine , pediatric diphtheria and tetanus toxoids and acellular pertussis , inacti vated poliovirus , hepatitis A, hepatitis B, and influenza vaccines). A lthough there is no exact lim it on the n u m b er o f injections, w ith a little flexibility, a provider can ensure that the prim ary series doses are given w ith o u t adm inistering too m any injections at each visit. To reduce the n um ber o f injec tions at the 12-through 15-m onth visit, the hepatitis B series and 3 doses o f IP V (20) can be adm inistered before the child's first birthday.\nT h ere are m any o ther examples o f ways the vaccination schedule provides flexibility. T h e m ajority o f children aged 1 year w'ho have received 2 H ib vaccine doses (polyribosylribitol phosphate-m eningococcal o u te r m em brane p ro te in ) or 3 H ib vaccine doses (PR P-tetanus ' P R P -T ) and 3 previous doses o f D TaP and P C V have protection against H ib, diphtheria, pertussis, tetanus, and pneum ococcus, w hich lasts th ro u g h o u t infancy (21,22). T h e third (P R P -O M P ) or fourth (PR P-T ) dose o f the H ib series and the fo u rth doses o f D TaP and P C V are critical in boosting antibody titer and ensuring continued protection (22-25). T he fourth dose o f D TaP is rec om m ended at age 15-18 m onths b u t m ay be adm inistered as early as age 12 m onths if 6 m onths have elapsed since the third dose and if there is concern that the child m ight n o t return by age 18 m onths (23). For infants at low risk for infection w ith hepatitis B virus (i.e., m other tested negative for hepatitis B surface antigen at the tim e o f delivery and is not in a high risk group), the hepatitis B series can be com pleted at any tim e for children aged 6-18 m onths (26). T h e m inim um age for adm inistration o f com bination vaccines is the oldest m inim um age for any o f the individual com ponents; the m ini m um interval betw een doses is equal to the greatest m inim um interval o f any o f the individual com ponents. W ith use o f the com bination H ib-hepatitis B vaccine, the m in im u m age o f adm inistration o f the final dose is 12 m onths because o f the m inim um age requirem ent for the last dose o f the H ib series (26). R ecom m ended spacing o f doses should be m aintained (Table 1).\n\n# Com bination Vaccines\n\n# Licensed Com bination Vaccines\nIn this report, a com b in atio n vaccine is defined as a p ro d uct containing com ponents that can be divided equally into indepen d en tly available routine vaccines. A dash ( -) between vaccine products indicates th at products are supplied in their final form by the m anufacturer and do n o t require mixing or reconstitution by the user. A slash ( / ) indicates th at the products m ust be mixed or reconstituted by the user. Seven com bination vaccines for w hich separate antigens or antigen com binations exist have been licensed by F D A since 1996 in the U nited States (Table 2) (39-45). In the future, com bina tion vaccines m ight include increasing num bers o f com ponents in different arrays to protect against these and other diseases. Situations m ight arise in w hich one com p o n en t o f a com bination vaccine is specifically preferred to another com po nen t in that same vaccine. Future research considerations for new ly licensed com bination vaccines should focus on safety o f doses th a t are n o t needed because a p atient is already vac cinated against the agents, w hether the com bination vaccine w ill im prove the tim eliness o f v accination, and p o ten tial reduced costs from disease prevention resulting from timely vaccination.\n\n# C om bination Vaccines and FDA Licensure\nO n ly com bination vaccines licensed by FD A should be used. V accination providers should not com bine separate vaccines into the same syringe to adm inister together unless m ixing is indicated for the p a tie n t's age and is explicitly specified on the FD A -approved p ro duct label inserts. O n ly two com bination vaccines (D T aP -IP V /H ib vaccine, m arketed as Pentacel, and D T aP /H ib , m arketed as T riH ibit) contain separate antigen com ponents for w hich FD A approves m ixing by the user. T h e safety, im m unogenicity, and effectiveness of unlicensed com binations are unknow n.\n\n# Interchangeability o f Form ulations\nF D A generally licenses a co m b in atio n vaccine based on studies dem onstrating th at the p ro d u ct's im m unogenicity (or efficacy) and safety are com parable or equivalent to m onova lent or com bination products licensed previously (46). FD A licensure also generally indicates that a com bination vaccine m ay be used interchangeably w ith m onovalent form ulations and o th e r co m b in atio n p ro d u cts w ith sim ilar c o m p o n en t antigens produced by the same m anufacturer to continue the vaccination series. For example, DTaP, D T aP /H ib , and future D T aP vaccines th at contain sim ilar acellular pertussis antigens from the same m anufacturer m ay be used interchangeably if licensed and indicated for the p atien t's age (45).\n\n# In terch an geability o f Com bination Vaccines from D ifferen t M anufacturers\nLicensure o f a vaccine by F D A does n o t necessarily indicate th at the vaccine is interchangeable w ith products from other m anufacturers. Such data are ascertained and interpreted more readily for diseases w ith know n correlates o f protective im m u nity (e.g., specific serologic m arkers). For diseases w ith o u t such surrogate laboratory m arkers, prelicensure field vaccine efficacy (phase III) trials or postlicensure surveillance generally are required to determ ine pro tectio n (47). A C IP prefers that doses o f vaccine in a series com e from the sam e m anufacturer; however, if this is n o t possible or if the m anufacturer of doses given previously is u n k now n, provid ers should adm inister the vaccine th at they have available.\n\n# Vaccine Supply\nA lth o u g h v accin atio n providers should stock sufficient quantities o f com bination and m onovalent vaccines needed to vaccinate children, adolescents, and adults against all diseases for w hich vaccines are recom m ended (20,28), all available types o r b rand-nam e products need n o t be stocked. Potential advantages o f stocking a lim ited n u m b er o f vaccines include 1) reducing confusion and p otential errors w hen staff m em bers m ust handle re d u n d a n t products and form ulations, 2) m inim izing waste w hen less com m only used products expire, 3) decreasing cold storage capacity requirem ents, and 4) m ini m izing adm inistrative costs related to accounting, purchasing, and handling.\n\n# Extra Doses o f Vaccine Antigens\nA dm inistering extra antigens contained in a com bination vaccine should be avoided in m ost situations. Using com bina tion vaccines containing certain antigens n o t indicated at the tim e o f adm in istratio n to a patient m ight be justified w hen 1) the extra antigen is n o t contraindicated, 2) products th at contain only the needed antigens are n o t readily available, and 3) potential benefits to the patient outw eigh the potential risk for adverse events associated w ith the extra antigens. An extra dose o f m any live-virus vaccines and H ib or hepatitis B vaccine has n o t been found to be harm ful (48). However, the risk for an adverse event m ight increase w hen extra doses are adm inistered at an earlier tim e than the recom m ended interval for certain vaccines (e.g., tetanus toxoid vaccines and PPSV) (16,24,49).\nA vaccination provider m ight n o t have vaccines available th at contain only the antigens needed as indicated by a child's vaccination history. Alternatively, although the indicated vac cines m ight be available, the provider m ight prefer to use a com bination vaccine to red uce the required n u m b er o f injec tions. In such cases, the benefits and risks o f adm inistering the com bination vaccine w ith an unneeded antigen should be care fully considered and discussed w ith the patient or parent. W h e n inactivated (i.e., killed), or particularly su b u n it vac cines (which are often adsorbed to alum inum -salt adjuvants), are adm inistered, the reactogenicity o f the vaccine m ust be considered in balancing the benefits and risks o f extra doses. Because clinical experience suggests low reactogenicity, an extra dose o f H ib or hepatitis B vaccine m ay be adm inistered as part o f a com bination vaccine to com plete a vaccination series for another com ponent o f the com bination. A dm inistration o f extra doses o f tetanus toxoid vaccines earlier than the recom m ended intervals can increase the risk for hypersensitivity reactions (16,24,50). Examples o f such vaccines include DTaP, D T aP /H ib, D T (for ch ild ren ),T d (for adolescents and adults), and T dap. Extra doses o f tetanus-toxoid-containing vaccines m ight be appropriate for certain patients, including for children w ho previously received D T o r T d vaccine and need protec tio n from pertussis (in D TaP or T dap) or for im m igrants w ith u ncertain vaccination histories.\n\n# C onjugate Vaccine Carrier Proteins\nC ertain carrier proteins in existing conjugated H ib vaccines also are used as com ponents o f other vaccines (e.g., p n eu m o coccal and m eningococcal vaccines) (51). Protein conjugates used in H ib conjugate vaccines produced in the U nited States include an outer m em brane protein com plex from Neisseria m eningitidis (in P R P -O M P ), and tetanus toxoid (in PR P-T ). Sim ultaneous adm inistration o f quadrivalent m eningococcal conjugate vaccine (M C V 4), PCV, and T d ap , all o f w hich con tain diphtheria toxoid, is n o t associated w ith reduced im m u nogenicity or an increase in local adverse events (24,51).\n\n# Nonsim ultaneous Administration\nT here is no evidence th at inactivated vaccines interfere w'ith the im m une response to o th er inactivated vaccines or to live vaccines. A ny inactivated vaccine can be adm inistered either sim ultaneously or at any tim e before or after a different inac tivated vaccine or live vaccine (Table 3).\nLim ited data are available regarding interference between live vaccines used in the U nited States. T h e im m une response to one live-virus vaccine m ight be im paired if adm inistered w ithin 28 days (i.e., 4 weeks) o f another live-virus vaccine (52,53). In a study conducted in two U.S. health m aintenance organiza tions, the risk for varicella vaccine failure (i.e., varicella d isease in a vaccinated person) am ong persons wrho received varicella vaccine w ith in 28 days o f M M R vaccination was threefold higher than am ong persons w ho received varicella vaccine >28 days after M M R vaccination (54). A no th er stu d y determ ined th at the response to yellow fever vaccine is n o t affected by m onovalent measles vaccine adm inistered 1-27 days earlier (18). T h e effect ofn o n sim u ltan eo u s adm inistration o f rubella, m um ps, varicella, and yellow fever vaccines is unknow n.\nTo m inim ize the potential risk for interference, injectable or nasally adm inistered live vaccines not adm inistered on the same day should be adm inistered >4 weeks apart (Table 3). If injectable or nasally adm inistered live vaccines are separated by 4 weeks after the last invalid dose. O ral vaccines (Ty21a typhoid vaccine and rotavirus) can be adm inistered sim ultaneously or at any interval before or after other live vaccines (injectable or intranasal) if indicated.\n\n# Spacing of Vaccines and Antibody-Containing Products\n\n# Live Vaccines\nTy21a typhoid, yellow fever, LAIV, zoster, and rotavirus vaccines m ay be adm inistered at any tim e before, concurrent w ith, o r after adm inistration o f any im m u n e globulin, hyper im m un e globulin, or intravenous im m une globulin (IGIV ) (55). Blood (e.g., w hole blood, packed red blood cells, and plasma) and oth er an tibody-containing blood products (e.g., im m un e globulin, h y p erim m u n e globulin, and IG IV ) can in hibit the im m u n e response to measles and rubella vaccines for >3 m onths. T h e effect o f blood and im m u n e globulin preparations on the response to m um ps and varicella vaccines is unknow n; however, commercial im m une globulin preparations contain antibodies to these viruses. Blood prod ucts available in the U nited States are unlikely to contain a substantial am ount of antib o d y to yellow fever vaccine virus. T h e length o f tim e th at interference w ith injectable live-virus vaccine (other th an yellow' fever) can persist after the antibody-containing product is a function of the am o u n t o f antigen-specific antib ody con tained in the p ro d u ct (56-58). T herefore, after an antibodycontaining prod u ct is received, live vaccines (other th an yellow fever, o ralT y 2 1 a typhoid, LAIV, zoster, and rotavirus) should be delayed u n til the passive antib o d y has degraded (Table 4). I f a dose o f injectable live-virus vaccine (other than yellow fever and zoster) is adm inistered after an an tibody-containing p roduct b u t at an interval shorter than recom m ended in this report, the vaccine dose should be repeated unless serologic testing is feasible and indicates a response to the vaccine. T h e repeat dose o r serologic testing should be perform ed after the interval indicated for the an tibody-containing p roduct (Table 5).\nA lthough passively acquired antibodies can interfere w ith the response to rubella vaccine, the low dose o f anti-R ho(D ) globulin adm inistered to p o stp artu m w om en has n o t been dem onstrated to reduce the response to the RA 27/3 strain rubella vaccine (59). Because o f the im portance o f rubella and varicella im m u n ity am ong w om en o f child-bearing age (4,60), the postpartum vaccination o f w om en w ithout evidence o f im m u n ity to rubella or varicella w ith M M R , varicella, or M M R V vaccines should n o t be delayed because o f receipt o f anti-R ho(D ) globulin or any other blood p ro d u ct during the last trim ester o f pregnancy or at delivery. T hese w om en should be vaccinated im m ediately after giving b irth and, if possible, tested >3 m onths later to ensure im m u n ity to rubella and, if appropriate, to measles (2).\nInterference m ight occur if adm inistration o f an antibodycontaining p ro d u ct becomes necessary after adm inistration o f M M R or varicella vaccines. Usually, vaccine virus replication and stim ulation o f im m u n ity occurs 1-2 weeks after vaccina tion. If the interval between adm inistration o f any o f these vac cines and subsequent adm inistration o f an antibody-containing product is <14 days, vaccination should be repeated after the recom m ended interval (Tables 4 and 5) unless serologic testing indicates a protective antibody response.\nA hum anized m ouse m onoclonal antibody p ro d u ct (palivizum ab) is available as prophylaxis for serious lower respiratory tract disease from respiratory syncytial virus am ong infants and young children. T his p ro d u ct contains only antibody to respi ratory syncytial virus and does n o t interfere w ith the im m une response to licensed live or inactivated vaccines.\n\n# Inactivated Vaccines\nA ntibody-containing products interact less w ith inactivated vaccines, toxoids, recom binant su bunit, and polysaccharide vaccines th an w ith live vaccines (61). Therefore, adm inistering inactivated vaccines and toxoids either sim ultaneously w ith or at any interval before or after receipt o f an antibody-containing p ro d u c t should n o t substantially im pair developm ent o f a protective antibody response (Table 4). T h e vaccine or toxoid and antibody preparation should be adm inistered at different sites using the standard recom m ended dose. Increasing the vaccine dose volum e or num ber o f vaccinations is n o t indicated or recom m ended.\n\n# Interchangeability of Single-Com ponent Vaccines from Different M anufacturers\nC ertain vaccines th at provide p ro tectio n from the same diseases are available from different m anufacturers, and these vaccines usually are n o t identical in antigen co n ten t or in am o u n t or m ethod o f form ulation. M anufacturers use differ ent production processes, and their products m ight contain different co ncentrations o f antigen per dose or a different stabilizer or preservative.\nAvailable data indicate th at infants w ho receive sequential doses o f different H ib conjugate, hepatitis B, and hepatitis A vaccines produce a satisfactory antib o d y response after a com plete prim ary series (62-65)-All brands o f H ib conju gate, hepatitis B ,î hepatitis A, rotavirus, and quadrivalent m eningococcal conjugate vaccines are interchangeable w ithin their respective series. I f different brands o f a particular vaccine require a different nu m b er o f doses for series com pletion (e.g., H ib and rotavirus vaccines) and a provider mixes brands, the higher n u m b er o f doses is recom m ended for series com pletion (e.g., 3 doses o f either rotavirus or H ib vaccines).\nLim ited data are available about the safety, im m unogenicity, and efficacy of using acellular pertussis (e.g., DTaP) vaccines from different m anufacturers for successive doses o f the per tussis series. D ata from one study indicate th at for the first 3 doses of the D TaP series, 1 -2 doses ofT ripedia (Sanofi Pasteur) followed by Infanrix (GlaxoSmithKline) for the rem aining dose (or doses) is com parable to 3 doses o fT rip ed ia w ith regard to im m unogenicity, as m easured by antibodies to diphtheria, tetanus, and pertussis toxoids, and filam entous hem agglutinin (66). However, in the absence o f a clear serologic correlate o f protectio n for pertussis, the relevance o f these im m unogenic ity data for protectio n against pertussis is unknow n. W h e n feasible, the same bran d o f D TaP vaccine should be used for all doses of the vaccination series. I f vaccination providers do n o t know or have available the type o f D TaP vaccine previ ously adm inistered to a child, any D TaP vaccine m ay be used to continue or com plete the series. For a child w ho needs 2 doses o f influenza vaccine (T IV or LAIV), it is preferable to use the sam e type o f vaccine for both doses. However, if the child is eligible for either T IV or LAIV, and the type o f vaccine used for the first dose is n o t available, either vaccine can be used for the second dose. For vaccines in general, vaccination should n o t be deferred because the brand used for previous doses is n o t available or is u n k n o w n (23,67).\n\n# Lapsed Vaccination Schedule\nV accination providers should adm inister vaccines as close to the recom m ended intervals as possible. However, intervals betw een doses th at are longer than recom m ended typically do n o t reduce final antibody concentrations, although protection m ight n o t be attained until the recom m ended num ber o f doses has been adm inistered. W ith exception o f oral typhoid vaccine, an in terru p tio n in the vaccination schedule does n o t require restarting the entire series o f a vaccine or toxoid or addition o f extra doses.\n\n# Unknown or Uncertain Vaccination Status\nV accination providers frequently encounter persons w ho do n o t have adequate d o cum entation o f vaccinations. W ith the exception o f influenza vaccine and PPSV, providers should only accept w ritten, dated records as evidence o f vaccination; self-reported doses o f influenza vaccine and PPSV are accept able (49,68). A lthough vaccinations should n o t be postponed if records cannot be found, an attem pt to locate missing records should be m ade by contacting previous health-care providers, reviewing state or local IISs, and searching for a personally held record. If records cannot be located w ithin a reasonable tim e, these persons should be considered susceptible and started on the age-appropriate vaccination sched ule. Serologic testing for im m u n ity is an alternative to vaccination for certain antigens (e.g., measles, rubella, hepatitis A, and tetanus). However, com m ercial serologic testing m ight n o t always be sufficiently sensitive o r standardized for detectio n o f vaccine-induced im m unity (with the exception o f hepatitis B vaccination at 1-2 m onths after the final dose), and research laboratory testing m ight not be readily available.\n\n# Contraindications and Precautions\nC ontraindications and precautions to vaccination are con ditions under w hich vaccines should n o t or likely should not be adm inistered. Because the m ajority o f contraindications and precautions are tem porary, vaccinations often can be adm inistered later if one or m ore exist. A con traindication is a condition in a recipient th at increases the risk for a serious adverse reaction. A vaccine should n o t be adm inistered w hen a c o n tra in d ica tio n is present; for exam ple, M M R vaccine should n o t be adm inistered to severely im m unocom prom ised persons. In contrast, certain conditions are com m only misperceived as contraindications (i.e., are n o t valid reasons to defer vaccination).\nN ational standards for pediatric vaccination practices have been established and include descriptions o f valid contraindica tions and precautions to vaccination. Persons w ho adm inister vaccines sh o u ld screen p atien ts for c o n train d icatio n s and p recautions to the vaccine before each dose o f vaccine is adm inistered (Table 6). Screening is facilitated by consistent use o f screening questionnaires, w hich are available from certain sta te v a c c in a tio n p ro g ram s a n d o th e r so u rces (e.g., th e Im m unization Action Coalition, w w .im m unize.org).\nT h e only co n train d icatio n applicable to all vaccines is a history o f a severe allergic reaction (i.e., anaphylaxis) after a previous dose o f vaccine or to a vaccine co m p o n en t (unless the recipient has been desensitized; see Special Situations section). In addition, severely im m uno co m p ro m ised persons generally should n o t receive live vaccines. C hild ren w ho experienced encephalopathy w ith in 7 days after adm inistration o f a pre vious dose o f d ip h th eria and tetanus toxoids and whole-cell pertussis vaccine (D T P ), DTaP, or T d ap n o t attributable to another identifiable cause should n o t receive additional doses of a vaccine th a t contains pertussis. Because of the theoreti cal risk to the fetus, w om en know n to be p regnant generally should n o t receive live, attenuated virus vaccines (see Special Situations section).\nA precaution is a condition in a recipient that m ight increase the risk for a serious adverse reaction or that m ight com prom ise the ability o f the vaccine to produce im m u n ity (e.g., adm in istering measles vaccine to a person w ith passive im m u n ity to measles from a blood transfusion or adm inistering influenza vaccine to som eone w ith a history o f G uillain-Barre syndrom e w ithin 6 weeks o f a previous influenza vaccination). A person m ight experience a m ore severe reaction to the vaccine than w ould have otherw ise been expected; however, the risk for this happening is less than the risk expected w ith a contraindication. In general, vaccinations should be deferred w hen a precaution is present. However, a vaccination m ight be indicated in the presence o f a p recaution if the benefit o f pro tectio n from the vaccine outweighs the risk for an adverse reaction. For example a dose o f D T aP should be considered for a person in a com m u n ity w ith a pertussis outbreak even if th at person previously developed G uillain-B arre syndrom e after a dose.\nT h e presence o f a m oderate or severe acute illness w ith or w ith o u t a fever is a precaution to adm inistration of all vaccines (Table 6). A personal or family history o f seizures is a precaution for M M R V vaccination. A recent study found an increased risk for febrile seizures in children w ho receive M M R V com pared w ith M M R and varicella vaccine (35).\nClinicians or other health-care providers m ight misperceive certain conditions or circumstances as valid contraindications or precautions to vaccination when they actually do not preclude vaccination (Table 7). These m isperceptions result in missed opportunities to administer recom m ended vaccines (69). Among the m ost com m on conditions mistakenly considered to be con traindications are diarrhea, m inor upper respiratory tract illnesses (including otitis media) w ith or w ithout fever, mild to moderate local reactions to a previous dose o f vaccine, current antimicrobial therapy, and being in the convalescent phase o f an acute illness. Routine physical exam inations and procedures (e.g., measur ing tem peratures) are n o t prerequisites for vaccinating persons w ho appear to be healthy. T h e provider should ask the parent or guardian if the child is ill. I f the child has a m oderate or severe illness, the vaccination should be postponed.\n\n# Preventing and M anaging\nAdverse R eactions\n\n# Benefit and Risk Com munication\nParents, guardians, legal representatives, and adolescent and adult patients should be inform ed about the benefits of and risks from vaccines in language th at is culturally sensitive and at an appropriate educational level. O p p o rtu n ity for questions should be provided before each vaccination. D iscussion o f the benefits o f and risks from vaccination is sound medical practice and is required by law.\nT h e N atio n al C h ild h o o d Vaccine In ju ry A ct o f 1 9 8 6 : : requires th at vaccine inform ation m aterials be developed for each vaccine covered by the act. T hese m aterials, know n as vaccine inform ation statem ents (VI Ss), m ust be provided by all public and private vaccination providers each tim e a vaccine is adm inistered. Copies ofV ISs are available from state health authorities responsible for vaccination and from C D C (h ttp :// www.cdc.gov/vaccines). Translations o fV IS s into languages o th er th an English are available from certain state vaccination programs and from the Im m unization A ction C oalition website ( w w .im m unize.org). T h e act does n o t require th at a signature be obtained; however, d o cu m en tatio n o f consent m ight be recom m ended or required by certain state or local h ealth authorities or school authorities. C ertain parents or patients question the need for or safety o f vaccinations and w ant to discuss the risks from and benefits o f certain vaccines. Some refuse certain vaccines or reject all vaccinations for personal or religious reasons. H aving a basic understanding of how patients and parents o f patients view vac cine risk and developing effective approaches to address vaccine safety concerns are im perative for vaccination providers.\nEach person understands and reacts to vaccine inform ation on the basis o f different factors, including previous experience, education, personal values, m eth o d o f data presentation, per ceptions o f the risk for disease and perceived ability to control these risks, and risk preference. Increasingly, decisions about vaccination are based o n inaccurate inform ation about risk provided by the m edia and certain websites. W ebsites and other sources o f vaccine info rm atio n m ight be inaccurate or incom plete. H ealth-care providers can be a pivotal source o f science-based credible inform ation by discussing w ith parents and patients the risks from and benefits o f vaccines, w hich helps patients m ake inform ed decisions. W h e n a parent or p atien t initiates a discussion about a per ceived vaccine adverse reaction, the health-care provider should discuss the specific concerns and provide factual inform ation, using appropriate language. Effective, em pathetic vaccine risk com m u n icatio n is essential in responding to m isinform ation and concerns, w'ith health-care providers recognizing that risk assessment and decision-making can be difficult and confusing. C ertain vaccines m ight be acceptable to a parent who is resistant to other vaccines. This partial acceptance can be used to facilitate additional communication. T heir concerns can be addressed using the VIS and offering other resource materials (e.g., vaccination inform ation from C D C : ).\nT h e A m erican A cadem y o f Pediatrics (AAP) does n o t rec om m en d th at providers exclude from their practice patients whose parents or guardians question or refuse vaccination. A lim ited nu m b er o f providers m ight exclude patients on this basis; however, an effective public health strategy is to identify com m on ground and discuss measures that need to be followed if the decision is to defer vaccination. H ealth-care providers should reinforce key p o in ts ab o u t each vaccine, including safety, and emphasize risks for disease am ong unvaccinated children. Parents should be advised o f state laws regarding entry to schools or child-care facilities, w hich m ight require th at unvaccinated children be excluded from the facility d u r ing outbreaks. T hese discussions should be docum ented in the patient's medical record, including the refusal to receive certain vaccines (i.e., inform ed refusal).\n\n# Preventing Adverse Reactions\nVaccines are intended to produce active im m u n ity to spe cific antigens. A n adverse reaction is an undesirable side effect th at occurs after a vaccination. Vaccine adverse reactions are classified as 1) local, 2) system ic, or 3) allergic (additional inform ation available at w w .fda.gov). Local reactions (e.g., redness) are usually the least severe and m ost frequent. Systemic reactions (e.g., fever) occur less frequently th an local reactions, and severe allergic reactions (e.g., anaphylaxis) are the least frequent reactions. Severe adverse reactions are rare.\nSyncope (vasovagal or vasodepressor reaction) can occur after vaccination and is m ost com m on am ong adolescents and young adults. In 2005, the Vaccine Adverse Event R eporting System (VAERS) began detecting a trend o f increasing syncope reports th at coincided w ith the licensure o f three vaccines for adolescents: h u m an papillom avirus (H PV ), M C V 4, and T dap (77). O f particular concern am ong adolescents has been the risk for serious secondary injuries, including skull fracture and cerebral hem orrhage. O f 463 VAERS reports o f syncope during January 1, 2005, to July 31, 2007, a total o f 41 listed syncope w ith secondary injury w ith inform ation on the tim ing after vaccination, and the m ajority o f these syncope reports (76% ) occurred am ong adolescents. A m ong all age groups, 80% o f reported syncope episodes occur w ithin 15 m inutes o f vaccine ad m in istratio n (additional in fo rm atio n available at h ttp :// w w w .cdc.gov/vaccinesafety/concern/syncope.htm ). Providers should take appropriate measures to prevent injuries if a patient becom es weak or dizzy or loses consciousness. Adolescents and adults should be seated or lying dow n during vaccination. Vaccine providers, particularly w hen vaccinating adolescents, should consider observing patients (with patients seated or lying down) for 15 m inutes after vaccination to decrease the risk for injury should they faint (77). I f syncope develops, patients should be observed until the sym ptom s resolve.\n\n# Managing Acute Vaccine Reactions\nA lthough anaphylactic reactions are rare after vaccination, their im m ediate onset and life-threatening nature require that all personnel and facilities providing vaccinations have proce dures in place for anaphylaxis m anagem ent. All vaccination providers should be fam iliar w ith the office em ergency plan and be currently certified in cardiopulm onary resuscitation. Epinephrine and equipm ent for m aintaining an airway should be available for im m ediate use.\nA naphylaxis usually begins w ith in m in u te s o f vaccine adm inistration (78-80). Rapid recognition and initiation o f treatm ent are required to prevent possible progression to car diovascular collapse. If flushing, facial edema, urticaria, itching, swelling o f the m o u th or throat, w heezing, dyspnea, or other signs or sym ptom s o f anaphylaxis occur, the patient should be placed in a recum bent position w ith the legs elevated if possible (81,82). A d m inistration o f epinephrine is the m anagem ent o f choice. A dditional drugs also m ight be indicated (Table 8) (83). M aintenance o f the airway and oxygen adm inistration m ight be necessary. A fter the p atien t is stabilized, arrangem ents should be m ade for im m ediate transfer to an em ergency facility for additional evaluation and treatm ent.\n\n# Reporting Adverse Events After Vaccination\nM o d ern vaccines are safe and effective; however, adverse events have been reported after adm inistration o f all vaccines (84). M ore com plete inform ation about adverse reactions to a specific vaccine is available in the package insert for each vac cine and from C D C at w w .cdc.gov/vaccines/vac-gen/ side-effects.htm . An adverse event is an untow ard event that occurs after a vaccination th at m ight be caused by the vaccine p roduct or vaccination process. These events range from com m on, m inor, local reactions to rare, severe, allergic reactions (e.g., anaphylaxis). Establishing evidence for cause and effect on the basis o f case reports and case series alone is usually n o t possible because health problem s that have a tem poral associa tion w ith vaccination do n o t necessarily indicate causality.\nM an y adverse events require m ore detailed epidem iologic studies to com pare th e incidence o f the event am ong vaccinees to the in cidence am o n g u n v accinated persons. R ep o rtin g adverse events, including serious events, to VAERS is a key m echanism for identifying p o tential vaccine safety concerns. Potential causal associations betw een reported adverse events after vaccination can be assessed th ro u g h epidem iologic or clinical studies.\nT h e N a tio n a l C h ild h o o d V accin e In ju ry A ct requires health-care providers and vaccine m anufacturers to report to VAERS specific adverse events th at occur after vaccination. T h e reporting requirem ents are different for m anufacturers and health-care providers. M anufacturers are required to report all adverse events th at occur after vaccination to VAERS, whereas health-care providers are required to report events th at appear in the reportable events table on the VAERS website at http:/./ vaers.hhs.gov/reportable.htm .\nIn add itio n to the m andated reporting o f events listed on the reportable events table, health-care providers should report to VAERS all events listed in p ro d u ct inserts as contraindica tions, as well as all clinically significant adverse events, even if they are u ncertain th at the adverse event is related causally to vaccination. Persons other than health-care providers also can report adverse events to VAERS.\n\n# National Vaccine Injury Com pensation Program\nT h e N a tio n a l V accine In ju ry C o m p e n sa tio n P rogram , established by the N ational C hild h o o d Vaccine In ju ry A ct o f 1986, is a no-fault system in w hich persons th o u g h t to have experienced an injury or to have died as a result o f adm inistra tion o f a covered vaccine can seek com pensation. T h e program became operational on O ctober 1, 1988, and is intended as an alternative to civil litigation un d er the traditional to rt system in th at negligence need n o t be proven. C laim s arising from covered vaccines m ust first be adjudicated through the program before civil litigation can be pursued.\nT h e program relies on the Vaccine In ju ry Table, w hich lists the vaccines covered by the program and the injuries (including death), disabilities, illnesses, and conditions for w hich com pensation m ight be awarded. T he table defines the tim e during w hich the first sym ptom or substantial aggravation o f an injury m ust appear after vaccination to be eligible. Successful claim ants receive a legal presum ption o f causation if a condition listed in the table is proven, thus avoiding the need to prove actual causation in an individual case. C laim ants also can prevail for conditions n o t listed in the reportable events table if they prove causation for covered vaccines. A dditional inform ation is avail able from the H ealth Resources and Services A dm inistration (H RSA ) (h ttp w w .h rsa.\n\n# V accine Administration\n\n# Infection Control and Sterile Technique\n\n# General Precautions\n\n# Needles and Syringes\nNeedles and syringes used for vaccine injections m ust be sterile and disposable. A separate needle and syringe should be used for each injection. C hanging needles betw een draw ing vaccine from a vial and injecting it into a recipient is not necessary unless the needle has been dam aged or contam i nated. D ifferent vaccines should never be mixed in the same syringe unless specifically licensed for such use, and no attem pt should be m ade to transfer betw een syringes. Single-dose vials and m anufacturer-filled syringes are designed for single-dose adm inistration and should be discarded if vaccine has been w ithdraw n or reconstituted and subsequently n o t used w ithin the tim e fram e specified by the m anufacturer. T h is typically is no longer th an th e sam e clinic day (typically recom m ended as a m axim um for inactivated vaccines).\nSom etim es providers prefill syringes themselves. A C IP dis courages the routine practice o f prefilling syringes because o f the potential for adm inistration errors and vaccine wastage. Because the m ajority o f vaccines have a similar appearance after being draw n into a syringe, prefilling m ight result in adm inis tration errors. In certain circum stances in w hich a single vac cine type is being used (e.g., in p reparation for a co m m u n ity influenza vaccination cam paign), filling a small n u m b er o f syringes m ay be considered. Vaccine doses should n o t be drawn into a syringe u n til im m ediately before adm inistration. W h e n syringes are filled, the type o f vaccine, lot num ber, and date o f filling m ust be labeled on each syringe, and the doses should be adm inistered as soon as possible after filling. U nused syringes filled by the end user (i.e., n o t filled by the m anufacturer) should be discarded at the end o f the vaccination session. In ad ditio n to adm inistration errors, prefilling o f syringes is a concern because F D A does n o t license adm inistration syringes for vaccine storage. U nused syringes th at are prefilled by the m anufacturer and activated (i.e., syringe cap removed or needle attached) should be discarded at the end o f the clinic day. T h e act directed O S H A to strengthen its existing bloodborne pathogen standards. T h e revised standards becam e effective in 2001 (86). These federal regulations require th at safetyengineered injection devices (e.g., needle-shielding syringes or needle-free injectors) be used for injectable vaccination in all clinical settings. T h e regulations also require m aintenance o f records docum enting injuries caused by needles and other m edical sharp objects and th at nonm anagerial employees be involved in the evaluation and selection o f safety-engineered devices before they are procured.\nSafety-engineered needles and syringes or needle-free injec tion devices are preferred and should be encouraged to reduce risk for injury. To prevent inadvertent needle-stick injury or reuse, safety m echanism s should be deployed after use and needles and syringes sh o u ld be discarded im m ed iately in labeled, p u n c tu re -p ro o f containers located in the same room w'here the vaccine is adm inistered. Used needles should never be recapped .\nN eedle-shielding or needle-free devices th at m ight satisfy the occupational safety regulations for adm inistering injectable vaccines are available in the U nited States (87-89). A dditional inform ation about im plem entation and enforcem ent of these regulations is available from O S H A ( w w .osha.gov).\n\n# Route of Administration\n\n# Oral Route\nRotavirus and oral typhoid vaccines are the only vaccines adm inistered orally in the U nited States. O ral typhoid capsules should be adm inistered as directed by the m anufacturer. T h e capsules should n o t be opened or mixed w ith any other sub stance. Rotavirus vaccines are licensed for infants. T here are two brands o f rotavirus vaccine, and they have different types o f applicators. Providers should consult the package insert for details. A dose of rotavirus vaccine need n o t be repeated if the vaccine is spit up or vom ited. T h e infant should receive the rem aining recom m ended doses o f rotavirus vaccine following the routine schedule.\n\n# Intranasal Route\nLAIV is licensed for healthy nonpregnant persons aged 2-A9 years and is the only vaccine administered by the intranasal route. T he adm inistration device is a nasal sprayer w ith a dose-divider clip that allows introduction o f one 0.1 -m L spray into each naris. T he tip should be inserted slightly into the naris before adm in istration. Even if the person coughs or sneezes immediately after adm inistration or the dose is expelled any other way, the vaccine dose need not be repeated . Introduction o f low levels o f vaccine viruses into the environm ent likely is unavoidable w hen adminis tering LAIV; however, no instances have been reported o f illness or attenuated vaccine virus infections am ong inadvertently exposed health-care providers or im m unocom prom ised patients. T h e risk for acquiring vaccine viruses from the environm ent is unknow n but is likely low; in addition, vaccine viruses are cold-adapted and attenuated and unlikely to cause sym ptom atic influenza. Severely immunosuppressed persons should not administer LAIV However, other persons at higher risk for influenza complications can adm inister LAIV. These include persons w ith underlying medical conditions placing them at higher risk or w ho are likely to be at risk, including pregnant w om en, persons w ith asthma, and persons aged >50 years (68).\n\n# Injectable Route\nW ith the exception o f bacille C alm ette-G uérin (BCG ) vac cine and sm allpox vaccine, injectable vaccines are adm inistered by the intram uscular or subcutaneous route. T h e m ethod o f adm inistratio n o f injectable vaccines is determ ined, in part, by the presence o f adjuvants in som e vaccines. A n adjuvant is a vaccine co m p o n en t d istinct from the antigen th at enhances the im m u n e response to th e antigen. Inactivated vaccines c o n tain in g an ad ju v an t sh o u ld be injected in to a m uscle because adm inistration subcutaneously or intraderm ally can cause local irritation, induration, skin discoloration, inflam m a tion, and granulom a form ation. Routes o f adm inistration are recom m ended by the m anufacturer for each im m unobiologic (Table 9). D eviation from the recom m ended route o f adm in istration m ight reduce vaccine efficacy (90, 91) or increase the risk for local adverse reactions (92)(93)(94).\n\n# Intramuscular Injections\n\n# N ee d le Length\nInjectable im m unobiologies should be adm inistered where local, neural, vascular, or tissue injury is unlikely. Use o f longer needles has been associated w ith less redness or swelling than occurs w ith shorter needles because o f injection into deeper muscle mass (92). A ppropriate needle length depends on age and body mass. Injection technique is the m ost im p o rtan t param eter to ensure efficient intram uscular vaccine delivery.\nF or all in tra m u sc u la r in jectio n s, th e need le sh o u ld be long enough to reach the m uscle mass and prevent vaccine from seeping into subcutaneous tissue, b u t not so long as to involve underlying nerves, blood vessels, or bone (91,(95)(96)(97). Vaccinators should be fam iliar w ith the anatom y o f the area into w hich they are injecting vaccine. Intram uscular injections are adm inistered at a 90-degree angle to the skin, prefer ably into the anterolateral aspect o f the thigh or the deltoid muscle o f the upper arm , depending on the age o f the patient (Table 10).\nA decision on needle size and site o f injection m ust be m ade for each person on the basis o f the size o f the muscle, the thickness o f adipose tissue at the injection site, the volum e o f the m aterial to be adm inistered, injection technique, and the depth below the muscle surface into w hich the m aterial is to be injected (Figure 1). A spiration before injection o f vaccines or toxoids (i.e., pulling back on the syringe plunger after needle insertion b u t before injection) is n o t necessary because no large blood vessels are present at the recom m ended injection sites, and a process th at includes aspiration m ight be m ore painful for infants (98).\n\n# In fan ts (Aged < 1 2 M on th s)\nFor the m ajority o f infants, the anterolateral aspect o f the thigh is the recom m ended site for injection because it provides a large m uscle mass (Figure 2). In certain circum stances (e.g., physical obstruction to other sites and no reasonable indication to defer doses), the gluteal muscle can be used. I f the gluteal muscle m ust be used, care should be taken to define the ana tom ic la n d m a r k s .I n je c tio n technique is the m ost im portant param eter to ensure efficient intram uscular vaccine delivery. I f the subcutaneous and m uscle tissue are bunched to m inim ize the chance o f striking bone (95), a 1-inch needle is required to ensure intram uscular adm inistration in infants aged >1 m onth. For the m ajority o f infants, a 1-inch, 22-to 25-gauge needle is sufficient to penetrate the thigh muscle. For neonates (first 28 days o f life) and preterm infants, a % -inch needle usually is adequate if the skin is stretched flat between the th u m b and forefinger and the needle is inserted at a 90-degree angle to the skin (97).\n\n# Toddlers (Aged 12 M o n th s -2 Years)\nFor toddlers, the anterolateral thigh muscle is preferred, and if used, the needle should be at least 1 inch long. T h e deltoid muscle can be used if the muscle mass is adequate. A % -inch needle is adequate only for the deltoid m uscle and only if the skin is stretched flat betw een th u m b and forefinger and the needle is inserted at a 90-degree angle to the skin.\n\n# C hildren (Aged 3 -1 8 Years)\nT h e deltoid m uscle is preferred for children aged 3-18 years (Figure 3); the needle size for deltoid site injections can range from 22 to 25 gauge and from Vs to 1 inch on the basis o f tech nique. Knowledge o f body mass can be useful for estim ating the appropriate needle length (99)', however, neither a physical exam ination n o r m easurem ent o f body mass is necessary to adm inister vaccines. M ost children in this age range require a %-or 1-inch needle (or interm ediate size, if available).\n\n# A dults (Aged > 1 9 Years)\nFor adults, the deltoid muscle is recom m ended for routine intram uscular vaccinations. T h e anterolateral thig h also can be used. For m en and w om en w ho weigh 200 lbs (>90 kg) or m en w ho w eigh >260 lbs (> 1 18 kg), a 1 Vi-inch needle is recom m ended (Table 10) (96).\n\n# Subcutaneous Injections\nSubcutaneous injections are adm inistered at a 45-degree angle, usually into the thigh for infants aged 12 m onths. Subcutaneous injections m ay be adm inistered into the upperouter triceps area o f an infant if necessary. A % -inch, 23-to 25-gauge needle should be inserted into the subcutaneous tissue (Figures 4 and 5).\n\n# Multiple Injections\nI f m ultiple vaccines are adm inistered at a single visit, adm in ister each preparation at a different anatom ic site. For infants and younger children, if m ore th an tw o vaccines are injected in a single lim b, the thigh is the preferred site because o f the greater muscle mass; the injections should be sufficiently sepa rated (i.e., >1 inch if possible) so th at any local reactions can be differentiated (92,100)\n\n# Jet Injections\nJet injectors are needle-free devices th at pressurize liquid m edication, forcing it th ro u g h a nozzle orifice into a narrow' stream capable o f penetrating skin to deliver a drug or vac cine into intraderm al, subcutaneous, or intram uscular tissues (101,102). Jet injectors prevent needle-stick injuries to health care providers (86) and can overcome im proper, unsterile reuse and other drawbacks o f needles and syringes in developing countries (87, . Im m u n e responses generated by jet injectors against b o th attenuated and inactivated viral and bacterial antigens are usually equivalent to, and occasionally greater than, im m une responses induced by needle injection. However, local reactions or injuries are som etim es m ore fre quent on delivery o f vaccine by jet injectors com pared w'ith needle injection, depending on the inherent irritability o f the vaccine and operator technique (102). Jet injectors that use the same nozzle for consecutive injections w ithout intervening sterilization were used in mass vaccination cam paigns from the 1950s through the 1990s (102); however, these were found to be unsafe because o f the possibility o f bloodborne pathogen transm ission (105-108) and should n o t be used. A new gen eration o f jet injectors w ith disposable cartridges and syringes has been developed since the 1990s. W ith a new, sterile dose cham ber and nozzle for each p atien t and correct use, these devices do n o t have the same safety concerns as m ultiple-use nozzle jet injectors. Several o f the new er devices have been approved by FD A for sale in the U nited States (102).\n\n# M ethods for Alleviating Discomfort and Pain Associated with Vaccination\nC o m fort measures, such as distraction (e.g., playing m usic or p re ten d in g to blow away the pain), ingestion o f sweet liquids, breastfeeding, cooling of the injection site, and topi cal analgesia, can help infants or children cope w ith the dis com fort associated w ith vaccination (109,110). P retreatm ent (30-60 m inutes before injection) w ith a 5% topical lidocaineprilocaine em ulsion m ight decrease the pain o f vaccination by causing superficial anesthesia (111,112)\n\n# Nonstandard Vaccination Practices\nRecommendations for route, site, and dosage o f immunobiolog ies are derived from data from clinical trials, practical experience, norm al periodicity o f health-care visits, and theoretical consider ations. A CIP discourages variations from the recommend ed route, site, volume, or num ber o f doses o f any vaccine.\nVariation from the recom m ended route and site can result in inadequate protection. In adults (but not in infants) (117), the im m unogenicity o f hepatitis B is substantially lower w hen the gluteal rather than the deltoid site is used for adm inistration (90). Hepatitis B administered intraderm ally might result in a lower seroconversion rate and final titer o f hepatitis B surface antibody than w hen administered by the deltoid intramuscular route (118,119). Hepatitis B administered by any route other than intramuscular, or in adults at any site other than the deltoid or anterolateral thigh, should not be counted as valid and should be repeated. Similarly, doses o f rabies vaccine administered in the gluteal site should not be counted as valid doses and should be repeated (120). M C V 4 should be administered intram uscu larly; however, revaccination is not necessary if a vaccine dose is administered subcutaneously (121). Inactivated influenza vaccine is im m unogenic w hen administered in a lower than standard dose by the intraderm al route to healthy adult volunteers (122). However, the im m unogenicity for persons aged >60 years is inadequate, and varying the recom m ended route and dose is not recomm ended.\nLive, attenuated injectable vaccines (e.g., M M R , varicella, and yellow fever) and certain inactivated vaccines (e.g., meningococ cal polysaccharide) are recom m ended by the manufacturers to be adm inistered by subcutaneous injection. PPSV and IPV are recom m ended by the m anufacturer to be administered by the subcutaneous or intram uscular route. Response to vaccines rec om m ended by the subcutaneous route are unlikely to be affected if the vaccines are administered by the intram uscular rather than subcutaneous route. Repeating doses o f vaccine administered by the intram uscular route w hen recom m ended to be by the subcutaneous route is not necessary.\nAdm inistering volumes smaller than recom m ended (e.g., inap propriately divided doses) m ight result in inadequate protection. Using reduced doses administered at m ultiple vaccination visits that equal a full dose or using smaller divided doses is not recom mended. Any vaccination using less than the standard dose should not be counted, and the person should be revaccinated according to age unless serologic testing indicates that an adequate response has developed. If less than a full recommended dose o f a parenteral vaccine is administered because o f syringe or needle leakage, the dose should be repeated. Using larger than recommended dosages can be hazardous because o f excessive local or systemic concentra tions of antigens or other vaccine constituents.\n\n# Storage and Handling of Im m unobiologies\n\n# Storage Temperature\nVaccines licensed for refrigerator storage should be stored at 35°F-46°F (2°C-8°C). L iquid vaccines containing an alum i num adjuvant perm anently lose potency w hen exposed to freez ing tem peratures. Live, attenuated virus vaccines th at should be frozen lose potency w'hen exposed to higher tem peratures because the viruses degrade m ore quickly at storage tem pera tures th at are w arm er than recom m ended (Table 11).\n\n# Storage Units\nRefrigerators and freezers used for vaccine storage m ust m aintain the required tem perature range year-round, be large enough to hold the year's largest inventory, and be dedicated to storage o f vaccines. Vaccine storage units m ust be carefully selected, used properly, and consistently m onitored to ensure that recom m ended tem peratures are m aintained. Refrigerators w ithout freezers and stand-alone freezers (either m anual defrost or autom atic defrost) are usually the m ost effective at m aintain ing the precise tem peratures required for vaccine storage. Such single-purpose units sold for hom e use are less expensive alter natives to medical specialty equipm ent (123) and are preferable to com bination units. A com bination refrigerator-freezer unit sold for hom e use m ight be adequate for storing lim ited qu an tities o f vaccines if the refrigerator and freezer com partm ents have separate external doors. Before using the refrigerator for vaccine storage, the tem perature should be allowed to stabilize and then be m easured in various locations w ithin the refrigera tor co m p artm en t to d o cum ent th at a consistent tem perature can be m aintained w ithin the co m p artm en t (Table 11) (124). N ew units m ight need >2 days o f operation to establish a stable operating tem perature; vaccine should n o t be stored in the unit until the u n it m aintains an appropriate and stable storage tem perature. Refrigerator tem peratures are m ost reflective o f the actual co m p artm en t tem perature after the door has rem ained closed and u n d istu rb ed for several hours (e.g., overnight). T h e refrigerator tem perature should be set at the m idpoint o f the recom m ended range (i.e., 40°F ) (125,126). A storage u n it should be sufficiently sized so that vaccines can be placed away from the walls in the p art o f the u n it best able to m aintain the constant, required tem perature. C o m bination units, w ith separate com partm ents o f sm aller size, can only be used to store lim ited quantities o f vaccines. Frequent opening and closing o f doors can cause fluctuations in com partm ent tem perature; food, beverages, and clinical specimens should n o t be stored in vaccine storage units. I f it becomes necessary to store clinical specim ens in the same u n it as vaccines, the clinical specim ens should be o n a shelf below the vaccine to prevent co n tam in atio n should the specim en leak.\n\n# Temperature Monitoring\nTem perature m onitoring is a critical com ponent o f tem pera ture m anagem ent. All office and clinical staff m em bers should be aware o f vaccine vulnerabilities and storage requirem ents. Assigning one person in the office the prim ary responsibility for m aintaining and reviewing tem perature logs (Figure 6) gener ally is m ost effective, w ith a second person assigned as backup. Tem peratures for b o th the refrigerator and freezer should be docum ented twice a day and recorded. T h e backup person should review the log at least once each week. Tem perature logs should be m aintained for 3 years unless state or local authorities require a longer tim e. A n autom ated m onitoring system th at alerts staff w hen a tem perature deviation occurs is optim al. However, even if an autom ated m o n ito ring system is used, tem peratures still should be m anually checked and recorded twice each day.\nT o f the m anufacturing process, this recom m endation refers to a second calibration process that occurs after m anufacturing b u t before m arketing and is docum ented w ith a certificate that comes w ith the product. Some products (e.g., continuous chart recorder therm om eters) usually include a m anufacturerdefined schedule for additional recalibration. For m any types o f therm om eters, replacem ent m ight be less expensive than recalibration. T herm om eters that require batteries need to have the batteries changed; review the d o cum entation th at comes w ith the p ro duct for guidance.\n\n# Response to Out-of-Range\nTemperature Reading\nA n o u t-o f-ra n g e te m p e ra tu re re a d in g sh o u ld p ro m p t im m ediate action. A plan should be d eveloped ahead o f tim e to address various types o f emergencies th at m ight require removal o f vaccine from the original storage unit. Transfer o f vaccines to a predesignated alternative em ergency storage site m ight be necessary if a tem perature problem cannot be resolved im m ediately (e.g., plugging in an unplugged unit or closing a door th a t has been left open). Vaccine should be m arked \"do n o t use\" and moved to the alternate site after verifying that the alternate u n it is at the proper tem perature. After the vac cine has been moved, determ ine w hether the vaccine is still useable by contacting the state or local health d epartm ent or m anufacturer. D am age to the im m unogenicity o f a vaccine exposed to tem peratures outside o f the recom m ended range m ight n o t be apparent visually. As a general rule, vaccines that have been stored at inappropriate tem peratures should not be adm inistered. I f such vaccines already have been adm inis tered, guidance is available from the state health departm ent or C D C . Vaccine exposed to inappropriate tem peratures that is inadvertently adm inistered should generally be repeated. Clinicians should consult w ith state or local health depart m ents in these situations.\n\n# Expiration Dates and Windows\nAll vaccines have an expiration date determ in ed by the m anufacturer th at m ust be observed. Providers should record the vaccine expiration dates and lot num bers on a stock or inventory record for each vaccine vial w hen a sh ip m en t is received. W h e n vaccines are rem oved from storage, clinicians and other health-care providers should note w hether an expira tion w indow exists for vaccine stored at room tem perature or at an interm ediate tem perature. For example, single-com ponent varicella vaccine th at is stored frozen m ust be discarded after 72 hours o f storage at refrigerator tem perature. Vaccine trans p o rt betw een the storage site and the adm inistration clinic is discouraged unless the cold chain is m aintained, and vaccine tran sp o rt by th e p a tie n t (e.g., tra n sp o rtin g zoster vaccine from a p harm acy to a clinic) is particularly discouraged. A n expiration w indow also applies to vaccines th a t have been reconstituted. For example, after reconstitution, M M R vac cine should be k ept at refrigerator tem perature and m ust be adm inistered w ithin 8 hours. Doses o f expired vaccines that are adm inistered inadvertently generally should n o t be counted as valid and should be repeated. Inactivated vaccines should be repeated as soon as possible. Live vaccines should be repeated after a 28-day interval from the invalid dose to reduce the risk for interference from interferon on the subsequent doses. A dditional inform ation about expiration dates is available at w w .cdc. gov/ vaccines/recs/storage.\n\n# Multidose Vials\nC ertain vaccines (i.e., quadrivalent m eningococcal poly saccharide vaccine , PPSV, TIV, IPV, and yellow fever) are available in m ultidose vials. Because several doses are w ithdraw n from the sam e vial, p roper technique m ust be followed to prevent contam ination. For m ultidose vials that do n o t require reconstitution, doses th at rem ain after w ith drawal of a dose can be adm inistered until the expiration date p rin ted on the vial or vaccine packaging if the vial has been stored correctly and the vaccine is n o t visibly contam inated, unless otherwise specified by the m anufacturer. M ultidose vials that require reco n stitu tio n m ust be used w ith in the interval specified by the m anufacturer. A fter reconstitution, the new expiration date should be w ritten on the vial.\n\n# Altered Im m unocom petence\n\n# General Principles\nA ltered im m u n o co m p eten ce, a term often used synony m ously w ith im m unosuppression and im m unocom prom ise, can be classified as prim ary or secondary. Prim ary im m unodefi ciencies generally are inherited and include conditions defined by an absence or quantitative deficiency o f cellular or hum oral com ponents or both that provide im m unity. Examples include congenital im m unodeficiency diseases such as X -linked agam m aglobulinem ia, severe com bined im m unodeficiency disease, and chronic granulom atous disease. Secondary im m unodefi ciency generally is acquired and is defined by loss or qualitative deficiency in cellular or hum oral im m u n e com ponents that occurs as a result o f a disease process or its therapy. Examples o f sec o n d a ry im m u n o d e fic ie n c y in c lu d e H IV in fe c tio n , hem atopoietic m alignancies, treatm en t w ith radiation, and treatm ent w ith im m unosuppressive drugs including alkylating agents and antim etabolites. T h e degree to w hich im m u n o su p pressive drugs cause clinically significant im m unodeficiency generally is dose related and varies by drug. Prim ary and sec ondary im m unodeficiencies m ight include a com bination o f deficits in both cellular and hum oral im m unity. In this report, the general term altered im m unocom petence also is used to include conditions such as asplenia and chronic renal disease, and treatm ents w ith therapeutic m onoclonal antibodies (spe cifically, the tu m o r necrosis factor inhibitors) (127-132) and prolonged adm inistration o f high-dose corticosteroids.\nD eterm in atio n o f altered im m un o co m p eten ce is im p o r tan t to the vaccine provider because incidence or severity o f som e vaccine-preventable diseases is higher in persons w ith altered im m unocom petence; therefore, certain vaccines (e.g., inactivated influenza vaccine and pneum ococcal vaccines) are recom m ended specifically for persons w ith these diseases (28,68). Vaccines m ight be less effective during the period o f altered im m unocom petence. Live vaccines m ight need to be deferred u n til im m une function has im proved. Inactivated vaccines adm inistered during the period o f altered im m u n o com petence m ight need to be repeated after im m une function has im proved. In ad d itio n , persons w ith altered im m u n o com petence m ight be at increased risk for an adverse reaction after adm inistration o f live, attenuated vaccines because o f uninhibited replication.\nT he degree o f altered im m unocom petence in a patient should be determ ined by a physician. T h e challenge for clinicians and other health-care providers is assessing the safety and effective ness o f vaccines for conditions associated w ith prim ary or sec ondary im m unodeficiency, especially w hen new therapeutic modalities are being used and inform ation about the safety and effectiveness o f vaccines has not been characterized fully in persons receiving these drugs (Table 13). Laboratory studies can be useful for assessing the effects o f a disease or drug on the im m une system. Tests useful to assess hum oral im m unity include im m unoglobulin (and im m unoglobulin subset) levels and spe cific antibody levels (e.g., tetanus and diphtheria). Tests that dem onstrate the status o f cellular im m unity include lymphocyte num bers (i.e., a com plete blood count with differential), a test that delineates concentrations and proportions o f lymphocyte subsets (i.e., B and T lymphocytes, C D 4 + T versus C D 8+ T lym phocytes), and tests th at measure T-cell proliferation in response to specific or nonspecific stimuli (e.g., lym phocyte proliferation assays) (133,134). T he ability to characterize a drug or disease condition as affecting cellular or hum oral im m unity is only the first step; using this inform ation to draw inferences about w hether particular vaccines are indicated or w hether cau tion is advised w ith use o f live or inactivated vaccines is more com plicated and m ight require consultation w ith an infectious disease or im m unology specialist.\n\n# Altered Im m unocom petence as an Indication to Receive a Vaccine\n\n# Vaccination with Inactivated Vaccines\nAll inactivated vaccines can be adm inistered safely to per sons w ith altered im m unocom petence w hether the vaccine is a killed w hole-organism or a recom binant, subunit, toxoid, polysaccharide, or polysaccharide protein-conjugate vaccine. If inactivated vaccines are indicated for persons w ith altered im m unocom petence, the usual doses and schedules are rec om m ended. However, the effectiveness o f such vaccinations m ight be suboptim al.\nExcept for inactivated influenza vaccine, vaccination during chem otherapy or radiation therapy should be avoided if pos sible because antibody response m ight be suboptim al. Patients vaccinated w ithin 14 days before starting im m unosuppressive therapy or while receiving im m unosuppressive therapy should be considered unim m unized and should be revaccinated at least 3 m onths after therapy is discontinued if im m une com petence has been restored.\n\n# Vaccination with Live, Attenuated Viral and Bacterial Vaccines\nSevere\n\n# Recipients of Hematopoietic Cell Transplants\nA hem atopoietic cell transplant (H C T ) results in im m u nosuppression because o f the hem atopoietic ablative therapy adm inistered before the transplant, drugs used to prevent or treat graft-versus-host disease, and, in som e cases, from the underlying disease process necessitating transplantation (152)(153)(154)\n\n# Conditions or Drugs that Might Cause Im m unodeficiencies\nAsplenia and use o f corticosteroids or certain drugs have the potential to be im m unosuppressive and are presum ed to cause som e degree o f altered im m unocom petence.\n\n# A natom ic or Functional Asplenia\nPersons w ith anatom ic asplenia (e.g., surgical removal or congenital absence o f the spleen) or functional asplenia (as occurs in persons w ith sickle cell disease) are at increased risk for infection by encapsulated bacteria, especially by S. Pneumococcal, m eningococcal, and H ib vaccinations should be adm inistered at least 14 days before elective splenectomy, if possible. If the vaccinations are n o t adm inistered before surgery, they should be adm inistered after the procedure as soon as the p atien t's condition is stable.\n\n# Corticosteroids\nT he am ount o f systemically absorbed corticosteroids and the duration o f adm inistration needed to suppress the im m une system o f an otherw ise im m u n o co m p eten t person are n o t well defined. C orticosteroid therapy usually is n o t a contraindica tion to adm inistering live-virus vaccine w hen adm inistration is 1) short term (i.e., 2 m g/kg o f body w eight or >20 m g/day o f prednisone or equivalent for persons w ho weigh >10 kg w hen adm inistered for >14 days as sufficiently im m unosuppressive to raise concern about the safety o f vaccination w ith live-virus vaccines (154). C orticosteroids used in greater than physiologic doses also can reduce the im m une response to vaccines. Vaccination providers should defer live-virus vaccination for at least 1 m o n th after discon tin u atio n of high-dose systemically absorbed corticos teroid therapy adm inistered for >14 days.\n\n# Other Immunosuppressive Drugs\nW h e n feasible, clinicians should adm inister all indicated vac cines to all persons before initiatio n o f chem otherapy, before treatm en t w ith oth er im m unosuppressive drugs, and before radiation or splenectom y. Persons receiving chem otherapy or radiation for leukem ia and other hem atopoietic m alignancies, for solid tum ors, or after solid organ tran sp lan t should be assumed to have altered im m unocom petence.\n\n# S pecial Situations\n\n# Concurrent Administration of Antimicrobial Agents and Vaccines\nW ith a few exceptions, use o f an antim icrobial agent is not a contraindication to vaccination. A ntibacterial agents have no effect on the response to live, attenuated vaccines, except live o ra lT y 2 la typhoid vaccine, and have no effect on inactivated, recom binant subunit, or polysaccharide vaccines or toxoids. T y 2 la typhoid vaccine should not be adm inistered to persons receiving antim icrobial agents until 24 hours after the last dose o f antim icrobial (14). I f feasible, to avoid a possible reduction in vaccine effectiveness, antibacterial drugs should n o t be started or resum ed until 1 week after the last dose ofT y21a.\nA n tiv ira l d ru g s used for tre a tm e n t o r p ro p h y lax is o f influenza virus infections have no effect on the response to inactivated influenza vaccine (68). However, live, attenuated influenza vaccine should n o t be adm inistered u n til 48 hours after cessation o f therapy w ith antiviral influenza drugs. If feasible, to avoid possible reduction in vaccine effectiveness, antiviral m edication should n o t be adm inistered for 14 days after LAIV adm inistration (68). A ntiviral drugs active against herpesviruses (e.g., acyclovir or valacyclovir) m ight reduce the efficacy o f live, attenuated varicella and zoster vaccines (4,55). These drugs should be discontinued at least 24 hours before adm inistration o f vaccines containing varicella zoster virus, including zoster vaccine, if possible. D elay use or resum ption o f antiviral therapy for 14 days after vaccination. N o data exist to suggest that com m only used antiviral drugs have an effect on rotavirus vaccine or M M R .\n\n# Tuberculosis Screening and Skin Test Reactivity\nMeasles illness, severe acute or chronic infections, H IV infection, and m aln u tritio n can create a relatively anergic state during w hich the tuberculin skin test (TST) m ight have a falsenegative reaction (156-158). A lthough any live, attenuated measles vaccine theoretically can suppress T S T reactivity, the degree o f suppression is likely less th an that occurring from acute infection from wild-type measles virus. A lthough routine T S T screening o f all children is no longer recom m ended, T S T screening is som etim es needed (e.g., for well child care, school entrance, or employee health reasons) at the same tim e as adm inistration o f a m easles-containing vaccine.\nT h e T S T and m easles-containing vaccine can be adm in istered at the same visit (preferred option). Sim ultaneously adm inistering the T S T and m easles-containing vaccine does n o t interfere w ith reading the T S T result at 4 8 -7 2 hours and ensures that the person has received measles vaccine.\nI f th e m easles-containing vaccine has been adm inistered recently, T S T screening should be delayed for at least 4 weeks after vaccination. A delay in perform ing the T S T removes the concern o f any theoretical b u t transient suppression o f T S T reactivity from the vaccine.\nT S T screening can be perform ed and read before adm inis tration of the m easles-containing vaccine. T h is o p tion is the least favored because it delays receipt o f the m easles-containing vaccine. If a person is suspected to have tuberculosis, n o t only should the M M R vaccine be w ithheld before the TST, it should be w ithheld u n til after treatm en t has been initiated because a person w ith active tuberculosis w ho is m oderately or severely ill should n o t receive M M R vaccine. In a general screening situation in w hich tuberculosis is n o t suspected, a T S T may be adm inistered sim ultaneously w ith live vaccines or should be deferred for 28 days after vaccination.\nN o data exist regarding the poten tial degree o f T S T sup pression that m ight be associated w ith other live, attenuated virus vaccines (e.g., varicella or yellow fever). However, in the absence o f data, following guidelines for m easles-containing vaccine w hen scheduling T S T screening and adm inistering other live, attenuated virus vaccines is p ru d en t. I f the oppor tu n ity to vaccinate m ight be missed, vaccination should not be delayed only because o f these theoretical considerations.\n\n# Because o f sim ilar concerns about sm allpox vaccine and T S T suppression, a T S T should n o t be perform ed until 4 weeks after sm allpox vaccination ( 1.59).\nA m ore specific test for diagnosis o f tuberculosis or latent tuberculosis infection was licensed in 2005-T h e interferon gam m a release assay (IGRA) requires only one visit to com plete and is less sensitive to the effects o f previous B C G vaccination (160). T h e same tim in g guidelines that apply to the interval betw een a live vaccine and T S T apply to IG R A (i.e., 28 days betw een live vaccine and IG R A if they do n o t occur on the same day), because IG R A (like T S T ) m ig h t be suppressed th ro u g h im m unologic m echanism s.\nT h e p o tential for T S T to cause boosting o f results should be considered in adults w ho m ight have latent tuberculosis and have a negative in itia lT S T (160). T h e tw o-step tuberculin test is recom m ended for certain situations (160). Because this test consists o f two TSTs (or a T S T followed by IGRA) separated by an interval o f 1-3 weeks, there is a greater w indow o f tim e during which live vaccine replication could suppress reactivity. If a live vaccine is adm inistered, the first dose o f a two-step T S T should be delayed for 4 weeks, and if additional doses of live vaccines are indicated thereafter, they should be delayed until the second T S T (or the IG R A after an initial T ST ).\nT S T or IG RA reactivity in the absence o f tuberculosis disease is n o t a contraindication to adm inistration o f any vaccine, including live, attenuated virus vaccines. Tuberculosis disease is n o t a contraindication to vaccination, unless the person is m oderately or severely ill. A lthough no studies have reported on the effects o f M M R vaccine on persons w ith untreated tuberculosis, a theoretical basis exists for concern that measles vaccine m ight exacerbate tuberculosis disease (2). As a result, before adm inistering M M R to persons w ith untreated active tuberculosis, initiating antituberculosis therapy is advisable (2). C onsidering w hether concurrent im m unosuppression (e.g., im m unosuppression caused by H IV infection) is a concern before adm inistering live, attenuated vaccines also is prudent.\n\n# Severe Allergy to Vaccine Com ponents\nVaccine co m ponents can cause allergic reactions am ong certain recipients. T hese reactions can be local or systemic and can include anaphylaxis or anaphylactic-like responses (e.g., generalized urticaria or hives, wheezing, swelling o f the m outh and throat, dyspnea, hypotension, and shock). Allergic reactions m ight be caused by the vaccine antigen, residual anim al protein, antim icrobial agents, preservatives, stabiliz ers, or o th er vaccine com ponents (161). C hildren w ho have had an apparent severe allergic reaction to a vaccine should be evaluated by an allergist to determ ine the responsible allergen and to m ake recom m endations regarding future vaccination. C o m ponents o f each vaccine are listed in the respective pack age insert. A n extensive list o f vaccine com ponents and their use, as well as the vaccines th at contain each com ponent, has been published (162) and also is available from C D C (h ttp :// www.cdc. gov/ vaccines).\nT h e m ost com m on anim al p rotein allergen is egg protein, w hich is found in influenza and yellow fever vaccines because they are prepared using em bryonated chicken eggs. Ordinarily, persons w ho are able to eat eggs or egg products safely can receive these vaccines; persons w ho have had an anaphylactic or anaphylactic-like allergy to eggs or egg proteins generally should n o t receive these vaccines. Asking persons if they can eat eggs w ith o u t adverse effects is a reasonable way to determ ine w hich persons m ight be at risk for allergic reactions from yel low fever and influenza vaccines. A regim en for adm inistering influenza vaccine to children w ith egg hypersensitivity and severe asthm a has been developed (163,164)\n\n# Latex Allergy\nLatex is sap from the com m ercial rubber tree. Latex contains naturally occurring im purities (e.g., plant proteins and pep tides) th at m ight be responsible for allergic reactions. Latex is processed to form natural rubber latex and dry, natural rubber. N atural rubber latex and dry, natural rubber m ight contain the same plant im purities as latex b u t in lesser am ounts. N atural ru b b er latex is used to p ro d u ce m edical gloves, catheters, and other products. Dry, natural rubber is used in the tip o f syringe plungers, the tip on prefilled syringes, vial stoppers, and injection ports on intravascular tubing. Synthetic rubber and synthetic latex also are used in m edical gloves, syringe plungers, and vial stoppers. Synthetic rubber and synthetic latex do n o t contain natural rubber or natural latex and do n o t contain im purities linked to allergic reactions. Latex or dry, natural rubber used in vaccine packaging generally is noted in the m anufacturers' package inserts.\nT he most com m on type o f latex sensitivity is a contact-type (type 4) allergy, usually as a result o f prolonged contact w ith latex-containing gloves (176). However, latex allergies associated w ith injection procedures have been described am ong patients w ith diabetes mellitus (177-179)-Allergic reactions (including anaphylaxis) after vaccinations are rare. A review o f reports to VAERS identified only 28 cases o f possible im m ediate-type anaphylactic reactions among more than 160,000 vaccine adverse event reports (180).\nIf a person reports a severe (anaphylactic) allergy to latex, vaccines supplied in vials or syringes th at co ntain natural rubber latex should n o t be adm inistered unless the benefit o f vaccination clearly outweighs the risk for a potential allergic reaction. In these cases, providers should be prepared to treat patients w ho are having an allergic reaction. For latex allergies other th an anaphylactic allergies (e.g., a history o f contact allergy to latex gloves), vaccines supplied in vials or syringes th at contain dry, natural rubber or natural rubber latex may be adm inistered.\n\n# Vaccination of Preterm Infants\nIn the m ajority o f cases, preterm infants (infants born before 37 weeks' gestation), regardless o f b irth w eight, should be vaccinated at the same chronological age and according to the same schedule and using the same precautions as for full-term I f a child aged at least 6 weeks has been in the hospital since birth, deferral o f rotavirus vaccine is recom m ended until the tim e of discharge (136). T h e rotavirus vaccine series should n o t be initiated for infants aged >15 weeks, 0 days.\n\n# Breastfeeding and Vaccination\nN eith er inactivated n o r live-virus vaccines adm inistered to a lactating w om an affect the safety o f breastfeeding for w om en or their infants. A lthough live viruses in vaccines can replicate in vaccine recipients (i.e., the m other), the m ajority o f live viruses in vaccines have been d em onstrated n o t to be excreted in hu m an milk. Varicella vaccine virus has n o t been found in h u m an m ilk (190). A lthough rubella vaccine virus m ight be excreted in h u m a n m ilk, the virus usually does n o t infect the infant. If infection does occur, it is well tolerated because the virus is attenuated (191). Inactivated, recom binant, subunit, polysaccharide, and conjugate vaccines, as well as toxoids, pose no risk for m others w ho are breastfeeding or for their infants. Breastfeeding is a contraindication for sm allpox vaccination o f the m o th er because o f the theoretical risk for contact trans m ission from m o th er to infant. Yellow fever vaccine should be avoided in breastfeeding w om en (19). However, w hen nursing m others can n o t avoid or postpone travel to areas endem ic for yellow fever in w hich risk for acquisition is high, these w om en should be vaccinated.\nLim ited data indicate that breastfeeding can enhance the response to certain vaccine antigens (192). T here are no data to suggest th at passive transfer o f antibodies in h u m a n m ilk can affect the efficacy o f live-virus vaccines. Breastfed infants should be vaccinated according to the recom m ended schedule (1 9 3 -1 9 5 ).\n\n# Vaccination During Pregnancy\nRisk to a developing fetus from vaccination o f the m other during pregnancy is theoretical. N o evidence exists o f risk to the fetus from vaccinating pregnant w om en w ith inactivated virus or bacterial vaccines or toxoids (196,197). Live vaccines adm inistered to a pregnant w om an pose a theoretical risk to the fetus; therefore, live, attenuated virus and live bacterial vac cines generally are contraindicated during pregnancy. Benefits o f vaccinating pregnant w om en usually outw eigh potential risks w hen the likelihood o f disease exposure is high, w hen infection would pose a risk to the m other or fetus, and w hen the vaccine is unlikely to cause harm . R ecom m endations for vaccination d u rin g pregnancy are developed using A C IP 's G uiding Principles fo r Development o fA C IP Recommendations fo r Vaccination D uring Pregnancy a n d Breastfeeding (198). Because vaccinating against influenza before the season begins is critical, and because predicting exactly w hen the season will begin is im possible, routine influenza vaccination is recom m ended for all w om en w ho are or will be pregnant (in any trim ester) durin g influenza season, w hich in the U nited States is usually early O cto b er th ro u g h late M arch (68).\nIPV can be adm inistered to p regnant w om en who are at risk for exposure to w ild -ty p e poliovirus in fectio n (201). H epatitis A, pneum ococcal polysaccharide, m eningococcal conjugate, and m eningococcal polysaccharide vaccines should be considered for w om en at increased risk for those infections (49,51,202). Pregnant w om en w ho m ust travel to areas where the risk for yellow fever is high should receive yellow fever vaccine because the lim ited theoretical risk from vaccination is outw eighed substantially by the risk for yellow fever infec tion (19,203). H epatitis B vaccine is n o t contraindicated in pregnancy and should be given to a pregnant w o m an w ho has an indication for hepatitis B vaccine (26,204).\nPregnancy is a contraindication for sm allpox (vaccinia) vac cine and measles-, m um ps-, rubella-, and varicella-containing vaccines. Sm allpox vaccine is the only vaccine know n to harm a fetus w hen adm inistered to a pregnant w om an. In addition, sm allpox vaccine should n o t be adm inistered to a household contact o f a preg n an t w om an (159). However, antibody testing was perform ed by using a hem ag glutination assay, w hich tends to underestim ate protection and cannot directly be com pared w ith antibody concentration (210). D ata are likely to rem ain lim ited for areas other than the People's Republic o f C hina, Russia, and E astern Europe. Health-care providers should ensure that household contacts o f international adoptees are vaccinated adequately, particularly for measles, hepatitis A, and hepatitis B (211).\nH ealth-care providers m ay use one o f m ultiple approaches if the im m unogenicity o f vaccines adm inistered to persons outside the U nited States is in question. Repeating the vaccina tions is an acceptable o p tio n that usually is safe and prevents the need to obtain and interp ret serologic tests. If avoiding unnecessary injections is desired, judicious use o f serologic testing m ight help determ ine w hich vaccinations are needed.\nFor som e vaccines, the m ost readily available serologic tests cannot d o cu m en t protection against infection. These recom m endations provide guidance on possible approaches to evalu ation and revaccination for each vaccine recom m ended in the U nited States (Table 14). b u t w aning antibody; serologic testing can be repeated after a booster dose if the vaccination provider w ants to avoid revac cination w ith a com plete series.\n\n# DTaP Vaccine\nA lternately, for a child whose records indicate receipt o f >3 doses, a single booster dose can be adm inistered followed by serologic testing after 1 m o n th for specific IgG antibody to both diphtheria and tetanus toxins. I f the child has a protective concentration, the recorded doses are considered valid, and the vaccination series should be com pleted as age appropriate. C hildren w ith an indeterm inate concentration after a booster dose should be revaccinated w ith a com plete series.\n\n# Hepatitis A Vaccine\n\n# Poliovirus Vaccine\nT h e sim plest approach to vaccinating w ith poliovirus vaccine is to revaccinate persons aged <18 years w ith IPV according to the U.S. schedule. Adverse events after IP V are rare {201). C hildren appropriately vaccinated w ith 3 doses o f O P V in econom ically developing countries m ig h t have suboptim al seroconversion, including to type 3 poliovirus {201). Serologic testing for neutralizing antib o d y to poliovirus types 1, 2, and 3 can be obtained com m ercially and at certain state health departm en t laboratories. Persons w ith protective titers against all three types do n o t need to repeat doses b u t should com plete the schedule as age appropriate.\n\n# Rotavirus Vaccine\nRotavirus vaccination should not be initiated for infants aged >15 weeks, 0 days. Infants w ho began the rotavirus vaccine series outside the U n ited States b u t who did n o t com plete the series and w ho are still aged <8 m onths, 0 days, should follow the routine schedule and receive doses to com plete the series. I f the brand o f a previously adm inistered dose is RV5 or unknow n, a total o f 3 doses o f rotavirus vaccine should be do cu m en ted for series com pletion. All doses should be adm inistered by age 8 m onths, 0 days.\n\n# Td and Tdap Vaccines\nC hildren aged >7 years w ho need the prim ary series doses o f tetanus-toxoid-containing vaccine should receive T d or T dap as age appropriate.\n\n# Varicella Vaccine\n\n# Varicella vaccine is n o t available in the m ajority o f countries. A person w ho lacks reliable evidence o f varicella im m u n ity should be vaccinated as age appropriate {4,20).\n\n# Zoster Vaccine\nZoster vaccination is recom m ended for all persons aged >60 years who have no contraindications, including persons who report a previous episode o f zoster or who have chronic medical conditions. T he vaccine should be offered at the patients first clinical encounter w ith the health-care provider. T h e vaccine is administered as a single 0.65-m L subcutaneous dose. Zoster vac cination is not indicated to treat acute zoster, to prevent persons with acute zoster from developing postherpetic neuralgia, or to treat ongoing postherpetic neuralgia. Before adm inistration o f zoster vaccine, patients do not need to be asked about their history o f varicella or to have serologic testing conducted to determ ine zoster immunity.\n\n# Vaccinating Persons with Bleeding Disorders\nBecause o f the risk for hem atom a form ation after injections, intram uscular injections are often avoided am ong persons w ith bleeding disorders by using the subcutaneous or intraderm al routes for vaccines th a t norm ally are adm inistered intram us cularly. In one study, hepatitis B vaccine was adm inistered intram uscularly to 153 persons w ith hem ophilia. T h e vac cination was adm inistered w ith a 23-gauge or sm aller caliber needle, followed by application o f steady pressure to the site for 1-2 m inutes. T h e vaccinations resulted in a low (4%) bruising rate, and no patients required factor supplem entation {213). W h e th er antigens that produce m ore local reactions (e.g., pertussis) w ould produce an equally low rate o f bruising is unknow'n. W h en hepatitis B or any other intram uscularly adm inistered vaccine is indicated for a p atien t w ith a bleeding disorder, the vaccine should be adm inistered intram uscularly if a physician fam iliar w ith the p atien ts bleeding risk determ ines th at the vaccine can be adm inistered by this ro u te w ith reasonable safety I f the patien t receives antihem ophilia or sim ilar therapy intram uscularly adm inistered vaccinations can be scheduled shortly after such therapy is adm inistered. A fine-gauge needle (23 gauge or smaller caliber) should be used for the vaccina tion, followed by firm pressure on the site, w ith o u t rubbing, for at least 2 m inutes. T h e p atien t or family should be given in form atio n o n the risk for h em ato m a from the injection. Patients receiving anticoagulation therapy presum ably have the same bleeding risk as patients w ith clotting factor disor ders and should follow the sam e guidelines for intram uscular adm inistration. tered, the vaccine m anufacturer, the vaccine lot num ber, and the nam e, address, and title of the person adm inistering the vaccine. In addition, the provider is required to record the edition date of the V IS distributed and the date those m ateri als were provided. T h e act considers a health-care provider to be any licensed health-care professional, organization, or institutio n , w hether private or public (including federal, state, and local departm ents and agencies), und er w hose authority a specified vaccine is adm inistered. T his inform ation should be kept for all vaccines, n o t just for those required by the act. Providers and staff m em bers also should system atically update patient's perm anent medical records to reflect any docum ented episodes of adverse events after vaccination and any serologic test results related to vaccine-preventable diseases (e.g., those for rubella screening and antib o d y to HBsAg).\n\n# Vaccination R ecords\n\n# Records of Health-Care Providers\n\n# Personal Records of Patients\nOfficial childhood vaccination records have been adopted by every state and territory and the D istrict o f C o lum bia to encourage u n iform ity o f records and to facilitate assessment o f vaccination status by schools and child-care centers. T h e records also are key tools in vaccination education program s aim ed at increasing parental and patient awareness o f the need for vaccines. A perm an en t vaccination record card should be established for each new born infant and m aintained by the parent or guardian. T h e parent or guardian should be educated about the im portance o f keeping the record up to date and instructed to keep the record indefinitely as part o f the child's perm anent medical record. These cards should be distributed to new m others before discharge from the hospital. Using vaccina tion record cards for adolescents and adults also is encouraged. Standardized adult vaccination records are available at h ttp :// w w w .im m unize.org.\n\n# Immunization Information Systems\n\n# Vaccination of Children and Adolescents\nPhysicians and other pediatric vaccination providers should adhere to the standards for child and adolescent vaccination practices (8). T hese standards were published by the N ational Vaccine A dvisory C o m m ittee and define appropriate vaccina tion practices for both public and private sectors. T h e standards provide guidance on practices that elim inate barriers to vaccina tion, including elim inating unnecessary prerequisites for receiv ing vaccinations, elim inating missed opportunities to vaccinate, im proving procedures to assess vaccination needs, enhancing knowledge about vaccinations am ong parents and providers, and im proving m anagem ent and reporting of adverse events. In addition, the standards address the im portance o f recall and rem inder systems and using assessments to m o n ito r clinic or office vaccination coverage levels. E nsuring adolescents receive rou tin e and catch-up vaccina tion and increasing vaccination coverage in this age group pres ent challenges. In general, adolescents do n o t visit health-care providers frequently. H ealth-care providers should prom ote annual preventive visits (217), including one specifically for adolescents aged 11 and 12 years. T h e annual visits should be used as o pportunities to provide routinely recom m ended vac cine doses, additional catch-up doses needed for lapsed vaccine series, vaccines recom m ended for high-risk groups, additional doses th at m ight have been recently recom m ended, and other recom m ended health-care services.\nAll vaccine doses should be adm inistered according to A C IP vaccine-specific statem ents and w ith the m ost recent schedules for b o th routine and catch-up vaccination. Before leaving any visit for m edical care, adolescents should be encouraged to schedule retu rn visits for any additional vaccine doses needed. D u rin g visits that occur outside o f influenza season, providers should discuss and recom m end seasonal influenza vaccination and m ake explicit plans for vaccination, including tim ing and anticipated setting (e.g., health-care provider's office, school, or pharm acy). C atch-up vaccination w ith m ultidose adolescent vaccines generally can occur according to the rou tine dosing schedule for these vaccines, although in some circumstances the clinician or health-care provider m ight use m in im u m intervals for vaccine doses. T hese circum stances include an outbreak th at increases risk for disease o r the likelihood th at doses will be missed in the future (e.g., because o f an im pending loss o f health-care coverage or tran sp o rtatio n challenges). Because o f lack o f efficacy data for H P V vaccine adm inistration using m inim um intervals, providers are encouraged, w h en possible, to use routine dosing intervals for females aged 11-26 years w ho have n o t yet received 3 H P V vaccine doses as recom m ended (20,28).\nO n e o f the challenges o f adolescent vaccination is ensur ing that current, com plete vaccination histories are available. Insurers, covered services, or reim bursem ent levels can change, and these changes m ight affect reim bursem ent for vaccine doses and vaccination services directly w hile also causing disruptions in an adolescent's access to vaccination providers or venues. In circum stances in w hich a vaccination record is unavailable, vaccination providers should attem p t to obtain this inform a tio n from various sources (e.g., parent, previous providers, or school records). M ore detail about how to obtain these records is available at from C D C at w w .cdc.gov/vaccines/ recs/im m uniz-records.htm . W ith the exception o f influenza and pneum ococcal polysaccharide vaccines, if d o cu m en ta tio n o f a vaccine dose is n o t available, the adolescent should be considered unvaccinated for th at dose. Regardless o f the venue in w hich an adolescent receives a dose o f vaccine, that vaccine dose should be docum ented in the p atien t's chart or in an office log, and the inform ation should be entered into an IIS. T h e adolescent also should be provided w ith a record card th at docum ents the vaccination history.\n\n# Adult Vaccination\nT h e incidence o f vaccine-preventable diseases in adults in the U nited States is high. A pproxim ately 4 5,000 adults die each year from vaccine-preventable diseases, the m ajority from influenza (222). In 2008, an estim ated 44,000 cases ofinvasive pneum ococcal disease were reported w ith approxim ately 4,500 deaths, the m ajority occurring am ong persons aged >35 years ( w w .cdc.gov/abcs/survreports/spneu08.htm ). Because o f recent licensure o f new vaccines approved for ad ults and new A C IP recom m endations for the use o f m any vaccines in adults, providers o f adult health care now share a greater responsibility for p u tting these recom m endations into practice. In 2009, an estim ated 4,070 deaths were caused by infection w ith the H P V strains causing the m ajority o f cervical cancers in this co untry th at are preventable w ith H P V vaccine and routine Papanicolaou sm ear testing ( w w .cancer.org/ docroot/hom e/index.asp). H erpes zoster causes considerable m orbidity in adults aged >50 years (55). A painful com plica tion o f herpes zoster infection is postherpetic neuralgia, w hich is characterized by severe pain that can persist for up to a year after the herpes zoster rash has subsided. A vaccine to prevent herpes zoster was licensed in 2006.\nIn Vaccination w ith vaccines recommended for all adults or for those in specific age groups is generally cost-effective, if n o t costsaving, for society. T h e N ational Com m ission on Prevention Priorities (N CPP) ranked clinical preventive services based on clinically preventable disease effects and cost-effectiveness (223) In the N C P P report, influenza vaccination for adults aged >50 years and pneumococcal vaccination for adults aged >65 years ranked high, w ith 8 o f 10 possible points in the scoring system used. M ost other studies have found influenza vaccination reduces or minimizes health care, societal, and individual costs or the pro ductivity losses and absenteeism associated w ith influenza illness {224-226). Economic analyses am ong adults aged >65 years have found influenza vaccination to be cost-effective (225)(226)(227).\nA 2008 study o f the cost-effectiveness o f PPSV dem onstrated that vaccination resulted in a gain o f $3,341 per quality-adjusted life year; the result is sensitive to vaccine uptake assumptions (228). PPSV administered at ages 50-65 years m ight be clini cally favorable and, depending on cost-effectiveness criteria used, economically favorable (228).\nH epatitis B vaccine is n o t recom m ended routinely for all adults. However, m ultiple studies have established the costeffectiveness o f providing hepatitis B vaccinations at counseling and testing sites for H IV and other sexually tran sm itted dis eases, correctional institutions, drug-abuse treatm en t centers, and other settings serving adults at risk for hepatitis B virus infection (229-230).\nFour studies have estim ated the cost-effectiveness o f a rou tine herpes zoster vaccination program o f im m u n o com petent persons aged >60 years (231-234). At a vaccine cost o f $150 per dose, the societal costs o f ro utinely vaccinating im m u n o com p eten t persons aged >60 years range from $27,000 to $ 112,000 per quality-adjusted life year gained (231-234). T he estim ated cost per quality-adjusted life year for zoster vaccina tion covers a wide range th at appears acceptable com pared with either standard thresholds or oth er established interventions b u t is at the interm ediate to high end o f that range.\nVaccination rates in adults are considered suboptimal (235-238). Healthy People 2010 goals for adult vaccination coverage with influenza and pneumococcal polysaccharide vaccines are 90% for each vaccine. For the 2007-2008 season, influenza vaccination coverage am ong adults aged 50-64 years was 34% , and cover age am ong adults aged >65 years was 66% (67). In 2008, 60% o f adults aged >65 years received a dose o f PPSV ( w w cdc.gov/nchs/data/hestat/vaccine_coverage.htm ). N ew Healthy People2 0 2 0 goals for influenza and pneumococcal polysaccharide vaccines include specific subsets o f adults, including institutional ized adults aged >18 years (for both influenza and pneumococcal polysaccharide vaccines) and noninstitutionalized adults at high risk aged >18 years (for pneumococcal polysaccharide vaccine) ( ?id=30&topicarea=immunization+and+infectious+diseases).\nT h e m ost substantial barrier to vaccination coverage is lack o f knowledge about these vaccines am ong adult patients and adult A com m on challenge for health-care providers is vaccinating adults w ith unknow n vaccination records. In general (except for influenza and pneum ococcal polysaccharide vaccines), adults should receive a vaccine dose if the dose is recom m ended and no record o f previous adm inistration exists. If an adult has a record of military service and does n o t have records available, providers can assume that the person has received all vaccines recom m ended by the military at the time o f service entry. Serologic testing m ight be helpful in clarifying im m une status if questions remain because at different times and depending on military assignments, there m ight be interservice and individual differences. 15).\n\n# Evidence-Based Interventions to Increase Vaccination Coverage\nIn 1997, the task force categorized as a recom m ended strat egy vaccination requirem ents for child care, school, and college (236). W hen appropriate, health agencies should take necessary steps to develop and enforce these requirem ents. Since 1995, all states receiving federal funds for vaccination program s have been required to cond u ct annual assessments of vaccination rates both in public health clinics and in pri vate provider offices. Prim arily to aid local and state health departm ents in their efforts to cond u ct assessments and assist providers, C D C has developed num erous software applications to m easure vaccination rates in provider practices.\n\n# Other General Programmatic Issues\nP ro g ram m atic challenges, evolving issues, and effective in te rv e n tio n s related to a d u lt and adolescent v accination program s have been described by oth er advisory groups and expert groups. Ad ditional evidence-based approaches are being developed for certain issues (e.g., settings for adolescent vac cination delivery) th ro u g h ongoing research and evaluation. A m ong current program m atic challenges, vaccine financing is especially difficult because certain problem s and solutions differ m arkedly from one state to another. Practitioners interested in beginning or contin u in g to provide vaccinations to patients are encouraged to consult w ith local and state public health vaccination program s to learn about publicly funded program s th at m ight be available in their areas for patients w ho need vac cination but have insufficient health insurance coverage and no financial resources. I f n o t already participating, providers wrho care for adolescents and children aged <19 years should enroll in the Vaccines for C hild ren Program ( w w .cdc.gov/ vaccines/program s/vfc/default.htm ). T h ro u g h this program 's provision o f A C IP-recom m ended, federally purchased vaccines, participating providers are able to fully vaccinate eligible chil dren w hose parents m ight n o t otherw ise be able to afford the vaccinations. Interested providers are encouraged to w ork w ith insurers, state and specialty-specific medical organizations, vac cine m anufacturers, and other stakeholders to address financial barriers to achieving high vaccination coverage. W ith avail ability o f safe and effective vaccines for 17 vaccine-preventable diseases, the capacity for realizing the potential benefits o f these products in the U nited States depends on reaching children, adolescents, and adults through dedicated, knowledgeable vac cination providers and efficient, strong vaccination program s at local, state, and federal levels.\n\n# V accine Information S ources\nIn addition to these general recom m endations, the following sources contain specific and updated vaccine inform ation.\n\n# CDC-INFO Contact Center\nT h e C D C -IN F O contact center is supported by C D C and provides public health-related inform ation, including vaccina tion inform ation, for health-care providers and the public, 24 hours a day, 7 days a week (telephone : 800-232-4636; telephone : 800-232-6348).\n\n# CDC's National Center for immunization and Respiratory Diseases\n\n# American Academy of Family Physicians (AAFP)\nInform ation from the professional organization o f family physicians is available at w w .aafp.org.\n\n# Immunization Action Coalition\n\n# National Network for Immunization Information\n\n# Vaccine Education Center\nLocated at the C h ild re n 's H o sp ital o f P h iladelphia, the Vaccine E ducation C en ter provides p atien t and provider vac cine inform ation ( w w .vaccine.chop.edu).\n\n# Institute for Vaccine Safety\nLocated at Johns H o p k in s U niversity S chool o f Public H ealth, the In stitute for Vaccine Safety provides inform ation about vaccine safety concerns and objective and tim ely infor m ation to physicians and health-care providers and parents ( w w .vaccinesafety.edu).\n\n# Group on Immunization Education of the Society of Teachers of Family Medicine\n\n# State and Local Health Departments\n\n# TABLE 1. (Continued) R ecom m en ded and m in im u m ages a n d intervals b e tw e e n vaccine doses'1 '\nAbbreviations: DTaP = diphtheria and tetanus toxoids and acellular pertussis; HepA = hepatitis A; HepB = hepatitis B; Hib = Haemophilus influenzae type b; IHPV = human papillomavirus; IPV = inactivated poliovirus; LAIV= live, attenuated influenza vaccine; MCV4 = quadrivalent meningococcal conjugate vaccine; MMR = measles, mumps, and rubella; MMRV= measles, mumps, rubella, and varicella; MPSV4 = quadrivalent meningococcal polysaccharide vaccine; PCV= pneumococcal conjugate vaccine; PPSV = pneumococcal polysaccharide vaccine; PRP-OMB = polyribosylribitol phosphate-meningococcal outer membrane protein conjugate; Td = tetanus and diphtheria toxoids;TIV = trivalent inactiated influenza vaccine;Tdap = tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis; Var = varicella vaccine. - Combination vaccines are available. Use o f licensed combination vaccines is generally preferred to separate injections o f their equivalent com ponent vaccines. When administering combination vaccines, the minim um age for administration is the oldest age for any o f the individual components; the m inimum interval between doses is equal to the greatest interval o f any o f the individual components. f Information on travel vaccines, including typhoid, Japanese encephalitis, and yellow fever, is available at . Information on other vaccines that are licensed in the United States but not distributed, including anthrax and smallpox, is available at . 5 Combination vaccines containing the hepatitis B component are available (see Table 2). These vaccines should not be administered to infants aged 7 months require fewer doses to complete the series. 1111 If PRP-OMP (Pedvax-Hib, Merck Vaccine Division) was administered at ages 2 and 4 months, a dose at age 6 months is not necessary. * A fourth dose is not needed if the third dose was administered at >4 years and at least 6 months after the previous dose. - Although MMR, DTaP, DT,Td, and Tdap are combination vaccines, they are not included on this list because they are not available in the United States as single-antigen products. f A dash ( -) between vaccine products indicates that products are supplied in their final form by the manufacturer and do not require mixing or reconstitution by the user. A slash ( / ) indicates that the products must be mixed or reconstituted by the user.\n\n# TABLE 3. G uidelines for spacing o f live and ina c tiv ate d antigen s Antigen com bination Recomm ended m inim um interval betw een doses\nTwo or more inactivated- May be administered simultaneously or at any interval between doses Inactivated and live May be administered simultaneously or at any interval between doses Two or more live injectable1 28 days m inimum interval, if not administered simultaneously Source: American Academy o f Pediatrics. Pertussis. In: Pickering LK, Baker, CJ, Kimberlin DW, Long SS, eds. Red book: 2009 report o f the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy o f Pediatrics; 2009:22. - Certain experts suggest a 28-day interval between tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine and tetravalent meningococcal conjugate vaccine if they are not administered simultaneously. T Live oral vaccines (e.g.,Ty2la typhoid vaccine and rotavirus vaccine) may be administered simultaneously or at any interval before or after inactivated or live inject able vaccines.\n\n# TABLE 4 . G uidelines for ad m in is te rin g a n tib o d y -c o n ta in in g p ro d u cts - and vaccines Type o f adm inistration Products adm inistered Recomm ended m inim um interval betw een doses\nSimultaneous (during the same office visit)\n\n# Nonsimultaneous\nAntibody-containing products and inactivated antigen Antibody-containing products and live antigen\n\n# Adm inistered first\nAntibody-containing products Inactivated antigen Antibody-containing products Live antigen\n\n# Adm inistered second\n\n# Inactivated antigen Antibody-containing products Live antigen Antibody-containing products\nCan be administered simultaneously at different anatomic sites or at any tim e interval between doses Should not be administered simultaneously.1 ' If simultaneous administration o f measles-containing vaccine or varicella vaccine is unavoidable, administer at different sites and revaccinate or test for seroconversion after the recommend ed interval (see Table 5)\n\n# No interval necessary\nNo interval necessary Dose related1-5 2 weeks1 \" - Blood products containing substantial amounts o f immune globulin include intramuscular and intravenous immune globulin, specific hyperimmune globulin (e.g., hepatitis B immune globulin, tetanus immune globulin, varicella zoster immune globulin, and rabies immune globulin), whole blood, packed red blood cells, plasma, and platelet products. 1 Yellow fever vaccine; rotavirus vaccine; oralTy2la typhoid vaccine; live, attenuated influenza vaccine; and zoster vaccine are exceptions to these recommendations.\nThese live, attenuated vaccines can be administered at any tim e before or after or simultaneously with an antibody-containing product. 5 The duration o f interference o f antibody-containing products with the immune response to the measles com ponent o f measles-containing vaccine, and possibly varicella vaccine, is dose related (see Table 5). - Events or conditions listed as precautions should be reviewed carefully. Benefits o f and risks for administering a specific vaccine to a person under these circum stances should be considered. If the risk from the vaccine is believed to outweigh the benefit, the vaccine should not be administered. If the benefit o f vaccination is believed to outweigh the risk, the vaccine should be administered. Whether and when to administer DTaP to children w ith proven or suspected underlying neurologic disorders should be decided on a case-by-case basis. I HIV-infected children may receive varicella and measles vaccine if CD4+ T-lymphocyte count is >15%. (Source: Adapted from American Academy o f Pediatrics.\n\n# TABLE 5. R ecom m en ded intervals b e tw e e n a d m in is tra tio n o f a n tib o d y -c o n ta in in g p roducts and m easles-or varicella-con tain ing vaccine, by p ro d u ct and ind icatio n for vaccination\nPassive immunization. In: Pickering LK, ed. Red book: 2009 report o f the comm ittee on infectious diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics: 2009.) 5 MMR and varicella vaccines can be administered on the same day. If not administered on the same day, these vaccines should be separated by at least 28 days. II Substantially immunosuppressive steroid dose is considered to be >2 weeks o f daily receipt o f 20 mg or 2 m g/kg body weight o f prednisone or equivalent. See text and Table 5 for details. t f Measles vaccination m ight suppress tuberculin reactivity temporarily. Measles-containing vaccine can be administered on the same day as tuberculin skin testing.\nIf testing cannot be performed until after the day o f MMR vaccination, the test should be postponed for >4 weeks after the vaccination. If an urgent need exists to skin test, do so w ith the understanding that reactivity m ight be reduced by the vaccine. 55 Hepatitis B vaccination should be deferred for infants weighing <2,000 g if the mother is documented to be HBsAg-negative at the tim e o f the infant's birth.\nVaccination can commence at chronological age 1 month or at hospital discharge. For infants born to HBsAg-positive women, hepatitis B immune globulin and hepatitis B vaccine should be administered w ithin 12 hours after birth, regardless o f weight. 1111 Vaccine should be deferred for the appropriate interval if replacement im mune globulin products are being administered (see Table 5). R e co m m e n d a tio n s a nd Reports\n\n# TABLE 7. C onditions com m o nly m isperceived as con traind ication s to vaccination Vaccine\n\n# Conditions com m only misperceived as contraindications (i.e., vaccination may be adm inistered under these conditions)\nGeneral for all vaccines, including Mild acute illness w ith or w ithout fever DTaP, pediatric DT, adult Td, Mild-to-moderate local reaction (i.e., swelling, redness, soreness); low-grade or moderate fever after previous dose adolescent- - Antibacterial drugs m ight interfere w ith Ty21a oral typhoid vaccine, and certain antiviral drugs m ight interfere with varicella-containing vaccines and LAIV. + Hepatitis B vaccination should be deferred for infants weighing <2,000 g if the mother is documented to be HBsAg-negative at the tim e o f the infant's birth.\nVaccination can commence at chronological age 1 month or at hospital discharge. For infants born to HBsAg-positive women, hepatitis B immune globulin and hepatitis B vaccine should be administered w ithin 12 hours after birth, regardless o f weight. 5 MMR and varicella vaccines can be administered on the same day. If not administered on the same day, these vaccines should be separated by at least 28 days.\nHIV-infected children should receive im mune globulin after exposure to measles. HIV-infected children can receive varicella and measles vaccine if CD4+T-lymphocyte count is >15%. If testing cannot be performed until after the day o f MMR vaccination, the test should be postponed for at least 4 weeks after the vaccination. If an urgent need exists to skin test, do so with the understanding that reactivity m ight be reduced by the vaccine. f t If a vaccinee experiences a presumed vaccine-related rash 7-25 days after vaccination, the person should avoid direct contact with im munocompromised persons for the duration o f the rash. J M e d V ir o l 1 9 8 6 ;1 9 :3 0 7 -1 1 .\n18. S tefano I, Sato H K , P a n n u ti CS, e t al. R ecent im m u n iz a tio n against measles does n o t inte rfere w ith the sero-response to y e llo w fever vaccine.\nV a ccine 1 9 9 9 ;1 7 :1 0 4 2 -6 .\n\n# G lossary\nAdverse event. An untoward event that occurs after a vaccination that might be caused by the vaccine product or vaccination process. Adverse events include those that have the following characteristics: 1) vaccine induced (caused by the intrinsic characteristic of the vaccine preparation and the individual response of the vaccinee): these events would not have occurred w ithout vaccination (e.g., vaccine-associated paralytic poliomyelitis); 2) vaccine potentiated: the events would have occurred anyway but were precipitated by the vaccination (e.g., first febrile seizure in a predisposed child); 3) programmatic error: the event was caused by technical errors in vaccine preparation, handling, or administration; and 4) coin cidental: the event was associated temporally with vaccination by chance or caused by underlying illness. Special studies are needed to determine whether an adverse event is a reaction to the vaccine or the result of another cause (Sources: Chen RT. Special m eth odological issues in pharmacoepidemiology studies o f vaccine safety. In: Strom BL, ed. Pharmacoepidemiology. 3rd ed. Sussex, England: John Wiley & Sons; 2000:707-32; and Fenichel GM, Lane DA, Livengood JR, Horwitz SJ, Menkes JH , Schwartz JF. Adverse events following immunization: assessing probability of causation. Pediatr Neurol 1989;5:287-90).\nAdverse reaction. An undesirable medical condition that has been demonstrated to be caused by a vaccine. Evidence for the causal relation is usually obtained through randomized clinical trials, controlled epidemiologic studies, isolation of the vaccine strain from the pathogenic site, or recurrence of the condition with repeated vaccination (i.e., rechallenge); synonyms include side effect and adverse effect.\nA djuvant. A vaccine com ponent distinct from the antigen that enhances the immune reponse to the antigen.\nA ntitoxin. A solution of antibodies against a toxin. Antitoxin can be derived from either hum an (e.g., tetanus im m une globulin) or animal (usually equine) sources (e.g., diphtheria and botulism antitoxin). Antitoxins are used to confer passive im m unity and for treatment.\nH y p e rim m u n e g lo b u lin (sp e c ific ). Special preparations obtained from blood plasma from donor pools preselected for a high antibody content against a specific antigen (e.g., hepatitis B immune globulin, varicella-zoster immune globulin, rabies immune globulin, tetanus im m une globulin, vaccinia immune globulin, cytomegalovirus im mune globulin, botulism im m une globulin).\nIm m u n e globulin. A sterile solution containing antibodies, which are usually obtained from hum an blood. It is obtained by cold ethanol fractionation of large pools of blood plasma and contains 15%-18% protein. Intended for intramuscular adminis tration, immune globulin is primarily indicated for routine main tenance of im m unity among certain immunodeficient persons and for passive protection against measles and hepatitis A.\nIm m u n o b io lo g ic. Antigenic substances (e.g., vaccines and toxoids) or antibody-containing preparations (e.g., globulins and antitoxins) from hum an or animal donors. These prod ucts are used for active or passive immunization or therapy. Examples of im m u nobiologies include antitoxin, immune globulin and hyperimmune globulin, monoclonal antibodies, toxoids, and vaccines.\nIntravenous im m une globulin. A product derived from blood plasma from a donor pool similar to the imm une globulin pool, but prepared so that it is suitable for intravenous use. Intravenous im m une globulin is used primarily for replacement therapy in primary antibody-deficiency disorders, for treatment of Kawasaki disease, imm une thrombocytopenic purpura, hypogammaglobu linemia in chronic lymphocytic leukemia, and certain cases of hum an immunodeficiency virus infection (Table 5).\nM onoclonal antibody. An antibody product prepared from a single lymphocyte clone, which contains only antibody against a single antigen.\nS im ultaneous. In the context of vaccine timing and spacing, occurring on the same clinic day, at different anatomic sites, and not combined in the same syringe.\nToxoid. A modified bacterial toxin that has been made nontoxic, but retains the ability to stimulate the formation of antibodies to the toxin.\nVaccination and im m unization. The terms vaccine and vaccina tion are derived from rncca, the Latin term for cow. Vaccine was the term used by Edward Jenner to describe material used (i.e., cowpox virus) to produce im m unity to smallpox. The term vaccination was used by Louis Pasteur in the 19th century to include the physical act of administering any vaccine or toxoid. Immunization is a more inclusive term, denoting the process of ind ucing or providing im m unity by administering an immunobiologic. Immunization can be active or passive. Active immunization is the production of antibody or other immune responses through administration of a vaccine or toxoid. Passive immunization means the provi sion of temporary im m unity by the administration of preformed antibodies. Although persons often use the terms vaccination and immunization interchangeably in reference to active immunization, the terms are not synonymous because the administration of an immunobiologic cannot be equated automatically with develop m ent of adequate immunity.\nVaccine. A suspension of live (usually attenuated) or inactivated microorganisms (e.g., bacteria or viruses) or fractions thereof administered to induce im m unity and prevent infectious disease or its sequelae. Some vaccines contain highly defined antigens (e.g., the polysaccharide of Haemophilus influenzae type b or the surface antigen of hepatitis B); others have antigens that are complex or incompletely defined (e.g., Bordetella pertussis antigens or live, attenuated viruses).\n\n# Advisory Committee on Immunization\n\n# TABLE 14. Approaches to evalu atio n a n d vaccination o f persons vaccinated o utsid e th e U n ite d States w h o have no (or q uestio nab le) vaccina tio n records"}}},{"rowIdx":95,"cells":{"id":{"kind":"string","value":"6f54b2765652e9c1ce06057c1089f86ea5ec3a8e"},"source":{"kind":"string","value":"cdc"},"text":{"kind":"string","value":"The Occupational Safety and Health Act of 1970 (Public Law 91-596) states that the purpose of Congress expressed in the Act is \"to assure so far as possible every working man and woman in the Nation safe and healthful working conditions and to preserve our human resources...by,\" among other things, \"providing for research in the field of occupational safety and health...and by developing innovative methods, techniques, and approaches for dealing with occupational safety and health problems.\" Later in the Act, the National Institute for Occupational Safety and Health (NIOSH) is charged with carrying out this policy. One method by which NIOSH responds to this charge is to publish recommendations for control of occupational safety and health hazards. the Occupational Safety and Health Administration (OSHA) for cons Occupational Safety and Health Centers for Disease Control iii ACKNOWLEDGMENTS The contributions to this publication by NIOSH staff, other Federal agencies, the review consultants, the reviewers selected by the American Industrial Hygiene Association (AIHA) and the Society for Occupational and Environmental Health (SOEH), and consultants William C. Nicoll and Robert B. O'Connor, M.D. are gratefully acknowledged. The Division of Standards Development and Technology Transfer, National Institute for Occupational Safety and Health, had primary responsibility for the development of this publication. The initial development was performed by Paul A. Schulte and Charles H. Gorski. The publication was completed by Howard R. Ludwig. Contributors to this document and previous unpublished versions of it are listed below and on the following pages. The NIOSH review of this publication was provided by Robert W.#\nThese publications critically review the scientific and technical information available on the prevalence of hazards, the existence of safety and health risks, and the adequacy of hazard control methods in an industry.\nThe information and recommendations presented should facilitate development of specific procedures for hazard control in individual workplaces.\nIn addition, these publications list the Federal standards applicable to the industry and the specific hazardous substances that are present in its work environment.\nIn the Interest of wide dissemination of this information, NIOSH distributes these publications to other appropriate governmental agencies, organized labor, industry, and public interest groups.\nWe welcome suggestions concerning the content, style, and distribution of these documents.\nThis document provides guidance for protecting workers involved in the manufacture of paint and allied coating products.\nIt was prepared by the staff of the\n\n# II. CHARACTERISTICS OF THE PAINT AND ALLIED COATING PRODUCTS\nThe handling of raw materials and finished products; dispersion of pigment or resin particles; thinning, tinting, and shading; filling; and laboratory functions are some of the operations in the paint and allied coatings industry that will be discussed in this publication. The recommendations are broad-based to accommodate variations between facilities and the wide range of operations and processes encountered. Many of the recommendations, such as those addressing the use of personal protective equipment, machine guarding, container labeling, and worker training, are consistent with the Occupational Safety and Health Administration (OSHA) General Industry Standards contained in 29 CFR 1910. Other recommendations, such as those concerning substitution of raw materials, engineering controls, or safe lifting techniques are addressed only generally in OSHA standards or not at all.\nThe recommendations are intended to enable management and labor to develop better work practices and training programs that will result in safer working environments.\nChapter II provides a discussion of basic characteristics for those persons who are not familiar with this industry. The document in its entirety provides safety and health information for organized labor; managers, technical consultants, and occupational safety and health personnel of companies involved in this industry; and the field staffs of various governmental agencies (i.e., NIOSH, OSHA, and EPA) responsible for the safety and health of workers.\n\n# II. C H A R A C T E R I S T I C S O F T H E P A I N T A N D A L L I E D C O A T I N G P R O D U C T S I N D U S T R Y A. Overview\nPaint and allied coating products constitute a general class of materials whose primary functions are the protection and decoration of surfaces. Coatings are also used for fire retardation, color coding, electrical insulation, and temperature control ,\nIn the most narrow sense, \"paint\" refers only to pigmented products such as interior (wall), exterior (house), masonry, and traffic coatings; terms for other coatings include enamel, undercoater, primer, sealer, varnish, lacquer, stain, and industrial finishes. Historically, however, the term \"paint\" has sufficed as the common description for coating materials consisting of a covering material (pigment), a film-forming material (usually an oil or resin), and viscosity modifiers (thinners and solvents).\nThe terms \"organic surface coating,\" \"paint and coating,\" or \"chemical coating\" are increasingly being used to describe a variety of products that are used for the protection or decoration of surfaces.\nRelated to the various types of surface coatings are allied products such as putties and paint and varnish removers.\nThe major types and end uses of paint and coating products are shown in Table II-l.\nThe manufacture of most coatings basically involves the incorporation of pigment particles in a film-forming matrix, thinning and adjusting the resultant product, and dispensing it into containers of various sizes for shipment and sale.\nThe manufacture of varnishes, which contain no pigments, is a different type of batch process which involves mixing ingredients and \"cooking\" them in a reactor vessel or kettle. Definitions of various terms used in the coatings industry are listed in the Glossary (Appendix A).\n\n# Thousands of different raw materials are used in the manufacture of approximately 20,000 different coating products .\nThe need for so many raw materials and products results from the great diversity of surfaces requiring treatment. There are numerous small manufacturers because paint-making is still largely a batch process that does not readily lend itself to automation or continuous flow processing , Few firms sell nationwide because of high shipping costs, the difficulty of maintaining production schedules, and other distribution problems.\n\n# I. Industry Trends\nGrowth in the total production of the U.S. paint and allied coating products industry has been about 2% annually since 1967 and is expected to continue at this rate through 1990 .\nIn 1981, over 900 companies produced architectural coatings, approximately 250 companies made product coatings for original equipment manufacturers, and approximately 250 companies made special purpose coatings .\nThe largest companies are active in all coatings categories; whereas, the smaller companies may specialize in only one segment of the industry .\n\n# Air pollution regulations limiting\nthe amount of volatile organic compounds that can be used in coatings and the rapid rise in solvent prices are responsible for the trend in the coatings industry to replace conventional low-solids, volatile organic solvent-based coatings with high-solids (i.e., over 70%) or low solvent or water-based formulations such as radiation-curable coatings, powder coatings, two-part catalyzed systems, and nonaqueous dispersions [1,2,6 In addition to the air pollution emission potential of various coating systems, a factor in their selection is the amount of energy required for application and for engineering controls to reduce occupational exposure.\nBecause of relatively high energy efficiencies, the use of high-solids and radiation-curable coatings is expected to increase ,\n\n# E x t e n t of E x p o s u r e\nAccording to the 1978 Annual Survey of Manufacturers , the paint and allied coating products industry in the United States employed about 61,500 workers in 1,700 individual plants. About 60% of the paint facilities had fewer than 20 workers, and only about 3% of the facilities (i.e., about 50) had more than 250 workers . These coatings include paints, lacquers, and powders and are applied during the manufacturing process to the surfaces of products made from metal, wood, or plastic. About 60-65% of these coatings have been solvent-based, but in recent years applications for water-based, high-solids, powder coatings, and two-part catalyzed systems have been increasing , \"Special purpose coatings\" may be stock-type or shelf goods, but they are formulated specifically for refinishing and specialty applications or for environmental conditions such as extreme temperatures or corrosivechemical atmospheres .\nThese coating types include high-performance industrial maintenance paints, automotive and machinery refinishes, and traffic paints and can be either solvent-or water-based ,\n\n# J o b C l a s s i f i c a t i o n s\nA scheme for the classification and description of jobs in this industry has been developed by Discher et al. .\n\n# A revised version of this classification is presented in Table II-2.\nA similar description of job classifications in the varnish manufacturing process is shown in Table II-3. In many smaller plants, one worker might perform a number of different jobs rather than just one particular task.\n\n# Raw materials handlers\nTransport and store raw materials in the plant.\n\n# Prebatch assemblers\nWeigh and assemble raw materials (usually dry) for the mixer, primarily in the raw materials storage and mixing areas.\n\n# Mixers (including mill operators)\nLoad mixing tanks or mills. Responsible for quality control checks for dispersion. May be responsible for cleaning the mills.\n\n# Tinters (including thinners, shaders, and body adjus ters)\nResponsible for the dispersed paint quality. Add solvents, driers, preservatives, and tinting paste.\nResponsible for quality control for color, viscosity, etc.\n\n# Fillers\nFill paint containers.\n\n# Set up the filling line (if mechanized).\n\n# Tank and tub cleaners\nClean portable tanks and tubs.\n\n# Laboratory personnel\nTest raw materials. Responsible for finished product testing and for research and development.\n\n# thers\nIncludes packagers, maintenance personnel, shippers, and loading personnel in the warehouse.\n\n# Adapted from Discher et al. \n\n# Varnish cookers\nCook varnish and maintain reaction conditions (applies only to open-kettle process).\n\n# Filter press opera tors\nFilter and reduce the varnish and clean the presses.\n\n# Fillers\nFill varnish containers.\n\n# Laboratory personnel\nTest raw materials. Responsible for finished product testing and for research and development.\n\n# Others\nIncludes packagers, maintenance personnel, shippers, and loading personnel in the warehouse.\n\n# Adapted from Discher et al. \n\n# B. Raw Materials\nLiquid paint is a suspension of pigment particles in a mixture of film-former and volatile solvent.\nThe solvent, which reduces viscosity to allow easy application, and the film-former hold the pigment in the dried film and cause it to adhere to the coated surface.\nThe pigment confers hiding and coloring power as well as durability to the dried film.\nVarious additives are used to obtain particular characteristics.\nAlthough drying is usually accomplished through evaporation of the solvent, drying may also be by polymerization of the film-former through oxidation (e.g., with oils and alkyds), by coalescence (e.g., with latexes), or by chemical reactivity (e.g., with epoxy resins) .\nIn 1980, an estimated 9.5 billion pounds of raw materials (excluding water) were used in the manufacture of paint and allied coating products ,\nThe four general categories of raw materials used (film-formers, pigments, solvents, and additives) are identified in Figure II-2. Linseed oil is the primary drying oil utilized as a film-former.\n\n# F I G U R E II-2. R A W M A T E R I A L S U S E D IN T H E M A N U F A C T U R E OF C O A T I N G\nNatural resin film-formers constituted less than 1% of all film-formers consumed in 1977 , in contrast to about 50% prior to World War II , Some of these natural resins include rosins and shellac.\n\n# Pigments\nPigments are incorporated into coatings to impart color, opacity, and properties such as durability, corrosion inhibition, and mildew control or to be a filler or extender . They are finely powdered solids that are essentially insoluble in the medium in which they are dispersed. Almost all of the pigments utilized in the U.S. (99%) are inorganic with titanium dioxide accounting for about one-third of total pigments used . Pigments are generally classified as white (opaque) pigments, colored and black pigments, extenders (non-opaque), and miscellaneous (mainly metallic powders). They are less expensive than many other types of organic solvents and have many uses.\nAn organic solvent-based coating material that contains no hydrocarbon solvent is unusual. Hydrocarbon solvents used in the paint industry are classified as either aliphatic naphthas or aromatics.\nAliphatic naphtha solvents such as mineral spirits or Varnish Makers' and Painters' (VM&P) naphtha are predominantly paraffins, with a smaller but appreciable content of cycloparaffins (naphthenes such as cyclopentane and cyclohexane). These solvents may also contain as much as 20-30% aromatics ,\nMineral spirits constitute about three-fourths of all hydrocarbon solvents used in the paint and allied coating products industry overall.\nThe aromatic hydrocarbon solvents such as toluene, xylene, high flash solvent naphthas, and aromatic naphthas predominantly exhibit higher solvency than aliphatic solvents.\n\n# b. Oxygenated Solvents\nOxygenated solvents are so designated because of the presence of oxygen which contributes polarity (a difference in the electric charge on various portions of the materials).\nThis polarity is the fundamental difference between oxygenated and hydrocarbon solvents, which are essentially nonpolar.\nBecause\n\n# A d d i t i v e s\nMany substances that contribute to the ease of manufacture, the stability of the paint in the package, the ease of application, or the quality or appearance of the applied film are used in relatively small quantities in paint formulations.\nThese\n\n# e. A n t i -s k i n n i n g A g e n t s\nSkinning refers to the drying of a coating, but at the wrong time and in the wrong place (e.g., while it is still packaged).\nOxidative polymerization of the film-formers at the air-liquid interface can lead to the formation of a solid or gelatinous skin on the surface. reactions. Production is begun by mixing the pigment, film-former, and solvent (organic solvent or water). This is followed by the dispersion operation, which is a manipulation of the mixture to achieve pigment particle separation, wetting, and stabilization.\nThe performance of the finished product depends on the maintenance of uniform interparticle distances in the dried film .\nA variety of equipment is used to effect dispersion.\nThe trend currently is to use equipment in which the paint formulation can be continuously mixed and dispersed, followed by thinning in the same unit , After dispersion, the resultant material is tested for viscosity, color, and other physical properties while being adjusted or thinned.\nAfter passing this inspection, the batch is strained and loaded into containers.\nThe manufacture of varnishes is one of the most complex processes in a coatings plant, primarily because of the large variety of different raw materials, products, and cooking formulae used ,\nVarnishes are classified on the basis of the resins used.\nOleoresinous varnishes are solutions of both oils and resins; whereas, spirit varnishes such as shellac are formed by dissolving a resin in a solvent.\nVarnish manufacture essentially consists of heating or cooking materials in a reactor vessel or kettle and then thinning and filtering the final product , 1. Paints a. Materials Handling Materials handling occurs primarily at both ends of the production process.\nRaw materials are available as liquids, solids, powders, pastes, and slurries.\n\n# b. Dispersion\nThe assembly of raw materials is followed by the mixing of pigments with film-formers, solvents, and additives and the dispersion of the pigment particles in the liquid matrix.\nDispersion consists of a deagglomeration or separation of aggregates of individual particles, the wetting of particles with solvent and film-former, and uniformly distributing particles in the liquid phase.\nTypes of dispersion equipment include high-speed shaft-impeHer dispersers, dough mixers, and a variety of mills such as roller, stone, pebble, media, stator-rotor, attritor, Uniroll, resonant, vibratory, and Kady® .\nAfter the dispersion operation, it may be necessary to clean the mills and tanks before a new batch is introduced.\nTank and mill cleaning can involve hand and power tools as well as caustic cleaners and solvents. c. T h i n n i n g , T i n t i n g , a n d S h a d i n g Thinning operations involve the further addition of a film-former or solvent to the batch following the mixing and dispersion operations. These operations may be performed in stationary tanks or in portable change cans. Tinting and shading operations involve adding color to white bases or adjusting the color of solid color bases that have been formulated as complete products.\nAfter these operations, the quality of the paint must be checked by sample collection and laboratory analysis.\n\n# d. Filling Operations and Finished Product Handling\nAfter the desired paint quality is achieved, the paint is strained or filtered to remove foreign material.\nFabric or metal screen filters, vibrating or variable-speed centrifugal clarifiers, vibrating screens, and cartridge filters can be used.\nAfter filtering, the coating is either manually or machine-filled into cans that are subsequently sealed, labeled, packed, and stored or shipped.\n\n# Lacquers\nLacquers differ from most other coatings in that the film dries or hardens entirely by evaporation. Therefore, it is impractical to manufacture lacquers in the customary manner because volatilization of the solvents results in deposits of a dry, solid film on processing equipment .\nThus, production is carried out in enclosed equipment such as tanks or mixers to reduce solvent loss, ensure ease of cleanup, and provide fire safety.\nHowever, lacquer is produced in the same general manner as paint.\n\n# Varnishes\nAll varnishes (i.e., oleoresinous and spirit) are solutions of film-formers in organic solvents. The manufacture of oleoresinous varnishes involves a cooking stage to render the oil and resin more compatible, to develop high molecular weight molecules or polymers, and to obtain solubility in the thinner or solvent. The manufacture of spirit varnishes usually involves cold cutting the resin with the solvent; however, mild heat may be used occasionally , Varnish is cooked in portable kettles or in large reactors, although kettles are now used only to a limited extent and primarily by smaller manufacturers .\nLarge closed reactors with capacities of 1,000 to 8,000 gallons are more common .\n\n# a. Operation of Kettles\nIn facilities where portable kettles are still used, resin and oil or resin alone is added to the kettle and then heated to about 600°F (316°C).\nNatural resins must be heated prior to adding the oils to make the resin more compatible with the oils.\nAll materials are poured in over the top of the kettle (150-375 gallon capacity). During the cooking phase, the kettles are covered with retractable hoods with exhaust pipes that may be fitted with solvent condensers. After the materials are cooked, the kettles are moved to rooms where the kettles are cooled quickly, often by water spray, and thinner and driers are added .\n\n# b. Operation of Reactor Vessels\nVarnish production is different when reactor vessels are used instead of kettles.\nMost reactors range in size from 500 to 8,000 gallons . Reactors are designed to give exact process control and usually can handle a variety of different varnishes, operate over a wide range of temperatures, and be cleaned easily.\nVarnish reactor vessels are similar to batch reactor equipment used in the chemical process industry.\nThe vessels are fitted with agitators, manholes, sight-glasses, lines to charge liquid reactants, condensers, temperature measuring devices, sampling devices, discharge lines, and heat sources.\n\n# c. Filtering\nFiltration of the thinned resin is the final step before the varnish is packaged. This is normally done while the resin is still hot. The filter press is the most commonly used filtering device .\n\n# Powder Coatings\nPowder coatings are solventless systems based on the melting and subsequent fusion of resin and other additive particles onto surfaces of heated objects.\nPowder coatings, which may be either thermosetting or thermoplastic, are made from various types of resins such as epoxies, polyethylene, polyesters, polyvinyl chloride, and acrylics.\n\n# Three methods have been used\nto manufacture powder coatings: dry blending, extrusion melt-mixing, and a combination of the two. Dry blending of powder coating ingredients is usually accomplished by placing all components (powdered resin, pigments, additives, and powdered curing agents) into a cooled pebble mill with high density porcelain grinding media.\nThe extrusion melt-mixing method involves premixing the dry components to ensure homogeneity and to reduce particle size.\nThe mix is placed in a specially-designed extruder where it is heated until molten.\nThe molten material is then deposited on a cooling belt, and when it has cooled to a friable state, it is transferred to a coarse granulator.\nThe granulated material is then passed through a fine grinder and particle size classifier and packaged.\nFigure shows a typical layout for the manufacture of powder coatings by the extrusion melt-mixing method. A wider range of pigments is used with interior stains.\n\n# Radiation-Curable Coatings\n\n# Radiation\nThe film-fortners for interior stains are usually very low-solids alkyd resin solutions.\nGenerally, the manufacture of stain is similar to that of paint.\n\n# Allied Coating Products\nMany of the allied or sundry products of the coatings industry are manufactured in the same plants as paint, with few variations in the processes previously discussed in this section.\n\n# a. Putties\nThe manufacture of putties involves the dispersion of calcium sulfate in oils and adjustment with small amounts of solvent in a dough-type mixer or in a mixer known as a putty chaser .\nThe viscous putty is usually put into containers directly from the dispersion stage.\n\n# Laboratory Functions\nAnalytical and developmental laboratory functions are integral to the manufacture of coatings.\nFour functional types of laboratories are found in coatings manufacture: analytical, quality control, formulation or product development, and research and development .\nMany companies combine the various laboratory functions in one space; whereas, others separate each function.\nAnalytical laboratories receive samples of incoming raw materials to be tested for conformity with purchase specifications.\nOther analytical laboratory functions include the analysis of competing products and \"bad batches\" of paint.\nQuality control laboratories test the product before it is packaged for various physical characteristics such as weight per gallon, viscosity, color, and drying time.\nIn the formulation or product development laboratory, existing products are refined.\nThis differs from the research and development laboratory which is involved with basic research and the development of completely new classes of products.\n\n# III. HEALTH AND SAFETY HAZARDS DURING THE MANUFACTURE OF PAINT AND ALLIED COATING PRODUCTS\n\n# A. Injury and Illness Statistics\nThe number and severity of injuries and illnesses in the Paints, Varnishes, Lacquers, Enamels, and Allied Coating Products Industry (SIC code 285) may be estimated from information reported by the Bureau of Labor Statistics (BLS), U.S. Department of Labor .\nTable III-l shows the average annual employment and injury and illness incidence rates (per 100 full-time workers) from 1980 through 1982 for total cases, lost workday cases, nonfatal cases without lost workdays, and lost workdays in SIC code 285. , 1980-1982 Average Incidence Rates per 100 Full-time Workers These data show an annual total of approximately 7,570 injuries and illnesses (employment times total case incidence rate divided by 100) in paint manufacturing facilities.\nPer 100 full-time workers, paint manufacturers had an average injury and illness incidence rate of 12.0 and an average lost workday incidence rate (severity rate) of 74.3, which are about the same as the average rates exhibited by \"All Manufacturing\" industries.\n\n# Also\n-f interest are data included in Table III-2, which address occupational injury and illness rates by employment size in the paint and allied coating products industry.\nThe highest incidence rates occurred in facilities with 20-249 workers. The most prevalent sources of injuries and illnesses were boxes, barrels, containers, packages, etc. (33.3%), working surfaces (10.7%), and chemicals (9.0%).\nThe most common types of accidents were overexertion (31.3%), struck by an object (15.4%), and struck against an object (9.6%). Sprains and strains (40.5%) were the most prevalent nature of injury, followed by contusions and bruises (15.2%), and cuts, lacerations, punctures, etc. (10.4%).\nThe back (24.4%) and fingers (11.5%) were the parts of the body most frequently affected .\nIn an attempt to better elucidate accident causal factors, 38 \"sources of injury\" (which included 81% of the total cases) were cross-tabula ted with the \"type of accident,\" \"nature of injury,\" and \"part of body affected.\" These data are summarized in Table III-5.\nAnother analysis of the SDS data is summarized in Table III-6 where 15 occupational groupings (which included 81% of the total cases) were similarly cross-indexed.\nMention needs to be made of some of the data constraints of the SDS reporting system.\nAlthough there are about 300 subcategories of \"sources of injury,\" and 425 occupational classification codes, in many instances the subgroupings are still not useful for the purpose of quantifying accidents specific to paint manufacturing.\nFor instance, there might not be specific SDS categories for the inclusion of equipment typically used in the paint industry which would necessitate its being grouped into a broad category such as \"Machines, Not Elsewhere Classified.\"\nSimilarly, although there is an occupational classification for mixing operatives, individual facilities when filling out the workers' compensation form could have coded paint mixers in a number of other categories (e.g., miscellaneous operatives, machine operatives, not specified, etc.).\nA further difficulty encountered in the data base, when using it for analysis of accident causal factors, is that, by definition, the \"source of injury\" is the object identified as most responsible for causing the injury.\nThis may, in fact, not be directly associated with the actual cause of the accident.\nFor example, if a worker cuts his finger while using a knife, the \"source of injury\" is the knife, which also is the tool most clearly associated with the cause of the accident.\nHowever, if a worker falls from a ladder and fractures his leg on the floor, the \"source of injury\" is the floor, which probably contributed very little to the actual cause of the accident.\nHowever, once the constraints of the SDS data are recognized, the information included can be applied to further identify some of the hazards associated with occupations, tasks, tools, and equipment used in paint manufacturing.\nIn Table III-5 the most frequent subcategories for each major heading are listed; all subcategories relate to the \"source of injury\" in the first column and are not expected to total with it.\nIn Table III As would be expected, Table III-5 indicates that injuries related to materials handling (i.e., containers, handtrucks, dollies, skids, pallets, etc.) were most often caused by overexertion and by being struck by falling objects.\nSprains, strains, contusions, bruises, cuts, and lacerations were the most common injuries; the back and fingers were the parts of the body most frequently affected.\nAn interesting finding was that 60% of the injuries caused by chemicals (i.e., 615 of 1,027) were from skin contact (absorption); 47% of these injuries were chemical burns of the skin.\nAnalysis of the SDS data by \"occupation\" yielded similar results. As Table III-6 indicates, various types of containers (i.e., barrels, boxes, crates, etc.) were the most common sources of injury (20-30%) in almost every occupational grouping.\nAs before, overexertion and \"struck by or against\" type accidents were the most prevalent, with the most common injuries also being sprains, contusions, and cuts. Exposure to chemicals again accounted for a significant proportion of injuries in many of the occupational groups, usually resulting in chemical burns of the skin. Nonproduction workers (clerks, salesmen, managers, chemists, secretaries, etc.), who make up about 51% of the workforce in SIC code 285 , accounted for 13% of the cases in the SDS file .\nConversely, production workers were involved in 87% of the injuries and illnesses in paint and allied coating products manufacturing although comprising only about 49% of the total workforce. Further analysis of the SDS data showed that workers under 26 years of age accounted for about one-third of the injuries and illnesses and that workers under 31 years of age accounted for over half (51.6%).\nAlthough only about one-third of the SDS cases had length of service data, 36.9% of those injuries occurred within the first year with the company, 5 0 . 4 % within the first 2 years, and 69.9% within the first 5 years .\nThe types and numbers of illnesses in the SDS data base are shown in Table III-7. Dermatitis was the most common illness noted (41.2%).\nThe SDS data show that only 5.7% of the total number of injuries and illnesses were due to illnesses .\nHowever, occupational illness data from the SDS suffer from the same degree of identification as that experienced in the BLS annual survey of occupational injuries and illnesses.\nRecognition of occupational illness depends on the \"state of the art.\" Nevertheless, despite the underestimate of the incidence of occupational illnesses, it is evident that reducing injuries should be a high priority of the paint and allied coating products industry. Workers in paint and allied coating products facilities may be exposed to a wide variety of hazardous conditions during the performance of their jobs. The majority of these hazards exist, to some extent, throughout industry, although certain characteristics in the paint industry may magnify the degree of risk.\nThe hazards associated with the manufacture of paint and allied coating products involve materials handling; toxic, flammable, or explosive substances; and physical agents such as electrical shock, noise, heat, and cold.\nThese hazards can be present at various stages of production.\nIn this section, there will be a discussion of the hazards involved with the storage and handling of raw materials and finished products for the industry in general, followed by other hazards associated with specific types of paint and allied coating products manufacture. Inhalation is a primary route of exposure for materials handlers, but skin exposure and ingestion are also possible.\nDry materials such as pigments and additives can become airborne when containers leak or are ruptured and when materials are transferred. Loading pigments into grinding equipment and discarding empty bags can cause the surrounding plant areas to become contaminated with dust. Solvents are volatile and their vapors can escape when transferred in the open or if containers develop minor leaks or are accidentally ruptured. Because of both toxicity and danger of fire, solvent spills present a serious hazard to workers.\nMany substances used in paint and allied coating products are highly volatile and flammable or are explosive.\nThe fire and explosion risk is high wherever organic solvents are present.\nCombustible material can be ignited by a spark or by high temperatures.\nSources Preventing the accumulation of static electricity in the handling of liquid raw materials requires special techniques and precautions. Static electricity may be produced when nonconducting liquids flow through pipes or hoses; when liquids fall through the air in droplets or as a spray; when liquids are splashed around in tanks --in the mixing, pouring, pumping, filtering, and agitation of liquids; or when air or other gases bubble through liquids ,\nIn addition to potential exposures to the m a n y raw materials handled, carbon monoxide emitted from engine exhausts may be a hazard on loading and shipping docks. Exposures may be greater in the winter when loading areas are often enclosed to minimize heat loss.\n2. M a n u f a c t u r e of P a i n t s a n d L a c q u e r s There are a number of potential hazards that confront workers in the various processes involved in the manufacture of paints and lacquers.\n\n# a. Dispersion\nPigment and resin particles may enter the breathing zones of workers when mixer and mill hoppers are filled.\nAirborne particles may also result when the mixers and the mills are operated. Workers may also be exposed to solvents during the loading, operation, and cleaning of mills.\nA noise hazard may be associated with the use of ball and pebble mills, especially when the mills are improperly adjusted, as well as with the use of high-speed dispersers.\nThe noise levels at dispersion equipment such as Kady® mills have been found to range from 109-114 dBA .\nSeveral mills operating simultaneously will have a combined sound pressure level greater than any individual mill.\nBall mills that do not have vibration isolators can be the source of structure-borne vibrations that could be reradiated by other objects in the building , Cleaning the dispersion equipment involves the use of solvents and may result in potential exposure by inhalation or skin absorption. Cleaning may be performed manually or by automatic solvent wash. Since roller mills are often cleaned manually, there is also the potential hazard of catching and crushing arms and fingers between rollers.\nTo Maintenance operations involve many of the same hazards associated with cleaning operations.\nNitrocellulose, which is used in lacquer production, is one of the most flammable materials used in the coatings industry; it will not burn when wet with water but becomes flammable when water is extracted and replaced with alcohol . When nitrocellulose is dry, it burns very rapidly and can be ignited by friction or impact , b. Thinning, Tinting, and Shading Although exposure to additives either as dusts or vapors can also occur, solvent exposure is the primary hazard associated with these adjustment procedures.\nSince quality control checks are often made during these operations, exposures can also occur during sampling and transport of samples to the laboratory. c. F i l l i n g Solvent exposure is also the primary hazard of filling operations. Such exposures may result from direct evaporation of the solvent as the coatings flow into containers or from the cleaning and maintenance of the filling apparatus, particularly the filters used in the first step of the operation.\nExtensive noise can be generated by the vibrating screens used for filtering.\nPackaging the products usually involves automated equipment with moving parts that may catch on clothing.\nBurns or vapor exposure may also result from the use of hot, melted glues to secure packaging and labels.\n\n# d. Handling Finished Products\nSafety hazards involved in handling finished coating products are similar to those involved in handling raw materials (e.g., lifting, slippery working surfaces, poor clearance, reduced visibility, etc.).\nFinished products are usually in sealed metal containers and present little respiratory hazard.\nAutomatic depalletizers are a potential source of excessive noise.\n\n# Manufacture of Varnishes\nVarnish production requires an external source of heat and, therefore, differs from paint and lacquer production. Temperatures associated with the manufacture of varnish are often 2 0 0°-6 0 0°F (93°-316°C) and cause the formation of gaseous substances during varnish cooking .\n\n# a. Kettle and Reactor Operation Hazards\nThe major hazards associated with the cooking stage in varnish production involve airborne exposures while loading the vessels or emissions while processing.\nLoading or charging the reactor vessel is usually done by pumping in the liquid reactants such as oils, glycols, or acid anhydrides.\nWhen dry materials are added, they can release irritant dusts or vapors of maleic, phthalic, or fumaric anhydride.\nSplattered molten anhydride can harm eyes and skin. Moreover, temperature changes at vents and orifices must be avoided so that vapors of these materials will not condense and form pressure plugs.\n\n# Since\nthese reaction vessels are mostly closed systems, only inadvertent or fugitive emissions present a hazard to workers during the reaction phase. In a few cases, however, open kettles may still be used in the manufacture of varnishes. Some of the emissions given off during the cooking of varnishes include acrolein, phenol, aldehydes, ketones, glycerin, fatty acids, and carbon dioxide .\nMaximum reactor vessel emissions occur during \"sparging,\" when an inert gas is blown through the reactor to remove the water of reaction. Emissions from solvent cooking operations do not vary significantly with the size of the reactor, but are more a result of the volatility of the solvent being used and the size and efficiency of the condenser.\nStartup, process upset, shutdown, and, particularly, emergencies offer further potential for worker exposure . Ambient temperatures around reactors generally are not hazardous. However, when insulation or climate controls are inadequate, ambient temperatures may rise and workers may be subject to heat stress.\nIn direct-fired kettles or reaction vessels, the constant heating and cooling can cause metal fatigue and subsequent cracks in the vessel. These cracks can be sources of vapor leaks and fire hazards.\nAlso, open kettles, especially portable ones, pose the hazard of burns from contact with hot surfaces or from splattering material.\n\n# b. Thinning and Filtering\nExposure to solvents may occur during the thinning stage of varnish production.\nThinning is usually done in separate tanks but may be performed in the varnish or resin kettle itself.\nSolvent exposure may also occur during filtering but is more likely during the subsequent cleaning of the filters.\n\n# c. Equipment Cleaning\nThe cleaning of equipment (e.g., reactors, kettles, thinning tanks, filters, etc.) is another source of worker exposure to toxic substances.\nCleaning operations in confined spaces are especially hazardous.\nWorkers may be exposed by skin contact or inhalation. Equipment is also sometimes cleaned with hot caustic solutions that may affect the skin, eyes, and respiratory tract.\nThe cleaning of filters may be performed manually or by automatic washing with solvents.\nRespiratory exposure to diatomaceous earths and dusts from other finely ground materials used as filter aids is possible.\n\n# Manufacture of Powder Coatings\nMany of the same types of hazards found during the manufacture of paints or varnishes also exist in the production of powder coatings.\nDust exposure can occur during the charging of hoppers, mixers, and grinders and in packaging.\nThe fine particle sizes associated with powder coatings increase the possibility of dust explosions , Inhalation of resin powders, pigments, curing agents, and other additives is the primary health hazard associated with the production of powder coatings.\n5. M a n u f a c t u r e of R a d i a t i o n -C u r a b l e C o a t i n g s Since the manufacture of radiation-curable coatings, which dry or cure as a result of radiation such as infrared, ultraviolet, and electron beam, is similar to that of other paints, so are most of its hazards. Radiation-curable coatings, however, contain reactive monomers in place of solvents.\nIn addition, ultraviolet-curable coatings also contain photoinitiators.\nBoth reactive monomers and photoinitiators may have acute or delayed effects on the skin, eyes, and respiratory tract causing skin sensitization and other effects .\nBecause of the likelihood of acute effects resulting from skin or eye contact with some components of radiation-curable coatings, this type of coating is manufactured in enclosed equipment.\nEnclosed equipment is also necessary to prevent vaporization of some components that have relatively high vapor pressures.\nVarious types of hazards are associated with acrylate monomers used in radiation-curable coatings.\nAcrylates cause irritation of the eyes, nose, throat, lungs, and skin.\nIn\n\n# Laboratory Functions\nIn addition to the hazards associated with the manufacture of coatings, the operations associated with laboratory functions may also expose workers to other chemical substances (e.g., reagents) and physical agents such as ultraviolet or infrared radiation, heat, cold, and ionizing radiation used in curing processes and in exposure tests.\nA potentially hazardous practice in laboratories involves spraying a coating to match colors.\nOften no exposure controls are used, and exposure to airborne coatings is likely.\nThis situation is easily remedied by providing a spray booth with negative pressure to remove the overspray and thus protect the worker.\n\n# C. Adverse Health Effects\nOSHA has promulgated occupational exposure standards for many of the chemicals used in the manufacture of paint and allied coating products. NIOSH has also evaluated many of these materials and has published Criteria Documents and other reports which have recommended occupational safety and health standards for them, including occupational exposure limits.\nThe current OSHA standards and the NIOSH-recommended exposure limits, as well as pertinent health effects, are listed in Appendix B.\nThe materials used in coatings vary greatly in their toxicity.\nSome have been shown to be biologically inert, and others are proven or potential occupational carcinogens.\nPigments are usually handled as finely divided solids that can readily become airborne; adhere to skin, hair, and clothing; and generally coat the work area with dust.\nThe primary routes of exposure to pigments are inhalation, skin contact, and eye exposure.\nIngestion of pigments can result from eating, smoking, or drinking in the work areas as well as from swallowing material gathered by the mucociliary clearance mechanism in the respiratory tract.\nThe volatility of m a n y organic solvents and resins at room temperature accounts for the likelihood that workers will be exposed to them by inhalation.\nExposure to solvents and resins by s k i n contact and skin absorption is also common.\nAn epidemiological study was conducted on a cohort of 16,243 men from 32 plants who were employed in the manufacture of paint or varnish for at least one year after January 1, 1946.\nThe total mortality data of these workers compared favorably with that of the United States white male population (i.e., 2,633 deaths observed, standardized mortality ratio of 86).\nHowever, a statistically significant increased mortality risk from colon and rectal cancer (65 and 26 deaths observed, SMR's of 138 and 139, respectively)\nwere found. The workers were also divided into seven subgroups on the basis of the type of exposure.\nIn one of these subgroups (the pigment workers) there was a significant increase of liver cancer (7 deaths observed, SMR of 273, p<0.05).\nLacquer workers had increased, although not significant, liver cancer and leukemia (SMR's of 255 and 212, respectively).\nThe investigators concluded that work in this industry presented no major health hazard. However, there were no analyses performed which took into account either exposure or latency.\nWithout such analyses, positive findings would likely be obscured by the dilution of the study population with persons with inadequate exposure and latency for chronic disease to manifest. There is no basis for the author's conclusions.\n\n# IV. M E T H O D S F O R W O R K E R P R O T E C T I O N\nThe occupational hazards that have been identified in the paint and allied coating products industry fall into three categories:\n(1) accidents, (2) fires and explosions, and (3) exposures to toxic substances and physical agents.\nInjuries are reported among coatings industry workers about 18 times more frequently than illnesses and are the major cause of lost worktime .\nThe possibility of fires and explosions exists where solvents and other flammable materials are used.\nWorkers who manufacture paint and allied coating products are also potentially exposed to numerous toxic solvents, pigments, film-formers, and additives.\nPossible adverse health effects resulting from exposure to m a n y of these materials, particularly components of some of the more recently developed products, are unknown.\nIn addition, workers are exposed to more than one substance at a time, and the possible synergistic or additive effects have not been determined.\n\n# A. Prevention of Accidents\nTo protect workers in the coatings industry, a critical objective is to reduce injuries. Sprains, strains, contusions, bruises, cuts, and lacerations constitute about 66% of the total injuries and illnesses in the coatings industry , The largest source of injuries and illnesses (about 33%) is associated with the handling of boxes, barrels, and containers . Accidents are caused by improper lifting, carrying a load that is too heavy, incorrect gripping, failure to wear appropriate protective clothing, and slips and falls resulting from sudden changes in friction between the shoes and the floor.\nIt is evident that reducing the number of injuries should be a high priority in the paint and allied coating products industry.\nGrimaldi and Simonds suggested that the causes of all injuries can be divided into two categories:\nunsafe physical conditions and unsafe personal acts.\nUnsafe physical conditions are due to defects in the condition of equipment, errors in design, faulty planning, or omission of essential safety requirements for maintaining a relatively hazard-free physical environment.\nUnsafe physical conditions were grouped by Grimaldi and Simonds o Removing safety devices or altering their operation so that they are ineffective.\n- Operating equipment at unsafe speeds.\n- Using unsafe or improper equipment (e.g., using a chisel with a \"mushroomed\" head, using the hands instead of a brush to remove chips from cutting machines, or using a screwdriver of incorrect size for the slot in the screwhead). o More stable qualities in the makeup of the workforce (i.e., more older, married workers with longer time on the job) were found.\nSafety control programs that have the preceding characteristics of workforces with low accident rates and that are oriented toward minimizing the number of unsafe conditions and acts should tend to reduce the number and severity of accidents and injuries in the coatings industry.\nHazard control programs are most effective when they include both specific corrective actions and demonstrable involvement by senior management.\nAlso, involvement of workers in decision processes leads to improvements in safety compliance .\n\n# Proper Lifting\nOverexertion in the workplace accounts for a large number of disabling injuries.\nMost of these injuries involve the act of manually handling materials.\nA detailed analysis of hazard identification and control involved in lifting is given in the NIOSH technical report, Work Practices Guide for Manual Lifting . It recommends that a job analysis be conducted for tasks associated with increased risk of injury; a detailed procedure for evaluating the analysis for lifting tasks is presented .\nFor workers to safely perform lifting jobs, employers should institute training, ergonomic/engineering controls, the use of materials handling aids and equipment, and the selection of appropriate individuals as discussed in the following sections.\n\n# a. T r a i n i n g\nThe training of workers in proper materials handling techniques is generally accepted as a potentially useful technique for reducing injuries.\nA The container itself affects safety directly through its weight and size and indirectly through the limitations it imposes on methods of holding and carrying it.\nContainers should be as small as possible. A compact load minimizes the compressive forces on the back because the center of gravity of the load can be brought close to the spinal column .\nWorker/container coupling affects the ability to exert forces on the object, to maintain grip, and to exercise control --all vital to safe handling. The major problems with most handles are insufficient hand clearance, sharp edges which can cut into the hand, and a handle diameter that is too small.\nHandle diameter should range from 2.5-3.8 cm (1.0-1.5 in). Handle width should be at least 11.5 cm (4.5 in) with 5.0 cm (2 in) clearance all around the handle.\nIf gloves are used, at least 2.5 cm (1 in) should be added to the width and the clearance .\nWorker/floor surface coupling is important for maintaining stability and preventing slips, trips, and falls.\nAccidents can be reduced by using good housekeeping procedures to reduce transient changes in surface friction such as spills, worn spots, and loose or irregular floors .\nAlthough manual materials handling operations rarely demand the fine visual discrimination of delicate assembly work, lighting can have a large effect on surface texture and depth perception. Low, angled illumination is recommended for enhancing surface texture to warn workers of changes in surface friction.\nColor contrasts should be used on the edges of steps, loading docks, and ramps.\n\n# c. Materials Handling Aids and Equipment\nThe use of materials handling aids (rollers, jacks, and platforms) and mechanical equipment (conveyors, cranes, hoists, hand trucks, and forklifts) can be helpful or necessary in many lifting tasks. Particularly useful are conveyors and other devices which convert lifting into sliding tasks.\nThe potential benefits of these devices, however, must be weighed against potential safety problems such as suspended loads with cranes and the many hazards in the use of hand-operated trucks and forklifts .\n\n# d. Selection of Appropriate Individuals\nTo avoid worker-job mismatch, selection of individuals for some jobs is considered desirable. Criteria for selection are lacking, however.\nFor many industries the principal method has been self-selection by the workers based on their initial tolerance for the demands of the job, a poor choice for obvious reasons.\nOther selection methods that have been used are questionnaires on health and medical history; and tests of visual, auditory, and pulmonary function, of blood pressure, mobility, etc., often with the addition of a chest x ray. However, such tests have poor predictive power.\nIn particular, x rays of the musculoskeletal system have little value in identifying workers who develop back injuries, and their routine use in screening employees is discouraged by medical authorities . The most useful procedure is a medical history coupled with an objective test of performance capacity (e.g., strength testing).\n\n# M a c h i n e G u a r d i n g / R e d e s i g n\nAn important area of occupational safety and health is that which protects the operator from the hazards of machine operations.\nOSHA requires in 29 CFR 1910.212 that one or more methods shall be provided to protect the operator and other workers in the machine area from hazards such as those created by point of operation, in-running nip points, rotating parts, flying chips, sparks, power transmission equipment, etc. Guards shall be affixed to the machine where possible.\nWorkers who use powered handtools in chipping operations are exposed to hand-arm vibration and potential risk of developing vibration syndrome (also known as vibration white finger and Raynaud's phenomenon). Vibration syndrome has adverse circulatory and neural effects in the fingers; the signs and symptoms include numbness, pain, and blanching (turning pale and ashen) .\nNIOSH recommends that jobs be redesigned to minimize the use of vibrating tools and that powered handtools be redesigned to minimize vibration .\n\n# Noise Control\nNoise must be controlled wherever it is excessive, both as a means of preventing accidents and as protection from hearing loss.\nThe noise in dispersion and filling operations is of special concern as is the use of powered handtools to chip layers of coatings from the insides of containers .\nUnder the provisions of the OSHA Occupational Noise Standard (29 CFR 1910.95), protection against the effects of noise exposure shall be provided when the sound levels exceed those shown in Table IV\n\n# S O U N D P R E S S U R E L E V E L S (dBA) A T D I F F E R E N T L O C A T I O N S A R O U N D A B A L L M I L L \n(Copyright by Communication Channels, Inc. Reprinted with permission by the Department of Health and Human Services.\nFurther reproduction prohibited without permission of copyright holder.)\n\n# P O S ITIO N G H iG H R EA D IN G W AS T A K E N W IT H W ASH S O LV E N T IN A STEEL B A LL M ILL; LOW R E A D IN G W AS FOR A W ATER JA C K E T E D LIN E D PEBBLE M IL L U S IN G H IG H D EN SITY G R IN D IN G BALLS.\n\n# B. P r e v e n t i o n of F i r e s a n d E x p l o s i o n s\nMany of the organic substances used in the manufacture of paint and allied coating products are highly flammable, and some are also explosive.\nThus, fires and explosions are a constant threat in most manufacturing operations where solvents and other flammable materials are used.\n\n# Static Electricity\nThe handling of the flammable or explosive liquid raw materials used in the coatings industry requires special techniques and precautions to prevent the accumulation of static electricity.\nThe object of such measures is .to provide a means whereby charges may recombine harmlessly before sparking potentials are attained or to avoid spark gaps where harmful discharges could occur .\nDuring the transfer of the solvents from one container to another (whether in bulk or in small amounts), effective bonding and grounding should be used to prevent the accumulation of static electricity , \"Bonding\" is the process of connecting two or more conductive objects together by means of a conductor , \"Grounding\" is the process of connecting a conductive object to the ground and is a specific form of bonding ,\nFill pipes should go to the bottom of tanks, drums, etc., to minimize the generation of static electricity in the free fall of flammable solvents . Drums cleaned by steam should be electrically bonded to steam lines, and the entire assembly should be grounded.\nBefore drums are emptied, they should be supported and blocked to prevent movement.\nExamples of bonding and grounding arrangements are shown in Figures IV-2, IV-3, IV-4, IV-5, and IV-6. Services.\n\n# FIGURE IV-2. BONDING AND GROUNDING FOR A MECHANICAL PUMPING DEVICE \nHOSE MAY BE EITHER C O N D U C T IN G OR N O N C O N D U C T IN G . C O N D U C T IN G H OSE A N D N O Z ZLE IN C O N T A C T W ITH C O N T A IN E R -NO O TH ER B O N D\nFurther reproduction prohibited without permission of copyright holder.)\n\n# F L E X IB L E AIR DUCT ( M E T A L -F A B R IC ) HANGING FROM R IG ID DUCT S Y S T E M FIGURE IV-6. TYPICAL GROUNDING ARRANGEMENT FOR THINNING OR MIXING EQUIPMENT \n(Copyright by The Sherwin-Williams Company.\n\n# Reprinted with permission by the Department of Health and Human\nServices.\nFurther reproduction prohibited without permission of copyright holder.)\n\n# Work Practices\nProcedures and precautions for preventing fires and explosions include:\n(1) regular inspection of equipment and storage tanks, (2) immediate repair of leaks, pumps, and lines, (3) periodic testing of pressure equipment, and (4) ventilation to reduce vapor concentrations.\nContainers of solvents or hot resins should be tightly covered at all times except when material is transferred.\nContainers of not more than five gallons capacity, having a spring-closing lid and spout cover and so designed to safely relieve internal pressure when subjected to fire exposure, should be used to hold working amounts of solvents.\nSince small amounts of residue may remain and present a fire hazard, containers that have held solvents should be thoroughly cleaned with steam and then drained and dried before re-use.\nFittings and open heaters should be prohibited except in specified areas.\nFire hazards around tank trucks and cars can be reduced by turning off their motors and not starting them during loading or unloading operations.\nGood housekeeping is also imperative to prevent fires.\nAfter eliminating potential sources of ignition, spills should be cleaned up immediately after the area is ventilated.\nStopping leaks and spills will eliminate fire hazards and help conserve raw materials, keep chemicals out of the effluent system, and reduce worker exposure. Combustible materials such as cleaning rags should be disposed of in metal containers filled with water . Specific OSHA requirements for the storage and handling of flammable and combustible liquids are given in 29 CFR 1910.106.\n\n# C. Controlling Exposures to Toxic Substances\nExposure to the thousands of raw materials (i.e., pigments, solvents, film-formers, and additives) used in the paint and allied coating products industry also poses a potential hazard.\nA variety of technologies such as process enclosure, modification of existing equipment, mechanical pumping systems, local exhaust ventilation, hazardous substance identification systems, protective clothing and equipment, and implementation of safe work practices can be used to control exposures to toxic substances.\nThe conclusions of a NIOSH-sponsored study indicate that the coatings industry relies on relatively well-known technology and uses equipment and procedures that are commonly used in a wide variety of other industries.\nThe effectiveness with which the coatings industry has controlled worker exposure to toxic substances can be evaluated somewhat by reviewing the records of OSHA compliance investigations.\nFor the industries within the SIC code 2851, data are available from OSHA health inspections completed during the period June 1979 to January 1984.\nTable IV-2 indicates the numbers of different samples collected and whether the concentrations found were above or below the Federal occupational standard in effect at the time ,\nThe majority of tests (94%) showed that the concentrations of the substances evaluated were within applicable Federal standards.\nOn the basis of these tests, it can be concluded that it is probably feasible in the coatings industry, through engineering controls and effective work practices, to limit exposures to most hazardous substances to within Federal s tandards. To identify specific hazards, comprehensive industrial hygiene evaluations (including appropriate measurements) should be conducted.\nSuch evaluations should be conducted at least yearly or when any change in process, raw material, or engineering control occurs which could result in increased exposure to toxic substances.\nThe results of these evaluations should be used to guide employers in implementing effective work practices and engineering controls, worker training, medical surveillance, and the use of personal protective clothing and equipment.\n\n# Informing Workers of Hazards\nOSHA on November 21, 1983, promulgated an occupational safety and health standard titled \"Hazard Communication.\" Under the provisions of this standard (29 CFR 1910(29 CFR .1200 The hazard communication program is to be written and is to be made available to workers and their designated representatives. Chemical manufacturers, importers, and distributors are required to ensure that containers of hazardous chemicals leaving their workplaces are labeled, tagged, or marked with the identity, appropriate hazard warnings, and the name and address of the manufacturer or other responsible party.\nEmployers must ensure that labels on incoming containers of hazardous chemicals are not removed or defaced unless they are immediately replaced with other labels containing the required information.\nEach container in the workplace must be prominently labeled, tagged, or marked with the identity of hazardous chemicals contained therein along with hazard warnings appropriate for worker protection.\nIf there are a number of stationary containers within a work area which have similar contents and hazards, the employer may post signs or placards which convey the hazard information required rather than individually labeling each container.\nEmployers may use various types of standard operating procedures, process sheets, batch tickets, or other such written materials as substitutes for individual container labels on stationary process equipment.\nHowever, these written materials must contain the same information as is required on the labels and must be readily accessible to workers in the work areas.\nPipes or piping systems are exempted altogether from the OSHA labeling requirements although NIOSH recommends that filler ports and outlets be labeled.\nIn addition, NIOSH recommends that a system should be set up to ensure that pipes containing hazardous materials are identified to avoid accidental cutting and discharge of hazardous materials.\nEmployers are not required to label portable containers into which hazardous chemicals are transferred from labeled containers and which are intended only for the immediate use of the worker who performs the transfer.\nAccording to the OSHA definition of \"immediate use,\" for the exemption to apply, the container must be under the control of the worker performing the transfer and must be used only within the workshift in which it is transferred.\nThe OSHA Hazard Communication standard requires chemical manufacturers and importers to develop a material safety data sheet (MSDS) for each hazardous chemical they produce or import. Employers in the manufacturing sector (which includes paint and allied coating products manufacturing) are required to obtain or develop a MSDS for each hazardous chemical used in their workplaces. The MSDS is required to provide specific information such as the chemical and common names for the hazardous chemical.\nFor hazardous chemical mixtures, each component which comprises 1% or more and which is itself a health hazard must be listed. Any chemical which is determined to be a carcinogen must be listed if it is present in quantities of 0.1% or greater.\nIngredients present in concentrations of less than one percent must also be listed if there is evidence that the permissible exposure limit may be exceeded or if it could present a health hazard in those concentrations.\nAdditional information on the MSDS must include data on the physical and chemical characteristics of the hazardous chemical, known acute and chronic health effects, precautionary measures, and emergency and first aid procedures. The NIOSH publication, A Recommended Standard--An Identification System for Occupationally Hazardous Materials , can be used as a guide when preparing the MSDS. Required information can be recorded on the \"Material Safety Data Sheet\" shown in Appendix C, or on a similar form.\nEmployers are to establish a training program for all workers exposed to hazardous chemicals.\nTraining is to be provided at the time of initial assignment and whenever a new chemical hazard is introduced into their work area.\nWorkers are to be informed of specific hazards involved in any operations in their work areas where hazardous chemicals are present.\nThis may be done by individual chemical or by categories of hazards, but in any case the worker is to be aware that information is available on the specific hazards of individual chemicals through the MSDS.\nWorkers are also to be trained regarding methods and observations that may be used to detect the presence or release of hazardous chemicals (e.g., monitoring conducted by the employer, continuous monitoring devices, visual appearance or odor of hazardous chemicals when being released, etc. Bulk handling methods for liquid raw materials which include techniques for bulk storage, piping, mechanical pumping (rather than pouring), and metering liquids minimize the opportunity for volatile liquids to contact ambient air.\nSystems for the bulk handling of pigments and other powdered materials also have been developed , The bulk handling system shown in Figure IV-8 uses bulk delivery vehicles, the transfer of materials by pipes to tanks that have lids, and built-in dust collectors and operates in the following manner.\nPigment is blown from trailers or rail cars into a steel storage silo.\nFrom the silo, pigment is blown through piping to a use bin located on the roof of the manufacturing building directly over the mixing area.\nWeighed quantities of pigment are delivered directly or via batch dollies to mixers.\nA low-level sensor actuates the transfer system to feed pigment from the silo when the pigment falls to a preselected level.\nPigment is added to the use bin until its level activates a flow-cutoff sensor .\nDespite precautions, the area around dispersion equipment often becomes quite dusty and frequent vacuum cleaning is recommended . Compressed air should not be used to remove pigment dust from clothing or work surfaces because it will result in the secondary generation of airborne dust.\nIt is also recommended that soiled clothing not be taken home for cleaning but be cleaned either by an industrial laundry or an on-site facility.\nWhen solvents or caustic solutions are used for cleaning dispersion equipment, it is important to avoid skin, eye, and inhalation exposures, which are especially likely to occur during manual cleaning.\nWhen using caustic solutions, care should be taken during the preparation of the solution to prevent excessive heat generation; dry caustic, typically 3 pounds per gallon , should be added slowly to the water . Caustic solutions should not be superheated because of the possibility that the tank will \"boil over\" .\nBecause caustics may react violently with aluminum, caustic solutions should not be used to clean out tanks that have contained aluminum paint .\nSpecial precautions should also be taken in the handling of aluminum paste or powder which can generate hydrogen gas when in contact with moisture . When this occurs in closed containers of aluminum pigments, sufficient pressure may build up to cause an explosion and fire .\nSpills are likely to occur during filling operations when automated equipment malfunctions.\nImmediate spill cleanup can reduce vapor release.\nWorker training programs that address techniques for spill cleanup are useful.\nFor major spills, some useful special procedures include the use of protective equipment (e.g., rubber boots), portable ventilation, absorbent material (e.g., floor sweeping compound, sawdust, -j Contact with coatings or their components (especially radiation-curable coatings) should be avoided, if possible, but should be followed by the immediate washing of contaminated skin with soap and water, immediate flushing of exposed eyes with copious amounts of water, and quick removal of contaminated clothing.\nHI & LOW LEVEL IN D IC A T O R USE BIN D IS C H A R G E A S S E M B LY (FLE XIB LE) SCALE M IX IN G T A N K S DUST C O LLE C T O R D ELIVER Y PIPE -U N L O A D IN G PIPE B IN A C T IV A T O R .FEEDER C O N V E Y IN G BLOW ER\nExposure of workers to toxic substances may also occur through the use of food, beverages, or tobacco products in areas where toxic substances are present.\nFor that reason, such activities (eating, smoking, etc.) should be prohibited in those areas. Good sanitation and hygiene practices should be encouraged by worker training, posting of warning signs, supervision, and provision for adequate eating and sanitation facilities, the latter of which should include change rooms, showers, and wash basins . For all work areas in which there is a potential for emergencies involving toxic materials, the employer should take necessary steps to ensure that workers are instructed in and follow the specified procedures.\nPrearranged plans should be established for administering first aid and emergency medical care and for transportation of injured workers.\nFirefighting procedures should also be established and implemented.\nPersonnel who may be required to shut off sources of solvents, clean up spills, and repair leaks should be properly trained in the appropriate procedures.\nIn case of fire, solvent sources should be shut off or removed.\nChemical foam, carbon dioxide, or dry chemicals should be used for fighting solvent fires, and proper respiratory protection and clothing should be worn.\nNonessential workers should be evacuated from exposure areas during emergencies.\nWarning or alarm systems should be considered to alert workers to possible hazardous exposures during emergencies .\nEntry into confined or enclosed spaces where there is limited egress, such as tanks, pits, trucks and tank cars, and process vessels, should be controlled by a permit system.\nPermits should be signed by an authorized employer representative and should certify that preparation of the confined space, precautionary measures, and personal protective equipment are adequate.\nFurther\n\n# Substitution of Raw Materials\nOccupational health hazards can also be controlled by the substitution of raw materials.\nBecause of their potential for environmental damage or consumer injury, the use of lead, chromates, and mercury compounds and various highly volatile solvents in many applications has been reduced or eliminated with replacement by other, less hazardous substances. An example is the use of zinc metal, zinc oxide, molybdates, and phosphates instead of lead and chromates as pigments in industrial maintenance coatings or the use of cuprous oxide or organotin compounds in antifouling paints rather than organic mercury, lead, and arsenic compounds .\nIn addition, many potent paint and varnish removers such as benzene, phenol, and cresols are no longer used , Another type of raw material substitution being utilized in paint manufacturing involves replacing dry pigments with pigment slurries .\nAs depicted in Figure IV-9, instead of storing and handling bagged dry pigments, slurries can be pumped from railroad cars into storage tanks and then to the mixing floor as needed, thus eliminating the release of pigment dust into the workplace air and simplifying pigment dispersion ,\n\n# Engineering Controls\nOccupational exposures to hazardous substances should be controlled at the source of the hazard wherever feasible.\nThis can be achieved by process or equipment modification, isolation of stored materials and processes, and local exhaust ventilation.\nOne of the most effective methods of dust control during the weighing and assembling of raw materials is a system that utilizes a closed fabricated metal booth that rests on top of the mixer and is connected by ducts to both a dust collector and an empty bag shredder.\nInside the booth, a bag of pigment is placed on a table and cut open as it is pushed over a mounted metal blade. The pigment falls through the cut in the bag into the mixer, and the empty bag is lifted slightly by the worker and is drawn upward and away by suction (Figure IV-10).\nAnother method that can effectively control dust and vapor is the use of a ventilated booth where materials are weighed or transferred. This results in reduced worker exposure and a decrease in the amount of dust and vapor released into the general workroom air. Dust-laden air that is exhausted should be collected in bag houses or forced through scrubbers or electrostatic precipitators.\nVapor-laden air can be scrubbed, incinerated, condensed, or adsorbed , Portable exhaust ventilation is another common control technique. This is accomplished with a hood attached to a flexible duct that leads to a fan. The effectiveness of this type of control varies, depending on the type of hood used, its placement, and its face velocity. Portable exhaust ventilation is generally, but not necessarily, less effective than ventilated hoods that enclose or confine a contaminant because exhaust volumes are large and control can be easily upset by cross drafts in the area .\n\n# HIGH SPEED MIXING TANK R E C O V E R E D P IG M E N T R E C Y C L E FO R DA RK P R IM E R P A IN T S TO SOLID WASTE DISPOSAL\nEnclosed equipment, such as ball or pebble mills, is free of vapor release during operation, but this is not the case with high-speed dispersers, which are open to the air. The use of covers and lids on containers can reduce vapor emissions. This is especially true during the thinning, tinting, and shading operations when temporary containers often remain open for long periods of time while laboratory analysis and subsequent adjustments are performed.\nSand mills often discharge into open portable tanks resulting in potential solvent emissions .\nSince vapors are emitted when containers are filled with solvent-based coatings, exhaust ventilation may be needed at the point of filling.\nBecause of the heat required and the by-products that need to be controlled, operations in varnish manufacture differ from other operations in the paint and allied coating products industry.\nBoth reactors and open and closed kettles are used to produce varnishes with the hazard of exposure to toxic emissions being greatest for open kettles.\nEmissions are generated during cooking processes when kettles are opened for charging or product sampling.\nMost kettles are currently fitted with retractable hoods and exhaust systems, some of which incorporate solvent condensers .\nFigure shows the control measures used in a typical varnish cooking room. Ventilation systems used to control vapors are most effective when designed to control vapors generated at temperatures higher than the ambient air .\nCondensed vapors collect to some extent as a sticky film on the relatively cool hood and duct walls, necessitating frequent cleaning and maintenance.\nHood design should provide for access to the kettle during use of the hood and should be designed to prevent contamination or exposure by the dripping of condensate from its inner surfaces . Varnish production vapor emissions can be controlled by water scrubbing, combustion, vapor incineration, high stack dispersal, or condensation ,\nBecause of the nature of the process, workers in varnish manufacturing operations may be subject to heat stress or to contact with hot surfaces.\nScreens or guards can be used to shield workers from contact with hot surfaces and from radiant heat.\nIn some cases, protective qlothing (particularly gloves) is useful.\nWith open kettles, the hot material can splatter on workers.\nThis hazard can be prevented, however, by covering the kettles or by using enclosures or splatter-gua rd s. Measurements of the effectiveness of the system should also be made as soon as possible after any change in production, process, or control which may result in any increase in airborne contaminants.\nIt is essential that any scheme that involves exhausting air from a work area should also provide for a positive means of bringing in at least an equal volume of air from the outside, conditioning it, and evenly distributing it throughout the exhausted area.\nThe\n\n# Personal Protective Clothing and Equipment\nWorkers should use appropriate personal protective clothing and equipment which must be carefully selected, used, and maintained to be effective. The SDS data indicated that 60% of the injuries or illnesses associated with chemicals or chemical compounds were caused by skin contact and 47% resulted in chemical burns.\nTo prevent skin contact, gloves, aprons, boots, etc. should be made of materials resistant to the hazardous substances in question, particularly the solvents. Splash-proof chemical safety goggles or face shields, (20-30 cm minimum) should be worn in any operation in which there is a likelihood of a solvent, caustic, or other toxic substance being splashed into the eyes.\n\n# Medical Surveillance\nThe medical officer responsible for the health of workers should be apprised of potential workplace hazards, based on safety and health evaluations, and appropriate medical surveillance should be conducted. The number and type of tests to be performed should be based on the substance or hazards to which the worker may be exposed. In any case, preplacement examinations should be performed and should include at least a medical and occupational history, a comprehensive physical examination, and a judgement of the worker's ability to use positive or negative pressure respirators.\nEmergency first-aid programs should be developed that are based on the results of the workplace occupational safety and health evaluation.\nPeriodic examinations should be carried out at the discretion of the responsible physician based on the adverse health effects and nature of the hazards identified.\nHealth hazards identified for which NIOSH has made specific recommendations should be addressed in accordance with those specific recommendations.\nPertinent medical records of all workers should be kept by employers for at least 30 years after termination of employment. Each worker should have access to information contained in his or her own medical records. A revolving cylindrical metal mill that uses steel balls, stones, or other media to grind or disperse the pigment in the film-former.\nFilm-forming material applied for protection or decoration of surfaces.\nThe mixing of materials, usually liquids, without the addition of heat.\nThe heating of the combined ingredients of a varnish.\nA machine that unloads a pallet of materials.\nA liquid that is blended with an active solvent to reduce cos t.\nAny heterogeneous system of solids, gases, or liquids.\nOils capable of absorbing oxygen from the air and becoming solid films.\nA pigment that contributes little hiding to the system but does reinforce the film and alter its gloss.\nThe nonvolatile binder portion of a coating.\nThese may be classified as either thermoplastic or convertible (see vehicle).\nThe lowest temperature at which a substance in an open vessel gives off enough vapors to produce a flash of fire when a flame is passed near the surface as described by American Society of Testing and Materials (ASTM) test procedures.\n\n# Flush Colors\nWater dispersions of organic and inorganic pigments that are supplied as organophilic pastes.\nThe ability of a paint to obscure the background over which it is applied.\nCoatings that contain more than 70% nonvolatile material.\nVessel used in the production of varnish.\nUsually indicates a material that dries by evaporation and forms a film from the nonvolatile constituents.\nA generic term describing stable dispersions of resin particles in a water system.\nAn increase in the consistency of paint resulting in a rubbery or coagulated mass.\nA general term for a water-insoluble viscous liquid usually consisting of triglycerides.\nA material that has been made by a combination of oil and resin.\nA dispersion formed by the suspension of resin particles (usually a vinyl resin) in a liquid consisting of volatile solvents.\nMills usually lined with porcelain or buhrstone in which flint pebbles or porcelain balls are used as the grinding media.\nA dispersion formed by the suspension of resin particles (usually vinyl) in a liquid consisting only of plasticizers.\nPigmented polymer coatings applied in powder form by various techniques such as electrostatic spray, fluidized bed, flocking gun, flame spray, or cloud chamber.\nThe phase of coatings production in which raw materials are weighed and assembled for mixing.\n\n# Coatings\nthat dry or cure as the result of initiation of polymerization by radiation such as infrared, ultraviolet, or electron beam. Resins that soften and flow when heated and, on cooling, regain their original physical and chemical properties.\n\n# Resin\n\n# Resins\nthat undergo a chemical change and become hard after heating and cannot be resoftened.\nWhen used as a film-former, they are often referred to as convertible film-formers.\nCoatings, usually urethane, formed by catalytic conversion that occurs so rapidly at ambient temperature that the components must be shipped in two separate containers.\nSolutions of film-formers in organic solvents, with no pigments.\nThe liquid portion of a coating material that forms the finished film and binds the pigments in the coating (see film-former). The \"%\" may be the approximate percentage by weight or volume (indicate basis) which each hazardous ingredient of the mixture bears to the whole mixture.\n\n# VIII. APPENDIX B SUMMARY OF HEALTH EFFECTS AND EXPOSURE LIMITS FOR SUBSTANCES POTENTIALLY PRESENT IN THE MANUFACTURE OF PAINT AND ALLIED COATING PRODUCTS\n\n# Agent\nThis may be indicated as a range or maximum amount, i.e., \"10-40% vol.\" or \"10% max.\nwt.\" to avoid disclosure of trade secrets.\nToxic hazard data shall be stated in terms of concentration, mode of exposure or test, and animal used, e.g., \"100 ppm LC50-rat,\" \"25 mg/kg LD50-skin-rabbit,\" \"75 ppm LC man,\" \"permissible exposure from 29 CFR 191029 CFR .1000 The data in Section III should be for the total mixture and should include the boiling point and melting point in degrees Fahrenheit (Celsius in parentheses); vapor pressure, in conventional millimeters of mercury (mmHg); vapor density of gas or vapor (air=l); solubility in water, in parts/hundred parts of water by weight; specific gravity (water=l); percent volatiles (indicated if by weight or volume) at 70°F (21.1°C); evaporation rate for liquids or sublimable solids, relative to butyl acetate; and appearance and odor. These data are useful for the control of toxic substances.\nBoiling point, vapor density, percent volatiles, vapor pressure, and evaporation are useful for designing proper ventilation equipment.\nThis information is also useful for design and deployment of adequate fire and spill containment equipment.\nThe appearance and odor may facilitate identification of substances stored in improperly marked containers or when spilled.\n\n# Section IV. Fire and Explosion Data\nSection IV should contain complete fire and explosion data for the product, including flash point and autoignition temperature in degrees Fahrenheit (Celsius in parentheses); flammable limits, in percent by volume in air; suitable extinguishing media or materials; special firefighting procedures; and unusual fire and explosion hazard information.\nIf the product presents no fire hazard, insert \"NO FIRE HAZARD\" on the line labeled \"Extinguishing Media.\"\n\n# Section V. Health Hazard Information\nThe \"Health Hazard Data\" should be a combined estimate of the hazard of the total product. This can be expressed as a TWA concentration, as a permissible exposure, or by some other indication of an acceptable standard.\nOther data are acceptable, such as lowest LD50 if multiple components are involved.\n\n# Ill\nUnder \"Routes of Exposure,\" comments in each category should reflect the potential hazard from absorption by the route in question.\nComments should indicate the severity of the effect and the basis for the statement if possible. The basis might be animal studies, analogy with similar products, or human experiences. Comments such as \"yes\" or \"possible\" are not helpful. Typical comments might be: Skin Contact-single short contact, no adverse effects likely; prolonged or repeated contact, possibly mild irritation.\nEye Contact-some pain and mild transient irritation; no corneal scarring.\n\"Emergency and First Aid Procedures\" should be written in lay language and should primarily represent first-aid treatment that could be provided by paramedical personnel or individuals trained in first aid.\nInformation in the \"Notes to Physician\" section should include any special medical information which would be of assistance to an attending physician including required or recommended preplacement and periodic medical examinations, diagnostic procedures, and medical management of overexposed workers.\n\n# Section VI. Reactivity Data\nThe comments in Section VI relate to safe storage and handling of hazardous, unstable substances.\nIt is particularly important to highlight instability or incompatibility to common substances or circumstances, such as water, direct sunlight, steel or copper piping, acids, alkalies, etc.\n\"Hazardous Decomposition Products\" shall include those products released under fire conditions.\nIt must also include dangerous products produced by aging, such as peroxides in the case of some ethers.\nWhere applicable, shelf life should also be indicated.\n\n# Section VII. Spill or Leak Procedures\nDetailed procedures for cleanup and disposal should be listed with emphasis on precautions to be taken to protect workers assigned to cleanup detail. Specific neutralizing chemicals or procedures should be described in detail.\nDisposal methods should be explicit including proper labeling of containers holding residues and ultimate disposal methods such as \"sanitary landfill\" or \"incineration.\"\nWarnings such as \"comply with local, state, and Federal antipollution ordinances\" are proper but not sufficient. Specific procedures shall be identified.\n\n# Section VIII. Special Protection Information\nSection VIII requires specific information. Statements such as \"Yes,\" \"No,\" or \"If necessary\" are not informative. Ventilation requirements should be specific as to type and preferred methods.\nRespirators shall be specified as to type and NIOSH or Mine Safety and Health Administration approval class, i.e., \"Supplied air,\" \"Organic vapor canister,\" etc. Protective equipment must be specified as to type and materials of construction. Section IX. Special Precautions \"Precautionary Statements\" shall consist of the label statements selected for use on the container or placard.\nAdditional information on any aspect of safety or health not covered in other sections should be inserted in Section IX.\nThe lower block can contain references to published guides or in-house procedures for handling and storage. Department of Transportation markings and classifications and other freight, handling, or storage requirements and environmental controls can be noted.\n\n# Signature and Filing\nFinally, the name and address of the responsible person who completed the MSDS and the date of completion are entered. This will facilitate correction of errors and identify a source of additional information.\nThe MSDS shall be filed in a location readily accessible to workers exposed to the hazardous substance.\nThe\n\n# V . RESEARCH NEEDS\nThere is Little published information on the health experience of workers engaged in the manufacture of paint and allied coating products.\nAdditional epidemiological studies are needed to determine the morbidity and mortality experience of workers in this industry.\nFrequent use of volatile solvents throughout the coatings industry increases the possibility that subtle behavioral and neurological effects will occur in workers.\nA potential problem of chronic deterioration of the central nervous system has recently been identified in Scandinavia among workers with long-term solvent exposures . More information is needed to evaluate tnese effects. Fortunately, the need for this type of information becomes less urgent as solvent-based coatings are being progressively replaced by water-based coatings.\nHowever, it has been estimated that considerable quantities of solvents will still be used by the coatings industry in 1990 .\n\n# Documentation of the exposures\nthat occur in operations where powder coatings and reactive coatings (e.g., radiation-curable coatings) are produced is needed since little is known of the hazards present during their manufac ture.\nResearch is needed to develop more comfortable and effective personal protective equipment, particularly respirators.\nIt is also important to determine the effect on respirator filter cartridge or canister life when there is a mixture of solvents in the surrounding air.\nCohen A: Factors in successful occupational safety programs. J Safety Research 9(4);168-77 (1977\n\n# IX. APPENDIX C MATERIAL SAFETY DATA SHEET\nThe following items of information which are applicable to a specific product or material shall be provided in the appropriate block of the Material Safety Data Sheet (MSDS).\nThe product designation is inserted in the block in the upper left corner of the first page to facilitate filing and retrieval. Print in upper case letters as large as possible.\nIt should be printed to read upright with the sheet turned sideways.\nThe product designation is that name or code designation which appears on the label or by which the product is sold or known by workers.\nThe relative numerical hazard ratings and key statements are those determined by the rules in Chapter V, Part The company identification may be printed in the upper right corner if desired.\n\n# Section I. Production Identification\nThe manufacturer's name, address, and regular and emergency telephone numbers (including area code) are inserted in the appropriate blocks of Section I.\nThe company listed should be a source of detailed backup information on the hazards of the material(s) covered by the MSDS.\nThe listing of suppliers or wholesale distributors is discouraged. The trade name should be the product designation or common name associated with the material.\nThe synonyms are those commonly used for the product, especially formal chemical nomenclature.\nNot every known chemical designation or competitor's trade name needs to be listed.\n\n# Section II. Hazardous Ingredients\nThe \"materials\" listed in Section II shall be those substances which are part of the hazardous product covered by the MSDS and which individually meet any of the criteria defining a hazardous material.\nThus, one component of a multicomponent product might be listed because of its toxicity, another component because of its flammability, while a third component could be included both for its toxicity and its reactivity.\nNote that a MSDS for a single component product must have the name of the material repeated in this section to avoid giving the impression that there are no hazardous ingredients. Chemical substances should be listed according to their complete name derived from a recognized system of nomenclature.\nWhere possible, avoid using common names and general class names such as \"aromatic amine,\" \"safety solvent,\" or \"aliphatic hydrocarbon\" when the specific name is known. 8 8 97 1 1 3 1 0 8 9 9 7 1 1 4 1 0 9 0 9 8 1 1 5 1 0 91 9 8 1 1 6 1 0 92 9 9 1 1 7 1 0 9 3 9 9 1 1 8 1 0 94 9 9 1 1 9 1 0 9 5 99 1 2 0 1 0 96 9 9 1 2 1 1 0 9 7 1 0 0 , 1 0 1 1 2 2 1 0 9 8 1 0 3 1 2 3 1 0 9 9 1 0 4 1 2 4 1 0 1 0 0 1 0 4 1 2 5 1 0 GOVERNMEN' PPiNTlNG OPFlCE '\n\n# MATERIAL SAFETY DATA SHEET 1 PRODUCT IDENTIFICATION M A N U F A C T U R E R S NAM E R E G U L A R TE LE PH O N E NO E M E R G E N C Y TELEPHO NE\n\n# PROCEDURES U N U S U A L FIRE A N D EXPLOSION H A Z A R D V HEALTH HAZARD INFORMATION H E A L T H H A Z A R D DA T A RO UTES OF EXPOSURE IN H A L A T IO"}}},{"rowIdx":96,"cells":{"id":{"kind":"string","value":"956e47509e52886649a7f807db121067a1d8cd75"},"source":{"kind":"string","value":"nice"},"text":{"kind":"string","value":"Integrated health and social care for people experiencing homelessness\n\nThis guideline covers providing integrated health and social care services for people experiencing homelessness. It aims to improve access to and engagement with health and social care, and ensure care is coordinated across different services.\n\n# Context\nThis guideline includes recommendations on ways to improve access to and engagement with health and social care services for people experiencing homelessness. It also gives advice on how commissioners, planners, providers and practitioners across disciplines and agencies can work together to support and improve outcomes for people experiencing homelessness.\nIn this guideline, 'people experiencing homelessness' means people aged 16 and over who:\nare sleeping rough\nare temporary residents of hostel, B&B, nightly-paid, privately managed accommodation and other types of temporary accommodation\nuse day centres that provide support for people experiencing homelessness\nare obliged to stay temporarily with other people\nare squatting\nare newly homeless\nhave a history of homelessness (as defined above), and are at high risk of becoming homeless again because of ongoing severe and multiple health and social care needs.\nUnderlying causes of homelessness include structural, societal and economic factors, and inequalities, such as poverty and deprivation, unaffordable housing, unemployment, exclusion and discrimination. People experiencing homelessness often experience severe and multiple disadvantage and unmet health and social care needs that may be contributing factors for becoming homeless as well as consequences of homelessness. Experience of psychological trauma and adverse childhood events are common in people experiencing homelessness, and the prevalence of people who are neuroatypical or have a brain injury is higher than in the general population. Homelessness and access to appropriate housing is a public health issue.\nPeople experiencing homelessness have far worse health and social care outcomes than the general population. The average age of death for the homeless population is around 30 years lower than for the general population according to the Office for National Statistics' Deaths of homeless people in England and Wales: 2019 registrations.\n'Inclusion health' is a term developed to address the health and care needs of groups that are traditionally excluded, including people experiencing homelessness. The needs of the homeless population overlap considerably with other inclusion health groups. Internationally, these groups have mortality rates that are 8 times higher than the general population for men and 12 times higher for women (Aldridge et al. 2017). Many of these premature deaths are from preventable and treatable conditions according to a 2019 study by the same authors (Aldridge et al. 2019). The Office for National Statistics' 2019 report showed that the causes of most deaths of people experiencing homelessness in England and Wales were registered as drug-related poisonings, suicides and alcohol-specific deaths.\nPeople experiencing homelessness use more acute hospital services and emergency care than the general population. When admitted to a hospital, the length of hospital stay is usually much longer because of multiple unmet needs. Barriers to access and engagement with preventive, primary care and social care services can mean that problems remain untreated until they become very severe and complex. These barriers include stigma and discrimination; lack of trusted contacts; fragmented, siloed and rigid services; strict eligibility criteria; and lack of information sharing and appropriate communication.\nIn addition to a moral responsibility, there is an economic imperative to tackle homelessness. The costs of homelessness to society are significant. The report by Pleace and Culhane (2016), published by Crisis, estimated the total public sector costs of a person experiencing homelessness to be as much as £38,736 per year in England (based on 2019/20 prices). This estimate included the NHS costs (£4,298), mental health services (£2,099), drug and alcohol services (£1,320), criminal justice sector costs (£11,991) and homelessness services (£14,808). On average, it was estimated that preventing homelessness for 1 year would reduce the public expenditure by approximately £10,000 per person. In 2020/21, 11,580 single households were assessed as rough sleeping in England (Ministry of Housing, Communities & Local Government, 2021), and if these people were prevented from experiencing 1 year of homelessness, annual public spending would fall by as much as £115.8 million. If other forms of homelessness were included, these cost savings would be substantially higher. Given the financial implications of homelessness to society and the far worse health and social care outcomes, most interventions that address homelessness are likely to be cost effective or even cost saving from the wider public sector perspective.\nThe Ministry of Housing, Communities & Local Government's rough sleeping strategy outlines its commitment to ending rough sleeping and preventing homelessness. The homelessness legislation includes duties for local authorities to assess, prevent and relieve homelessness. The NHS Long Term Plan includes a commitment to improve access to specialist homelessness mental health support for people sleeping rough in areas with the highest rates of rough sleeping. During the COVID‑19 pandemic, local authorities, health services, and the voluntary and charity sector have worked in partnership to respond to homelessness, including the 'Everyone In' initiative, recognising that rough sleeping and homelessness are public health issues. This has shown that with appropriate funding, integrated working and prioritisation of the most vulnerable in the society, there are opportunities for positive change.\nThis guideline provides guidance on models of service provision, for services that are specific to people experiencing homelessness, as well as improving access and engagement with mainstream services. It aims to integrate services as much as possible as a way to improve outcomes for people experiencing homelessness and contribute to ending homelessness.# Recommendations\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# General principles\nRecognise that more effort and targeted approaches are often needed to ensure that health and social care for people experiencing homelessness is available, accessible, and provided to the same standards and quality as for the general population.\n\n## Co-design and co-delivery of services\nRecognise the value of co-designing and co-delivering services with people with lived experience of homelessness, to improve the quality of health and social care (see the section on the role of peers). See also the section on involving people in service design and improvement in NICE's guideline on people's experience in adult social care services and NICE's guideline on community engagement.\n\n## Supporting engagement with services\nPromote engagement by providing services that:\nare person-centred, empathetic, non-judgemental\naim to address health inequalities\nare inclusive and pay attention to the diverse experiences of people using the service.\nConsider using psychologically informed environments and trauma-informed care. Recognise that people's behaviour and engagement with services is influenced by their traumatic experiences, socioeconomic circumstances and previous experiences of services.\n\n## Sustaining engagement with services\nRecognise the importance of longer contact times in developing and sustaining trusting relationships between frontline health and social care staff and people experiencing homelessness (see also recommendation 1.2.9 in the section on planning and commissioning).\nPromote shared decision making, building self-reliance and using strengths-based approaches to care (also known as assets-based approaches). See also NICE's guideline on shared decision making.\nRecognise that people experiencing homelessness, especially those with experience of rough sleeping, need services that provide a long-term commitment to care to promote recovery, stability and lasting positive outcomes (see the section on long-term support).\n\n## Supporting re-engagement with services\nBe aware that some people experiencing homelessness may find it difficult to look after themselves because of their circumstances and may find services difficult to engage with. For people who disengage from or refuse health and social care services:\nactively support re-engagement\nenable people to re-engage with services at the same point as they left, if appropriate.\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on general principles .\nFull details of the evidence and the committee's discussion are in:\nevidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\nevidence review C: views and experiences of health and social care for people experiencing homelessness.\nLoading. Please wait.\n\n## Communication and information\nFollow the recommendations on communication and information in NICE's guidelines on:\npatient experience in adult NHS services\npeople's experience in adult social care services\nservice user experience in adult mental health\nbabies, children and young people's experience of healthcare.\nHealth and social care staff working with people experiencing homelessness should:\nbe empathetic, non-judgemental and use recovery-oriented language that avoids jargon and acronyms\nuse communication methods based on the person's preferences, for example, phone call, text message, email, letter, face to face\nsend clear information about contacts or appointments and reminders that reach people in time, and follow up people who do not attend.\nTake into account each person's communication and information needs and preferences, and their circumstances. For example:\nprovide translation and interpretation services if needed\nensure that written information is available in different formats and languages, including Easy Read\nprovide extra support for people with low literacy levels or with speech, language and communication difficulties\nconsider the person's access to phone or internet.\nConsider involving an advocate to support communication, even when this is not a statutory requirement. This may be someone nominated by the person or an independent advocate who can, for example:\nsupport people to overcome stigma and previous negative and traumatic experiences\nhelp people with low literacy levels to access information and services\nreinforce information about available services and appointments.\nGive people experiencing homelessness information about:\ntheir rights to health and social care services, including for those with no or limited recourse to public funds\nhow to access health and social care services, including:\nprimary care services and how to register with a GP without a permanent address\nspecialist health services that can be accessed directly, such as maternity, blood-borne virus, drug and alcohol recovery, mental health, sexual health, and family planning services\n-utreach services\nlocal authority services, including housing services and social care\nvoluntary and charity sector services.\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on communication and information .\nFull details of the evidence and the committee's discussion are in evidence review C: views and experiences of health and social care for people experiencing homelessness.\nLoading. Please wait.\n\n# Planning and commissioning\nThese recommendations are for commissioners of health and social care and housing services.\n\n## Planning integrated multidisciplinary health and social care services\nCommissioners of health, social care and housing services should work together to plan and fund integrated multidisciplinary health and social care services for people experiencing homelessness, and involve commissioners from other sectors, such as criminal justice and domestic abuse, as needed. These services should contribute to the government's aim of ending rough sleeping and preventing homelessness.\nRecognise that people experiencing homelessness often need additional resources and a more targeted service delivery to:\nensure that resources are allocated according to need and disadvantage\ntake into account the social determinants of health\nimprove long-term outcomes and address health inequalities.\n\n## Local homelessness health and social care needs assessment\nConduct and maintain an up-to-date local homelessness health and social care needs assessment and use this to design, plan and deliver services according to need. Include thorough engagement with service providers (including voluntary and charity sector service providers) and experts by experience.\nLocal homelessness health and social care needs assessments should:\nquantify and characterise the population experiencing homelessness or at risk of homelessness, including health inequalities, diversity and inclusion issues and specific needs and identify trends\nassess the quality and capacity of existing mainstream and specialist service provision to inform the need for service development and investment\nassess access to and engagement with current services by people experiencing homelessness\nidentify opportunities for more integrated service delivery\ntake into consideration relevant findings from Safeguarding Adults Reviews.\n\n## Recording housing status\nWork with health and social care providers to improve recording of housing status so that the information can be used by services to:\nbest meet people's needs and\nplan, audit and improve services.\n\n## Developing services\nWhen developing services for people experiencing homelessness, commissioners should:\nwork together to strategically plan and deliver health and social care across larger areas, recognising that people move between areas\nwork with other relevant services, such as prison and probation services and domestic abuse services\nenable long-term support for those who need it (see the section on long-term support)\nensure that health and social care services are designed to meet the level and type of local need (see the section on models of multidisciplinary service provision)\ndefine and measure outcomes, including health and social outcomes and service use\nconsider the likely benefits of using long-term contracts for providers\nsupport statutory bodies to fulfil their legal responsibilities and use their powers\nencourage and enable the contribution of peers (experts by experience) in supporting people experiencing homelessness and delivering and designing more effective services (see the section on the role of peers).\nConsider providing services and support aimed at the needs of particular groups of people experiencing homelessness, as appropriate, such as:\nwomen (also see the NICE guideline on pregnancy and complex social factors)\nyoung people\n-lder people\ndisabled people\npeople with no or limited recourse to public funds because of their immigration status\nLGBT+ people\npeople from different minority ethnic or religious backgrounds.\nDevelop strategies across services to improve access to health and social care for people experiencing homelessness. See the section on improving access to and engagement with health and social care.\nEnsure that there are processes to:\nsupport people experiencing homelessness to register with a GP and\ndocument and address any problems with GP registrations for people experiencing homelessness.\nConsider reducing caseloads and lengthening contact time for health and social care practitioners working with people experiencing homelessness to enable them to use approaches that sustain engagement with services.\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on planning and commissioning .\nFull details of the evidence and the committee's discussion are in:\nevidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\nevidence review C: views and experiences of health and social care for people experiencing homelessness.\nLoading. Please wait.\n\n# Models of multidisciplinary service provision\n\n## Homelessness multidisciplinary teams\nProvide care through specialist homelessness multidisciplinary teams across sectors and levels of care, tailored according to local needs.\nHomelessness multidisciplinary teams should act as expert teams, providing and coordinating care across outreach, primary, secondary and emergency care, social care and housing services. Homelessness multidisciplinary teams may include:\nexperts by experience (see the section on the role of peers)\nhealthcare professionals with relevant specialist expertise (for example, drug and alcohol treatment, mental health, primary care, emergency care, palliative care)\nsocial workers\nhousing options officers or homelessness prevention officers\n-utreach and homelessness practitioners\nvoluntary and charity sector professionals\nstaff with practical expertise in accessing benefits and entitlements for people experiencing homelessness.\nHomelessness multidisciplinary teams should have protocols and systems in place for communication and sharing information to support integrated working within the team and between services.\nHomelessness multidisciplinary teams should:\nidentify people experiencing homelessness through outreach or when they present to health and social care services\nsupport mainstream providers to identify and refer people to the homelessness multidisciplinary team\nundertake and support assessments for safeguarding, physical and mental health, alcohol and drug treatment needs, and social care, including informing Care Act assessments (see the section on assessing people's needs)\nsupport mainstream providers to ensure safe, timely and appropriate hospital discharge and engagement with onward care (see the section on transitions between different settings).\nHomelessness multidisciplinary teams should:\n-ffer person-centred case management by a designated practitioner within the multidisciplinary team and ensure continuity of care for as long as it is needed by the person\n-ffer wraparound health and social care support that encompasses the person's needs, including:\nphysical health\nmental health and psychological support (such as psychological therapies)\nphysical rehabilitation (such as occupational therapy and physiotherapy)\ndrug and alcohol treatment\nsocial care\npalliative care\ncommunication support\npractical support, such as help with benefits, housing and referral for legal advice.\nHomelessness multidisciplinary teams should engage in reflective practice, including opportunities to share experience and learning with other relevant teams, including homelessness multidisciplinary teams, and to review complex or difficult situations.\nHomelessness multidisciplinary teams should directly contribute to local needs assessments, service quality improvement, and reviews of complex or difficult situations including Safeguarding Adults Reviews.\nHomelessness multidisciplinary teams should advise homelessness leads, when needed, in nearby areas that do not have a homelessness multidisciplinary team and share examples of good practice.\n\n## Homelessness leads in mainstream services\nIn areas assessed as not needing a full-time homelessness multidisciplinary team because of low numbers of people experiencing homelessness, establish links with multidisciplinary teams in nearby areas and designate homelessness leads in all relevant mainstream services, for example, in primary, secondary and emergency care, palliative care and in adult and child social services.\nThe homelessness leads should:\nsupport their organisation to provide appropriate care for people experiencing homelessness and implement this guideline\nhave detailed local knowledge of specialist services to support the care of people experiencing homelessness\nwork with and coordinate care with homelessness leads in other mainstream services\nconsult homelessness multidisciplinary teams in nearby areas, as needed.\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on models of multidisciplinary service provision .\nFull details of the evidence and the committee's discussion are in:\nevidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\nevidence review C: views and experiences of health and social care for people experiencing homelessness.\nLoading. Please wait.\n\n# The role of peers\nInvolve peers (experts by experience) in delivering and designing services, for example by:\ndirectly delivering health and social care interventions, for example, as part of outreach\nproviding a user perspective to influence the design and development of services\nproviding training for health and social care staff\ncarrying out participatory research and data collection, for example, to support service audits, needs assessments and quality improvement.\nOffer peer support to people experiencing homelessness, for example to help with:\nunderstanding how others with similar experiences have changed their lives (role modelling)\ndeveloping self-efficacy\nnavigating services\nsupporting attendance at appointments\nproviding peer advocacy at appointments or in A&E\nforming trusting relationships with practitioners and improving communication.\nSupport peers to deliver services effectively and maintain their own wellbeing and development by providing:\ntraining, supervision and governance structures appropriate to the role and tailored to the person's needs\npsychological and social support, for example reflective practice, according to their changing needs and circumstances\ntailored support for professional development, including access to further training and inclusive employment opportunities.\nTake into account the experience, background and language skills of peers and how these can be used to meet the needs and preferences of people experiencing homelessness.\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on the role of peers .\nFull details of the evidence and the committee's discussion are in:\nevidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\nevidence review C: views and experiences of health and social care for people experiencing homelessness.\nLoading. Please wait.\n\n# Improving access to and engagement with health and social care\n\n## Supporting access to and engagement with services\nDesign and deliver services in a way that reduces barriers to access and engagement with health and social care, for example, by providing:\n-utreach services (see the section on outreach services)\nlow-threshold services\nflexible opening and appointment times\nself-referral\ndrop-in services\n'one-stop shops' for multiple services\nincentives and help to access care, such as transport support, vouchers or digital connectivity\nadvocates (see recommendation 1.1.12 in the section on communication and information)\npeer support (see the section on the role of peers)\ncare navigation\npsychologically informed environments and trauma-informed care.\nDo not penalise people experiencing homelessness for missing appointments, for example, by discharging people from the service. Consider seeking specialist help, such as peer supporters or independent advocates, to support the person to attend appointments and re-engage with care after missing appointments (see the section on the role of peers).\nEnsure that people can access help when needed, including through emergency care, and avoid policies that withdraw support and close cases after a standard duration, unless a safe transfer of care to another service has been agreed with the person or the person agrees that they no longer need the service.\nCommissioners and service providers should follow the recommendations on improving access to services in NICE's guideline on common mental health problems.\nEnsure that people experiencing homelessness with multiple health or social care needs are not excluded from services because of restrictive eligibility criteria. For example, people with mental health problems are not denied access to mental health services because they have drug and alcohol treatment needs (see also NICE's guideline on coexisting severe mental illness and substance misuse).\nEnsure that people experiencing homelessness who are assessed as frail and in need of social care and support get long-term care packages, including residential care or supported housing, irrespective of their age.\nEnsure that paper or digital forms needed to access health or social care or to get help with NHS costs are readily available and that people are supported to fill them in, including providing translation when needed.\nEnsure that people experiencing homelessness can access online health and social care information and are supported to use online services, for example by providing internet access at places where people experiencing homelessness spend time, such as day centres or hostels.\nPrimary care service providers should ensure that people without an address can register with a GP practice, in line with the NHS Primary medical care policy and guidance manual.\nEnsure that frontline health and social care staff who come into contact with people experiencing or at risk of homelessness are able to fulfil their duties under the Homelessness Reduction Act 2017.\nEnsure that frontline health and social care staff are able to identify when a person needs to be referred for specialist homeless health and social care, and that processes are in place to support timely referral.\nConsider moving people up waiting lists for health and social care appointments if they are experiencing homelessness because their circumstances may mean they are at higher risk of deterioration and premature death.\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on supporting access to and engagement with services .\nFull details of the evidence and the committee's discussion are in:\nevidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\nevidence review C: views and experiences of health and social care for people experiencing homelessness.\nLoading. Please wait.\n\n## Outreach services\nTake health and social care services to people experiencing homelessness by providing multidisciplinary outreach care in non-traditional settings, such as on the street, hostels or day centres.\nOffer outreach services that include support for people who:\nhave primary healthcare needs\nhave drug and alcohol treatment needs\nhave mental healthcare needs\nfear engaging with services, for example, because of previous negative experiences from providers, discomfort using male-dominated services or concerns about eligibility including immigration status\nmay lack mental capacity or need support to recognise their care needs and engage with providers.\nUse outreach to identify health problems earlier, promote health and support engagement with care, for example by:\nsupporting access to national screening programmes\nassessing people for long-term conditions, infectious diseases and mental health needs\nproviding preventive health opportunities, such as vaccination, drug and alcohol treatment services, harm minimisation, smoking cessation and nutrition advice.\nOffer collaborative, assertive outreach to start and maintain engagement with health and social care for people experiencing homelessness with coexisting severe mental health and drug or alcohol treatment needs. See also the section on maintaining contact with services in NICE's guideline on coexisting severe mental illness and substance misuse.\nConsider assertive outreach for all people experiencing homelessness who could benefit from support but who find services difficult to engage with.\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on outreach services .\nFull details of the evidence and the committee's discussion are in:\nevidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\nevidence review C: views and experiences of health and social care for people experiencing homelessness.\nLoading. Please wait.\n\n# Assessing individual needs\nBe aware that health and social care practitioners have a statutory and professional duty to identify immediate risk of harm to self or others. See also the section on assessment and treatment under the Mental Health Act in NICE's guideline on service user experience in adult mental health.\nAssess the health and social care needs of the person experiencing homelessness. When carrying out the assessment:\ntake into account their capacity, rights to autonomy and self-determination, and any safeguarding issues and\navoid unnecessary and potentially distressing repetition of their history if it is already on record\ninvolve peers or advocates as appropriate (see also the section on the role of peers).\nInclude in the assessment:\nA comprehensive assessment of the person's physical and mental health needs (including acute and long-term conditions) and social care needs. This should take into consideration their housing and benefits situation, bearing in mind the need to address health inequalities, and be responsive to diversity, and inclusion needs.\nAsking if the person has children or dependents and assessing how this affects their needs.\nUnderstanding the historical context of their situation, including past psychological trauma and experience of services.\nIn assessments to inform a health and social care plan for people who might benefit from high levels of support, use a multidisciplinary approach to enable a comprehensive and holistic assessment of their needs, involving:\nthe person, and their advocate if one is nominated or appointed\ninput from professionals with specialist expertise and practitioners who have detailed knowledge of the person's health and social care needs, including staff working in homelessness and housing services.\nUse hospital admissions as an opportunity to offer a comprehensive, holistic needs assessment, including referral, if indicated.\nUse the multidisciplinary assessment to inform the local authority-led care and support needs assessment, under the Care Act 2014 (see the section on care and support needs assessment and care planning in NICE's guideline on people's experience in adult social care services).\nReview the person's needs, strengths and aspirations whenever their circumstances change or whenever they request a review, rather than using standard review periods.\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing people's needs .\nFull details of the evidence and the committee's discussion are in evidence review C: views and experiences of health and social care for people experiencing homelessness.\nLoading. Please wait.\n\n# Intermediate care\nProvide intermediate care services with intensive, multidisciplinary team support for people experiencing homelessness who have healthcare needs that cannot be safely managed in the community but who do not need inpatient hospital care. These may be for people who are:\ndischarged from hospital (step-down care)\nreferred from the community who are at acute risk of deterioration and hospitalisation (step-up care).See also NICE's guideline on intermediate care including reablement.\nFor a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on intermediate care .\nFull details of the evidence and the committee's discussion are in evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches.\nLoading. Please wait.\n\n# Transitions between different settings\nHomelessness multidisciplinary teams or leads should support people experiencing homelessness through transitions between settings (such as the street, hostels, Housing First and other supported housing, hospital, mental health services, social care, residential or community drug and alcohol treatment, and custody) and consider providing time-limited intensive support, which includes:\nhaving a key practitioner coordinating care\nbuilding a relationship of trust\nproviding links to services in the community\ngradually lowering the intensity of support, as appropriate.\nPractitioners in any setting supporting people experiencing homelessness should:\nensure that all handovers of care responsibilities are planned and coordinated, and relevant information is shared if agreed\n-ffer pre-emptive, structured support before, during and after transitions\nrecognise that people may be vulnerable during periods of transition, but also that there may be opportunities for intervention.\nClinical teams, working with hospital discharge teams and specialist homelessness multidisciplinary teams, where available, should have procedures to:\nminimise self-discharge and\nprevent discharge to the street. If self-discharge or discharge to the street happens, review the circumstances and implement learning.\nFor people moving between different care settings, follow the recommendations in NICE's guidelines on:\ntransition between inpatient mental health settings and community or care home settings\ntransition between inpatient hospital settings and community or care home settings for adults with social care needs\ntransition from children's to adults' services for young people using health or social care services.\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section for transitions between different settings .\nFull details of the evidence and the committee's discussion are in:\nevidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\nevidence review C: views and experiences of health and social care for people experiencing homelessness.\nLoading. Please wait.\n\n# Housing with health and social care support\nThese recommendations are for commissioners and service providers working together across health, social care and housing services.\nRecognise that providing accommodation suitable for the person's assessed health and social care needs (see the section on assessing people's needs) can support access to and engagement with health and social care services and long-term recovery and stability.\nProvide wraparound health and social care support that is flexible to the person's changing needs and circumstances, and helps them maintain suitable accommodation.\nRecognise the need for a range of accommodation types that are suitable for the varied needs of people experiencing homelessness, such as self-contained accommodation and accommodation with specialist onsite support for people who are particularly at risk or who might otherwise benefit from higher levels of support.\nBe aware that moving to independent accommodation in the community with tenancy responsibilities can be an extremely challenging, stressful and isolating experience for some people. Provide emotional and practical support for as long as it is needed.\nWhen a person experiencing homelessness moves into new accommodation, help them to assess the risks associated with their new living arrangement, while also recognising their strengths, and plan ways to mitigate the risks.\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on housing with health and social care support .\nFull details of the evidence and the committee's discussion are in:\nevidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\nevidence review C: views and experiences of health and social care for people experiencing homelessness.\nLoading. Please wait.\n\n# Safeguarding\nAlso see the NICE guideline on domestic violence and abuse.\nDesignate a person to lead on safeguarding the welfare of people experiencing homelessness, including engagement and face-to-face practical safeguarding support.\nWhere a social worker is embedded in the homelessness multidisciplinary team, local authorities should consider appointing them to lead on safeguarding enquiries about people experiencing homelessness.\nLocal authorities should consider having a lead for people experiencing homelessness on the Safeguarding Adults Board.\nSafeguarding Adults Boards should ensure that specific reference is made to people experiencing homeless in their annual reports and strategic plan.\nSafeguarding Adults Boards should share recommendations and key learning related to homelessness from Safeguarding Adults Reviews with key stakeholders.\nSafeguarding Adults Boards should establish ways of analysing and interrogating data on safeguarding notifications about people experiencing homelessness so that they can check that local safeguarding arrangements offer the necessary protection.\nCommissioners and service providers should support health and social care staff to understand and apply laws relevant to people experiencing homelessness and who are in need of safeguarding. This should include ensuring that they can recognise signs of abuse and neglect (including self-neglect) and how to make a safeguarding referral.\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on safeguarding .\nFull details of the evidence and the committee's discussion are in evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches.\nLoading. Please wait.\n\n# Long-term support\nFor people who struggle to engage with services, plan long-term engagement to help meet the person's needs at their own pace.\nGive priority to building a relationship of trust, for example by:\ntaking time with the person, particularly at the beginning of the relationship\nbeing prepared to meet in an informal setting, such as a park or café (with appropriate lone worker policies in place)\nhaving regular contact\nensuring consistency of practitioner, so that they meet with 1 person or a small team\naiming to meet immediate expressed needs to encourage long-term engagement.\nRecognise that people experiencing homelessness do not always follow a linear recovery journey and that apparent progress may hide risks.\nConsider providing 'open-door' services that people can self-refer to and access after any initial support ends, to reduce the risk of becoming homeless again because of unmet health, care and support needs.\nRecognise that some people experiencing homelessness experience frailty at an earlier age (both physical and cognitive) than the general population and their long-term care should be tailored to meet this.\nIf a person experiencing homelessness is likely to be approaching the end of their life, for example, if death would not be unexpected in 6 to 12 months, discuss palliative care needs with the person and the multidisciplinary team, and provide coordinated palliative care to meet the person's needs.\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on long-term support .\nFull details of the evidence and the committee's discussion are in:\nevidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\nevidence review C: views and experiences of health and social care for people experiencing homelessness.\nLoading. Please wait.\n\n# Staff support and development\nConsider providing training for all health and social care practitioners, at a level suitable for their professional role, covering:\nunderstanding the health and social care needs of people experiencing homelessness, and their rights to access services\nhomelessness as part of equality and diversity training, including being responsive to health inequalities, diversity issues and inclusion needs and understanding the impact of discrimination and stigma, and how intersectional, overlapping identities can affect people experiencing homelessness\npsychologically informed environments and trauma-informed care\nlegal duties and powers\nlegal entitlements for migrants.\nHealthcare professionals working within secondary care mental health services should follow the recommendations in the section on competence in NICE's guideline on coexisting severe mental illness (psychosis) and substance misuse.\nConsider regular and ongoing support, professional supervision and reflective practice for staff working with people experiencing homelessness.\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on staff support and development .\nFull details of the evidence and the committee's discussion are in:\nevidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\nevidence review C: views and experiences of health and social care for people experiencing homelessness.\nLoading. Please wait.\n\n# Terms used in this guideline\nThis section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local, Act Personal's Care and Support Jargon Buster.\n\n## Assertive outreach\nA proactive and persistent approach to outreach that involves repeated contact with people who are initially unable to or unwilling to engage.\n\n## Care navigation\nHelping people navigate the complex health and social care systems to overcome barriers in accessing services. This could be done by case workers, other practitioners or peers supporting the person, or by designated care navigators.\n\n## Health inequalities\nSystematic, unfair and avoidable differences across the population and between different groups within society in relation to health and social outcomes. They arise because of the conditions in which people are born, grow, live, work and age. These conditions influence people's opportunities, health and wellbeing.\n\n## Homelessness leads\nPeople working in mainstream health and social care services who, as part of their role, lead on homelessness issues within their service. Homelessness leads are designated in areas assessed as not needing a full-time homelessness multidisciplinary team.\n\n## Homelessness multidisciplinary team\nA multidisciplinary team involves a range of professionals across disciplines as well as agencies working together to assess and support the needs of a person experiencing homelessness.\n\n## Inclusion needs\nA need to have equal access and opportunities to participate in society and not facing barriers to services, social situations, different spaces and environments; being treated with dignity and not experiencing discrimination or intolerance due to the person's identity. See also health inequalities.\n\n## Intermediate care\nA range of integrated services that: promote faster recovery from illness; prevent unnecessary acute hospital admissions and premature admissions to long-term care; support timely discharge from hospital; and maximise independent living. Intermediate care is given on a time-limited basis, but duration can vary depending on the person's needs.\n\n## Low-threshold services\nServices that avoid restrictive eligibility criteria and make minimal demands on the client.\n\n## Mainstream services\nServices designed to be delivered to the general population.\n\n## Outreach\nBringing health and care services to people who might not otherwise have access to or engage with existing services, provided in a mobile way in the locations where people are, for example on the street, in temporary accommodation facilities and in day centres. This can be done by mainstream services or dedicated outreach teams.\n\n## Peers\nPeople with lived experience of homelessness who are using their experience to support people experiencing homelessness through different means such as direct support, advocacy, research and co-production of services.\n\n## People experiencing homelessness\nIn the context of this guideline, people experiencing homelessness is defined as people aged 16 and over who:\nare sleeping rough (people without homes who sleep outside or somewhere not designed for habitation)\nare temporary residents of hostel, B&B, nightly-paid, privately managed accommodation and other types of temporary accommodation\nuse day centres that provide support (such as food, showers, clothing and advice) for people experiencing homelessness\nare obliged to stay temporarily with other people\nare squatting\nare newly homeless.\nIt also includes people with a history of homelessness (as defined above) who are at high risk of becoming homeless again because of ongoing severe and multiple health and social care needs.\n\n## Psychologically informed environment\nService provision and practice that takes into account individuals' psychological and emotional needs, and their experiences of trauma. It includes building organisational awareness of psychological and emotional needs; physical environment and social spaces; staff training and ongoing support; service evaluation and learning; and reflective practice. For more information and resources, see the Homeless Link's webpage on trauma informed care and psychologically informed environments. See also trauma-informed care.\n\n## Recovery-oriented language\nLanguage that is person-centred, respectful, non-judgemental and strengths based. It conveys a sense of hope and commitment to the potential of every person and their recovery journey. It includes non-verbal aspects of communication and aims for consistency between verbal language and body language. If recovery is unlikely, this approach might focus on exploring what is important to the person and what living well means to them.\n\n## Reflective practice\nA process to:\nreflect on previous practice\ntalk about why they made the decisions they made, and why they acted or behaved in particular ways\ntalk about their emotional responses to their actions and the actions of others\nengage in continuous learning.\nReflective practice may also provide insight into personal values and beliefs, and help understand how these influence action and decision making.\n\n## Safeguarding\nThe collective responsibility and process to protect the health, wellbeing and human rights of people at risk, enabling them to live safely, free from harm, abuse and neglect. See also the Think Local, Act Personal's Care and Support Jargon Buster definition for safeguarding.\n\n## Safeguarding Adults Board\nA statutory multi-agency group set up by a local authority made up of different professionals from a local authority, the NHS and police to prevent abuse or neglect of adults who have care and support needs, and to make sure that action is taken if abuse occurs. See also the Think Local, Act Personal's Care and Support Jargon Buster definition for Safeguarding Adults Board.\n\n## Safeguarding Adults Review\nA statutory multi-agency learning process arranged by a Safeguarding Adults Board that reviews cases if:\nthere is reasonable cause for concern that partner agencies could have worked more effectively to protect an adult and\nserious abuse or neglect is known or suspected and\ncertain conditions are met, in line with section 44 of the Care Act 2014 and related statutory guidance.\n\n## Severe and multiple disadvantage\nMultiple and overlapping disadvantages that are often persistent and interrelated and affect a person's life. These disadvantages include the experience of homelessness, harmful drug or alcohol use, criminal justice involvement, poor mental health, and the experience of domestic violence and abuse. People experiencing severe and multiple disadvantage have often experienced underlying adverse childhood experiences, poverty, psychological trauma, stigma and discrimination. People with these experiences may have had sporadic and inconsistent contact with services or been serially excluded from services. People who experience severe and multiple disadvantage tend to have much poorer physical and mental health, have higher social care needs, and die at a much younger age than people without severe and multiple disadvantage.\n\n## Social care staff\nPeople working in social services and social care providing practical and emotional support to improve people's wellbeing and quality of life. This includes both local authority social workers with legal responsibilities to assess and protect people at risk of harm as well as frontline social care practitioners that may work in residential care, hostels and homelessness services in either the public sector or voluntary and charity sector.\n\n## Social determinants of health\nSocial factors and wider determinants that influence health and wellbeing. These include circumstances in which people are born, grow up, live, work, and age, and the social and economic policies and systems, political agendas, social norms, environmental factors and other wider forces.\n\n## Strengths-based approaches\nSometimes called assets-based approaches. These involve the person who uses services and the practitioners who support them working together to achieve the person's intended outcomes, in a way that draws on the person's strengths. The quality of the relationship between those providing support and those being supported is particularly important, as are the skills and experience that the person using support brings to the process (see Social Care Institute for Excellence's Care Act guidance on strengths-based approaches). See also NICE's quick guide on evidence for strengths and asset-based outcomes.\n\n## Trauma-informed care\nAn approach to planning and providing services that involves understanding, recognising and responding to the effects of all types of trauma. It emphasises physical, relational and emotional safety, and helps survivors of trauma to rebuild narratives of connection, control and empowerment. See also psychologically informed environment.\n\n## Wraparound health and social care support\nA multidisciplinary team-based collaborative approach to support the person experiencing homelessness holistically, taking into consideration their individual needs, including physical and mental health needs, drug and alcohol treatment needs, care and social needs, and practical needs, in addition to their housing needs.# Recommendations for research\nThe guideline committee has made the following recommendations for research.\n\n# Psychologically informed environments\nWhat is the effectiveness and acceptability of clinical psychology-led psychologically informed environments and psychological approaches for people experiencing homelessness?\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on general principles .\nFull details of the evidence and the committee's discussion are in evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches.\nLoading. Please wait.\n\n# Health and social care to support housing\nWhat structural and systems factors help or hinder commissioning and delivery of wraparound health and social care that is integrated with housing, for people experiencing homelessness?\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on housing with health and social care support .\nFull details of the evidence and the committee's discussion are in evidence review C: views and experiences of health and social care for people experiencing homelessness.\nLoading. Please wait.\n\n# Longer health and social care contacts\nWhat is the effectiveness and cost effectiveness of longer health and social care contacts compared with usual care for people experiencing homelessness?\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on planning and commissioning .\nFull details of the evidence and the committee's discussion are in evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches.\nLoading. Please wait.# Rationale and impact\nThese sections briefly explain why the committee made the recommendations and how they might affect practice or services.\n\n# General principles\nRecommendations 1.1.1 to 1.1.8\n\n## Why the committee made the recommendations\nThere was qualitative evidence that people experiencing homelessness feel that they are offered less or lower quality care than the general population. Although the committee agreed that there were some limitations to the evidence, their experience corresponded with this. The evidence also highlighted various barriers to accessing care. Considering the multiple disadvantages and disproportionately poor outcomes observed in this population, the committee agreed that more effort and targeted approaches are often needed to level up outcomes. This also aligns with the NHS Constitution's first key principle of providing comprehensive service available to all, and its 'wider social duty to promote equality through the services it provides and to pay particular attention to groups or sections of society where improvements in health and life expectancy are not keeping pace with the rest of the population'.\nGood qualitative evidence showed that people experiencing homelessness want to give feedback on processes and their care, but ways to do this were not always available. Based on their experience, the committee agreed that people often do not feel able to do this because of their experience of stigma and discrimination. However, involving people with lived experience of homelessness in service design is likely to improve services and people's engagement with services. Involving people in service design was also highlighted in the NICE guideline on people's experience in adult social care services, which references the Local Government and Public Involvement in Health Act 2007. The 2007 Act mandates local authorities to provide opportunities for people who use services to be involved in strategic decision making about services. NICE's guideline on community engagement also gives guidance on community engagement approaches for local authorities and health bodies.\nThe committee's experience as well as both qualitative and effectiveness evidence showed that using peers to deliver health and social care services can also be beneficial for people experiencing homelessness. The committee agreed that there are likely benefits for the peers themselves and for the service.\nGood qualitative evidence highlighted that many people experiencing homelessness encounter or perceive stigma, discrimination and lack of understanding from health and social care practitioners. There was also limited evidence showing that many service providers are not aware of the impact that traumatic experiences can have on a person's life and how it can manifest in their behaviour. From their experience, the committee agreed that psychological trauma is common among most people experiencing homelessness, and is particularly prevalent among certain groups, such as women and young people. They also heard from experts who highlighted the importance of 'professional curiosity' in understanding the person's backstory and the use of trauma-informed practices. They agreed to highlight the importance of using approaches that take into account the impact of trauma and consider the person's past experiences as well as their current situation.\nThere was a lack of evidence on psychologically informed environments and psychological approaches to care, so the committee developed a research recommendation on the effectiveness and acceptability of clinical psychology-led psychologically informed environments and psychological approaches for people experiencing homelessness and they agreed that research in this area should consider inequalities and collect data that enable the impact on different groups to be studied. The equality impact assessment provides further information on equalities considerations for this guideline.\nGood qualitative evidence showed that many people experiencing homelessness reported feelings of apprehension, fear and distrust when receiving care. Some people reported a lack of trust in service providers or in the healthcare system, mostly because of previous negative experiences. They felt judged, stereotyped and disrespected in healthcare settings, leading to unwillingness to engage with care.\nThere was good qualitative evidence highlighting that people reported positive experiences with care providers and increased engagement with services when they were able to develop a trusting relationship with a provider who paid attention, showed sincere interest and had time available for them. The importance of a genuine, friendly relationship in which the professional listens, remembers, uses humour and shows concern helps to build a trusting relationship, which in turn enables the person to feel safe in the health or social care environment. The committee agreed that this was key to promoting engagement. There was also good qualitative evidence that people experiencing homelessness value non-judgemental communication from professionals that is responsive to people's individual experiences and needs, for example, related to gender, culture, ethnicity and being part of the LGBT+ community. The committee also recognised the importance of service providers addressing the underlying inequalities that people may face, which are underpinned by social determinants of health that shape people's experiences and health and social care needs. The evidence emphasised the importance of staff understanding the impact that trauma may have.\nGood qualitative evidence showed that people experiencing homelessness valued continuity of care and spoke positively about practitioners with whom they had formed trusting relationships. The evidence also emphasised respect as an essential component in sustaining trusting relationships. The committee's experience aligned with the evidence, and they emphasised that consistency and continuity of care throughout a person's journey can lead to improved engagement and better outcomes.\nThe qualitative evidence also showed that the length of appointments or contacts in current practice is often inadequate to meet the needs of many people experiencing homelessness, particularly those with severe and multiple disadvantage. Despite some limitations in the evidence, the committee agreed with this and discussed how longer appointment times can give an opportunity to better assess, engage and build trust with people who may otherwise rarely have contact with services, and who are marginalised and have disproportionately worse outcomes. Good qualitative evidence and information from experts emphasised that giving people agency – involving them and promoting shared decision making – helps to improve engagement in care. High-quality evidence from qualitative studies highlighted that focusing on the person's strengths and assets encouraged people experiencing homelessness to use services.\nGood evidence from qualitative studies showed that people experiencing homelessness often experience lack of consistency and continuity from health and social care services, which can lead to disengagement. The evidence also showed that ongoing, sustained support and a service provider's patience and continued attempts to re-engage can improve the person's engagement when they might otherwise be resistant to support. The committee were aware that the Safeguarding Adults Reviews highlighted the prominence of 'self-neglect' in people experiencing homelessness. The committee discussed how some people experiencing homelessness find it difficult to look after their health and personal care because of their environment and circumstances. 'Self-neglect' can also include disengagement with health and social care whether or not the person has capacity. This is made more difficult by barriers to access and engagement with services. This emphasises the importance of actively supporting re-engagement. The committee discussed that re-engagement might not be successful if the person has to start and repeat the process from the beginning of the pathway, instead enabling re-entry from the point they left is more likely to support re-engagement, if appropriate.\n\n## How the recommendations might affect services\nThe recommendations outline principles of good practice that in the committee's view should be happening across all services for people experiencing homelessness. However, practice is variable, and this may represent a change in practice for some services. Most recommendations would not lead to a significant resource impact, but may involve staff training and longer contact times. Any additional costs are likely to be offset by the benefits of improved engagement with care, for example, by accessing care before a crisis and reducing the burden on emergency services.\nEconomic analysis also suggested that reducing caseloads (and thus increasing time spent with clients) for practitioners working with people experiencing homelessness could be cost effective.\nReturn to recommendations\n\n# Communication and information\nRecommendations 1.1.9 to 1.1.13\n\n## Why the committee made the recommendations\nThere was good qualitative evidence that people experiencing homelessness often experience stigma and discrimination and feel oppressed and unwelcome. Good evidence also reported that insensitive communication and closed body language are common experiences for them. Service users reported preferring simple language and explanations, instead of jargon, because it gives a sense of comfort and is more accessible.\nThe committee agreed with the evidence and discussed the merits of non-judgemental, recovery-oriented language. They agreed that the way in which practitioners communicate can have an impact on people's recovery journey, their willingness to engage with services, their sense of hope and their potential for recovery. The committee discussed the importance of using sensitive language that does not lead to the person feeling blamed for their issues (for example, avoiding phrases like substance 'abuse' or 'failed' to attend).\nThere was limited qualitative evidence on people's preferred communication methods, which reported that receiving appointment information by letter was ineffective for people without a reliable address. The committee discussed that letters are still the main method of communication for many service providers. Good qualitative evidence also showed that people without access to the internet and those without a phone have difficulties accessing healthcare (digital exclusion). The evidence corresponded with the committee's experience, recognising that various methods based on the person's preferences and communication needs should be available to improve timely contact and access to services.\nThe committee discussed that resources and forms are often written in a complex way and mostly available only in English. They agreed that this is a further barrier for people whose first language is not English. Good qualitative evidence also suggested that low literacy levels among some people experiencing homelessness can add to difficulties in accessing care. The committee agreed that this could include some migrants and people with learning disabilities or acquired brain injury. They therefore emphasised the need to tailor communication and information provision to people's needs and preferences, taking into account a wide range of possible speech, language and communication difficulties.\nGood qualitative evidence showed that the presence of an advocate (including a peer advocate) helps people experiencing homelessness to gain confidence and a sense of control over their health and care needs. The committee had confidence in the evidence and agreed, based on their experience, that advocates (including peer advocates) can play a significant role in supporting people with correspondence and attending appointments, and in bridging the gap between practitioners and people experiencing homelessness. The committee were also aware that NICE is developing a guideline on advocacy services for adults with health and social care needs (publication expected September 2022).\nThe committee noted that the advocate could be someone who the person is familiar with, such as a family member or a friend. But they also noted that some people may be entitled to an independent advocate under certain circumstances. For example, the Care Act 2014 mandates that local authorities must arrange an independent advocate to support and represent a person to assist in their involvement in specified social care processes if the person has substantial difficulty in being involved in the process, and if they do not have an appropriate person to support them.\nModerate-quality evidence from qualitative studies showed that people experiencing homelessness felt that there was a lack of help or information about services available to them (such as overall entitlement to care, oral health, maternity services, screening and infectious diseases). This corresponded with the committee's experience, and they agreed that to improve engagement with health and social care services, it is important to give people information, support access, and make sure that they know their rights to health and social care. They considered this particularly relevant for migrant populations who may not be familiar with the local health and social care system and their entitlements, or who may have limited or no recourse to public funds.\n\n## How the recommendations might affect services\nThese recommendations reinforce existing NICE guidelines on communication and information provision for the general population. However, there are some aspects that may need particular attention when working with people experiencing homelessness. There may be a need for some extra staff training on communication, and on the available health and social care services and support for people experiencing homelessness, including legal entitlements for care.\nGiving everyone – including staff – the right information about what services are available will help relationship and trust building, and may lead to better access and engagement with services. For example, people may be more likely to access primary care services or specialist services directly instead of relying on emergency services. This can lead to problems being picked up and dealt with earlier, reducing morbidity and mortality, and associated costs such as for crisis care, and unplanned or emergency care.\nServices already use various communication methods to support access to and engagement with services. But tailoring the method to each person's preferences and needs may need some reorganisation of current practice.\nAdvocate roles could be carried out by a professional or a peer supporter, or sometimes a family member or a friend. There are various advocacy models aimed at facilitating the relationship with service providers, and supporting people to access information and services or attend appointments. Any additional costs could be offset by the beneficial effect on the person's recovery including potential reductions in morbidity and mortality. For example, there is a link between non-attendance at appointments and increased morbidity and mortality in people experiencing homelessness.\nReturn to recommendations\n\n# Planning and commissioning\nRecommendations 1.2.1 to 1.2.10\n\n## Why the committee made the recommendations\nThe rough sleeping strategy by the Ministry of Housing, Communities & Local Government highlights the need for agencies to work together to end rough sleeping and prevent homelessness. Cooperation and integrated working between agencies and partners are also mandated in legal frameworks including the Care Act 2014 and the National Health Service Act 2006.\nBased on their experience, the committee discussed that integrated working among commissioners across different sectors is essential to bring all the knowledge and services together to ensure that there is a strategy and funding for coordinated and holistic support for people experiencing homelessness. Joined-up working is also likely to improve long-term outcomes; improve people's experience of services; minimise duplication of work and make services more efficient; improve understanding of the needs of the homeless population in the local area; and improve practitioners' work by making it easier to collaborate with colleagues.\nPeople experiencing homelessness are to varying degrees disadvantaged and marginalised, and their outcomes are considerably worse than the general population, including having disproportionate rates of premature mortality. The committee discussed the concept of 'proportionate universalism', introduced in Marmot et al. (2010) Fair Society Healthy Lives (The Marmot Review), meaning that resourcing and delivering of services are done universally but at a scale and intensity proportionate to the level of need or disadvantage. The committee agreed that more resources and targeted approaches are justified to address the inequalities facing this population.\nThe committee agreed that to plan and commission adequate services to meet the needs of the homeless population in a local area, a comprehensive homelessness health and social care needs assessment should be carried out and kept up to date. This assessment will help understand the scale and nature of homelessness, and how existing services could be developed and integrated to better meet the needs of the people experiencing homelessness. The committee agreed that it should involve experts by experience to fully understand the needs, experiences, circumstances and service use of people experiencing homelessness. The committee also agreed that to improve services and to prevent abuse, neglect and death, service planning and design should be informed by Safeguarding Adults Reviews. They heard from an expert who also highlighted this.\nThe committee discussed, based on their experience, that data on the needs and service use of people experiencing homelessness can come from housing status in the person's health and care records if this is accurately recorded. Public Health England's Homelessness: applying 'All Our Health' advises frontline health and care professionals to ask about and record people's housing circumstances. The committee recognised that recording this information can create fear of stigmatisation in people experiencing homelessness. But they agreed that this was outweighed by the benefits of accurate data that can be used to improve services, both for the individual and as a whole, and ensure that there are adequate resources. The data can also be used to help identify and reduce health inequalities.\nMany people experiencing homelessness have multiple intersecting issues or high support needs, such as physical and mental health issues, drug and alcohol treatment needs and social care needs. High-quality evidence from qualitative studies highlighted the importance of joint working to address complex unmet health and social care needs. The evidence suggested that many services work in silos with minimal coordination and cooperation between agencies. People felt that their issues were often dealt with individually by different providers rather than holistically addressing all of their intersecting needs. The committee heard from experts about adult social care and safeguarding, who similarly highlighted the need for joint commissioning and integrated working across agencies and professions.\nThe committee agreed, based on their experience and expertise, that commissioners working across larger areas and across sectors could help services collaborate to meet strategic aims, cover varying and intersecting needs, share resources and enable economies of scale. This could be at the level of integrated care systems or place-based systems, with collaboration across an area's health, social care and housing partners in different sectors, as well as with prison, probation and domestic abuse services.\nThe committee also agreed on the importance of enabling long-term, consistent support regardless of contract lengths so that people experiencing homelessness who may need high levels of support, including long-term medical care, can progress in their recovery journey. They agreed that long-term contracts can provide stability and can support the improvement and extent of services as long as there is flexibility to adapt to changing local needs.\nThe committee heard from expert witnesses about the importance of supporting service providers and practitioners to exercise their legal duties and powers when working with people experiencing homelessness. The committee agreed that the current systems do not always support public bodies and practitioners to do this, for example the duty to refer based on the Homelessness Reduction Act 2017.\nThe committee also agreed that commissioners should define and measure outcomes related to homelessness, including health and social care outcomes and service use, to inform local and national homelessness assessments, and help improve and design relevant policies and services.\nEffectiveness evidence showed that peers (experts by experience) can be a useful and cost-effective way of supporting people experiencing homelessness and delivering services. Based on their knowledge and experience, the committee also agreed that peers are valuable in co-designing services. Involving peers can improve people's engagement with services, leading to better outcomes; improve the quality of services; and reduce pressure on practitioners, as well as having benefits to the peers themselves.\nThe committee agreed that the particular needs of specific population groups need to be considered. For example, women may have different needs and vulnerabilities compared with men, and young people compared with older people. People with limited or no recourse to public funds have particular disadvantages and risks for poor outcomes because of barriers to accessing care and support. Specialised support for the particular needs of LGBT+ people, disabled people or people with a particular family background or from a particular faith group may be helpful in reaching people and providing appropriate support. The committee agreed to give examples of groups that may need specific consideration, although they recognised the list is not exhaustive. The equality impact assessment for the guideline provides further information.\nThe committee discussed how the causes of homelessness are complex. Some people may experience homelessness as a result of disparities in access to or appropriateness of services because of a certain characteristic they have. People may face particular challenges because of their characteristics, such as their age, gender, disability status, family background or being a migrant, including different intersections of these, which may multiply inequalities.\nQualitative evidence of mixed quality from many different studies highlighted various barriers to accessing health and social care, such as transport costs and services being too far away, siloed or in multiple locations. The committee agreed that it is important for commissioners to consider ways to remove barriers to local services to improve access and engagement among people experiencing homelessness.\nThere was good qualitative evidence that people experiencing homelessness faced challenges registering for GP services and were sometimes refused registration if they did not have an address or ID. Being denied access to GP services can further alienate, cause distrust and prevent already marginalised people from engaging with services. The evidence also corroborated the committee's experience that when people are refused access to GP services, they turn to emergency care services.\nThe NHS Primary medical care policy and guidance manual outlines that everyone in England can register with a primary care provider free of charge. This includes people experiencing homelessness, people without a stable address, asylum seekers and refugees. The committee agreed that commissioners and planners need to ensure that there are processes in place to support GP registration, and document, challenge and redress refusals. There is also NHS England practical resource on improving access for all: reducing inequalities in access to general practice services.\nReducing caseloads for practitioners working with people experiencing homelessness would allow them to spend longer with each client. Longer contact time is likely to improve engagement with services, help build a trusted relationship and ultimately lead to improved outcomes and sustained recovery. There would also be likely benefits from improved staff satisfaction and retention, and continuity of care. The committee made a research recommendation to better understand the effectiveness and cost effectiveness of longer health and social care contacts for people experiencing homelessness and they agreed that research in this area should consider inequalities and collect data that enable the impact on different groups to be studied. The equality impact assessment provides further information on equalities considerations for this guideline.\n\n## How the recommendations might affect services\nAlthough there are legal requirements to collaborate under the Care Act 2014 and the National Health Service Act 2006, health, social care and housing services have different legislative and commissioning frameworks and the committee discussed that collaboration is sometimes challenging and the level of integration varies.\nServices working in silos can increase the risk of undiagnosed or misdiagnosed conditions across the mental, physical and disability spectrum, cause morbidity and mortality, and result in substantial costs to services. Commissioners and planners will need to ensure that frameworks are in place to support integrated multidisciplinary health and social care services where this is not already happening. For example, by facilitating coordinated multi-agency and multidisciplinary working, and strengthening information sharing and communication systems.\nImproving integrated service provision should lead to improved outcomes, more appropriate use of services, and a lower need for emergency care and hospital admissions, reducing associated costs. Services will need targeted efforts to improve outcomes and to meet the needs of people experiencing homelessness, and commissioners will need to plan for more funding per person than in mainstream services. However, this should lead to savings later on.\nJoint Strategic Needs Assessments are done by public health teams within local authorities, but there is some variation in the extent to which the health and social care needs of people experiencing homelessness are considered, and service users and experts by experience are involved. When done thoroughly and with all the relevant information, including relevant findings from Safeguarding Adults Reviews, it can inform targeted and efficient provision (for example, specialist service provision) and identify opportunities for more integrated services. This will also ensure that services meet local needs, and improve access and engagement. This will reduce morbidity and mortality, and reduce public sector costs associated with homelessness.\nMost services have ways to record data on housing status for audit purposes. This would not be a new practice, although some services might not be doing it or do not have processes flexible enough to record it in a meaningful way. Services could improve this by adjusting existing data-recording methods.\nCompared with current practice, commissioners may need to look across a larger footprint to develop services. This approach will also enable them to account for mobility and people experiencing homelessness not being tied to a specific place. This may mean commissioning groups coming together to form partnerships.\nInvolving peers in delivering care or support and co-designing services is already happening in some areas and organisations, particularly in the voluntary and charity sector. It will involve costs in terms of training and support for peers and potential incentives or remunerations; however, involving peers can reduce pressure on practitioners and therefore result in cost savings. There was evidence that it can be cost effective.\nAccess and engagement with services may not be straightforward in this population, so commissioners will need to ensure multiple ways of enhancing access to care. There are examples of good practice across the country, but practice is variable. Services will have to consider approaches that can be tailored to the specific needs of the person. Currently, because of the lack of flexible services, people often end up in crisis and use expensive emergency services, or do not access services, resulting in disproportionately complex morbidity and premature mortality.\nGP registration refusals are relatively common in current practice and commissioners and planners will need to reinforce NHS guidance and support GP practices to ensure that people experiencing homelessness can access GP services.\nFinally, economic analysis carried out for the guideline suggested that reducing caseloads for practitioners who work with people experiencing homelessness could be cost effective.\nLower caseloads will mean that services will have to recruit more staff, which might be challenging in some areas. However, availability of trained staff should not be a barrier; for example, services may find it easier to recruit staff to junior roles and provide on-the-job training.\nReturn to recommendations\n\n# Models of multidisciplinary service provision\nRecommendations 1.3.1 to 1.3.10\n\n## Why the committee made the recommendations\nThe committee discussed that people experiencing homelessness often have overlapping and intersecting care needs, which need the expertise and skills of different professionals to assess, plan and manage care jointly. They may also have needs and challenges that are not typical to the general population, so the committee recognised the value of practitioners with specialist knowledge on homelessness issues.\nGood qualitative evidence from various studies described health and care systems as siloed, complex and fragmented, with little coordination between agencies and providers. There was also evidence from qualitative studies that people experiencing homelessness want more individualised care that meets their needs, and hope to develop trusting relationships with service providers.\nThere was limited effectiveness evidence available on multidisciplinary team approaches to health and social care support for people experiencing homelessness. There was evidence on the Housing First approach, mainly from Canada, involving intense case management or assertive community treatment by a multidisciplinary team for people with moderate to severe mental health problems experiencing homelessness. This showed a positive impact on housing status and tenancy sustainment. There was also some economic evidence showing that having multidisciplinary homelessness teams resulted in some cost savings and improved outcomes for people experiencing homelessness. Furthermore, the committee heard from experts who emphasised the importance of integrated and collaborative working, and a multidisciplinary approach with clear roles and responsibilities and effective communication and information sharing.\nBased on the evidence and their own experience, the committee agreed that the best way to provide health and social care to people experiencing homelessness would be through specialist homelessness multidisciplinary teams. A combination of expertise from a variety of disciplines and agencies would enable holistic and individualised care based on the person's needs.\nThe committee discussed that a successful joined-up care approach, providing holistic wraparound support based on individual needs would integrate service providers from a range of health and social care settings.\nThe committee discussed the various experts who could form the multidisciplinary team. The qualitative evidence highlighted that people experiencing homelessness value support from peers who have similar experiences and can be role models in their recovery journey. Some qualitative evidence also reported the benefits of involving people with lived experience of homelessness in shaping and providing care. The committee agreed that experts by experience can bring an important service-user point of view to a multidisciplinary team to help better meet the needs of people experiencing homelessness. The committee discussed that other members of the multidisciplinary team could be an array of different professionals and practitioners spanning different agencies and disciplines, including healthcare, social work, housing, and the voluntary and charity sector. They discussed that voluntary and charity organisation staff often have the closest relationships to the client. The committee were aware that the characteristics of people experiencing homelessness vary across different areas and agreed that it is important to use the local needs assessment to tailor the composition of the team to local needs.\nThe committee discussed that multidisciplinary teams can provide person-centred, tailored support with personalised case management by a designated person working within the multidisciplinary team, which can improve continuity of care and help build trusted relationships with service providers that could improve engagement with services and long-term outcomes. Multidisciplinary teams can coordinate care based on the person's needs by providing care themselves or signposting to other services. Having a dedicated team with specialist knowledge can help streamline support and make it more efficient, avoid duplication of work and inappropriate referrals, and improve staff motivation. The committee were confident that there would be benefits for the person being supported, the team members and services in general.\nThe committee also discussed that the specialist multidisciplinary teams could bring value and expertise in working with other 'inclusion health' groups (groups of people who are traditionally socially excluded) who may be at risk of homelessness and whose needs often overlap considerably with people experiencing homelessness.\nHomelessness multidisciplinary teams have a comprehensive understanding of the needs and service use of people experiencing homelessness, so the committee agreed that these teams make a crucial contribution to assessing local needs, improving quality of services, and reviewing complex cases including Safeguarding Adults Reviews.\nThe committee discussed that working with people experiencing homelessness can be challenging and can have a psychological impact on those providing care. They agreed that homelessness multidisciplinary teams should be given time, in a protected space, to reflect on their practice and experiences to promote continuous learning and professional wellbeing.\nThe committee also recognised that specialist homelessness multidisciplinary teams would not be feasible in areas where levels of homelessness are low. For example, in some areas services might encounter 1 person experiencing homelessness per month. In areas where forming a homelessness multidisciplinary team is not justified, the committee agreed that existing practitioners could act as homelessness leads in mainstream services, for example, in general practice, A&E departments, hospitals, drug and alcohol treatment services, mental health services, palliative care services, sexual assault referral centres, maternity care, disability services and adult and child social services. The homelessness leads would champion, coordinate, advise and collaborate with colleagues and professionals within and across services to enable appropriate provision of care and support for people experiencing homelessness. Partnering with homelessness multidisciplinary teams in nearby areas for advice could further improve care and support for people experiencing homelessness in these areas.\n\n## How the recommendations might affect services\nModels of service provision vary in current practice. In some areas with high rates of homelessness, there are no specialist homelessness multidisciplinary teams, or services are often focused on a single aspect of care or are mainly medically led; for example, mental health teams, drug and alcohol treatment services, community-based or hospital-based multidisciplinary teams, or housing-related multidisciplinary teams. Many multidisciplinary teams do not cover the wide range of support that is needed. Services will need to involve practitioners from across multiple agencies to make sure that the team has relevant expertise.\nRecommendations on multidisciplinary teams may mean a change in service configuration. However, there may not be a need to employ new staff but to reorganise, collaborate with other agencies and form a team from existing professionals. Forming a multidisciplinary team may entail pulling together a team from different services working with a person experiencing homelessness. Alternatively, it may involve having a permanent integrated multidisciplinary team under single management within a service (that is, a coexisting co-located team), which would represent a more substantial change.\nIn areas with low rates of homelessness, having designated leads on homelessness may be a change in practice, but it is unlikely to have a significant resource impact because these are not expected to be entirely new job roles. These arrangements will be different across the country, and will depend on the demand and the level of need.\nThere is economic evidence that homelessness multidisciplinary teams represent value for money and are potentially cost saving. Having specialist multidisciplinary teams or designated leads should mean better integration and efficiency of services, more streamlined and personalised care and improved engagement with care and support, which in turn should lead to reduced morbidity, mortality and associated costs. There will likely be a reduction in wider public sector costs, including local authority homelessness services and the criminal justice system costs, because people will be more likely to progress in their recovery journey and maintain their accommodation. Such a service model can also mean better management of resources, for example, a reduction in inappropriate referrals, inappropriate use of hospital beds, and duplication of effort.\nReturn to recommendations\n\n# The role of peers\nRecommendations 1.4.1 to 1.4.4\n\n## Why the committee made the recommendations\nThere was some effectiveness evidence that suggested that peer support to navigate hepatitis C screening and services might help people to engage with services, and this was found to be cost effective. Other effectiveness studies also suggested that peers could increase uptake of tuberculosis screening and hepatitis vaccination to the same degree as professional staff. Although there were some concerns about the quality of the evidence on peer approaches, the committee were confident, based on their experience, that involving peers in delivering care or support and co‑designing services is efficient and beneficial, not only for the services and the people experiencing homelessness but also for the peers themselves. They also heard from expert witnesses who highlighted the value of involving people with lived experience in the development of policies, procedures and protocols.\nThe qualitative evidence also highlighted that people experiencing homelessness value support from peers who have similar experiences and have recovered and grown from that experience. The committee highlighted their experience and knowledge of the beneficial impact of being a peer, describing how peers can progress to become professionals if supported.\nBased on the evidence and their expertise, the committee agreed to list ways in which peers may be able to support people experiencing homelessness and how peers can improve services. Peers can take up different roles in terms of intensity, responsibility and tasks, and may gradually progress in these roles. The committee emphasised that it is important to support peers with adequate supervision and governance structures, including confidentiality and data protection. Training needs of peers might include, for example, first aid and mental health first aid, safeguarding, trauma-informed care, advocacy and risk management.\nQualitative evidence highlighted the obstacles and challenges that peers might encounter, including supporting someone with similar issues to their own while trying to maintain their own recovery. The committee agreed that peers should be supported to continue their own recovery journey and development by encouraging them to progress to become professionally employed, which is beneficial in many ways for the person acting as peer support, the people they are supporting, and services.\nThe committee also discussed that it is important to consider how to match the peers with people they support. For example, some people may prefer or request peer support from someone with the same cultural or language background, but sometimes this may be a reason for a person to refuse peer support because of the risk of stigma or confidentiality breech.\n\n## How the recommendations might affect services\nThere are existing peer networks, for example, for people recovering from drug or alcohol dependency issues. There are also peers working with people experiencing homelessness in some areas and in some organisations, in the voluntary and charity sector in particular. But the committee agreed that there is the potential to involve more experts by experience in service design and delivery. Peer support has the potential to improve access to and engagement with services, and reduce morbidity and mortality, and associated public sector homelessness costs. There may also be important benefits to peers themselves, leading to better long-term outcomes.\nPeers could be recruited through homelessness services or in collaboration with voluntary and charity sector organisations and housing associations. Services will also need to provide support and training for peers as well as incentives or remuneration. Involving peers can reduce pressure on practitioners and can result in cost savings. Organisations may need to adjust their recruitment practices and policies to lower barriers to the employment of peers.\nReturn to recommendations\n\n# Supporting access to and engagement with services\nRecommendations 1.5.1 to 1.5.12\n\n## Why the committee made the recommendations\nPeople experiencing homelessness are often unable to access health and social care because of barriers at systemic, local and individual levels. Various themes from mixed qualitative evidence highlighted examples, such as strict eligibility criteria, rigidity of appointment systems, limited opening times, short appointments, long waiting lists, siloed services in multiple locations, cost of transport and experiences of stigma and discrimination. The committee also drew on their own knowledge and experience of these barriers to access.\nThe committee agreed that an outreach model, in which the services go to the people instead of expecting people to come to them, is a helpful established approach to reaching people who do not access services. There is limited effectiveness evidence on outreach models, although evidence on a London-based outreach service to screen vulnerable people for hepatitis C and offer peer support for getting treatment in secondary care was shown to be cost effective. Moderate-quality evidence from qualitative studies suggested various benefits of outreach services, including increased access to immediate care and increased knowledge of health issues, available services, and healthcare entitlements. The evidence also highlighted that outreach services can be more flexible than traditional healthcare services and that bringing services to people builds a feeling of trust and connection with service providers while reducing the sense of isolation. The committee considered outreach services important to identify people who might otherwise be missed. They had confidence in the evidence and agreed that it corresponded with their experience.\nThere was good but limited effectiveness evidence that community drop-in services are helpful in reaching people and are preferred by service users. There was also good qualitative evidence that services are often complex, fragmented and difficult to navigate. The committee agreed that providing information and support to navigate care and services can improve people's access to and engagement with health and social care. Based on their knowledge and experience, the committee suggested approaches that could improve access and engagement. For example, low-threshold services that avoid restrictive eligibility criteria and make minimal demands on the client by offering support and care without trying to influence their habits; providing food, vouchers, transport support, internet access or other practical help can incentivise and enable people to engage with care; and providing psychologically informed environments and trauma-informed care can improve engagement with people who often have underlying negative and traumatic experiences.\nThe rigidity of appointment systems can lead to people being dropped from services if they miss appointments. There was some limited qualitative evidence illustrating the difficulties people experiencing homelessness face when they miss appointments. Some services have policies that prevent people accessing care at that service again or financial penalties for missing appointments. Based on the committee's experience, this is a major problem for many people experiencing homelessness and they agreed that services should show flexibility and understanding to facilitate engagement. The committee discussed the clear association between missed appointments and premature death and agreed that providing more flexible appointment systems and alternative ways of accessing care is therefore essential in improving outcomes.\nHigh-quality evidence from qualitative studies highlighted that strict eligibility criteria to access healthcare services sometimes forced people into crisis situations before help could be provided, or excluded them from accessing services altogether. Based on the committee's expertise, this is particularly prevalent among people with coexisting mental health problems and drug or alcohol treatment needs, which are common among people experiencing homelessness. Sometimes, people with coexisting mental health problems and learning disability can be excluded from accessing the respective services.\nSome services, particularly in social care, may have minimum age criteria that can stop people getting the support they need. Premature aging and frailty, defined by the British Geriatrics Society, the Royal College of General Practitioner, and Age UK as 'a distinctive health state related to the ageing process in which multiple body systems gradually lose their in-built reserves', are common among people experiencing homelessness with severe and multiple disadvantage, so care and support should be based on assessed need, not biological age. Flexibility in the eligibility criteria could prevent the situation from escalating and help people to receive support earlier, leading to better outcomes.\nGood qualitative evidence highlighted that some people are unaware of the free or low-cost services available to them, particularly dental care, if relevant paperwork has been processed. The committee discussed their experience that often these forms that enable free access to essential services such as eye care, prescription costs and dental care (such as HC1 and HC2) are not readily available, or are only available electronically. The forms can be challenging to fill in and only available in English.\nThe committee considered digital exclusion to be a major barrier to accessing health and social care. Qualitative evidence showed that people without access to the internet and those without a phone experienced difficulties in accessing healthcare.\nThe NHS Primary medical care policy and guidance manual states that everyone in England can register with a primary care provider free of charge. This includes people experiencing homelessness, people without a stable address, asylum seekers and refugees. However, according to good qualitative evidence and the committee's experience, many people experiencing homelessness are still refused registration with a GP. Resources are available from the NHS on improving access for all: reducing inequalities in access to general practice services.\nThe committee were keen to highlight the legal duties of public sector workers as mandated by the Homelessness Reduction Act 2017. In particular, the duty to refer anyone who is identified as being homeless or at risk of homelessness to the local authority. They discussed that despite the legal requirement, this does not always happen in current practice because processes are not in place to do this, and frontline staff lack time and knowledge. An expert also highlighted the need for health and social services to improve legal knowledge among their staff. Guidance on duty to refer from the Department for Levelling Up, Housing & Communities and Ministry of Housing, Communities & Local Government gives an overview of the legal duty. The Department for Levelling Up, Housing and Communities' code of guidance advises local authorities on how they should exercise their homelessness functions in accordance with the Homelessness Reduction Act 2017. The committee discussed that every encounter with a person experiencing homelessness could be an opportunity for engagement with care and support. Approaches such as Making Every Contact Count and Making Every Adult Matter could be used to facilitate this and help frontline staff better understand the services available for onward referral.\nThe qualitative evidence highlighted that long waiting times are a barrier to accessing and engaging with health and social care, affecting people experiencing homelessness in particular. The committee agreed that people experiencing homelessness are a priority because their multiple disadvantages put them at an increased risk of deterioration and premature mortality and morbidity. They discussed that long waiting times can be particularly challenging for people experiencing homelessness and can mean that the opportunity to engage with them is missed altogether, for example, if the person moves to another area or forgets about the appointment. They also discussed that people experiencing homelessness may have particular difficulty coping psychologically with long waiting times because of the fundamental feeling of unsafety and exclusion that homelessness causes. Long waiting times could lead to further deterioration of physical and mental health, and could compound feelings of disengagement and exclusion.\n\n## How the recommendations might affect services\nCurrent practice is variable. For services that do not have multiple points of access to care or flexible services, these recommendations will represent a change in practice. Services will need a variety of approaches that can be tailored to specific needs. Currently, because of the lack of flexible services, people are using expensive emergency services or are not accessing services at all, resulting in excess morbidity and mortality, and associated high public sector homelessness costs. For example, inflexible appointment systems increase the risk of missing appointments, and there is a link between missed appointments and premature mortality. Missed appointments also cost the NHS millions of pounds a year; for example, missed GP appointments in the general population cost NHS England around £216 million a year in addition to the disruption for staff and other patients (Missed GP appointments costing NHS millions, NHS England 2019).\nTransport costs are a considerable barrier to access to and engagement with services, and continuity of care. Practice is variable between different areas. People experiencing homelessness often have multiple morbidities, which could make them eligible for a free travel pass, but often do not have one because of bureaucratic challenges. Currently, a clinician (usually a doctor) needs to sign the paperwork for a free travel pass. Services could broaden the list of professionals able to approve applications, which could make free travel easier to access. The cost of providing free travel will be relatively low compared with the cost of missed appointments and the costs relating to unaddressed needs. For example, an annual bus pass in London costs approximately £900 (Transport for London bus and tram fares), but if a person with a leg ulcer misses multiple appointments, then this may lead to an infection and in some cases amputation, costing the NHS at least £8,000 (NHS England National cost collection for the NHS), in addition to the impact on the person. Services will need to work collaboratively to agree who will cover travel costs within their local system.\nSome mental health or drug and alcohol recovery services will need to modify their eligibility criteria. This may lead to more people accessing services. But there may also be savings from avoiding crisis situations and unplanned care and providing more efficient support, leading to better long-term outcomes.\nMore practitioner time may be needed to help people with forms and other paperwork. But this can help prevent deterioration and the need for more expensive care, for example, emergency care, in the future.\nIn recent years, there has been an increase in the use of digital approaches to providing support within the homelessness sector. To avoid this leading to digital exclusion, some services may need to improve access to online health and social care information and support. There may be some costs associated with this, but providing access to digital services and information can improve engagement with services and avoid the need for costly emergency care.\nA significant barrier to accessing health and care services for people experiencing homelessness is that GP practices ask for an address when registering. Recommendations on this reinforce NHS guidance and should result in more people registering with a GP and accessing services that they are eligible for and entitled to. This has the potential for substantial reductions in morbidity and mortality, and public sector costs associated with homelessness.\nThere is variation in the extent to which frontline staff are aware of their legal duties under the Homelessness Reduction Act 2017, including the duty to refer. Services may need to support their staff in legal literacy and to have the skills and knowledge to identify and support people experiencing homelessness. Training could be delivered in low-cost ways, such as remotely, using pre-recorded sessions, and could coincide with existing training. Both governmental and voluntary organisations have produced materials that are readily available online. The cost for this is therefore not expected to be significant and it could lead to better and more efficient care. Timely and appropriate care can avert the need for expensive crisis care and A&E visits, and reduce other public sector costs associated with homelessness.\nLong waiting times for appointments in current practice are a significant barrier for engagement and timely care. Situations can quickly deteriorate, or the person might disengage because their needs are not being met. Shorter waiting times for people experiencing homelessness may avoid a crisis, lower the chances of needing expensive emergency services, and prevent complex morbidity and premature death.\nReturn to recommendations\n\n# Outreach services\nRecommendations 1.5.13 to 1.5.17\n\n## Why the committee made the recommendations\nQualitative evidence highlighted that people experiencing homelessness often face barriers to accessing services through standard routes, and are often disengaged with health and social care. Outreach is an established way to bring services to people who may otherwise find it hard to reach them. There is limited effectiveness evidence on outreach models, although evidence on a London-based outreach service to screen vulnerable people for hepatitis C and offer peer support for getting treatment in secondary care was shown to be cost effective.\nModerate-quality evidence from qualitative studies suggested various benefits of outreach services, including increased access to immediate care and increased knowledge of health issues, available services, and healthcare entitlements. The evidence also highlighted that outreach services can be more flexible than traditional healthcare services and that bringing services to people builds a feeling of trust and connection with service providers while reducing the sense of isolation. The committee considered outreach services important to identify people who might otherwise be missed.\nBecause people experiencing homelessness have a wide range of health and social care needs, the committee agreed that outreach teams should be multidisciplinary and also equipped to respond to needs of people with different, intersecting experiences relating to, for example, gender, ethnicity and being part of the LGBT+ community. Evidence from several economic studies showed that a multidisciplinary approach in general provided value for money in relation to the homeless population. While this was not specific to outreach teams, the committee agreed that given the severe and multiple disadvantage people experiencing homelessness often face, multidisciplinary outreach teams are justified and essential for meaningful response to people's needs.\nGood qualitative evidence showed that some people who are resistant to support or who feel overwhelmed by it might feel more motivated if ongoing support is available, including repeated attempts to engage with the person without placing pressure on them. The committee agreed, based on their knowledge and experience, that an 'assertive outreach' approach is useful in improving engagement for those who may be reluctant to engage with services and who would benefit from a high level of support. 'Assertive outreach' is most often used for people with complex mental health needs and drug or alcohol treatment needs. This is in line with the recommendations about maintaining contact with services in the NICE guideline on coexisting severe mental illness and substance misuse. The committee agreed that this approach could also be considered for other people experiencing homelessness who are likely to benefit from health and social care but who are disengaged, for example, because of lack of trust or previous negative experiences.\n\n## How the recommendations might affect services\nOutreach is used in current practice in many areas to deliver a range of services, including primary care, mental health, opiate prescribing, and testing for chronic or infectious diseases such as hepatitis and tuberculosis, although the services provided through outreach vary depending on location. Outreach can happen in multiple settings, such as streets, parks, hostels, day centres or soup kitchens. Services generally understand its value in enabling access and engagement with health and social care, but commissioning of outreach services for people experiencing homelessness varies.\nAdditional resources may be needed to set up outreach in areas where it is not happening already. However, it has great potential to support this population, and improve engagement with services and long-term outcomes. It can also bring savings, for example, by avoiding missed appointments and visits to the A&E department.\nAssertive outreach is used in some areas in current practice, particularly when engaging with people with complex mental health needs. It takes more practitioner time and may be more expensive, but persevering with people and improving engagement among people who would benefit from support is likely to substantially improve the health and wellbeing of people who have been marginalised, and reduce morbidity and mortality, and associated public sector homelessness costs.\nReturn to recommendations\n\n# Assessing people's needs\nRecommendations 1.6.1 to 1.6.7\n\n## Why the committee made the recommendations\nThere was no evidence on the effectiveness of different approaches to improving access to services through needs assessments, so the committee used their knowledge and experience to make the recommendations.\nThe committee were keen to emphasise the statutory and professional duty that health and social care professionals have to identify immediate risk of harm to self or others, in line with the Care Act 2014 and the Mental Health Act 1983, and professional codes such as the Nursing and Midwifery Council Code, General Medical Council's Good medical practice and Social Work England's Professional standards. The committee were aware of case reviews and Safeguarding Adults Reviews on people experiencing homelessness showing that this risk had been missed, leading to death. This is particularly relevant in the context of homelessness because there is a significant link between homelessness and risk of abuse, neglect and violence, serious mental health problems, self-harm and self-neglect, underpinning the disproportionate rate of premature mortality in this population.\nThe committee agreed that a comprehensive, holistic health and social care needs assessment within the context of the individual's wider circumstances improves access to health and social care and support that matches the person's needs. They agreed that a multidisciplinary approach is needed to ensure that the full range of health and social care needs are identified, including considering risk and safeguarding issues. Collaborative working also reduces unnecessary duplication and improves communication between professionals working in different services.\nThe committee were concerned that assessment is commonly perceived by people experiencing homelessness as a process of exclusion. People often have to keep repeating their stories and the assessments can turn into an assessment of eligibility for support rather than a person-centred attempt to understand a person's needs and circumstances. The committee agreed that involving the person in their own assessment process and involving a peer or an advocate could help improve the assessment process. Peers and advocates (who may be peer advocates) can play an important role in bridging the gap between the person experiencing homelessness and professionals. They can make the assessment process feel less formal and therefore more acceptable or accessible to people experiencing homelessness.\nThe committee were aware that hospital admissions related to homelessness have been increasing. They agreed, based on their knowledge and experience, that hospital admissions are an opportunity for a comprehensive and holistic assessment of a person's needs to enable appropriate personalised care planning that integrates health, social care and housing needs. A hospital stay can be an opportunity to start addressing the often complex and underlying issues that have led people to their situation.\nThe committee agreed that a comprehensive understanding of the person's physical, mental and social care needs as well as the underlying circumstances of their situation will help when conducting the statutory care and support needs assessment under the Care Act 2014, which sets out local authorities' duties to assess people's needs and their eligibility for publicly funded care and support. The committee noted that the recommendations on care and support needs assessment and care planning in NICE's guideline on people's experience in adult social care services provides advice on conducting the care and support needs assessment under the Care Act.\nThe committee were also aware that some people may be entitled to an independent advocate under certain circumstances. For example, the Care Act 2014 mandates that local authorities must appoint an independent advocate to support and represent a person in the local authority-led care, and support needs assessment or safeguarding enquiry if the person has substantial difficulty in being involved in the process, and if they do not have an appropriate person to support them.\nThe committee pointed out that after the person's needs are established and support planned to meet these needs, many people experience difficulties with ongoing support. Because the needs assessment process can be challenging, the committee agreed that the person's support needs should be reviewed as needed, when their situation changes or if they request it, but not based on standard review periods.\n\n## How the recommendations might affect services\nIdentifying immediate risk of harm to self or others reinforces a statutory and professional duty, and does not represent a change in practice.\nA comprehensive assessment of health and social care and support needs involves a multidisciplinary approach, can be time-consuming and needs collaboration between professionals from different agencies. This should be happening across all services. However, practice is variable and these recommendations may represent a change in practice and result in a resource impact for some services.\nHospital admissions are good opportunities to provide a comprehensive and holistic assessment of safeguarding, physical and mental health, drug and alcohol treatment needs, and social care needs for people experiencing homelessness. This does not often happen in current practice and the committee thought that this was a missed opportunity to assess the person's comprehensive needs and start integrated care. The recommendations in this area may mean that services will need to plan for more tests, procedures and practitioner time. This could prolong a hospital stay, although discharge to the community would likely be safer and future admissions could be avoided. Such a proactive approach could have benefits in the long term, such as preventing people from getting into crisis because of unidentified needs, and reducing morbidity and mortality, and associated homelessness costs.\nAs a result of the recommendations, more people experiencing homelessness who may benefit from high levels of support may have an assessment of social care needs and go on to engage with services. But an appropriate assessment of the health and social care needs of some of the most marginalised people in society will ensure timely and appropriate care and support for them, with a potential for reduced morbidity, mortality and associated public sector costs.\nReturn to recommendations\n\n# Intermediate care\nRecommendation 1.7.1\n\n## Why the committee made the recommendation\nIntermediate care is a multidisciplinary service that helps people to be as independent as possible and provides support and rehabilitation to people at risk of hospital admission or who have been in hospital. Evidence from several economic studies suggested that it is cost effective and potentially cost saving. The committee agreed that providing such services would help avoid hospital admissions and ensure safe and timely discharge from hospital and transition to the community. Intermediate care can also prevent or shorten expensive inpatient care and provide appropriate care and support to people in need of more intense support than otherwise provided in the community.\n\n## How the recommendation might affect services\nIntermediate care, including step-down and step-up care, would represent a change in practice because this service is currently rare for people experiencing homelessness. This would need some funding but there is evidence that intermediate care represents value for money. Furthermore, considering the immense human and societal costs of homelessness, providing care that can support recovery and prevent repeat homelessness is likely to be beneficial to society overall. Intermediate care can be delivered in the community, such as in suitable hostels, or in designated facilities.\nReturn to recommendation\n\n# Transitions between different settings\nRecommendations 1.8.1 to 1.8.4\n\n## Why the committee made the recommendations\nThe committee discussed that people experiencing homelessness can be vulnerable during transition periods. However, testimony by expert witnesses also highlighted that these can also be opportunities for engagement and intervention. The committee agreed that transition periods can be a chance to build foundations for lasting support in the community.\nThe committee noted that a phased, focused and person-centred approach to transitions is currently unusual. Often the person is discharged or moves between services, settings or areas without thorough planning, follow up or coordination. For example, sometimes the person's homeless status and related needs are identified only at the point of discharge from hospital into the community. Identifying needs and collaboration between professionals and agencies is therefore essential.\nEffectiveness evidence comparing 'critical time intervention' (time-limited intensive support during a transition period) with usual care among people experiencing homelessness, including discharge from psychiatric inpatient care and moving from a homeless shelter to the community, showed benefits in terms of mental health service use, housing status and reduced psychiatric re-hospitalisation, although no difference in quality of life was reported. Despite some methodological limitations and mixed results in the evidence, the committee agreed that the general approach and key principles of critical time intervention should form the basis of recommendations on support for key transitions. This is because any transition between settings can be challenging, with a risk of people falling through the gaps, but with appropriate support, it can also be an opportunity for improved engagement and recovery.\nThe 'critical time intervention' model includes establishing a trusting and enduring relationship, and a gradual decrease in the intensity of support over a fixed period of time. The time period in the studies was 9 months, but the committee agreed that the length of time needed for intense support during transition would depend on the circumstances and needs of the person. The committee agreed that, to make successful transitions, it is fundamental to start support before the move and continue it during and after transition. This needs an effective and coordinated handover across teams and practitioners. Good qualitative evidence highlighted that staff from all types of services recognised that most care is provided in silos with minimal coordination between agencies and providers. The findings emphasised the need for a more coordinated approach with appropriate information sharing. Good-quality evidence from qualitative studies also emphasised the importance of information sharing between practitioners so that people do not have to repeatedly give the same information. A trusting relationship is also more likely when support is from a single person throughout, or a coordinated team, reducing the need to repeat life stories and any associated trauma. Critical time interventions are seen as a holistic approach to support. The committee wished to reflect this, emphasising the need to link people with other services and the wider community, according to their needs and preferences.\nIrregular discharge (self-discharge against medical advice) represents a missed opportunity for services to engage with a person experiencing homelessness and to start integrated care. A common cause of self-discharge is when people experiencing homelessness have a history of problem opioid use and do not have access to the right dose of methadone according to their treatment plan in the community, so they self-discharge to address their withdrawal symptoms.\nFor some people with drug and alcohol treatment needs, a hospital admission is an opportunity to detox. If people experiencing homelessness return to the streets without appropriate support after detox, they have an increased risk of overdose and a risk that any care plans will fail. It is important that there are procedures to minimise self-discharges and prevent discharges to the street so that risks can be reduced, and discharges are as safe as possible. Reviewing incidents of self-discharge or discharge to the street can improve procedures and care in the future. The Department of Health and Social Care's Hospital discharge and community support: policy and operating model refers to the King's College London's support tool and briefing notes on transforming out-of-hospital care for people who are homeless, which outlines how safe and timely transfers of care can be delivered.\nThe committee also highlighted other NICE guidelines that cover important transition periods that may be applicable to people experiencing homelessness.\n\n## How the recommendations might affect services\nThere is wide variation in the support provided during transitions between settings. The recommendations should increase sustained support and lead to a more coordinated response to needs. This in turn could lead to reduced re-attendance after leaving hospital or breakdown of tenancy, and reduced morbidity and mortality.\nProcedures to review cases when a person experiencing homelessness has self-discharged or has been discharged to the street may be a change in practice for some hospitals. But, by learning from these situations and improving practice, there would be an opportunity to prevent irregular discharge in the future and improve outcomes for patients. Having a dedicated homelessness multidisciplinary team or designated homelessness lead working with the discharge team can help strengthen links to community services where people get methadone to ensure they continue to receive the right dose in hospitals. Enhanced connections with social services and local authorities will help link people experiencing homelessness to the right support. This may need additional resources, but reductions in morbidity, mortality and associated costs should offset additional costs in the long run. There was evidence that effective hospital discharge represents value for money.\nReturn to recommendations\n\n# Housing with health and social care support\nRecommendations 1.9.1 to 1.9.5\n\n## Why the committee made the recommendations\nAccess to suitable accommodation is a key determinant of health and social care outcomes. The committee discussed, based on their knowledge and experience, that there are various aspects of accommodation that can either hinder or help a person's recovery process and their engagement with health and social care. These might include practical and logistical considerations, such as the distance to health or social care services, accessibility, aids, and appropriate storage for medication.\nThere was good effectiveness evidence from the Housing First trials that people are more likely to stay housed if their accommodation has wraparound health and social care support. There was also evidence that this approach could be cost effective. The committee's experience of health and social care services designed to support housing was positive, and tenancy sustainment was commonly achieved through this wraparound approach. The committee agreed, based on their knowledge and experience, that the level of support depends on the person's needs, with some people needing specialist onsite support. These could be people with high levels of need or severe and multiple disadvantage who are vulnerable to abuse and exploitation, young people who have no experience of independent living, people who have experienced domestic abuse, or people with particular care needs who need support in everyday life because of premature aging, acquired brain injury or disability.\nThe committee discussed the lack of evidence on how to improve needs-based wraparound support for people with severe and multiple disadvantage and premature frailty, particularly those who have experience of rough sleeping. The committee made a research recommendation on the structural and systems factors in health and social care that could help or hinder commissioning and delivery of wraparound support integrated with housing and they agreed that research in this area should consider inequalities and collect data that enable the impact on different groups to be studied. The equality impact assessment provides further information on equalities considerations for this guideline.\nMoving into independent accommodation may seem like a positive transition, but based on the committee's experience, this can be one of the most difficult times for people who may have a history of traumatic experiences, have severe and multiple disadvantage, feel profoundly unsafe or have low self-confidence. Such a transition often causes the person to reflect on what has happened to them, which can be triggering and cause re-experiencing of trauma. It can lead to relapses in recovery, including problems with drug or alcohol use. Furthermore, people living in temporary accommodation or on the streets can form bonds with their peers that provide mutual support and a sense of belonging. This may be replaced by a feeling of isolation and loneliness when moving into independent accommodation. Effectiveness evidence on 'critical time interventions' showed that time-limited intense support, gradually lowered over time during transition periods, did not sustain all benefits over time, so the committee agreed that emotional and practical support should be provided for as long as is needed in this situation.\nThe committee also agreed that an assessment of the risks that could jeopardise the person's recovery, alongside recognition of their strengths, can help recovery, inform appropriate support needs and help people to stay in housing.\n\n## How the recommendations might affect services\nThere is variation in current availability and provision of health and social care support associated with housing. The recommendations aim to reduce variation in practice.\nThe Housing First model has been used in England to some extent and there is evidence that it represents value for money, but the associated wraparound support is variable and sometimes lacking. To provide wraparound care and support, better collaboration is needed between housing, health and social care services. Services may need to reorganise existing resources, including improving communication between agencies and services and allowing more practitioner time.\nLocal authorities should already have a range of housing options for differing support needs, although in some areas, accommodation with onsite support might be limited.\nAdditional costs of providing wraparound support with accommodation, according to needs, are likely to be offset by improved health and social care engagement and outcomes, sustained tenancy, reduced use of expensive emergency services and a reduced return to homelessness and associated costs.\nRisk assessment at the start of residency is a low-cost intervention that can potentially mitigate significant harmful outcomes.\nReturn to recommendations\n\n# Safeguarding\nRecommendations 1.10.1 to 1.10.7\n\n## Why the committee made the recommendations\nNo effectiveness evidence was identified on the role of adult social work, and safeguarding in particular, in an integrated response to the needs of people experiencing homelessness. The recommendations on safeguarding are based on testimony by experts who were invited by the committee to speak about the role of social work and adult safeguarding.\nThe experts highlighted the importance of understanding the person's backstory and historical context that led to the current situation, recognising the link between homelessness and self-neglect, the impact of trauma and how risk-taking can be a coping strategy. Because of the value of having a trusting relationship with the person experiencing homelessness, the experts emphasised the importance of having a single key person as a safeguarding lead in an integrated service model.\nSection 42 of the Care Act 2014 requires local authorities to make a safeguarding enquiry if an adult with care and support needs is experiencing or at risk of abuse or neglect. The committee agreed that a social worker within a homelessness multidisciplinary team would often be best placed to lead on these enquiries for people experiencing homelessness because of their professional expertise on the assessment and related legal duties and powers.\nThe experts suggested that safeguarding issues related to homeless populations have historically not been widely considered by Safeguarding Adults Boards. The committee agreed that having a homelessness lead in the Safeguarding Adults Boards could enhance learning and improve practice. The committee also agreed that Safeguarding Adults Boards have an important role in promoting understanding and best practice within local agencies related to safeguarding people experiencing homelessness, including through their statutory strategic plan and annual report and learning from Safeguarding Adults Reviews. By analysing and interrogating safeguarding notifications related to homelessness, the Safeguarding Adults Boards can also enhance their understanding of the appropriateness of local safeguarding arrangements.\nFinally, the experts highlighted the need for health and social care staff to understand the legal duties and powers related to safeguarding people experiencing homelessness, so that their welfare could be protected, concerns could be identified and addressed early, and harm mitigated.\n\n## How the recommendations might affect services\nThere are legal duties for safeguarding under the Care Act 2014 and the recommendations in this area only highlight the existing safeguarding responsibilities of service managers and local authorities. Teams involved in active safeguarding cases should already have legal literacy around safeguarding relevant legislation and the intersection of homelessness and multiple disadvantages, but may need more training.\nCurrently, based on the committee's experience, people experiencing homelessness often fall through the gaps, and safeguarding concerns are not identified and safeguarding notifications are not made. There may be a resource impact for services with practices that are sub-optimal and not aligned with legislation. Safeguarding will ensure that appropriate support plans are in place to manage the risks identified. For example, a person might be supported to move to more suitable accommodation.\nReturn to recommendations\n\n# Long-term support\nRecommendations 1.11.1 to 1.11.6\n\n## Why the committee made the recommendations\nPeople experiencing homelessness often need support due to severe and multiple disadvantage, including intersecting physical and mental health needs, psychological trauma, drug and alcohol treatment needs, and social care needs. The committee agreed that sustained effort and commitment from services is needed to support their recovery journey, which may often be non-linear.\nGood-quality evidence from qualitative studies showed that people experiencing homelessness often experience a lack of consistency and continuity from health and social care services. There was also good qualitative evidence that ongoing, sustained support, and a service provider's patience and continued attempts to offer support, can improve the person's engagement when they might otherwise be resistant to support. Conversely, discontinuity or interruption of care could lead to disengagement with services.\nThere was plenty of good-quality evidence from qualitative studies emphasising the importance of a trusting and respectful relationship between the person experiencing homelessness and the person supporting them. The evidence showed that continuity of care enabled people to form a relationship with their care provider. The committee agreed, based on their experience, that a trusting relationship is rarely built through a short-term contact but usually needs consistent and sustained contact from 1 main lead or a small team of people who are part of integrated services across agencies.\nGood qualitative evidence suggested that people experiencing homelessness often prioritise their immediate needs over receiving care. The committee discussed that addressing immediate needs can be an opportunity to build long-term engagement with services.\nFrom their knowledge and experience, the committee were aware that people experiencing homelessness did not always follow a linear recovery journey and can encounter a relapse or crisis. Therefore, the committee thought it was important that services were flexible in allowing people to easily re-engage with services so that their situation would not escalate or deteriorate further.\nPremature ageing and frailty is common in people experiencing severe and multiple disadvantage and homelessness, and the committee discussed that improvements in their wellbeing can be made if long-term care and support plans take this into account.\nThe committee also recognised that not all people will recover and risk of premature death is higher in people experiencing homelessness compared with the general population. Palliative care has often not been available for people experiencing homelessness and those who are approaching the end of their lives may remain in for example hostel accommodation without provision of appropriate end of life care that supports the person's preferences.\n\n## How the recommendations might affect services\nThe recovery journey for some people can take a long time, and services need to be persistent, invest in building trust, and recognise that the process will often not be linear. Currently, long-term continued support is quite rare, and funding of services is often not aligned with such an approach. For example, tenancy sustainment teams are often underfunded and only offer time-limited support of varying quality. Offering long-term support could cost more because it may, for example, need lower caseloads, although for many people, the intensity and frequency of support will likely lessen over time. But the value of investing in systems that facilitate longer-term support and sustained care and engagement is likely to outweigh additional costs through, for example, reduced homelessness and morbidity and mortality, and associated public sector costs. Investing in longer-term support will likely help prevent people from returning to homelessness and needing more acute support. Services may need more capacity initially, but longer-term provision of timely help can stabilise people and prevent a crisis, which will be more detrimental for the person and more costly to services.\nCurrently, people experiencing homelessness have limited access to palliative care services. This should be improved with the introduction of homelessness multidisciplinary teams, coordinated care and improved access to specialist services, including palliative care. Palliative care services already exist, and should become more accessible to people experiencing homelessness.\nReturn to recommendations\n\n# Staff support and development\nRecommendations 1.12.1 to 1.12.3\n\n## Why the committee made the recommendations\nGood qualitative evidence showed that healthcare professionals felt ill-equipped and had insufficient knowledge of social determinants of health and homelessness, and the associated health needs for complicated health problems such as addiction and mental health problems. The evidence also showed that people experiencing homelessness felt that service providers did not understand the practicalities of being homeless and their specific needs. The committee discussed that further training and support was needed to strengthen the capacity of health and social care providers to address people's severe and multiple disadvantage and diverse needs.\nThe qualitative evidence also showed that training would raise awareness and improve provider knowledge in this area, and improve sensitivity and understanding for this population, so that care providers overcome preconceived ideas and judgemental behaviour. Good qualitative evidence showed that most people experiencing homelessness reported experience of discrimination on some level, with many recounting some form of prejudiced behaviour from service providers. The committee discussed that health and care providers should be trained to consider people's preferences rather than making assumptions about their needs and care solely based on their behaviour or appearance, for example. Furthermore, the committee discussed the importance of practitioners understanding and responding to the intersectionality of multiple disadvantages that people experiencing homelessness may face because of their characteristics.\nLimited evidence from qualitative studies among service providers also showed that some lack awareness of the impact that trauma has on a young person's life and how it may manifest in their behaviour. The evidence suggested that providers who do not operate from a trauma-informed care approach may inadvertently serve as a barrier.\nExperts also highlighted the importance of health and social care professionals' legal literacy and understanding of their duties and powers in relation to homelessness, mental capacity and safeguarding.\nThe committee were aware that there are various existing training and materials that organisations could use, such as e-learning for healthcare resources on tackling homelessness, free online training modules by the Faculty for Homeless and Inclusion Health and Public Health England's guidance on homelessness: applying 'All Our Health' and further resources in Health Education England's inclusion health education mapping and review.\nExperts highlighted the importance of staff support and supervision, which enables reflection on experiences and practices to enable continuous learning for staff and development of both the staff and practices. The committee agreed that reflective practice and supervision can increase staff motivation and wellbeing, quality of care and services.\n\n## How the recommendations might affect services\nCurrently, there is variation in training opportunities for health and social care staff who encounter people experiencing homelessness. Most statutory agencies regularly train their staff, but training on some issues relevant to homelessness, such as legal duties and powers, is not common practice for all services. This extra training could be delivered alongside existing staff training programmes in a variety of low-cost ways, for example, by remotely using pre-recorded sessions, and could coincide within existing training. Because of existing training and materials, there is no expected significant resource impact.\nTraining to understand the needs of people experiencing homelessness may mean that more people access specialist homelessness services. Training and ongoing support will facilitate joined-up and more connected services, for example, between specialist services and mainstream services, and ensure a holistic approach and a framework of support. Improved knowledge and understanding will improve access and care for people experiencing homelessness. Practitioners will be better placed to give information about available health and social care services, and enable services to meet people's needs before their problems escalate. For example, most people could be legally housed by local authorities and councils if more professionals had a better understanding of homelessness law and guidance.\nThe recommendations encourage services to include these elements in their training more consistently. They can also influence the development of professional competencies for trainees and future practitioners.\nReturn to recommendations"}}},{"rowIdx":97,"cells":{"id":{"kind":"string","value":"5393c6d6c50e5551d8774a44490402fd149d8ab6"},"source":{"kind":"string","value":"nice"},"text":{"kind":"string","value":"Babies, children and young people's experience of healthcare\n\nThis guideline describes good patient experience for babies, children and young people, and makes recommendations on how it can be delivered. It aims to make sure that all babies, children and young people using NHS services have the best possible experience of care. It is recognised that parents and carers play a key role, and where appropriate, we took their views into account when developing the recommendations.\n\n# Introduction from the young people involved in the development of this guideline\nWhen babies, children and young people access healthcare, it is important that their experience is as positive as possible. This guideline has been written with children and young people who know what it's like to be a patient. It has been an opportunity to share what has and has not worked, and hopefully improve the healthcare experience of many babies, children and young people in the future.\nAdults often see children and young people as passive recipients of healthcare. This can lead to children and young people not being listened to, having a lack of understanding of their own condition and may lead to problems that can affect future care (for example, finding it difficult to trust healthcare professionals or feeling very anxious before procedures). However, having a positive experience can make a child or young person feel confident, empowered and supported to manage decisions about their own health and healthcare, and can improve their perception of their diagnosis and treatment. This positive experience should also ensure that babies, children and young people are treated as individuals with a life outside healthcare, and not just as their condition or diagnosis.\nThis guideline aims to improve the healthcare experience of babies, children and young people with the hope that this can improve their health outcomes and their wellbeing.# Context\nOptimising patient experience has long been recognised as an integral part of effective healthcare for adults. The healthcare experience of babies, children and young people has received less attention in the past, despite the legal rights of children to participate in decisions that affect them. Unfamiliar environments, and having to meet and interact with a range of healthcare professionals, can be particularly unsettling for babies, children and young people, and may lead to anxiety and distress.\nMany NHS providers of healthcare services for children and young people currently carry out user surveys directly with children and young people as well as with their parents or carers, and some run focus groups to obtain feedback from children and young people and their parents or carers, with a view to improving the provision of services and the experience of healthcare. However, surveys of children and young people's healthcare experiences have identified that feedback from children themselves is generally less positive than their parents' responses, with a third of children in 1 survey reporting that they did not always understand what staff said, and over half feeling they were not involved enough in making decisions about their care or treatment.\nAlthough there are some examples of good practice and initiatives to improve babies, children and young people's experience of healthcare, there is variation in practice across the country.\nThis guideline covers babies, children and young people (aged 17 and under) accessing NHS physical or mental health services, or local authority-commissioned healthcare services. Babies, children and young people are entitled to always receive the same high-quality healthcare experience, and so the recommendations in this guideline apply to all healthcare experiences and settings. For some babies, children and young people, interaction with healthcare services may be limited to visits to a dentist or GP, whereas other babies, children and young people may have medical conditions that need frequent interactions, inpatient stays and an ongoing healthcare relationship with professionals, so a personalised approach to implementation is needed.\nThe guideline provides evidence-based information for healthcare professionals, children, young people and their parents or carers about communication, information, support, the healthcare environment, access and continuity of care. It also provides guidance on maintaining usual activities because babies, children and young people need the opportunity to grow, learn and develop alongside their peers, despite their healthcare needs.# Recommendations\nHealthcare professionals should involve children and young people in decisions about their healthcare in ways that are appropriate to their maturity and understanding. Some children and young people will be able to give informed consent themselves, some will be able to contribute to the discussion, and others may not be able to be involved at all. For more information, see NICE's information on making decisions about your care.\nA parent or carer, who has parental responsibility for a child (as defined by the Children's Act 1989), will have a key role to play in planning and making decisions about their child's health and care, particularly when they are young. As children grow older and develop the maturity and understanding to make decisions for themselves, that role will diminish, particularly if the child wants it to. Where relevant, parents and carers should be given information and support to enable them to do this, as set out in the NHS Constitution and summarised in NICE's information on making decisions about your care.\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding that should be used alongside this guidance.\n\n# Overarching principles\n\n## Safeguarding\nAdhere to all relevant legislation and follow all national and local safeguarding policies and professional guidelines when implementing these recommendations and when planning and delivering healthcare services for all babies, children and young people, in any setting. See further guidance in the NICE advice on safeguarding and the Children's Act 1989 (and subsequent updates).\n\n## Disabilities\nAdhere to all relevant legislation relating to the rights of disabled babies, children and young people to access healthcare, and make reasonable adjustments as required by legislation to enable this access. See the Equality Act 2010.\n\n## Competence\nInvolve all children and young people in decisions about their healthcare, unless they do not wish (or are unable) to be involved (see recommendations 1.1.4 to 1.1.7). Recognise that:\nYoung people aged 16 or 17 years with mental capacity to make decisions about their healthcare are entitled to do so, and to consent to treatment. There is a presumption that a person above the age of 16 has capacity unless and until assessed otherwise.\nChildren and young people under 16 years can make decisions about their healthcare and consent to treatment if they are assessed by a healthcare professional to be Gillick competent. The conclusion that a child or young person is competent relates to that specific healthcare decision.\n\n## Age- and developmentally appropriate care\nEnsure that all methods of communication, information and discussions are tailored for the age, developmental stage and level of understanding of the baby, child or young person.\nRecognise that needs and preferences may change as children mature, and that it is necessary to revisit these needs and preferences on a regular basis and to adapt support, information and complexity of discussions accordingly.\n\n## Changes in needs and preferences\nRecognise that children and young people's needs, preferences and engagement with healthcare professionals and healthcare services (for example, how much they would like to be involved in decision making or how much support they need) may vary from day to day, at different encounters or may be affected by other factors (for example, how unwell they are feeling).\nEnsure that previously expressed needs, preferences or engagement levels are revisited, and give additional or alternative opportunities for discussions or decisions, particularly if personal or clinical circumstances have changed.\n\n## Digital access\nRecognise that not all children and young people, or the parents or carers of babies and young children, are able to access digital resources (for example, online information, messaging or video-calling, apps or other digital tools).\nEnsure that non-digital methods of attending appointments, communicating, and providing information are available, and provide an equal level of service, for anyone who cannot access (or prefers not to use) digital methods.\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on overarching principles .\nFull details of the evidence and the committee's discussion are in:\nevidence review A: planning healthcare and making shared decisions\nevidence review C: consent privacy and confidentiality\nevidence review D: providing information\nevidence review E: understanding the risks and benefits of healthcare decisions\nevidence review F: involving parents or carers in healthcare and healthcare decisions\nevidence review G: support from healthcare staff\nevidence review M: healthcare environment.\nLoading. Please wait.\n\n# Communication and information\n\n## Communication by healthcare staff\nEnsure that children and young people, and their parents or carers have a positive experience by:\nintroducing yourself and anyone else present\nasking them how they wish to be addressed (for example, their preferred name and pronouns)\nputting the child or young person and their parents or carers at ease by being friendly and welcoming (for example smiling, saying hello, using eye contact)\nbuilding a rapport to develop trust\nencouraging children, young people and the parents and carers of babies and young children to contribute to, and be active participants in, discussions and decisions about their care. See also the section on support from healthcare staff.\nCommunicate with children and young people and their parents or carers with:\nkindness, compassion and respect\ncultural sensitivity\na non-judgemental attitude.\nWhen communicating with babies, children and young people, particularly those with ongoing health needs, develop an understanding of them as individuals, not only based on their health condition or diagnosis (for example, referring to the baby, child or young person by name, asking them what is important to them in their healthcare).\nTake time to listen to and address the concerns and fears of children and young people, and of the parents or carers of babies and young children and:\ntreat their concerns and feelings (such as fear and embarrassment) with empathy and understanding\ngive reassurance that these concerns are very common and are nothing to feel embarrassed or upset about (for example, by saying 'it's OK to be scared').\nIdentify who is the most appropriate person to communicate with a child or young person, or the parent or carer of a baby or young child (for example, this could be a healthcare professional or other member of the multidisciplinary team, or another professional such as a youth worker or social worker). When deciding on the person, take into account:\nthe clinical circumstances\nthe subjects to be discussed\nthe preferences of the child or young person.\nIdentify the child or young person's preferred forms of communication and use these when communicating with them. Ask their advice, or ask their parents or carers what these are. Take into account that:\nEnglish may not be their first language\nthese may be non-verbal (for example, sign language, Makaton)\nidentification of a 'yes' or 'no' response (which might be non-verbal) can allow a direct conversation between a child or young person and a healthcare professional\nthese might need additional resources (for example, foreign language or sign language interpreters, picture boards, computer-based systems)\nindividuals with additional communication needs might need more time and specialist support for alternative forms of communication (for example, augmentative and alternative communication).\nBe aware that parents or carers may have communication preferences and needs of their own that may affect their ability to discuss their baby or child's care.\nUse developmentally appropriate creative and interactive tools to help effective communications with babies, children and young people (for example, play dough, pictures, diagrams and writing).\nHelp engage babies, children and young people in communication by:\nusing both verbal and non-verbal methods (for example, sitting at the same level as them, using body language to show attentive listening, reassuring babies by positive touch or containment holding before or during procedures)\npausing and allowing time for responses.\nWhen communicating with children and young people, always check they have taken the information in and understood it (for example, by asking children or young people to explain back to you in their own words).\nIf a child or young person is uncomfortable or having difficulty communicating, try alternatives that may help. This may include:\ntrying again at a different time\ntrying again in a different, quieter or more private setting (see recommendations 1.4.8 and 1.4.9)\nseeing them without their parents or carers\ninvolving a different person (for example, another healthcare professional or an adult trusted by the child or young person)\nusing a different means of communication.\nRespect times when children and young people do not wish to communicate, and be aware that their wish to communicate may vary at different times.\nIn urgent or emergency situations when time may be limited, give children and young people opportunities to communicate whenever possible, and the opportunity to discuss afterwards.\nBe aware that babies, children and young people may not communicate pain, distress or anxiety verbally so you may need to:\nask parents or carers what is usual behaviour for their child or young person\nbe alert to physical cues (for example, lack of or abnormal movements to reduce pain) or behavioural cues (for example, crying, refusing to speak or pushing away, or behaviour that appears aggressive such as anger, defiance or biting).\nAll staff involved in providing healthcare services to babies, children and young people should have skills and competencies in relevant communication skills.\nFor guidance on communicating with children with life-limiting conditions, see the NICE guideline on end of life care for infants, children and young people with life-limiting conditions.\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on communication by healthcare staff .\nFull details of the evidence and the committee's discussion are in evidence review B: communication by healthcare staff.\nLoading. Please wait.\n\n## Providing information\nAsk children and young people, and the parents or carers of babies and young children, about the quantity and type of information they wish to receive, and how they wish to receive it. This should include, but not be limited to, details of:\ntheir condition and any treatment options and issues related to these (including diagnosis, possible side effects, long-term outcomes, and symptoms they may experience)\nany preventative action or lifestyle changes they can make\nwhere they will be seen\nlikely timescales and waiting times for their treatment, including keeping them informed about waits or delays at appointments\nwho will be involved in providing their healthcare\nwhat will happen at key points in their care (for example, on transfer from one healthcare setting to another, when being referred to a different healthcare team). Follow the recommendations on age and developmentally appropriate care and the recommendations on changes in needs and preferences.\nWhen giving information to the child or young person, or the parents or carers of babies and young children:\nuse their preferred method whenever possible; this may be in person face-to-face or other methods (for example email, phone call, text message or video call)\ntake into account that the child or young person's preferences for, and ability to access, digital resources may differ from those of their parents and carers\nprovide written and digital information to back up and supplement face-to-face contact, telephone calls or video calls and to refer to later.\nEnsure information for children and young people is provided privately when appropriate, for example:\nwithout their parents or carers present if this is what they would prefer\nby telephoning or texting them directly\nby addressing letters to children or young people themselves, and not their parents or carers.\nDiscuss with children and young people if there is information that should be provided to their parents or carers, to help their parents or carers support them or look after them (for example, dietary information, post-operative care, or symptoms to look out for).\nProvide information for children and young people or the parents or carers of babies and young children that is:\nin simple, clear language that is easy to understand, avoiding jargon and explaining any medical terms used\nevidence based\nappropriate for their individual needs\nculturally sensitive\nnot judgemental\npresented in accessible formats and language that can be understood by them (for example, through an interpreter, translated into another language, or as an easy-read version using pictures and symbols)\ngiven consistently by all members of the healthcare team\nin line with the NHS Accessible Information Standard.\nProvide written or digital information (for example leaflets, websites, apps) for children and young people that is:\ncreated in partnership with children and young people\nengaging for children and young people (for example, containing appealing images, video, audio or animations).\nProvide information at a suitable time, place and pace, for example:\nwhen possible, at regular, predictable times such as during ward rounds or clinic reviews\nin stages if necessary, so children, young people, parents or carers are not overloaded with too much information at one time.\nWhen children, young people, parents or carers have had time to absorb and reflect on information they are given:\ncheck they have understood it, and how it applies to them (see recommendation 1.2.10)\nallow time to discuss the information again\nactively encourage them to ask questions\nmake sure they know what to do if they do not understand, or have questions about their healthcare that come up later on.\nWhen giving information to children and young people about their care, take into account:\nthe possible emotional impact of any information provided (for example, children and young people may be upset by what they have been told)\nthat support might be needed to help them think about and process the information\nthat they may feel intimidated by the healthcare professional providing information (if they feel that individual is in a position of authority), and might need reassurance and support.\nWarn children and young people, parents or carers that some of the medical information available which they have not been directed to by the healthcare team (for example, online, on social media or from friends) may be inaccurate or have a limited evidence base.\nSupport children and young people to identify reliable sources of information related to their care or condition, and ensure that recommended sources are:\nup to date\nprofessional, credible and evidence based (for example, NHS resources, charities and support groups).\nAdvise children and young people to check the validity of information with their healthcare professional if they are unsure about its accuracy.\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on providing information .\nFull details of the evidence and the committee's discussion are in evidence review D: providing information.\nLoading. Please wait.\n\n# Planning healthcare\n\n## Shared decision making\nRespect and support the right of children and young people to be involved in making decisions about their healthcare. This should include:\nensuring early and ongoing involvement in discussions about their healthcare\nproviding opportunities for them to share their opinions\nsupporting them to make decisions independently\ntaking into account previous discussions or decisions, and checking if their decisions have changed\nincluding them in any decisions when there is a choice of options, including where there is no impact on health or treatment outcomes (for example, what colour plaster cast they would prefer, whether they prefer their medicine as liquid or tablets).\nWhen involving children and young people in decision making, take into account that:\nthe extent and level of their involvement may vary, between individuals and on different occasions; follow the recommendations on changes in needs and preferences\n-n occasions, some children and young people might not wish to be involved in shared decision making, and that this choice should be respected\nthey might wish to have help from their parents or carers, or another person or advocate, for support, to help understand information or to help make decisions\nthey might need time to think about decisions, so planning discussions in advance to allow for this might be helpful.\nWhen discussing and making decisions about treatment options with children and young people:\nfollow the recommendations on communication by healthcare staff and the recommendations on providing information\nclearly articulate the options, and adapt the description of the treatment options so they are understood by the child or young person you are talking to\nuse alternative methods for discussions and decisions if necessary (for example, children and young people might prefer to write down or pre-record questions or opinions if they are not comfortable talking about them)\nconsider using decision aids to support complex decisions, or if children and young people are having difficulty making a decision.\nInvolve parents or carers in discussions and decisions relating to the care of their baby or young child (for example, for inpatient care, by allowing parents to be present at ward rounds when their baby or child's care is discussed whenever possible). Follow the same principles as shown in recommendations 1.3.1 to 1.3.3.\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on shared decision making .\nFull details of the evidence and the committee's discussion are in evidence review A: planning healthcare and making shared decisions.\nLoading. Please wait.\n\n## Risks and benefits\nOffer children, young people and the parents or carers of babies and young children information about the potential risks and benefits of healthcare options to allow them to make informed decisions. Follow the recommendations on communication by healthcare staff and the recommendations on providing information.\nEnsure this information is:\nprovided in a way they can understand, and they can see how it applies to them\nrelevant to their individual needs and personal circumstances (for example, health setting, health status, age and developmental stage).\nDiscuss with children and young people how much information they would like about risks and benefits, and take this into consideration. Recognise that some children and young people:\nmight not want to know more about the risks than is needed for informed consent\nmight not want to know about risks on a particular occasion\nmight need additional opportunities to think about and discuss risks and benefits\nmight benefit from alternative methods of communicating risks and benefits\nmight need to take a break when discussing risk, and to come back to the topic later\nmight want to discuss the risks and benefits without their parents or carers present.\nWhen discussing the risks and benefits of healthcare options with the child or young person, parent or carer:\ncheck their understanding of what the risks mean to them and what the benefits to them would be (see recommendation 1.2.10)\nask them if they have any particular concerns or worries they would like to talk about (for example, fear about procedures such as injections, or children may want to ask about the risk of death, however unlikely this may be)\nanswer any questions they may have and address any concerns.\nReconfirm understanding of risks and benefits on an ongoing basis. Follow the recommendations on changes in needs and preferences.\nExplore, acknowledge and respond to any concerns that children and young people or their parents or carers have about risk, and provide opportunities to discuss concerns and what will be done to reduce risk.\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on risks and benefits .\nFull details of the evidence and the committee's discussion are in evidence review E: understanding the risks and benefits of healthcare decisions.\nLoading. Please wait.\n\n# Consent, privacy and confidentiality\nDiscuss consent, assent, privacy and confidentiality directly with children and young people if:\nthey are able to understand what these concepts mean (with appropriate explanation)\nthey can relate them to their own situation.\nWhen discussing consent, assent, privacy and confidentiality:\nensure that children and young people, and parents or carers, understand their rights and responsibilities\nexplain when parents or carers might have to make decisions on behalf of children and young people.\nFor detailed advice on best practice around consent, privacy and confidentiality, refer to relevant professional guidance (for example, the General Medical Council's ethical guidance for doctors on decision making and consent and the 0–18 years: guidance for all doctors, the Nursing and Midwifery Council's Code and the guidance on consent in the General Dental Council's standards for the dental team).\n\n## Consent\nSupport children and young people to make informed decisions to assent to, consent to or refuse treatment, taking into account their individual capacity or competence (which may be different for different decisions).\nProvide children and young people with clear explanations about why treatment in their best interests had to go ahead if it is not possible to obtain their consent or assent before treatment (for example, in an emergency situation).\nIf there is a difference of opinion about consent, assent or refusal for a procedure (for example, if the views of the child or young person are different from those of their parents or carers, or the views of the child, young person or parent or carer are different from those of healthcare professionals):\nrecognise that all discussions and decisions should focus on what is in the best interests of the baby, child or young person\nconsider involving others, such as another member of the multidisciplinary team, another healthcare professional, an independent advocate, or a named or designated professional for child protection\ndiscuss with the child, young person and their parent or carer that you would like to involve other people\nensure that the child, young person and parent or carer are offered support.\nReconfirm a child or young person's understanding and consent decisions on an ongoing basis. Follow the recommendations on changes in needs and preferences.\n\n## Privacy and confidentiality\nMaintain privacy and dignity during discussions, examinations and care. Take into account individual preferences, circumstances and cultural sensitivities whenever possible.\nDiscuss potentially sensitive topics in places where they are less likely to be overheard, when possible, for example, in a clinic room or side room rather than behind bed space curtains.\nWhen using digital or virtual methods for consultations or discussions:\nask if the child or young person is able to speak without being overheard to discuss potentially sensitive topics\nconfirm with them that they are able to talk freely, or if they would prefer an alternative time or method of communication.\nBe aware that information sharing, privacy and confidentiality laws also apply to babies, children and young people. Only share their information:\nwith their consent for the purposes of care and treatment or\nwhen in the baby, child or young person's best interests to do so or\nwhen otherwise required to do so by law.\nOffer children and young people the opportunity to see and talk to a healthcare professional without the presence or involvement of their parent or carer, and explain that this discussion will be confidential.\nIf children and young people who usually rely on their parents or carers for help communicating want to have private conversations with healthcare professionals without the presence or involvement of their parent or carer, ensure additional support is provided (for example, by determining mechanisms to enable children and young people to express a 'yes' and 'no' response (which may be non-verbal), or including other people in conversations and meetings). See recommendation 1.2.6.\nExplain to children and young people that it may be necessary to share confidential information without their consent in certain circumstances (for example, if they or others may be in danger).\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on consent, privacy and confidentiality .\nFull details of the evidence and the committee's discussion are in evidence review C: consent, privacy and confidentiality.\nLoading. Please wait.\n\n# Advocacy and support\n\n## Involvement of parents or carers\nInvolve parents or carers in discussions and decisions about the care of babies and young children, and recognise that parents or carers will be their principal caregivers and advocates.\nGive all children and young people opportunities to express their opinions about their health needs independently, including:\nasking them about the extent to which they want their parent or carer to be involved in their healthcare\n-ffering to see them separately from their parents or carers for part of the consultation.\nBe aware that their wish for parental involvement may depend on the circumstances (for example, what the appointment is about, if they have to have any procedures) or may vary. Follow the recommendations on changes in needs and preferences.\nEncourage children and young people to develop their confidence in making decisions for themselves (for example, by giving them opportunities to do this), and encourage their parents or carers to support them with this.\nEncourage parents and carers to talk to their child or young person about how they will be involved in decisions about their healthcare. This might include:\nfinding out whether the child or young person would like to know more about what will happen at appointments (for example, what healthcare procedures might take place), even if the parent or carer might feel they should leave out details so as not to worry them\nthe parent or carer reassuring their child or young person that they can have part or all of an appointment without them being present if they would prefer that\nregularly confirming with their child or young person that they can change their mind at any time about how involved they want them to be.\nEnsure that children or young people who do not have a parent or carer to support them, or whose parents or carers are not able to support them, are offered other sources of support (for example, a family member, advocate, social worker, youth worker, nurse or play specialist). Young people may wish to be supported by a friend or partner.\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on involvement of parents or carers .\nFull details of the evidence and the committee's discussion are in evidence review F: involving parents or carers in healthcare and healthcare decisions.\nLoading. Please wait.\n\n## Support from healthcare staff\nAll staff involved in providing healthcare services to babies, children and young people should uphold children's rights in accordance with the United Nations Convention on the Rights of the Child.\nAdvise children and young people about how they can be supported by healthcare staff in a specific setting and encourage them to express their preferences about the support they would find helpful.\nBe aware that some children and young people may need more support from healthcare staff than others and that this support may change over time. Follow the recommendations on changes in needs and preferences.\nWhen building a healthcare relationship with children and young people:\nintroduce yourself, explain your role and how you can help support them\nlisten to and be seen to believe their experiences (for example, symptoms such as discomfort, how they are feeling)\nreassure them that you will take their concerns seriously\nprovide calm and positive emotional support and encouraging words\ndiscuss with them how you will act on what they have said.\nHelp children and young people to speak up about things that matter to them, and their views and preferences by:\nadvocating for them and upholding their preferences if they are unable or unwilling to do this themselves\nacting as a trusted person for them to talk to when they feel their concerns are not being listened to.\nEncourage children and young people to ask for the support they need to help with their healthcare experiences or encourage them to use coping techniques they have already developed. These could include:\ntheir parent or carer to be with them or someone's hand to hold\nmusic to listen to, a soft toy to cuddle, playing a game on a phone or tablet, a support animal or pet to stroke\nindividual coping techniques. Ask them if these techniques help or if they would like to try other techniques.\nProvide advice about and access to other forms of support available (for example, from the education or voluntary sector).\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on support from healthcare staff .\nFull details of the evidence and the committee's discussion are in evidence review G: support from healthcare staff.\nLoading. Please wait.\n\n## Self-advocacy\nFacilitate self-advocacy in children and young people. This may include:\nallowing enough time in consultations and appointments\nproviding confidential and private spaces\nproviding information on their rights to advocate for themselves\nestablishing and using the child or young person's preferred method of communication, paying particular attention to those who do not communicate verbally (see recommendation 1.2.6 and recommendation 1.4.13).\nAssume that all children and young people have views and opinions about their own healthcare, and actively encourage them to express what matters to them. In particular:\ndo not make assumptions that certain groups of children or young people will not want or will not be able to advocate for themselves\nrecognise that children and young people from different backgrounds may have different levels of confidence or skills to advocate for themselves.\nEmpower children and young people to advocate for themselves by:\nproviding information so they can develop an understanding of their own condition and health needs\nmaking them central to discussions about their healthcare\nagreeing with them when and how they would like their parents or carers included in discussions and decision making, and ensure this agreement is followed\nworking collaboratively with them to discuss healthcare needs and treatment options and include them in decisions about their care\ntaking into account their own culture, experiences, needs, wishes and feedback\nconsidering the use of age- and developmentally appropriate healthcare-management applications, such as smartphone apps; apps should meet the criteria specified in the NICE evidence standards framework for digital health technologies; see the NHS Apps library for details of NHS approved apps.\nSupport children and young people to develop skills in advocating for themselves by offering opportunities to be involved in feedback, service design or improvement or other engagement activities (see recommendations 1.7.1 to 1.7.9).\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on self-advocacy .\nFull details of the evidence and the committee's discussion are in evidence review H: empowering children and young people to advocate for themselves.\nLoading. Please wait.\n\n## Independent advocates\nChildren and young people must have access to an independent advocate in line with statutory requirements. This includes the Mental Health Act 2007, the Care Act 2014 and the Mental Capacity Act 2005.\nWhere children and young people are eligible, inform them that, they can have another person, known as an independent advocate, present with them when speaking to healthcare professionals, rather than their parent or carer. See also recommendation 1.3.2 about support from other people for shared decision making.\nProvide children and young people who are eligible for support from an independent advocate with information about independent advocates. Include:\nthe role of an independent advocate (including confidentiality and independence from the healthcare team)\nthe option to express a preference for an advocate of a particular gender, or how to change advocate.\nSupport eligible children and young people to meet with an independent advocate (for example, by providing a private space and time to meet).\nIndependent advocates should work with eligible children and young people to support and empower them in discussions and decisions about their healthcare. This should include:\nidentifying and using the child or young person's preferred method of communication and using additional support to communicate if necessary (see recommendation 1.2.6)\nbuilding a trusting relationship, ensuring continuity where possible\nensuring confidentiality\nproviding guidance on healthcare systems, pathways and processes, where necessary\nproviding explanations of medical information and terminology, where necessary\nempowering children and young people to make their own decisions.\nIndependent advocates should provide a mechanism for children or young people to give feedback on the advocacy service and to check that the relationship is working effectively for the benefit of the child or young person.\nCommissioners should consider expanding the availability of independent advocates services to support children or young people who are not eligible under legislation, but who are not adequately represented by their parents or carers or other professionals.\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on independent advocates .\nFull details of the evidence and the committee's discussion are in evidence review I: independent advocacy in healthcare for children and young people.\nLoading. Please wait.\n\n# Improving healthcare experience\n\n## Food\nEnsure babies, children and young people who are inpatients have access to food that meets their needs. This should include:\na balanced healthy diet that will help with their recovery\na choice of food options at every meal that are culturally and dietetically appropriate and will appeal to a range of tastes\nflexibility in availability of food, for example access to snacks outside meal times\nfood choices and menus that have been developed in conjunction with children and young people. For babies who are breast or bottle fed, ensure there are suitable facilities to support this.\n\n## Pain-related anxiety\nReduce the fear and anxiety about pain that may be experienced by babies, children and young people during healthcare interventions by:\npreparing them with information about interventions or procedures (for example, blood tests and injections)\nbeing honest about possible pain and what will be done to alleviate pain\nusing therapeutic play and distraction techniques and creating a calm environment before, during and after interventions or procedures that are likely to be painful\nupholding children and young people's experiences of pain, showing them they are believed, and avoiding language that minimises the child or young person's experience of pain (for example, do not say a procedure they found painful \"didn't really hurt\").\nEnsure adequate pain assessments are carried out and acted on. See NICE guidelines for the management of pain in specific conditions, such as the NICE guideline on cerebral palsy for under 25s for advice on assessing pain in verbal and non-verbal children and young people, the NICE guideline on end of life care for infants, children and young people with life-limiting conditions and the NICE guideline on sickle cell disease.\n\n## Staff uniforms and healthcare clothing\nEnsure children and young people, and parents or carers of babies and young children can easily identify members of staff. This could include:\nvisible name badges with easy to understand job roles or titles\nrecognisable uniforms, particularly if they help differentiate between professions.\nBe aware that healthcare clothing (for example gowns, masks or visors) can be frightening for babies, children and young people and they may be unable to recognise staff or see their facial expressions or smiles. This is particularly important for children who rely on lip reading or facial cues for communication.\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on improving healthcare experience .\nFull details of the evidence and the committee's discussion are in evidence review J: improving experience of healthcare.\nLoading. Please wait.\n\n# Involvement in improving healthcare experience\n\n## Design of healthcare services\nWhen designing services that will be used by babies, children and young people:\ninvolve children and young people and obtain their views, or for babies and young children, involve their parents or carers\nactively seek out children and young people (or the parents or carers of babies and young children) from under-represented groups (for example, black, Asian and minority ethnic groups, people with physical, sensory or learning disabilities, people from a disadvantaged background, LGBT+ people, people who have not been able to, or have chosen not to, use the services before, looked-after children).\nAssume that all children and young people have relevant opinions on services they use and their care, and will give them if asked in a suitable way.\nMake it as simple as possible for children and young people to contribute to service design by:\nusing appropriate methods to engage them, capture their views and enable them to contribute (for example, internet surveys, social media, forums and groups)\naddressing any practical issues that could be barriers to involvement (for example, transport, timing, language, travel costs, disabilities or communication difficulties).\nEnsure that feedback about the design of services from children, young people and parents or carers is shared and used. Explain how their input has shaped design of services (for example, using social media or posters to describe methods such as 'Ask Listen Do' and 'You Said We Did').\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on design of healthcare services .\nFull details of the evidence and the committee's discussion are in evidence review K: design of healthcare services.\nLoading. Please wait.\n\n## Measuring experience\nCollect feedback (for example, using questionnaires or surveys) directly from children and young people at different points in their healthcare experience. Collect feedback for babies and young children from their parents or carers.\nActively seek out feedback from children and young people (or the parents or carers of babies and young children) from under-represented groups (for example, black, Asian and minority ethnic groups, people with physical, sensory or learning disabilities, people from a disadvantaged background, LGBT+ people, people who have not been able to, or have chosen not to, use the services before, looked-after children).\nMake it easier for people to give meaningful feedback by using tools that:\nhave been co-produced with the appropriate age group\nare appropriate for, and selected together with, the intended group (including taking into account any disabilities or communication preferences)\nare provided at a convenient time and place, and by a convenient method, for respondents (for example, voting systems in a healthcare setting, or an online survey to be completed at home).\nEnsure that the feedback on healthcare experiences from children, young people and parents or carers is shared and used. Explain how their input has been used to improve healthcare experiences (for example, using social media or posters to describe methods such as 'Ask Listen Do', 'You Said We Did').\nInform children and young people, and the parents or carers of babies and young children, of their right to complain. Ensure that it is easy for children and young people to make a complaint if they need to.\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on measuring experience .\nFull details of the evidence and the committee's discussion are in evidence review L: measuring experience.\nLoading. Please wait.\n\n# Healthcare environment\nCare for babies, children and young people in an environment that:\nmeets their clinical and personal needs\ntakes into account their preferences about their place of care (or the preferences of parents or carers for babies or young children)\nis appropriate for their age and developmental stage, is physically accessible and has adaptations available, if needed.\nProvide a healthcare environment that supports:\nprivacy and dignity\nconfidence in healthcare delivery (for example, equipment is available when needed)\nfamily-centred care for inpatients (for example, the option for a parent or carer to stay and sleep, including in non-paediatric areas)\nparents or carers to give developmentally appropriate care to their children (for example, changing their baby's nappy, helping children wash and dress)\n-ther family members, siblings, or those important to the child or young person to be present (if this is what they would like)\neasily accessible, age-appropriate play and recreation for children and young people, including to reduce boredom and anxiety while waiting for appointments or interventions\nchildren and young people who are inpatients to mix with friends, peers or partners (for example, flexible visiting times, access to social media, spaces away from clinical areas to meet)\na feeling of safety (for example, easy access to call bells or other means of summoning help, knowing that someone is around to help).\nProvide a healthcare environment that:\nis clean, comfortable and feels homely\nis calm, with as little disturbance from background noise as possible\nseparates treatment areas from those for play and recreation\nis designed and decorated in a suitable way for the age group it is for (including use of colours, layout, lighting and clear signs)\nin an inpatient setting is quiet enough for rest and sleep, particularly at night.\nProvide children and young people who are inpatients with information about the facilities and routine on the ward (for example, where the bathrooms are located, what times meals are served, where play and recreation facilities are located and how they can be accessed, where there are quiet areas), and answer any questions they may have.\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on healthcare environment .\nFull details of the evidence and the committee's discussion are in evidence review M: healthcare environment.\nLoading. Please wait.\n\n# Maintaining usual activities\nGive children and young people ongoing opportunities to identify aspects of their lives that are important to them (for example, physical, social and recreational activities, schooling and education, their developmental, cultural and emotional needs).\nDiscuss with children and young people, particularly those with ongoing health needs:\nhow their health condition and their healthcare will impact on their ability to engage in usual activities\nwhat their expectations and goals may be for their future involvement in usual activities, and how they can be helped achieve them.\nEnsure that babies, children and young people are able to continue with their usual activities of daily life with minimal disruption while receiving healthcare and, when clinically appropriate, make reasonable adjustments to their environment to support this (for example, providing a quiet space for studying).\nIn an inpatient setting, ensure free internet access over Wi-Fi, and that any Wi-Fi codes or passwords are freely available so that children and young people can maintain their usual contacts and networks.\nAdvise children and young people that use of social media or technology (for example, phones, noisy computer games) must not compromise the privacy or the environment of other people.\nRecognise that the wishes and needs of each baby, child and young person to engage in the activities they have identified as important to them will vary between individuals and over time. Integrate these needs into the delivery of healthcare.\nMake sure that the baby, child or young person's usual support networks (for example, parents and carers, siblings, partners and friends) can be involved in maintaining activities of daily living (for example, changing nappies, washing, getting dressed, eating) and other usual activities.\nEnsure coordination between healthcare, education and social care to maintain an individual's usual activities, including education and learning. This could include education support roles, Early Help or making adjustments such as scheduling treatment appointments around school commitments.\nHelp children and young people to use cultural, spiritual or religious beliefs that they find helpful in their lives as a source of support if they wish. This could include facilitating religious activities such as prayer time, or letting them know about chaplaincy services or other religious support available.\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on maintaining usual activities .\nFull details of the evidence and the committee's discussion are in:\nevidence reviews N: supporting participation in usual activities\nevidence review J: improving experience of healthcare.\nLoading. Please wait.\n\n# Accessibility, continuity and coordination\n\n## Accessing healthcare\nProvide children and young people with targeted information about:\nwhen an illness or condition means they should seek medical help\nwhat services are available (for example, using the NHSGo app)\nwhen and how they can access services. Follow the recommendations on providing information.\nReassure children and young people that:\nhealthcare services are there to help them\nfeeling afraid or embarrassed about asking for help is normal but healthcare professionals will understand and provide support.\nDevelop information about healthcare and healthcare services with input from children and young people themselves, and in collaboration with healthcare professionals (for example, play specialists, child psychologists) and other sectors (for example, education, social care, the voluntary sector).\nProvide information for parents and carers to support them in accessing healthcare services for their baby or child (for example, the eRedbook app).\nActively seek out groups of parents or carers who may face barriers accessing healthcare services for their children (for example, those who would benefit from translated materials or those who may have limited internet access), to ensure they have accessible information about what care their children can receive, and are encouraged to use those services.\nProvide information to children and young people on:\nwhat services they can access with or without their parents or carers\nwhether their parents or carers will need to be told if they access services.\nTake into account the views of children and young people, and for babies and young children the views of their parents and carers, when designing or redesigning healthcare services. Include:\npersonal factors, such as the age range, gender and developmental stages of the children and young people using the service\nsocial factors, such as the religious, cultural or social background of the children and young people using the service. See recommendations 1.7.1 to 1.7.4 on involving children and young people in design of healthcare services.\nProvide children and young people with support and help to access the healthcare system. Ensure additional support, such as one-to-one support from a named healthcare or social care professional, is available for those who need it (for example, children with learning disabilities, looked-after children, children in institutional care, care leavers).\nTake into account access needs specific to children and young people. This might include:\naccommodating preferences about the gender of the healthcare professional who they see\n-ffering flexible appointments that meet an individual's and family's needs, for example minimising regular appointments during school hours\nproviding services in locations that are easier for children and young people to access, or co-locating with other services that children and young people access (for example, youth centres and schools).\nUse flexible methods where clinically appropriate, agreed with the child or young person to deliver healthcare services (for example, telephone or video calls, digital media such as websites and apps) as alternatives to in person face-to-face services to help overcome access difficulties, such as travelling to appointments or relying on parents for transport.\nUse feedback from children and young people to improve the accessibility of healthcare services. See recommendations 1.7.5 to 1.7.9 on measuring experience of care.\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on accessing healthcare .\nFull details of the evidence and the committee's discussion are in evidence review O: accessing healthcare.\nLoading. Please wait.\n\n## Continuity and coordination of care\nMaintain continuity of care by providing healthcare from the same professionals or teams when clinically appropriate.\nEnsure clear and timely exchange of relevant patient information:\nbetween healthcare professionals and children and young people or the parents or carers of babies and young children\nbetween healthcare professionals\nbetween healthcare, education and social care professionals.\nPay particular attention to communication between healthcare professionals and services and the coordination of ongoing care:\nat key points in care (for example, on transfer from one healthcare setting to another, or when being referred to a different healthcare team)\nfor children and young people who might need additional support (for example, children with learning disabilities, looked-after children, care leavers, young people who are homeless). For advice on transition to adult services, see the NICE guideline on transition from children's to adults' services.\nEnsure systems are in place so that children and young people and the parents or carers of babies and young children do not need to unnecessarily repeat their healthcare history when being seen by different healthcare professionals (for example, by using health passports or digital health records).\nEnsure children and young people and the parents or carers of babies and young children have access to their healthcare records. Access must meet the requirements of the Access to Health Records Act 1990.\nProvide contact information so that children and young people know how to obtain advice from the same service or team in the future.\nFor a short explanation of why the committee made these recommendations, see the rationale and impact section on continuity and coordination of care .\nFull details of the evidence and the committee's discussion are in evidence review P: continuity of care.\nLoading. Please wait.\n\n# Terms used in this guideline\nThis section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary.\n\n## Accessible\nSomething (for example, a service or information format) designed in a way so that people who have a disability or impairment are able to use it with a similar level of time, effort and skill needed as someone who does not.\n\n## Assent\nAgreement given by a child or young person to a course of action or procedure, when they are not legally empowered to give consent.\n\n## Consent\nAgreement (which can be verbal, non-verbal or written) to a course of action or procedure, after a discussion of the risks and benefits, when they are legally empowered to give consent.\n\n## Containment holding\nPlacing both hands firmly but gently on a baby and holding the position very still, to provide reassurance and comfort.\n\n## Cultural sensitivity\nKnowledge, awareness and respect for other people's cultural background, identity and differences, without making assumptions about them.\n\n## Focus and reference groups\nA series of focus and reference groups with children and young people were held to obtain their views and opinions. These views and opinions were considered by the committee as part of their review of the evidence.\n\n## Gillick competent\nChildren under the age of 16 can consent to their own treatment if they're believed to have enough intelligence, competence and understanding to fully appreciate what's involved in their treatment. Also see the NHS website on consent to treatment – children and young people.\n\n## National surveys\nA review of recent national surveys of children and young people's views on healthcare was carried out. The findings of these surveys were considered by the committee as part of their review of the evidence.\n\n## Non-judgemental\nNot criticising or demonstrating a negative attitude about another person's feelings or actions, based on personal opinions or personal biases.\n\n## Parents or carers\nParents or carers refers to the primary caregivers for a baby or child at any given time. This can include birth or adoptive parents with parental responsibility, other members of the extended family who provide care such as siblings, grandparents, aunts and uncles, others nominated by the parents, or legal guardians. For looked-after children or those who lack mental capacity, it can also include those acting instead of parents such as a social worker, key worker, foster carers or guardians. It does not refer to nurses, healthcare assistants or other healthcare professionals who are acting in their professional capacity.\n\n## Positive touch\nHuman touch that aims to give babies the experience of touch that is not for a clinical purpose, but is given tenderly, lovingly and gently, and that which responds to and does not ignore their behaviour.\n\n## Usual activities\nActivities that form part of a baby, child or young person's daily life and which may be disrupted by illness or the need to access healthcare services. This may include activities of daily living (bathing, showering, eating), interactions with family and friends, social and emotional development, education and schooling, sports, hobbies and interests, social activities and use of social media.# Recommendations for research\nThe guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Risks and benefits\nWhat decision aids are the most cost effective and acceptable when explaining the risks and benefits of healthcare interventions to children and young people?\nFor a short explanation of why the committee made this research recommendation, see the rationale section on risks and benefits .\nFull details of the evidence and the committee's discussion are in evidence review E: understanding the risks and benefits of healthcare decisions.\nLoading. Please wait.\n\n## Independent advocacy\nHow can the views of babies, children and young people be best represented by independent advocates?\nFor a short explanation of why the committee made this research recommendation, see the rationale section on independent advocates .\nFull details of the evidence and the committee's discussion are in evidence review I: independent advocacy in healthcare for children and young people.\nLoading. Please wait.\n\n## Improving healthcare experience\nWhat elements of healthcare matter most to babies, children and young people to create positive experiences of healthcare?\nFor a short explanation of why the committee made this research recommendation, see the rationale section on improving healthcare experience .\nFull details of the evidence and the committee's discussion are in evidence review J: improving experience of healthcare.\nLoading. Please wait.\n\n## Measuring experience\nHow can the experience of babies, children and young people be measured so as to improve their experience of healthcare?\nFor a short explanation of why the committee made this research recommendation, see the rationale section on measuring experience .\nFull details of the evidence and the committee's discussion are in evidence review L: measuring experience.\nLoading. Please wait.# Rationale and impact\nThese sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Overarching principles\nRecommendations 1.1.1 to 1.1.9\n\n## Why the committee made the recommendations\nThe committee were aware, based on their own knowledge and experience, that safeguarding is an important consideration that applies to all aspects of healthcare services, and so made an overarching recommendation to state this. Similarly, the committee were aware that it is necessary for all services to make reasonable adjustments as required by legislation in order to meet the needs of disabled babies, children and young people, and so made an overarching recommendation to state this.\nBased on stakeholder feedback, the committee added an overarching recommendation to clarify the rights of children and young people to make decisions about their healthcare and to consent to treatment.\nThere was evidence from a number of reviews: that all discussion, support and information need to be suitable for the age, developmental stage and level of understanding for an individual child or young person; that, as children develop and mature, their healthcare needs and preferences change; and that determining needs and preferences is not a static one-off decision.\nAs a number of recommendations throughout the guideline relate to the use of digital resources, the committee clarified that alternative methods should be available as access to these digital resources is not universal.\n\n## How the recommendations might affect practice\nThe recommendations are in line with current practice and should have little impact on resources, but may mean extra time is needed to revisit needs and preferences on a regular basis, or to provide alternatives to online information.\nReturn to recommendations\n\n# Communication by healthcare staff\nRecommendations 1.2.1 to 1.2.16\n\n## Why the committee made the recommendations\nThere was good evidence that children and young people like healthcare professionals to communicate in a friendly, compassionate and respectful manner, reading behavioural cues, giving them sufficient time, listening to them and getting to know them on a personal level.\nThere was good evidence that different methods of communication should be used when appropriate, and this includes using verbal and non-verbal communication, and identifying the best way to communicate for individuals, particularly those who have additional communication needs.\nThe committee were also aware of the need for healthcare professionals to ensure that different methods of communication are used if necessary to meet the requirement of the Mental Capacity Act 2005 that a person is not to be treated as unable to make a decision unless all practicable steps to help them to do so have been tried.\n\n## How the recommendations might affect practice\nHealthcare professionals might need more time to communicate with children and young people and this could mean some consultation times are longer, which would create a resource impact for the NHS. Additional help to communicate may be needed (for example, use of foreign language or sign language interpreters) and that may also have a resource impact for the NHS.\nEnsuring that all staff are competent to communicate effectively might also need additional time and resources for training and skill development.\nReturn to recommendations\n\n# Providing information\nRecommendations 1.2.17 to 1.2.28\n\n## Why the committee made the recommendations\nThere was good evidence from the systematic literature review on the preferred sources of information, with in person face-to-face information provided by a healthcare professional one of the preferred and most trusted forms of information. The evidence showed that healthcare professionals should provide information clearly in a way that is easy for children and young people to understand, and that it is important that healthcare professionals consider when and how to deliver information, as sufficient information needs to be provided, but this should not be overwhelming. The evidence also showed that children and young people, and the parents of babies and young children, want information in a variety of formats, including written materials, websites and smartphone applications and any other digital sources, and that these sources should be clear and easy to understand and relevant.\nThere was evidence that children and young people would want their parents or carers to have information tailored to their condition and needs in order to provide support and look after them.\nThere was evidence that whatever the format, information should be age- and developmentally appropriate, and should be available in different versions (for example, easy-read versions) and languages to allow as many people to access it as possible.\nThe evidence from the focus and reference groups and some limited evidence from the national surveys reinforced the systematic literature review evidence, showing that the quantity of information should not be overwhelming, and that there is a need for clear, understandable verbal and written information.\n\n## How the recommendations might affect practice\nThe recommendations may mean additional time and resources are needed to deliver and produce information in suitable formats (for example leaflets, websites, apps) in partnership with children and young people. However, it was acknowledged that many services are already using a variety of alternative ways of proving information to children or young people and the overall resource impact in this area will be modest.\nReturn to recommendations\n\n# Shared decision making\nRecommendations 1.3.1 to 1.3.4\n\n## Why the committee made the recommendations\nThere was evidence from the systematic literature review, focus and reference groups and from the national surveys that most children and young people want to be involved in making shared decisions about their healthcare, but that the level of preferred involvement may vary between different children, on different occasions and may change as children get older.\nThe committee were also aware of the requirement of the Mental Capacity Act 2005 that a person is not to be treated as unable to make a decision unless all practicable steps to help them to do so have been taken without success. Healthcare professionals therefore need to tailor their approach to discussions (with advice from other specialists or those who know the person well if necessary) to ensure this.\nThere was some evidence on children and young people's preferences for how the shared decision-making process should be undertaken, for example by starting discussions as soon as possible, making sure information is presented clearly, tailoring its complexity, providing it at a suitable pace and using decision aids if they are available.\nThe committee also used their knowledge and experience to make additional recommendations to adhere to these principles when making shared decisions with parents and carers on behalf of babies and young children.\n\n## How the recommendations might affect practice\nAdditional time may be needed to carry out meaningful discussions around shared decision making. Ensuring that all staff are competent to implement shared decision making effectively might also need additional time and resources for training and skill development.\nReturn to recommendations\n\n# Risks and benefits\nRecommendations 1.3.5 to 1.3.10\n\n## Why the committee made the recommendations\nThere was limited evidence that decision aids improve knowledge about risks and benefits and reduce decisional conflict, but as there was insufficient evidence to allow the committee to give advice on their use, a research recommendation was made on this topic (see research recommendation 1). There was some evidence from the focus and reference groups that children and young people vary in their views about how much information they like to receive on risks. Based on this evidence, and on their knowledge and experience, the committee made recommendations on the best ways to discuss risk and benefits with children and young people, including pacing this information, having discussions without parents and carers, and ensuring understanding.\n\n## How the recommendations might affect practice\nThe recommendations might mean additional time and resources are needed to help children, young people and the parents or carers of babies and young children understand the risks and benefits of healthcare decisions. Ensuring that all staff are competent to discuss risks and benefits effectively might also need additional time and resources for training and skill development.\nReturn to recommendations\n\n# Consent, privacy and confidentiality\nRecommendations 1.4.1 to 1.4.14\n\n## Why the committee made the recommendations\nNo evidence relating to consent was found, but the committee discussed that children and young people have the legal right to consent to, or refuse, treatment as set out in UK law and the UN Convention on the Rights of the Child. These rights are dependent on their age and competence and as the committee agreed it was such an important principle, they included these details in an overarching recommendation at the beginning of the guideline.\nThe committee used their experience and expertise to make recommendations on how children and young people could be best supported to make decisions on consent. The committee also used their knowledge and experience of how differences of opinion over consent, assent or refusal of treatment should be approached. This could include involving other healthcare professionals, but the committee also recognised that the child, young person, parents or carers should be offered support so that they did not feel outnumbered in discussions.\nThere was some low-quality evidence on privacy and confidentiality, which showed that children are aware of the risks to anonymity and privacy with digital information applications, but that they also recognised that in some cases, it was valuable to share information (for example, with parents, or to allow peer-to-peer support). The committee therefore also used their experience and expertise on best practice at maintaining privacy (particularly when using digital or virtual methods for consultations, or with children or young people who needed additional support to communicate without their parents or carers), discussing private and confidential information with children and young people, and the sharing of information with parents or carers.\n\n## How the recommendations might affect practice\nThere are already examples of good practice across the NHS concerning consent, privacy and confidentiality, and these recommendations are designed to increase consistency throughout the NHS. Implementing these recommendations might mean extra time is needed for healthcare professionals to discuss and explain issues surrounding consent, privacy and confidentiality with children and young people. There may also be a need to consider the environment in which healthcare is delivered to provide privacy and ensure confidentiality.\nReturn to recommendations\n\n# Involvement of parents or carers\nRecommendations 1.5.1 to 1.5.6\n\n## Why the committee made the recommendations\nThere was evidence that children and young people want to be able to express their opinions independently from their parents, but they also value their parent or carers' presence or support. There was evidence that the extent of support they want varies depending on the circumstances and the child or young person, and that it should be discussed between parents or carers and their children. The committee were aware from their knowledge and experience that certain groups of children and young people did not have parents or carers to support them, and that it is particularly important that these children and young people should be offered alternative support.\n\n## How the recommendations might affect practice\nThe recommendations are in line with current practice and should have little impact on resources, but may need extra time to have these discussions, and to see children with their parents or carers and separately.\nReturn to recommendations\n\n# Support from healthcare staff\nRecommendations 1.5.7 to 1.5.13\n\n## Why the committee made the recommendations\nThere was evidence that children and young people have differing preferences for the support they wish to receive from healthcare professionals, so this should be personalised based on their preferences at any time (as these preferences can change depending on different factors). There was also evidence around needing to build a trusting relationship. Based on their knowledge and experience, the committee agreed that it was essential that healthcare professionals support children and young people's rights and advocate for them where necessary. There was also evidence that children and young people appreciate support to identify and use coping techniques, and to be advised on other sources of support.\n\n## How the recommendations might affect practice\nAdditional time may be needed to build trust, discuss and provide the support according to the preferences and needs of children and young people.\nReturn to recommendations\n\n# Self-advocacy\nRecommendations 1.5.14 to 1.5.17\n\n## Why the committee made the recommendations\nThere was evidence from the systematic literature review and the focus and reference groups for strategies that would enable children and young people to advocate for themselves with respect to their healthcare and related decisions. This includes providing time, space and adequate information.\nThere was evidence that some children and young people felt as though healthcare professionals have a preconceived idea of their ability and motivation to engage with healthcare decisions. This often results in missed opportunities to encourage vulnerable children and young people to engage in their care and advocate for their choices.\nThe evidence also showed that engaging children and young people in feedback, service design and other activities could improve and facilitate their self-advocacy skills.\nBased on the evidence and their knowledge and experience, the committee identified approaches to empower children to advocate for themselves.\n\n## How the recommendations might affect practice\nAdditional time may be needed to discuss and provide the adequate support to children and young people so they can be empowered to advocate for themselves.\nReturn to recommendations\n\n# Independent advocates\nRecommendations 1.5.18 to 1.5.24\n\n## Why the committee made the recommendations\nThe recommendations reflect current UK legislation in respect of access to independent advocates in certain situations for children and young people. Based on their knowledge and experience, the committee recognised the potential benefits to children and young people of independent advocacy in wider healthcare situations, not currently covered by the legislation. These benefits include support to understand healthcare processes and procedures, to express views and opinions, and with decision making.\nThere was evidence from an expert witness and the focus and reference groups that eligible children and young people may have limited knowledge about independent advocacy services. Therefore, they should be provided with this information and supported throughout the process.\nThere was evidence from the expert witness and the focus and reference groups about the role of independent advocates, which involves supporting children and young people in decisions about their healthcare and that, in order to be most effective, independent advocates should take time to build a trusting and confidential relationship with children and young people.\nAs there was no evidence from the systematic review of the literature for this review, the committee made research recommendation 2.\n\n## How the recommendations might affect practice\nThe recommendations on access to an independent advocate are in line with current UK legislation, with little additional impact on resources. However, the suggested expansion of this service to children and young people who are not adequately represented by parent and carers may lead to an increase in the number of independent advocates needed by NHS services, which will need an increased level of funding. There may be an increased amount of time for healthcare professionals to facilitate this use of independent advocates.\nReturn to recommendations\n\n# Improving healthcare experience\nRecommendations 1.6.1 to 1.6.5\n\n## Why the committee made the recommendations\nThe qualitative and quantitative evidence identified 4 aspects of healthcare that were important to children and young people but which were not covered in other evidence reviews. These were food, pain-related anxiety, staff uniforms and healthcare clothing, and religious, cultural and spiritual support. Based on their expertise and experience, the committee made additional recommendations on these topics. The committee agreed that the recommendations on religious support related to maintaining usual activities, and therefore they placed this recommendation in that section of the guideline.\nAs there was limited quantitative evidence on the elements of healthcare that matter most to babies, children and young people to create a positive experience of healthcare, the committee made research recommendation 3.\n\n## How the recommendations might affect practice\nThe recommendations reflect best practice and may reduce variation in practice.\nReturn to recommendations\n\n# Design of healthcare services\nRecommendations 1.7.1 to 1.7.4\n\n## Why the committee made the recommendations\nThere was some evidence that children and young people are keen to contribute to the design of healthcare services, and appreciate the opportunity to do so. There was also evidence that the children and young people recognise there could be practical difficulties with involvement (for example, time, travel, number of events, and content not being age- or developmentally appropriate). There was evidence that ways to obtain feedback should be age- and developmentally appropriate. There was evidence that children and young people want their views to be taken seriously, and that they appreciate being told how their input had changed practice.\nThe committee and stakeholders identified that there may be particular groups who may be less likely to be involved in the design of healthcare services and so recommended that the views of these groups should be actively sought. However, the list is not exhaustive and other groups may be identified according to local circumstances or demographics.\n\n## How the recommendations might affect practice\nThere are already examples of good practice across the NHS, but practice is inconsistent. These recommendations aim to standardise how children, young people, parents and carers should be involved in the design of services, to encourage more consistent practice across the whole NHS.\nImplementing this across the NHS might mean increased resources are needed to develop the tools, identify participants, aid involvement, and evaluate and feedback the results.\nReturn to recommendations\n\n# Measuring experience\nRecommendations 1.7.5 to 1.7.9\n\n## Why the committee made the recommendations\nThere was some evidence from the focus and reference groups that children and young people are keen to provide feedback, that they are willing to use a variety of methods to do this, and that surveys should be quick and easy to complete. The evidence also showed that children and young people prefer giving their feedback at or towards the end of treatment but based on their knowledge and experience, the committee agreed this should be at various points in treatment. There was a very small amount of evidence from the national surveys on the problems children and young people had had using complaints systems. The committee also used their own knowledge and experience on helping people give feedback to optimise responses.\nThe committee and stakeholders identified that there may be particular groups who may be less likely to be involved in providing feedback on healthcare services and so recommended that the views of these groups should be actively sought. However, the list is not exhaustive and other groups may be identified according to local circumstances or demographics.\nAs there was very limited evidence from the systematic review of the literature on measuring children and young people's experience, the committee made research recommendation 4.\n\n## How the recommendations might affect practice\nExperience may already be measured in a number of different ways across the NHS and these recommendations will increase measurement of experience, reinforce best practice and make practice more consistent.\nImplementing this across the NHS might mean more resources are needed to co-produce the tools, identify participants, aid involvement and evaluate and feedback the results.\nReturn to recommendations\n\n# Healthcare environment\nRecommendations 1.8.1 to 1.8.4\n\n## Why the committee made the recommendations\nThere was some evidence from young people about their preferences, and from parents of babies in neonatal units, and the committee agreed that all babies and young children (represented by their parents), children and young people, should be able to express views about the preferences for place of care. The committee used this and their own knowledge and experience to agree how settings should be appropriate, comfortable, welcoming and acceptable to the people who need to use them. There was evidence that young people prefer their care environment to be age-appropriate, and that they may feel uncomfortable in paediatric settings aimed at young children. There was also evidence that they like to be able to meet visitors in an appropriate space, to have areas for recreation facilities, to have adequate signs, and for there not to be too much noise. They also expressed wanting to feel safe in healthcare environments.\nThere was evidence from parents or carers of babies about the need for privacy, comfortable furniture and furnishings, and facilities so they have the option to stay with their babies. Although there was no evidence about privacy for children and young people, the committee agreed that offering privacy is important, based on their knowledge and experience.\n\n## How the recommendations might affect practice\nThe recommendations aim to make best practice more consistent across the NHS. Some changes to improve the healthcare environment might be easy to make, but changing or redesigning healthcare environments can be an expensive process, and some of the recommendations could need considerable resources to implement.\nReturn to recommendations\n\n# Maintaining usual activities\nRecommendations 1.9.1 to 1.9.9\n\n## Why the committee made the recommendations\nBased on their knowledge and experience, the committee made recommendations on the importance of determining what usual activities were important to children and young people, and making adjustments to allow these to continue. The committee agreed that providing support to continue with usual activities would need to be personalised to account for different needs, preferences and developmental stages. The committee recognised the benefits to the wellbeing of children and young people of continuing with usual activities, which may include a reduction in boredom, anxiety and distress. There was evidence that some children prefer to receive help with personal care from their family, as would happen if the child were at home. There was also evidence that children and young people want to continue with social activities and keeping in touch with their friends. There was no evidence from the systematic literature review specifically about Wi-Fi access but the committee agreed that the ability to instantly contact friends was a part of everyday life for most children and young people and this was reinforced by evidence from the focus and reference groups and the national surveys.\nThe evidence on educational support reinforced the committee's experience that maintaining educational provision and liaison with education services is very important.\nThere was evidence that some children and young people found religious or spiritual support or beliefs helpful when they were unwell. Other aspects from this evidence are reflected in the recommendations on improving healthcare experience, where this evidence is described in more detail.\n\n## How the recommendations might affect practice\nThe recommendations aim to reduce variation in practice across the NHS, and might mean extra staff time or changes in practice are needed to implement them.\nReturn to recommendations\n\n# Accessing healthcare\nRecommendations 1.10.1 to 1.10.11\n\n## Why the committee made the recommendations\nThere was evidence from the systematic review of the literature about factors that could be barriers for children and young people to access health services. This included factors relating to practical aspects of accessing healthcare such as location and timing of appointments, as well as trust and relationships with healthcare professionals and lack of knowledge about when to access healthcare, and what services to access. The focus and reference groups also provided evidence about the perceived barriers and these included fear and embarrassment, being too busy to access healthcare or not wanting to miss out on school or social activities, and being aware of the capacity issues within the NHS. The committee then used this evidence to make recommendations designed to overcome these barriers. The evidence from the national surveys also identified that certain groups of children and young people may need additional help and support to access and navigate the health system.\n\n## How the recommendations might affect practice\nAdditional resources may be needed to promote and deliver accessible and flexible services.\nReturn to recommendations\n\n# Continuity and coordination of care\nRecommendations 1.10.12 to 1.10.17\n\n## Why the committee made the recommendations\nThere was good evidence that children and young people prefer to see the same healthcare professionals whenever possible, and that this promotes improved engagement and continuity of care. The committee were aware that children and young people prefer to be able to contact their healthcare professionals or teams directly.\nThere was good evidence that children and young people do not want to have to repeat their healthcare history on multiple occasions, and that good and timely communication between healthcare professionals, services, and children and young people and the parents or carers of babies and young children could help with this. There was also some evidence for the use of different methods to help improve communication and continuity of care, and in particular the use of electronic health records.\n\n## How the recommendations might affect practice\nThere are some electronic and paper methods to improve communication already in use, including electronic health records. Implementing more integrated systems to share information with and between healthcare professionals, other services and children and young people or the parents and carers of babies and young children will have resource implications for the NHS. In addition, there may be a need for improved administration support to help with the sharing of information, which will also have some resource implications.\nReturn to recommendations"}}},{"rowIdx":98,"cells":{"id":{"kind":"string","value":"9cb75b1f551a384f6e1fcdc552a322b78e4c2de5"},"source":{"kind":"string","value":"nice"},"text":{"kind":"string","value":"Brain tumours (primary) and brain metastases in over 16s\n\nThis guideline covers diagnosing, monitoring and managing any type of primary brain tumour or brain metastases in people aged 16 or over. It aims to improve diagnosis and care, including standardising the care people have, how information and support are provided, and palliative care.\n\n# Recommendations\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Investigation of suspected glioma\n\n## Imaging for suspected glioma\nOffer standard structural MRI (defined as T2 weighted, FLAIR, DWI series and T1 pre- and post-contrast volume) as the initial diagnostic test for suspected glioma, unless MRI is contraindicated.\nRefer people with a suspected glioma to a specialist multidisciplinary team at first radiological diagnosis for management of their tumour.\nConsider advanced MRI techniques, such as MR perfusion and MR spectroscopy, to assess the potential of a high-grade transformation in a tumour appearing to be low grade on standard structural MRI.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on imaging for suspected glioma .\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nLoading. Please wait.\n\n## Use of molecular markers to determine prognosis or guide treatment for glioma\nReport all glioma specimens according to the latest version of the World Health Organization (WHO) classification of tumors of the central nervous system. As well as histopathological assessment, include molecular markers such as:\nIDH1 and IDH2 mutations\nATRX mutations to identify IDH mutant astrocytomas and glioblastomas\np/19q codeletion to identify oligodendrogliomas\nhistone H3.3 K27M mutations in midline gliomas\nBRAF fusion and gene mutation to identify pilocytic astrocytoma.\nTest all high-grade glioma specimens for MGMT promoter methylation to inform prognosis and guide treatment.\nConsider testing IDH-wildtype glioma specimens for TERT promoter mutations to inform prognosis.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on use of molecular markers to determine prognosis or guide treatment for glioma .\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nLoading. Please wait.\n\n# Management of glioma\n\n## Initial surgery for suspected low-grade glioma\nThe surgical expertise in the multidisciplinary team should include:\naccess to awake craniotomy with language and other appropriate functional monitoring and\nexpertise in intraoperative neurophysiological monitoring and\naccess to neuroradiological support and\naccess to intraoperative image guidance.\nConsider surgical resection as part of initial management (within 6 months of radiological diagnosis) to:\n-btain a histological and molecular diagnosis and\nremove as much of the tumour as safely possible after discussion of the possible extent of resection at multidisciplinary meeting and with the person with the brain tumour, and their relatives and carers.\nIf surgical resection is not appropriate, consider biopsy to obtain a histological and molecular diagnosis.\nConsider active monitoring without a histological diagnosis, for lesions with radiological features typical of very low-grade tumours, for example, DNET (dysembryoplastic neuroepithelial tumour) or optic pathway glioma.\nIf people having active monitoring show radiological or clinical disease progression, discuss this at a multidisciplinary team meeting and consider:\nsurgical resection or\nbiopsy if surgical resection is not possible.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on initial surgery for suspected low-grade glioma .\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nLoading. Please wait.\n\n## Further management of newly diagnosed low-grade glioma\nAfter surgery, offer radiotherapy followed by up to 6 cycles of PCV chemotherapy (procarbazine, CCNU and vincristine) for people who:\nhave a 1p/19q codeleted, IDH-mutated low-grade glioma (oligodendroglioma) and\nare aged around 40 or over, or have residual tumour on postoperative MRI.\nAfter surgery, consider radiotherapy followed by up to 6 cycles of PCV chemotherapy for people who:\nhave a 1p/19q non-codeleted, IDH-mutated low-grade glioma (astrocytoma) and\nare aged around 40 or over, or have residual tumour on postoperative MRI.\nConsider active monitoring for people who are aged around 40 or under with an IDH‑mutated low‑grade glioma and have no residual tumour on postoperative MRI.\nConsider radiotherapy followed by up to 6 cycles of PCV chemotherapy for people with an IDH‑mutated low‑grade glioma who have not had radiotherapy before if they have:\nprogressive disease on radiological follow‑up or\nintractable seizures.\nWhen delivering radiotherapy for people with IDH-mutated low-grade glioma, do not use a treatment dose of more than 54 Gy at 1.8 Gy per fraction.\nBe aware that the prognosis for people with histologically confirmed IDH-wildtype grade II glioma may be similar to that of people with glioblastoma if other molecular features are consistent with glioblastoma. Take this into account when thinking about management options.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on further management of newly diagnosed low-grade glioma .\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nLoading. Please wait.\n\n## Management of newly diagnosed grade III glioma following surgery or if surgery is not possible (or has been declined)\nFor guidance on using temozolomide for treating newly diagnosed grade III glioma, see the NICE technology appraisal guidance on carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma.\nAfter surgery, offer sequential radiotherapy and 4 to 6 cycles of PCV chemotherapy to people who have:\na Karnofsky performance status of 70 or more and\na newly diagnosed grade III glioma with 1p/19q codeletion (anaplastic oligodendroglioma).\nAgree with the person with the anaplastic oligodendroglioma the order of PCV chemotherapy and radiotherapy after discussing the potential advantages and disadvantages of each option with them (see table 1).\nPCV first\nRadiotherapy first\nOverall survival\nNo clinically important difference.\nNo clinically important difference.\nProgression-free survival\nNo clinically important difference.\nNo clinically important difference.\nFertility preservation\nTrying to preserve fertility may cause a delay in the start of treatment.\nAllows additional time for fertility preservation without delaying treatment.\nPlanning treatment around important life events\nInitially much less contact with the health system, but potentially more fatigue.\nHarder to give a precise date for when radiotherapy will start, as people's tolerance of chemotherapy is less predictable.\nInitially much more contact with the health system: daily visits to radiotherapy department lasting several weeks.\nTiming of start of chemotherapy much more predictable.\nAfter surgery, offer radiotherapy followed by up to 12 cycles of adjuvant temozolomide to people who have:\na Karnofsky performance status of 70 or more and\na newly diagnosed IDH-wildtype or mutated grade III glioma without 1p/19q codeletion (anaplastic astrocytoma).\nDo not offer nitrosoureas (for example, CCNU ) concurrently with radiotherapy to people with newly diagnosed grade III glioma.\nIf asked, advise people with an initial diagnosis of grade III glioma (and their relatives and carers, as appropriate) that the available evidence does not support the use of:\ncannabis oil\nimmunotherapy\nketogenic diets\nmetformin\nstatins\nvalganciclovir.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on management of newly diagnosed grade III glioma after surgery, or if surgery is not possible or the person declines surgery .\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nLoading. Please wait.\n\n## Management of newly diagnosed grade IV glioma (glioblastoma) following surgery or if surgery is not possible (or has been declined)\nThe recommendations in this section are also viewable as a visual summary.\nFor guidance on using temozolomide for treating newly diagnosed grade IV glioma (glioblastoma), see the NICE technology appraisal guidance on carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma.\nOffer radiotherapy using 60 Gy in 30 fractions with concomitant temozolomide, followed by up to 6 cycles of adjuvant temozolomide, for people aged around 70 or under who have:\na Karnofsky performance status of 70 or more and\nhad maximal safe resection, or biopsy when resection is not possible, for a newly diagnosed grade IV glioma (glioblastoma).\nOffer radiotherapy using 40 Gy in 15 fractions with concomitant and up to 12 cycles of adjuvant temozolomide for people aged around 70 or over who have:\na Karnofsky performance status of 70 or more and\na newly diagnosed grade IV glioma (glioblastoma) with MGMT methylation.\nConsider radiotherapy using 40 Gy in 15 fractions with concomitant and up to 12 cycles of adjuvant temozolomide for people aged around 70 or over who have:\na Karnofsky performance status of 70 or more and\na newly diagnosed grade IV glioma (glioblastoma) without MGMT methylation or for which methylation status is unavailable.\nConsider best supportive care alone for people aged around 70 or over who have:\na grade IV glioma (glioblastoma) and\na Karnofsky performance status of under 70.\nFor people with an initial diagnosis of grade IV glioma (glioblastoma) not covered in recommendations 1.2.19 to 1.2.22, consider the treatment options of:\nradiotherapy using 60 Gy in 30 fractions with concurrent and up to 6 cycles of adjuvant temozolomide\nradiotherapy alone using 60 Gy in 30 fractions\nhypofractionated radiotherapy\nup to 6 cycles of temozolomide alone if the tumour has MGMT methylation and the person is aged around 70 or over\nbest supportive care alone.\nAssess the person's performance status throughout the postoperative period and review treatment options for grade IV glioma (glioblastoma) if their performance status changes.\nDo not offer bevacizumab as part of management of a newly diagnosed grade IV glioma (glioblastoma).\nDo not offer tumour-treating fields (TTF) as part of management of a newly diagnosed grade IV glioma (glioblastoma).\nIf asked, advise people with an initial diagnosis of grade IV glioma (and their relatives and carers, as appropriate) that the available evidence does not support the use of:\ncannabis oil\nimmunotherapy\nketogenic diets\nmetformin\nstatins\nvalganciclovir.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on management of newly diagnosed grade IV glioma (glioblastoma) following surgery, or if surgery is not possible or the person declines surgery .\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nLoading. Please wait.\n\n## Management of recurrent high-grade glioma (recurrent grade III and grade IV glioma)\nWhen deciding on treatment options for people with recurrent high-grade glioma, take into account:\nKarnofsky performance status\nthe person's preferences\ntime from last treatment\ntumour molecular markers\nwhat their last treatment was.\nConsider PCV or single agent CCNU (lomustine) as an alternative to temozolomide for people with recurrent high-grade glioma.\nFor guidance on using temozolomide as an option for treating recurrent high-grade glioma, see the NICE technology appraisal guidance on temozolomide for the treatment of recurrent malignant glioma (brain cancer).\nConsider best supportive care alone for high-grade glioma if other treatments are not likely to be of benefit, or if the person would prefer this. Refer to the NICE cancer service guidance on improving supportive and palliative care for adults with cancer.\nFor people with focally recurrent high-grade glioma, the multidisciplinary team should also consider the treatment options of:\nfurther surgery\nfurther radiotherapy.\nDo not offer bevacizumab, erlotinib or cediranib, either alone or in combination with chemotherapy, as part of management of recurrent high-grade glioma.\nDo not offer tumour treating fields (TTF) as part of management of recurrent high-grade glioma.\nIf asked, advise people who have recurrent high-grade glioma (and their relatives and carers, as appropriate) that the available evidence does not support the use of:\ncannabis oil\nimmunotherapy\nketogenic diets\nmetformin\nstatins\nvalganciclovir.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on management of recurrent grade III and grade IV glioma (recurrent high-grade glioma) .\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nLoading. Please wait.\n\n## Genomic biomarker-based treatment for glioma\nThe point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based cancer treatments.\n\n## Techniques for resection of glioma\nIf a person has a radiologically enhancing suspected high-grade glioma and the multidisciplinary team thinks that surgical resection of all enhancing tumour is possible, offer 5‑aminolevulinic acid (5‑ALA)-guided resection as an adjunct to maximise resection at initial surgery.\nConsider intraoperative MRI to help achieve surgical resection of both low-grade and high-grade glioma while preserving neurological function, unless MRI is contraindicated.\nConsider intraoperative ultrasound to help achieve surgical resection of both low-grade and high-grade glioma.\nConsider diffusion tensor imaging overlays in addition to standard neuronavigation techniques to minimise damage to functionally important fibre tracts during resection of both low-grade and high-grade glioma.\nConsider awake craniotomy for people with low-grade or high-grade glioma to help preserve neurological function.\nDiscuss awake craniotomy and its potential benefits and risks with the person and their relatives and carers (as appropriate) so that they can make an informed choice about whether to have it. Only consider the procedure if the person is likely not to be significantly distressed by it.\nInvolve other specialists as appropriate, such as neuropsychologists and speech and language therapists, before, during and after awake craniotomy.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on techniques for resection of glioma .\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nLoading. Please wait.\n\n# Follow-up for glioma\nOffer regular clinical review for people with glioma to assess changes in their physical, psychological and cognitive wellbeing.\nBase decisions on the timing of regular clinical reviews and follow‑up imaging for people with glioma on:\nany residual tumour\nlife expectancy\nthe person's preferences (see table 2 for factors to discuss with them)\ntreatments used before\ntreatment options available\ntumour subtype.\nPossible advantages of more frequent follow‑up\nPossible disadvantages of more frequent follow‑up\nMay identify recurrent disease earlier which may increase treatment options or enable treatment before people become symptomatic.\nThere is no definitive evidence that identifying recurrent disease early improves outcomes.\nMay help provide information about the course of the illness and prognosis.\nMay increase anxiety if changes of uncertain significance are detected on imaging.\nSome people can find more frequent imaging and hospital contact reassuring.\nProvides an opportunity to identify patient or carer needs (such as psychosocial support and late side effects of treatment).\nSome people can find more frequent imaging and hospital contact burdensome and disruptive – they feel their life revolves around their latest scan.\nThere may be a financial cost from taking time off work and travelling to appointments.\nMore imaging and follow‑up is resource intensive for the NHS.\nConsider the follow‑up schedule given in table 3 for people with glioma.\nConsider standard structural MRI (defined as T2 weighted, FLAIR, DWI series and T1 pre- and post-contrast volume) as part of regular clinical review for people with glioma, to assess for progression or recurrence, unless MRI is contraindicated.\nConsider advanced MRI techniques, such as MR perfusion, diffusion tensor imaging and MR spectroscopy, if findings from standard imaging are unclear about whether there is recurrence and early identification is potentially clinically useful.\nFor people with glioma having routine imaging:\nexplain to them, and their relatives and carers, that imaging can be difficult to interpret and results can be of uncertain significance and\nbe aware that having routine imaging and waiting for the results may cause anxiety.\nConsider a baseline MRI scan within 72 hours of surgical resection for all types of glioma.\nConsider a baseline MRI scan 3 months after the completion of radiotherapy for all types of glioma.\nArrange a clinical review, including appropriate imaging, for people with glioma who develop new or changing neurological symptoms or signs at any time.\nGrade of tumour\nClinical review schedule\nGrade I\nScan at 12 months, then:\nconsider discharge if no tumour visible on imaging unless completely-resected pilocytic astrocytoma\nconsider ongoing imaging at increasing intervals for 15 years for completely-resected pilocytic astrocytoma\nconsider if ongoing imaging is needed at a rate of once every 1 to 3 years for the rest of the person's life if the tumour is visible on imaging.\nGrade II 1p/19q non-codeleted, IDH mutated\nGrade II 1p/19q codeleted\nGrade III 1p/19q codeleted\nFrom 0 to 2 years, scan at 3 months, then every 6 months\nFrom 2 to 4 years, review annually\nFrom 5 to 10 years, review every 1 to 2 years\nFor more than 10 years and for the rest of life consider ongoing imaging every 1 to 2 years.\nGrade II IDH wildtype\nGrade III 1p/19q non-codeleted\nGrade IV (glioblastoma)\nFrom 0 to 2 years, review every 3 to 6 months\nFrom 2 to 4 years, review every 6 to 12 months\nFrom 5 to 10 years, review annually\nFor more than 10 years and for the rest of life - consider ongoing imaging every 1 to 2 years.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on follow up for glioma .\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nLoading. Please wait.\n\n# Investigation and management of meningioma\n\n## Investigation of suspected meningioma\nOffer standard structural MRI (defined as T2 weighted, FLAIR, DWI series and T1 pre- and post-contrast volume) as the initial diagnostic test for suspected meningioma, unless MRI is contraindicated.\nConsider CT imaging for meningioma (if not already performed) to assess bone involvement if this is suspected.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on investigation of suspected meningioma .\nFull details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.\nLoading. Please wait.\n\n## Management of confirmed meningioma following surgery or if surgery is not possible (or has been declined)\nBase management of meningioma after surgery, or if surgery is not possible or the person declines surgery, on the extent of any surgery and grade of meningioma, as described in table 4.\nGrade\nCompletely excised (Simpson 1 to 3)\nIncompletely excised (Simpson 4 to 5)\nNo excision (radiological only diagnosis)\nRecurrent\nI\nOffer active monitoring.\nConsider further surgery (if possible), radiotherapy or active monitoring.\nConsider active monitoring or radiotherapy.\nConsider further surgery or radiotherapy (if not previously used).\nII\nOffer a choice between active monitoring and radiotherapy.\nConsider further surgery (if possible). Offer radiotherapy if surgery is not possible, including if the person declines surgery, or if the tumour is incompletely excised afterwards.\nConsider active monitoring or radiotherapy\nConsider further surgery and offer radiotherapy (if not previously used).\nIII\nOffer radiotherapy.\nConsider further surgery (if possible) and offer radiotherapy.\nConsider active monitoring or radiotherapy\nConsider further surgery and offer radiotherapy (if not previously used).\nBefore a decision is made on radiotherapy for meningioma, take into account:\ncomorbidities\nlife expectancy\nneurological function\n-edema\nperformance status\nrate of tumour progression\nsize and location of tumour\nsurgical and radiotherapy morbidity\nthe person's preferences (see table 5 for factors to discuss with them)\ntreatments used before.\nRadiotherapy\nNo radiotherapy\nControl of tumour\nThere is evidence that radiotherapy is effective in the local control of a tumour.\nReceiving no radiotherapy means the tumour may continue to grow.\nRisk of developing subsequent symptoms\nControlling the tumour will reduce the risk of developing symptoms from the tumour in the future.\nIf the tumour grows, it can cause irreversible symptoms such as loss of vision.\nRisk of re-treatment\nLess risk of needing second surgery compared with no radiotherapy.\nHigher risk of needing second surgery compared with radiotherapy.\nIf the tumour has progressed, then the surgery might be more complex.\nIf the tumour has progressed, then not all radiotherapy techniques may be possible.\nEarly side effects of treatment\nEarly side effects from radiotherapy can include:\nfatigue\nhair loss\nheadache\nnausea\nseizures\nskin irritation.\nNo side effects from treatment.\nLate side effects of treatment\nLate side effects from radiotherapy can include:\neffect on cognition\nrisk of stroke\nrisk of radionecrosis\nrisk of second tumours\ncranial nerve effects\nhypopituitarism\ncataracts.\nNo side effects from treatment.\nManagement of side effects\nIncreased use of steroids to manage side effects.\nNo side effects from treatment.\nWhen deciding on the radiotherapy technique for people with meningioma, take into account:\nthe preferences of the person (for example, to minimise the number of appointments or travel distance)\ntumour grade\ntumour location (proximity to optic nerves, optic chiasm and brainstem)\ntumour size. From the suitable radiotherapy techniques, choose the one which maximises the chances of local tumour control while minimising the radiation dose to normal brain tissue.\nIf the multidisciplinary team thinks that radiotherapy may be appropriate, offer the person the opportunity to discuss the potential benefits and risks with an oncologist.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on management of confirmed meningioma following surgery, or if surgery is not possible or the person declines surgery .\nFull details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.\nLoading. Please wait.\n\n## Genomic biomarker-based treatment for meningioma\nThe point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based cancer treatments.\n\n# Follow-up for meningioma\nOffer regular clinical review for people with meningioma to assess changes in their physical, psychological and cognitive wellbeing.\nBase decisions on the timing of regular clinical reviews and follow‑up imaging for people with meningioma on:\nany residual tumour\nlife expectancy\nthe person's preferences (see table 6 for factors to discuss with them)\ntreatments used before\ntreatment options available\ntumour grade.\nPossible advantages of more frequent follow‑up\nPossible disadvantages of more frequent follow‑up\nMay identify recurrent disease earlier which may increase treatment options or enable treatment before people become symptomatic.\nThere is no definitive evidence that identifying recurrent disease early improves outcomes.\nMay help provide information about the course of the illness and prognosis.\nMay increase anxiety if changes of uncertain significance are detected on imaging.\nSome people can find more frequent imaging and hospital contact reassuring.\nProvides an opportunity to identify patient or carer needs (such as psychosocial support and late side effects of treatment).\nSome people can find more frequent imaging and hospital contact burdensome and disruptive – they feel their life revolves around their latest scan.\nThere may be a financial cost from taking time off work and travelling to appointments.\nMore imaging and follow‑up is resource intensive for the NHS.\nConsider the follow‑up schedule given in table 7 for people with meningioma.\nConsider standard structural MRI (defined as T2 weighted, FLAIR, DWI series and T1 pre- and post-contrast volume) as part of regular clinical review for people with meningioma, to assess for progression or recurrence, unless MRI is contraindicated.\nFor people with meningioma having routine imaging, be aware that having routine imaging and waiting for the results may cause anxiety.\nArrange a clinical review, including appropriate imaging, for people with meningioma (including incidental meningioma) who develop new or changing neurological symptoms or signs at any time.\nGrade I: no residual tumour\nGrade I: residual tumour\nGrade I: after radiotherapy\nGrade II\nGrade III\nto 1 years\nScan at 3 months\nScan at 3 months\nScan 6 months after radiotherapy\nScan at 3 months, then 6 to 12 months later\nEvery 3 to 6 months\nto 2 years\nAnnually\nAnnually\nAnnually\nAnnually\nEvery 3 to 6 months\nto 3 years\nAnnually\nAnnually\nAnnually\nAnnually\nEvery 6 to 12 months\nto 4 years\nOnce every 2 years\nAnnually\nOnce every 2 years\nAnnually\nEvery 6 to 12 months\nto 5 years\nOnce every 2 years\nAnnually\nOnce every 2 years\nAnnually\nEvery 6 to 12 months\nto 6 years\nOnce every 2 years\nOnce every 2 years\nOnce every 2 years\nOnce every 2 years\nAnnually\nto 7 years\nOnce every 2 years\nOnce every 2 years\nOnce every 2 years\nOnce every 2 years\nAnnually\nto 8 years\nOnce every 2 years\nOnce every 2 years\nOnce every 2 years\nOnce every 2 years\nAnnually\nto 9 years\nOnce every 2 years\nOnce every 2 years\nOnce every 2 years\nOnce every 2 years\nAnnually\n9 years (for the rest of life)\nConsider discharge\nConsider discharge\nConsider discharge\nConsider discharge\nAnnually\nFor asymptomatic incidental meningioma: scan at 12 months and if no change, consider discharge or scan at 5 years.\nNote: the presence of any residual tumour can only be established after the first scan at 3 months.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on follow up for meningioma .\nFull details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.\nLoading. Please wait.\n\n# Investigation of suspected brain metastases\nOffer standard structural MRI (defined as T2 weighted, FLAIR, DWI series and T1 pre- and post-contrast volume) as the initial diagnostic test for suspected brain metastases, unless MRI is contraindicated.\nTo help establish current disease status, offer extracranial imaging (appropriate to the primary tumour type) to people with any radiologically suspected brain metastases that may be suitable for focal treatment.\nPerform all intracranial and extracranial diagnostic imaging and, if appropriate, biopsy of extracranial disease, before referral to the neuro-oncology multidisciplinary team.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on investigation of suspected brain metastases .\nFull details of the evidence and the committee's discussion are in evidence review C: investigation, management and follow-up of brain metastases.\nLoading. Please wait.\n\n# Management of confirmed brain metastases\nWhen choosing management options for brain metastases, take into account:\nextracranial disease\nleptomeningeal disease\nlocation of metastases\nresection cavity size\nthe number and volume of metastases\nthe person's preference (based on a discussion of the factors listed in tables 8 and 9)\ntheir age\ntheir performance status\nthe primary tumour site, type, and molecular profile.\nConsider systemic anti-cancer therapy for people who have brain metastases likely to respond effectively, for example, germ cell tumours or small-cell lung cancer.\nConsider maximal local therapy with either surgery, stereotactic radiosurgery or stereotactic radiotherapy for people with a single brain metastasis.\nBase the choice of treatment for people with a single brain metastasis on:\ncomorbidities\nextent of oedema\nlocation of metastasis\nthe person's preference (see table 8)\ntumour size.\nSurgery\nStereotactic radiosurgery / radiotherapy\nOverall survival\nNo clinically important difference.\nNo clinically important difference.\nRisk of needing additional treatment\nRisk that stereotactic radiosurgery / radiotherapy may be needed in any case.\nRisk that surgery may be needed in any case. However, has higher local control rate than surgery (meaning surgery is less likely after radiotherapy than the other way around).\nKey benefit of treatment\nHas more rapid control of symptoms.\nAdditionally, surgery allows for obtaining an up-to-date pathological diagnosis which may guide future treatment, making it more effective.\nHas a higher local control rate than surgery, meaning more treatment is less likely to be needed.\nAdditionally, is an outpatient treatment and does not need a general anaesthetic.\nKey risks of treatment\nSurgical procedures carry known risks that vary depending on the person and the tumour. These include infection, stroke, a prolonged hospital stay and death.\nSurgery is more painful than radiotherapy during recovery.\nRadiation carries the risk of delayed effects such as radionecrosis, which might need surgical resection.\nThere is an increased risk of seizures with this technique, although this appears to mostly affect people who have pre-existing epilepsy.\nSteroid use\nEarly reduction in steroid dose.\nLikely to need steroids for longer, and at a higher dose. Steroids have significant side effects when used long-term, such as changes in mood, heart problems and changes in body fat.\nPlanning treatment around important life events\nThe wound from the surgery may affect the ability to carry out certain activities in the short term, such as air travel and sport.\nThe cosmetic appearance of the wound from surgery may be important to some people, and should be discussed.\nSome people find the techniques used in radiotherapy challenging or upsetting, especially the equipment which immobilises the head. This is especially likely to be true for people with claustrophobia.\nOther considerations\nRadiotherapy can reach some areas of the brain that surgery cannot, and might be the only appropriate technique for certain tumour types.\nDo not offer adjuvant whole-brain radiotherapy to people with a single brain metastasis treated with stereotactic radiosurgery/radiotherapy or surgery.\nSee NHS England's clinical commissioning policy on stereotactic radiosurgery and stereotactic radiotherapy to the surgical cavity following resection of cerebral metastases. \nConsider stereotactic radiosurgery/radiotherapy for people with multiple brain metastases who have controlled or controllable extracranial disease and Karnofsky performance status of 70 or more. Take into account the number and total volume of metastases.\nDo not offer whole-brain radiotherapy to people with:\nnon-small-cell lung cancer and\nbrain metastases that are not suitable for surgery or stereotactic radiosurgery/radiotherapy and\na Karnofsky performance status of under 70.\nFor people with multiple brain metastases who have not had stereotactic radiosurgery/radiotherapy or surgery, decide with them whether to use whole-brain radiotherapy after a discussion with them and their relatives and carers (as appropriate) of the potential benefits and risks (see table 9).\nWhole-brain radiotherapy\nNo whole-brain radiotherapy\nOverall survival\nNo clinically important difference.\nNo clinically important difference.\nQuality of life\nShort-term deterioration in quality of life because of treatment.\nNo impact on quality of life because of treatment, but deterioration because of the disease progression.\nPotential benefits\nCan stabilise or reduce the brain metastases.\nBrain metastases may continue to grow.\nSide effects\nTemporary hair loss and fatigue. Potential for accelerated cognitive loss because of radiotherapy.\nPotential for cognitive loss because of disease progression.\nTime commitment\nRequires 5 to 10 hospital visits.\nNo time commitment.\nOther considerations\nPeople with non-small-cell lung cancer will not benefit from treatment if their overall prognosis is poor.\nDo not offer memantine in addition to whole-brain radiotherapy to people with multiple brain metastases, unless as part of a clinical trial.\nDo not offer concurrent systemic therapy to enhance the efficacy of whole-brain radiotherapy to people with multiple brain metastases, unless as part of a clinical trial.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on management of confirmed brain metastases .\nFull details of the evidence and the committee's discussion are in evidence review C: investigation, management and follow-up of brain metastases.\nLoading. Please wait.\n\n# Follow-up for brain metastases\nOffer regular clinical review for people with brain metastases to assess changes in their physical, psychological and cognitive wellbeing.\nBase decisions on the timing of regular clinical reviews and follow‑up imaging for people with brain metastases on:\nextracranial disease status\nlife expectancy\nprimary cancer\nthe person's preferences (see table 10 for factors to discuss with them)\ntreatment options available.\nPossible advantages of more frequent follow‑up\nPossible disadvantages of more frequent follow‑up\nMay identify recurrent disease earlier which may increase treatment options or enable treatment before people become symptomatic.\nThere is no definitive evidence that identifying recurrent disease early improves outcomes.\nMay help provide information about the course of the illness and prognosis.\nMay increase anxiety if changes of uncertain significance are detected on imaging.\nSome people can find more frequent imaging and hospital contact reassuring.\nProvides an opportunity to identify patient or carer needs (such as psychosocial support and late side effects of treatment).\nSome people can find more frequent imaging and hospital contact burdensome and disruptive – they feel their life revolves around their latest scan.\nThere may be a financial cost from taking time off work and travelling to appointments.\nMore imaging and follow‑up is resource intensive for the NHS.\nConsider the follow‑up schedule given in table 11 for people with brain metastases.\nConsider standard structural MRI (defined as T2 weighted, FLAIR, DWI series and T1 pre- and post-contrast volume) as part of regular clinical review for people with brain metastases, to assess for progression or recurrence, unless MRI is contraindicated.\nConsider advanced MRI techniques, such as MR perfusion, diffusion tensor imaging and MR spectroscopy, if findings from standard imaging are unclear about whether there is recurrence and early identification is potentially clinically useful.\nFor people with brain metastases having routine imaging:\nexplain to them, and their relatives and carers, that imaging can be difficult to interpret and results can be of uncertain significance and\nbe aware that having routine imaging and waiting for the results may cause anxiety.\nArrange a clinical review, including appropriate imaging, for people with brain metastases who develop new or changing neurological symptoms or signs at any time.\nYears after end of treatment\nClinical review schedule\nto 1 years\nEvery 3 months\nto 2 years\nEvery 4 to 6 months\nyears and onwards\nAnnually\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on follow up for brain metastases .\nFull details of the evidence and the committee's discussion are in evidence review C: investigation, management and follow-up of brain metastases.\nLoading. Please wait.\n\n# Care needs of people with brain tumours\nBe aware that the care needs of people with brain tumours represent a unique challenge, because (in addition to physical disability) the tumour and treatment can have effects on:\nbehaviour\ncognition\npersonality.\nDiscuss health and social care support needs with the person with a brain tumour and their relatives and carers (as appropriate). Take into account the complex health and social care support needs people with any type of brain tumour and their relatives and carers may have (for example, psychological, cognitive, physical, spiritual, emotional).\nSet aside enough time to discuss the impact of the brain tumour on the person and their relatives and carers (as appropriate), and to elicit and discuss their health and social care support needs.\nHealth and social care professionals involved in the care of people with brain tumours should address additional complex needs during or at the end of treatment and throughout follow‑up. These include:\nchanges to cognitive functioning\nfatigue\nloss of personal identity\nloss of independence\nmaintaining a sense of hope\npotential for change in personal and sexual relationships\nthe challenges of living with uncertainty\nthe impact of brain tumour-associated epilepsy on wellbeing (see the NICE guideline on epilepsies: diagnosis and management).\nProvide a named healthcare professional with responsibility for coordinating health and social care support for people with brain tumours and their relatives and carers, for example, a key worker (often a clinical nurse specialist) as defined in NICE cancer service guidance on improving outcomes for people with brain and other central nervous system tumours.\nGive information to the person with a brain tumour and their relatives and carers (as appropriate):\nin a realistic and empathetic manner\nin suitable formats (written and spoken, with information available to take away), following the principles in the NICE guideline on patient experience in adult NHS services (also see NHS England's guidance on the Accessible Information Standard).\nat appropriate times throughout their care pathway.\nExplain to the person that they have a legal obligation to notify the Driver and Vehicle Licensing Agency (DVLA) if they have a brain tumour, and that this may have implications for their driving.\nProvide and explain clinical results, for example, imaging and pathology reports, to the person with a brain tumour and their relatives and carers (as appropriate) as soon as possible.\nOffer supportive care to people with brain tumours and their relatives and carers (as appropriate) throughout their treatment and care pathway\nIn people aged between 16 and 24 years old, refer to the NICE quality standard on cancer services for children and young people.\nDiscuss the potential preservation of fertility with people with brain tumours where treatment may have an impact on their fertility (see the recommendations on people with cancer who wish to preserve fertility in NICE's guideline on fertility problems).\nIf the person with a brain tumour is likely to be in their last year of life, refer to the NICE quality standards on end of life care for adults and, when appropriate, care of dying adults in the last days of life.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on care needs of people with brain tumours .\nFull details of the evidence and the committee's discussion are in evidence review D: supporting people living with a brain tumour.\nLoading. Please wait.\n\n# Neurorehabilitation needs of people with brain tumours\nConsider referring the person with a brain tumour for a neurological rehabilitation assessment of physical, cognitive and emotional function at diagnosis and every stage of follow‑up.\nOffer people with brain tumours and their relatives and carers (as appropriate) information on accessing neurological rehabilitation, and on what needs it can help address.\nGive people with brain tumours and their relatives and carers (as appropriate) information on:\nneurological rehabilitation options in the community, as an outpatient, or an inpatient and\nhow to get a neurological rehabilitation assessment.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on neurorehabilitation needs of people with brain tumours .\nFull details of the evidence and the committee's discussion are in evidence review D: supporting people living with a brain tumour.\nLoading. Please wait.\n\n# Surveillance for the late-onset side effects of treatment\nBe aware that people with brain tumours can develop side effects of treatment months or years after treatment, which can include:\ncataracts\ncavernoma\ncognitive decline\nepilepsy\nhearing loss\nhypopituitarism\ninfertility\nneuropathy (for example, nerve damage causing visual loss, numbness, pain or weakness)\nradionecrosis\nsecondary tumours\nSMART (stroke-like migraine attacks after radiotherapy)\nstroke.\nAssess the person's individual risk of developing late effects when they finish treatment. Record these in their written treatment summary and explain them to the person (and their relatives and carers, as appropriate).\nEncourage people who have had cranial radiotherapy to follow a healthy lifestyle, including exercise, a healthy diet and stopping smoking (if applicable), to decrease their risk of stroke. See the NICE guidelines on obesity prevention, physical activity and tobacco: preventing uptake, promoting quitting and treating dependence.\nFor people who are at risk of stroke, consider checking their blood pressure, HbA1c level and cholesterol profile regularly.\nConsider ongoing neuropsychology assessment for people at risk of cognitive decline.\nIf a person has had a radiotherapy dose that might affect pituitary function, consider checking their endocrine function regularly after the end of treatment.\nConsider referring people who are at risk of visual impairment for an ophthalmological assessment.\nConsider referring people who are at risk of hearing loss to audiology for a hearing test.\nConsider referring the person to stroke services if an MRI during active monitoring identifies asymptomatic ischaemic stroke.\nFor a short explanation of why the committee made these recommendations and how they might affect practice see the rationale and impact section on surveillance for the late-onset side effects of treatment .\nFull details of the evidence and the committee's discussion are in evidence review D: supporting people living with a brain tumour.\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Active monitoring\nThis is regular clinical and radiological review of a person with a brain tumour or brain metastases who are not currently having treatment for their cancer.\n\n## Regular clinical review\nThis is outpatient review of the person with a brain tumour or brain metastases at a planned interval from the previous visit in order to assess symptoms and care needs, to provide support and treatment and to perform imaging when appropriate.# Recommendations for research\nThe guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Managing glioma: management of IDH wildtype grade II glioma\nDoes the addition of concurrent and adjuvant temozolomide to radiotherapy improve overall survival in patients with IDH wildtype grade II glioma?\nThe World Health Organization (WHO) 2016 reclassification of brain tumours recognised that the molecular characteristics of glioma are extremely important in helping differentiate between disease entities with very different outcomes. Although evidence exists to guide management recommendations for certain molecular gliomas, such as codeleted and non-codeleted grade III glioma, currently no studies have investigated the best approach for the management of grade II glioma with IDH wildtype. The biological behaviour of these tumours is more like a high-grade glioma with a much shorter prognosis than IDH-mutated grade II glioma.\nBecause of this, some clinicians have advocated treating such tumours with concurrent chemoradiation recommended for grade IV glioma (glioblastoma multiforme, GBM). However, there is currently no research evidence to support this approach and this regimen is more intensive and people experience increased acute and late side effects compared to radiotherapy alone.\nResearch is needed to establish whether or not this approach is beneficial in terms of improved survival, and at what cost in terms of toxicity and, potentially, reduced quality of life.\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on managing glioma .\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nLoading. Please wait.\n\n## Managing glioma: supportive care clinics for low-grade glioma\nDoes a dedicated supportive care clinic in addition to standard care improve outcomes for people with low-grade gliomas?\nPeople with low-grade gliomas have significant symptoms and complex healthcare needs across multiple physical, cognitive, emotional and social domains. This is often from the initial diagnosis onwards. There are indications from research literature and patient reports that these needs are currently unmet. Helping people with low-grade gliomas maintain their quality of life and function is important, especially as there is currently no cure, because earlier supportive care interventions and care plans may help reduce unplanned or emergency contact with secondary and tertiary providers.\nAs no research literature exists which establishes the effectiveness of a specific healthcare intervention, uncertainty exists about the most appropriate intervention to address unmet needs and improve patient-reported outcome measures (or to establish whether current healthcare provision can meet these needs). Current uncertainty is likely to have led to variations in service provision across the UK. It is also possible that no specific intervention is available in some areas.\nResearch is needed to identify whether, in addition to standard care, a specific supportive care intervention can significantly improve patient-reported outcome measures, and if so to establish what this intervention should consist of.\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on supportive care clinics for low-grade glioma .\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nLoading. Please wait.\n\n## Managing glioma: early referral to palliative care for glioblastoma\nDoes early referral to palliative care improve outcomes for people with glioblastomas in comparison with standard oncology care?\nPeople with grade IV brain tumours (glioblastomas) have a poor prognosis which has not improved in over a decade. Median overall survival is 14–18 months even with gold-standard chemoradiation following surgery.\nFrom initial diagnosis people experience multiple complex symptoms resulting from neurological impairment. These can significantly impact on their quality of life, function and psychological wellbeing. Their caregivers report high levels of distress and carer burden.\nThe aim of palliative care is to relieve symptoms and improve people's quality of life and function – not just towards the end of life but throughout the duration of illness. There is some evidence that early palliative care referral significantly improves overall survival, quality of life and mood.\nResearch in this area is important because this group of people have substantial health needs, which use significant healthcare resources. Supportive care interventions such as early palliative care may improve quality of life and function throughout the duration of illness. It may also help people to manage the distress associated with a reduced life expectancy and participate in advanced care planning.\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on early referral to palliative care for glioblastoma .\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nLoading. Please wait.\n\n## Managing glioma: early detection of recurrence after treatment\nDoes early detection of recurrence after treatment improve overall survival/outcomes in molecularly stratified glioma?\nPrognosis for brain tumours is inherently uncertain, and recent advances in treatment mean many people with a brain tumour will live for a long time after the initial diagnosis. For these individuals, follow‑up is the longest component of their treatment and it is both expensive for the NHS and (sometimes) a burden for the person. There is no high-quality evidence that follow‑up after treatment is beneficial, no high-quality evidence on the optimal frequency of imaging, and clinical uncertainty about whether such follow‑up is likely to alter outcomes of importance to people with tumours (such as overall life expectancy or quality of life).\nResearch is needed to establish at what point the value of identifying recurrence early is outweighed by the harms of increasing burden to patients.\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on the early detection of recurrence after treatment .\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nLoading. Please wait.\n\n## Managing meningioma: immediate versus deferred radiotherapy for incompletely excised grade I meningioma\nIs immediate or deferred radiotherapy better for incompletely excised grade I meningioma?\nThere are no randomised studies on the use of radiotherapy/radiosurgery in the treatment of grade I meningioma. Though case series have shown that people with inoperable and incompletely excised grade I meningioma treated with radiotherapy have high rates of control of their tumour, treatment risks significant side effects. The side effects include: neuropathy, radionecrosis, significant oedema, neuro-cognitive effects, increased risk of stroke and secondary tumours. Therefore the timing of treatment is a balance between control of tumour and side effects. It is not known if early treatment has a greater or lesser chance of long-term tumour control or risk of tumour complications, or if this just risks complications of treatment earlier.\nPeople with grade I meningioma have traditionally been overlooked as a priority area for research. This is likely because of the slow nature of the disease resulting in need for long-term follow‑up and the difficulty to obtain funding for radiotherapy-only studies. However, this lack of research is inequitable, hence the reason for its prioritisation by the committee.\nA study on this topic would provide clear information to guide clinicians and people with meningiomas, hopefully leading to overall improvement in quality of life. Because of the slow-growing characteristics of grade I meningioma, treatment decisions made early in the management pathway will have long-term effects on the person with the meningioma's overall quality of life outcomes, and potentially overall survival.\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on managing meningioma .\nFull details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.\nLoading. Please wait.# Rationale and impact\nThese sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Investigations for suspected glioma: imaging\nThe discussion below explains how the committee made recommendations 1.1.1–1.1.3.\n\n## Why the committee made the recommendations\nThe evidence indicated that standard structural MRI is useful in distinguishing high-grade from low-grade glioma. The committee noted that this knowledge will inform management. Based on their experience, the committee recommended a protocol that they defined as a minimum standard for imaging acquisition.\nNo evidence was found on more advanced MRI techniques. However, the committee agreed that in their experience such techniques can be useful for assessing malignant features of a tumour – in particular, for ensuring that high-grade tumours are not misdiagnosed as low-grade tumours, which could have serious consequences for people who receive suboptimal management as a result. However the committee explained that a specialist multidisciplinary team would be needed to interpret features of the scan and decide management, even if advanced techniques were used.\n\n## How the recommendations might affect practice\nCurrently, various imaging strategies are used in different centres and depending on the person's circumstances. These recommendations aim to reduce variation in practice, and ensure that images obtained at different sites and using different equipment can be more accurately compared. Some centres may need to change their imaging protocols. This might increase or reduce costs depending on the imaging protocols which are currently in place.\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nReturn to recommendations\n\n# Investigations for suspected glioma: molecular markers\nThe discussion below explains how the committee made recommendations 1.1.4–1.1.6.\n\n## Why the committee made the recommendations\nMolecular markers are an emerging and important area in the treatment of brain tumours. The committee looked for evidence on these markers but did not find any. However, they noted that there are some molecular markers for which the evidence of benefit if tested is overwhelming, as reported in studies identified in searches for other review questions. This applies in particular for MGMT promoter methylation and TERT promoter mutations in IDH-wildtype glioma, although the committee agreed the evidence was of a higher quality in the first case than the second. The committee agreed that even these markers are not being consistently tested for and that testing should be standardised. Therefore they made recommendations based on their knowledge and experience, highlighting the World Health Organization (WHO) classification, to ensure that all centres follow a consistent process for assessing and interpreting information on molecular markers. This was important, since failure to consistently report molecular markers can mislead clinicians or limit treatment options.\n\n## How the recommendations might affect practice\nAs testing for molecular markers is relatively new, practice can vary widely and this is to be expected. In principle there should not be a major change, although the time taken to implement the new molecular tests will vary significantly between centres.\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nReturn to recommendations\n\n# Management of glioma: initial surgery for low-grade glioma\nThe discussion below explains how the committee made recommendations 1.2.1–1.2.5.\n\n## Why the committee made the recommendations\nThere was evidence that optimal resection of a large percentage of the tumour improved survival for people with low-grade glioma. The committee noted that it is sometimes not appropriate to offer maximal safe resection (for example, if the balance of risks and benefits favours not resecting all areas) and that a specialist surgical team should look at the value of doing an operation given its safe extent. They agreed that biopsy should be considered in these cases, based on limited evidence showing improved overall survival after biopsy compared with active monitoring. However, the committee also concluded that some tumours were of such limited risk that the risks of surgery outweighed the possible gain of biopsy or resection.\nThe committee described how there was no evidence for immediate intervention, but that intervention should not be delayed due to the probability that surgical resection would have benefit for the person with the tumour. They therefore recommended intervention within 6 months, to allow for time to discuss treatment options with the person with the tumour. This also allows for the possibility of a second imaging sequence to be done later to look for progression and to assess for symptom change, as the committee also recognised that a proportion of low-grade gliomas have unfavourable gene profiles (for example, IDH wildtype) that make them more like high-grade tumours from a prognostic perspective.\nA small number of people might have had initial treatment before it was standard practice to save a tissue sample for biopsy, and these people would currently be actively monitored. Based on their experience the committee agreed that these people may not need further surgery as long as their condition is stable (that is, they are not showing radiological or clinical disease progression).\n\n## How the recommendations might affect practice\nThe recommendations are likely to change practice at some centres, and remove unnecessary variation. There are currently differences between centres in which molecular diagnoses are performed and in treatment of very low-risk, low-grade tumours. This is partly because low-grade gliomas may be managed by non-expert surgical teams.\nThe recommendation about the management of low-grade gliomas that have been managed but then progress is unlikely to substantially change practice, as management would be largely unchanged.\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nReturn to recommendations\n\n# Management of glioma: further management of low-grade glioma\nThe discussion below explains how the committee made recommendations 1.2.6–1.2.11.\n\n## Why the committee made the recommendations\nThere was evidence that PCV chemotherapy (procarbazine, CCNU and vincristine) after radiotherapy improved overall survival and progression-free survival compared with radiotherapy alone. The committee discussed how the evidence for the exact regime was complex, and used their judgement to recommend possible sequence and dose. In addition, the committee noted that there are some circumstances where radiotherapy and PCV might not be appropriate (particularly for the very lowest-concern and highest-concern low-grade tumours) and made recommendations based on their experience in these cases.\nThe committee included approximate age cut‑offs based on evidence showing that treatment improved survival in people aged around 40 or over with or without residual tumour, and their clinical judgement that treatment would be unlikely to be of benefit for people aged around 40 or under without residual tumour.\nThe committee found no evidence on the treatment of IDH wildtype grade II glioma. They determined that management of this type of glioma was likely to be different from other low-grade glioma, as IDH wildtype grade II glioma behaves more like a high-grade glioma. The committee therefore made a research recommendation on whether treating this tumour type more like a grade II glioma or grade IV glioma was most beneficial.\n\n## How the recommendations might affect practice\nThese recommendations aim to standardise practice. They will probably result in the same amounts of chemotherapy and radiotherapy being given, but these treatments will be more precisely targeted and it is possible that they will be given earlier. This would result in more people requiring long-term treatment for the side effects of radiation and chemotherapy. More people are likely to have active monitoring alone, which is not likely to create a resource impact.\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nReturn to recommendations\n\n# Management of glioma: grade III glioma following surgery\nThe discussion below explains how the committee made recommendations 1.2.12–1.2.17.\n\n## Why the committee made the recommendations\nThe committee considered evidence for grade III and grade IV glioma separately.\nBased on randomised controlled trial evidence, the committee recommended radiotherapy and either PCV or temozolomide chemotherapy, depending on tumour subtype and performance status, for people with grade III glioma.\nBased on the available evidence, the committee recommended that some treatments should not be offered because they were harmful. They also agreed, based on their experience, that it would be useful for healthcare professionals to tell people with glioma that no evidence had been found to indicate that certain treatments are beneficial.\n\n## How the recommendations might affect practice\nAdjuvant PCV for treating codeleted grade III glioma is standard practice, but adjuvant temozolomide for non-codeleted grade III gliomas is a change in practice. However, some centres may already have started to adopt this as standard care, since the results of the study supporting this treatment were made publicly available in 2016.\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nReturn to recommendations\n\n# Management of glioma: grade IV glioma following surgery\nThe discussion below explains how the committee made recommendations 1.2.18–1.2.27.\n\n## Why the committee made the recommendations\nThe committee considered evidence for grade III and grade IV glioma separately.\nThe committee saw some evidence demonstrating improved overall survival in some groups of people with grade IV glioma who had radiotherapy with concurrent and adjuvant temozolomide (compared with radiotherapy alone). However, based on their clinical experience they were unsure that these results could be generalised to all people with grade IV glioma, so suggested a range of possible treatments that can be considered for other groups, depending on the exact clinical characteristics of the tumour.\nApproximate age cut‑offs for people with grade IV glioma were specified by the committee based on evidence that a radiotherapy dose of 40 Gy did not result in lower survival in people aged around 70 or over compared with a 60 Gy dose. Therefore a lower radiotherapy dose is likely to cause fewer side effects without compromising clinical effectiveness for this group.\nThe committee were aware that the prognosis of people with a grade IV glioma and a low performance status was poor, and recommended palliative care be considered. However the committee did not find any evidence on whether earlier or later palliative care was most beneficial for people who might need it. They therefore made a research recommendation on this topic, with the aim of finding out the point in the treatment pathway when it would be most beneficial for people with this type of glioma to have palliative care.\nBased on the available evidence, the committee recommended that certain treatments should not be offered. This included tumour treating fields (TTF) based on published health economic evidence that they are not an efficient use of NHS resources. They also agreed, based on their clinical experience, that it would be useful for healthcare professionals to tell people with glioma that no evidence had been found to suggest that certain treatments are beneficial.\n\n## How the recommendations might affect practice\nFor younger people with a grade IV glioma and a good performance status, a course of radiotherapy with concurrent and adjuvant temozolomide is standard care. However, for people aged around 70 and over, particularly those with a glioma with methylated MGMT, the use of concurrent and adjuvant temozolomide with 15 fractions of radiotherapy is a change of practice that will probably result in more people being treated. This is a relatively small group of people, and so the recommendation is unlikely to have a significant resource impact.\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nReturn to recommendations\n\n# Management of glioma: recurrent high-grade glioma\nThe discussion below explains how the committee made recommendations 1.2.28–1.2.35.\n\n## Why the committee made the recommendations\nBased on the available evidence, the committee recommended that treatment options for people with recurrent glioma should include temozolomide, PCV and single-agent CCNU (lomustine). No evidence was found to indicate which of these 3 options is likely to lead to the best outcomes, and on the basis of their clinical experience the committee concluded that the choice of treatment should take several factors into account, including the individual features of the tumour and the preferences of the person. The committee also highlighted the possibility of considering supportive care alone.\nBased on the available evidence, the committee recommended that certain treatments should not be offered. This included tumour treating fields (TTF) on the basis of evidence of some clinical benefit but indirect published health economic evidence, in people with newly diagnosed high-grade glioma, that they are not cost effective. They also agreed, based on their clinical experience, that it would be useful for healthcare professionals to tell people with glioma that no evidence had been found to suggest that certain treatments are beneficial.\n\n## How the recommendations might affect practice\nThese recommendations reflect standard treatment for recurrent high-grade glioma, and therefore should not represent a substantial change in practice.\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nReturn to recommendations\n\n# Management of glioma: techniques for resection of glioma\nThe discussion below explains how the committee made recommendations 1.2.36–1.2.42.\n\n## Why the committee made the recommendations\nThere was evidence that 5‑aminolevulinic acid (5‑ALA), intraoperative MRI and diffusion tensor imaging could improve either the extent or safety of resection (particularly the preservation of neurological function). The committee noted that a combination of techniques might be needed to optimise both the extent and safety of resection for a particular surgical plan. The committee concluded that the evidence for MRI could be generalised to intraoperative ultrasound on the basis of their clinical experience, and therefore that clinicians should be able to choose either technique depending on availability.\nThe evidence for awake craniotomy was equivocal (non-significant differences compared with surgery under general anaesthesia), therefore from the evidence it was not possible to conclude that awake craniotomy would benefit all people with glioma. This is in line with the committee's clinical experience that some people benefit from the procedure (in terms of preserving language, motor and visual function) but others are harmed – particularly from psychological effects which act as a contraindication to awake craniotomy. The committee described how better preoperative procedures could reduce the number of people distressed by the procedure.\n\n## How the recommendations might affect practice\nSome techniques recommended by the committee require a very high level of intraoperative skill, and this might have resource implications for hospitals recruiting people with these specialist skills. There is significant variation in the current provision of psychological support for people before and during awake craniotomy, and implementing this could carry a high cost to an individual unit.\nIf a unit does not have access to intraoperative ultrasound or MRI, the cost of acquiring this equipment could be substantial (MRI is relatively expensive, ultrasound is relatively cheap). However the committee concluded that most units should have access to one or the other already. Therefore the only resource impact would be if a unit currently using intraoperative ultrasound decided that the additional evidence for preservation of neurological function in intraoperative MRI justified the cost of switching machines. However, the committee thought this was unlikely to happen.\nUsing 5‑ALA is associated with a high cost, and 5‑ALA-guided surgery needs a non-standard fluorescence-detecting microscope. Therefore the resource impact of this recommendation is likely to be high in all settings, and very high in settings without access to a fluorescence-detecting microscope. The anticipated resource impact of this recommendation is greater than £1 million per year.\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nReturn to recommendations\n\n# Follow-up for glioma\nThe discussion below explains how the committee made recommendations 1.3.1–1.3.9.\n\n## Why the committee made the recommendations\nIn the absence of evidence, the committee made recommendations based on their clinical experience. They recommended regular clinical review as the only plausible way of identifying and potentially managing recurrence or changing symptoms. They also recommended the review schedule take into account all of the person's relevant characteristics, including grade of tumour. As this is quite difficult to work out, the committee suggested a schedule of clinical reviews that is likely to be beneficial for a 'typical' person, which can be amended as needed to take into account individual variation. The committee did not uncover evidence on who should do the follow‑up and so did not make a recommendation on this topic as it would vary according to clinical need, but discussed how it could be – for example – the local oncologist, neuro-oncologist, neurologist, neurosurgeon, clinical nurse specialist or GP.\nAs regular clinical review should include imaging, based on their experience the committee suggested an MRI sequence which they believed would be suitable to monitor for recurrence. They discussed how advanced MRI techniques might be valuable, but as these techniques are time-consuming and difficult to interpret the committee concluded they should only be recommended under certain circumstances where extra information was likely to substantially alter treatment plans. The committee recommended that any change in neurological signs or symptoms (which would include changes in behavioural, emotional and psychological signs and symptoms) be treated as a sign of a potential change to the tumour, and therefore recommended clinical review outside the usual schedule in order to investigate this.\nThe committee believed that a dedicated supportive care clinic could improve outcomes for people with low-grade glioma, but did not find any evidence on this. Therefore they made a research recommendation on improving the long-term outcomes of people with low-grade glioma.\n\n## How the recommendations might affect practice\nThe recommendations are in line with current best practice, and should standardise practice. They are unlikely to cause a significant increase in resource use, but there may be some additional costs or changes in service configuration if practice differs in a particular centre.\nThe imaging sequences are recommended on the basis of evidence for the appropriate sequences for initial diagnosis, and so might not be the standard sequence for follow‑up in all centres. As a result, adopting the recommended sequences might create some additional workload for some centres. However the recommendations for exact schedules are examples based on consensus in the committee, and there is therefore flexibility for centres to adapt these to their own models, limiting resource impact.\nFull details of the evidence and the committee's discussion are in evidence review A: investigation, management and follow-up of glioma.\nReturn to recommendations\n\n# Investigation of suspected meningioma\nThe discussion below explains how the committee made recommendations 1.4.1 and 1.4.2.\n\n## Why the committee made the recommendations\nEvidence indicated that standard structural MRI is useful in distinguishing high-grade from low-grade glioma, and the committee agreed that it is appropriate to extrapolate from this evidence to a belief that MRI can be used to distinguish meningioma from healthy brain tissue. In the committee's experience, CT scans can be more accurate than MRI for assessing meningioma with bone involvement.\n\n## How the recommendations might affect practice\nCurrently, various imaging strategies are used depending on the centre and the person's circumstances. These recommendations aim to reduce variation in practice, and ensure that images obtained at different sites and using different equipment can be more accurately compared. Some centres may need to change their imaging protocols as a result, but this should not require the purchase of additional equipment.\nFull details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.\nReturn to recommendations\n\n# Management of confirmed meningioma following surgery or if surgery is not possible (or has been declined)\nThe discussion below explains how the committee made recommendations 1.4.3–1.4.6.\n\n## Why the committee made the recommendations\nBased on limited evidence and their clinical experience, the committee concluded that management of this group of meningiomas will depend on the type of meningioma. They noted that evidence for 1 grade of meningioma could not normally be used to suggest best management for another grade. Therefore the committee made recommendations for each grade of meningioma separately, using evidence if this was available and their judgement if it was not. The committee identified that management could be more conservative if the tumour grade was lower and initial resection more complete, and should be more aggressive if the tumour grade was higher or initial resection more partial.\nThe committee agreed that the 3 management options – further radiotherapy, surgery and active monitoring – had different balances of benefits and harms in different situations. However they also agreed that serious harm could be done to a person with a tumour if they were over- or under-treated given the risk profile of their tumour, and so made recommendations according to this risk. For example, for a low-grade almost completely-resected tumour (grade I, Simpson 2 excision), radiotherapy or further surgery could expose the person to risk of harm for no expected clinical gain.\nBased on limited evidence, the committee made recommendations on how to deliver radiotherapy or radiosurgery where this was appropriate. They used their experience to highlight features of the tumour or preferences of the person that might help select the most appropriate radiotherapy or radiosurgery modality, and explained that the best results would come through minimising the dose of radiation delivered to healthy brain tissue while maximising the chance of local control.\nThe committee were unable to find evidence comparing different timings of radiotherapy in incompletely excised grade I meningioma. As the disease is slow growing it can be difficult to assess the risks of immediate side effects from treatment compared to the longer-term benefits of tumour control. Therefore the committee made a research recommendation to investigate this topic.\n\n## How the recommendations might affect practice\nThe recommendations reflect standard practice in many centres, and should make treatment more consistent.\nAn appointment with an oncologist for all people who may have radiotherapy is not currently standard practice. However, for most people this is likely to mean a change in the timing of their first appointment with an oncologist, rather than many more people having oncologist appointments.\nFull details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.\nReturn to recommendations\n\n# Follow-up for meningioma\nThe discussion below explains how the committee made recommendations 1.5.1–1.5.6.\n\n## Why the committee made the recommendations\nIn the absence of evidence, the committee made recommendations based on their clinical experience. They recommended regular clinical review as the only plausible way of identifying and potentially managing recurrence or changing symptoms. They also recommended the review schedule take into account all of the person's relevant characteristics, including grade of tumour. As this is quite difficult to work out, the committee suggested a schedule of clinical reviews that is likely to be beneficial for a 'typical' person, which can be amended as needed to take into account individual variation. The committee did not uncover evidence on who should do the follow‑up and so did not make a recommendation on this topic as it would vary according to clinical need, but discussed how it could be – for example – the local oncologist, neuro-oncologist, neurologist, neurosurgeon, clinical nurse specialist or GP.\nAs regular clinical review should include imaging, based on their experience the committee suggested an MRI sequence which they believed would be suitable to monitor for recurrence. They discussed how advanced MRI techniques might be valuable, but as these techniques are time-consuming and difficult to interpret the committee concluded they should only be recommended under certain circumstances where extra information was likely to substantially alter treatment plans. The committee recommended that any change in neurological signs or symptoms (which would include changes in behavioural, emotional and psychological signs and symptoms) be treated as a sign of a potential change to the tumour, and therefore recommended clinical review outside the usual schedule in order to investigate this.\n\n## How the recommendations might affect practice\nThe recommendations are in line with current best practice, and should standardise practice. They are unlikely to cause a significant increase in resource use, but there may be some additional costs or changes in service configuration if practice differs in a particular centre.\nThe imaging sequences are recommended on the basis of evidence for the appropriate sequences for initial diagnosis, and so might not be the standard sequence for follow‑up in all centres. As a result, adopting the recommended sequences might create some additional workload for some centres. However the recommendations for exact schedules are examples based on consensus in the committee, and there is therefore flexibility for centres to adapt these to their own models, limiting resource impact.\nFull details of the evidence and the committee's discussion are in evidence review B: investigation, management and follow-up of meningioma.\nReturn to recommendations\n\n# Investigation of suspected brain metastases\nThe discussion below explains how the committee made recommendations 1.6.1–1.6.3.\n\n## Why the committee made the recommendations\nIn the absence of evidence, the committee recommended standard structural MRI based on their experience, because it is important to establish the exact number of metastases in the brain, which can guide further treatment. The committee described how failing to establish this could be dangerous. Extracranial imaging, biopsy of the extracranial disease (where indicated) and performing all imaging before multidisciplinary team discussions should ensure that all necessary information is available so that appropriate decisions are made and delays in treatment avoided.\n\n## How the recommendations might affect practice\nThe recommendations reinforce current best practice and should reduce delays to local intracranial treatment.\nFull details of the evidence and the committee's discussion are in evidence review C: investigation, management and follow-up of brain metastases.\nReturn to recommendations\n\n# Management of confirmed brain metastases\nThe discussion below explains how the committee made recommendations 1.7.1–1.7.11.\n\n## Why the committee made the recommendations\nThe committee made recommendations based on the available evidence and their judgement. They described how features of brain metastases, including the number and volume (which is important for establishing prognosis), should be evaluated before starting treatment, and decisions about treatment made on the basis of these features and the person's preferences.\nThe committee described how systematic anti-cancer therapies were widely used in the management of other types of metastases, and therefore they might be expected to work for brain tumours. In the absence of evidence, the committee recommended considering systematic anti-cancer therapies on the basis of their clinical experience. Whether or not these therapies should be given depends on the type of metastasis: if it is not likely to respond then the side effects would not justify giving the therapy, whereas if the metastasis was likely to respond then the therapy was likely to be beneficial.\nEvidence indicated that surgery, stereotactic radiosurgery and stereotactic radiotherapy are effective for treating a single brain metastasis, but there was no evidence to recommend 1 technique over the other. There was some evidence that irradiation of the cavity site improved local control, so the committee recommended it on the basis that improving local control should improve quality of life.\nJanuary 2021: the recommendations on this surgical cavity radiosurgery and radiotherapy have been updated. For details see the update information.\nFor people with multiple brain metastases, the committee described how treatment options are more variable, and that resection, stereotactic radiosurgery, stereotactic radiotherapy and whole-brain radiotherapy could all be considered in certain circumstances.\nThe committee recommended that neither memantine nor concurrent systemic therapy should be offered to enhance the efficacy of whole-brain radiotherapy, on the basis of evidence of no benefit and a potential risk of harm. However, there were biological reasons to think these treatments might be beneficial in some settings, so the committee agreed these therapies could be offered in the context of a clinical trial to investigate this.\n\n## How the recommendations might affect practice\nCurrent practice varies greatly between centres. Some of the variation reflects clinically relevant factors such as expertise in a particular technique or the patient population. The recommendations should help to standardise care and prevent some harmful and wasteful practices from continuing. Economic modelling identified that the recommendations will likely increase costs, but the committee believed that this was still an efficient use of NHS resources, as the improvement to quality of life was significant.\nFull details of the evidence and the committee's discussion are in evidence review C: investigation, management and follow-up of brain metastases.\nReturn to recommendations\n\n# Follow-up for brain metastases\nThe discussion below explains how the committee made recommendations 1.8.1–1.8.7.\n\n## Why the committee made the recommendations\nIn the absence of evidence, the committee made recommendations based on their clinical experience. They recommended regular clinical review as the only plausible way of identifying and potentially managing recurrence or changing symptoms. They also recommended the review schedule take into account all of the person's relevant characteristics, including grade of tumour. As this is quite difficult to work out, the committee suggested a schedule of clinical reviews that is likely to be beneficial for a 'typical' person, which can be amended as needed to take into account individual variation. The committee did not uncover evidence on who should do the follow‑up and so did not make a recommendation on this topic as it would vary according to clinical need, but discussed how it could be – for example – the local oncologist, neuro-oncologist, neurologist, neurosurgeon, clinical nurse specialist or GP.\nAs regular clinical review should include imaging, based on their experience the committee suggested an MRI sequence which they believed would be suitable to monitor for recurrence. They discussed how advanced MRI techniques might be valuable, but as these techniques are time-consuming and difficult to interpret the committee concluded they should only be recommended under certain circumstances where extra information was likely to substantially alter treatment plans. The committee recommended that any change in neurological signs or symptoms (which would include changes in behavioural, emotional and psychological signs and symptoms) be treated as a sign of a potential change to the tumour, and therefore recommended clinical review outside the usual schedule in order to investigate this.\n\n## How the recommendations might affect practice\nThe recommendations are in line with current best practice, and should standardise practice. They are unlikely to cause a significant increase in resource use, but there may be some additional costs or changes in service configuration if practice differs in a particular centre.\nThe imaging sequences are recommended on the basis of evidence for the appropriate sequences for initial diagnosis, and so might not be the standard sequence for follow‑up in all centres. As a result, adopting the recommended sequences might create some additional workload for some centres. However the recommendations for exact schedules are examples based on consensus in the committee, and there is therefore flexibility for centres to adapt these to their own models, limiting resource impact.\nFull details of the evidence and the committee's discussion are in evidence review C: investigation, management and follow-up of brain metastases.\nReturn to recommendations\n\n# Care needs of people with brain tumours\nThe discussion below explains how the committee made recommendations 1.9.1–1.9.12.\n\n## Why the committee made the recommendations\nBased on the evidence and their own experience, the committee determined that people with brain tumours have very specific needs that are often not met. In particular, they highlighted ways in which the care needs of people with brain tumours differ from those of people with other types of cancer, such as the impact on the person's sense of identity and legal requirements related to driving. Losing the ability or legal right to drive can have a profound effect on the patient's independence, employment status and self-esteem. The committee's aim was to improve the support and information offered to people with brain tumours.\nThe committee described how the care needs of people with brain tumours were often more complex than could be considered in a single guideline. In particular, young people, people wishing to preserve their fertility, and people nearing the end of their life have especially complex needs. In order to address these needs, the committee signposted to existing NICE guidance in the specific area.\n\n## How the recommendations might affect practice\nThe recommendations should improve care for both people living with brain tumours and their relatives and carers. It is likely that there will be a short-term resource impact in some areas, as supportive care for people with brain tumours is currently variable, with very little support available in some areas.\nFull details of the evidence and the committee's discussion are in evidence review D: supporting people living with a brain tumour.\nReturn to recommendations\n\n# Neurorehabilitation needs of people with brain tumours\nThe discussion below explains how the committee made recommendations 1.10.1–1.10.3.\n\n## Why the committee made the recommendations\nNo evidence was found for this topic. Based on their experience, the committee agreed that neurological rehabilitation is likely to be suitable for many people with brain tumours. Given that neurological rehabilitation is time-consuming (especially if the person with a tumour lives a long way from the rehabilitation centre) and sometimes not appropriate, the committee agreed that assessment should be carried out at every stage of diagnosis and follow‑up to identify which, if any, forms of rehabilitation are suitable for the person. The aim of the recommendations is to ensure that neurological rehabilitation is considered at every stage of treatment and follow‑up.\n\n## How the recommendations might affect practice\nThere is currently variation in practice in assessing whether people with a brain tumour need neurological rehabilitation. Some of this reflects the availability of neurological rehabilitation services. The recommendations reinforce current best practice, and will mean a change in practice in some areas, including where assessment is 'ad hoc' rather than systematic.\nPeople with a brain tumour make up a small percentage of people referred for neurological rehabilitation, so only a small increase in demand on resources is expected. There should not be any extra training needs because professionals already have the knowledge and skills to provide the services.\nFull details of the evidence and the committee's discussion are in evidence review D: supporting people living with a brain tumour.\nReturn to recommendations\n\n# Surveillance for the late-onset side effects of treatment\nThe discussion below explains how the committee made recommendations 1.11.1–1.11.9.\n\n## Why the committee made the recommendations\nNo evidence was found for this topic. Some people experience late effects after treatment for a brain tumour. With the possible exception of stroke risk it is unknown if these late effects can be prevented, but the committee agreed that any negative impact can be managed through clinical vigilance and referral into appropriate specialist monitoring pathways. The committee explained that it was important to consider referral for anyone at risk of late effects – not just those at 'high' risk – but that there may be no value in such a referral overall in lower risk groups.\n\n## How the recommendations might affect practice\nThe recommendations should not significantly alter practice, as they reflect common clinical practice.\nFull details of the evidence and the committee's discussion are in evidence review D: supporting people living with a brain tumour.\nReturn to recommendations# Context\nIt is estimated there are around 10,000 new cases of primary brain tumours per year. These tumours come from the brain tissue or its coverings – the meninges. Malignant high-grade gliomas (anaplastic gliomas and glioblastomas) and pre-malignant low-grade gliomas come from the brain tissue glial cells, and make up over 60% of primary brain tumours. Meningiomas make up a further 30%. Although often thought benign, meningiomas can have an acute presentation and are associated with significant long-term neurological morbidity. Because of this, they can behave in a malignant fashion in terms of recurrence and impact.\nOver 60% of people with primary brain tumours present at, and are diagnosed by, accident and emergency services rather than from conventional GP or specialist referral. This causes a significant demand on these services. Although primary malignant brain tumours represent only 3% of all cancers, they result in the most life-years lost of any cancer. There is concern that the true incidence of these tumours is rising.\nCancers that have spread to the brain from somewhere else in the body are called secondary brain tumours, or brain metastases. Many different cancer types can spread to the brain, with lung and breast cancers being the most common. More people with systemic cancers are surviving longer and are referred to neuroscience multidisciplinary teams for management of their brain metastases. The number of people needing assessment for cranial treatment is now over 10,000 per year in the UK and rising.\nThe specialist nature of neuro-imaging and the need for complex diagnostic and reductive surgery emphasises the importance of well-organised service delivery by dedicated units. The singular effects of brain tumours on mental performance (both psychological state and cognitive decline) are a particular challenge to carers and professionals alike, especially in delivering support to people at home. The peak age of presentation of brain cancer is between 65 and 69, and there are concerns that delivery of all services to these older people is suboptimal. There are also concerns that the transition from paediatric to adult units could create a care gap. This would most specifically affects patients who are between 18 and 30 years old.\nSurvival with malignant brain tumours has remained poor despite some improvements in surgery, radiotherapy and chemotherapy, and a greater understanding of molecular classification. The management of a low-grade glioma that is likely to transform to high grade remains controversial, and presents issues for ongoing care. Follow‑up for people with meningiomas after primary treatment is often long term, and there is variation in both follow‑up and treatments for recurrence.\nConventional whole-brain irradiation as optimal therapy for brain metastases is being challenged by concerns about its effectiveness and toxicity, as well as the availability and immediacy of surgery and stereotactic radiotherapy."}}},{"rowIdx":99,"cells":{"id":{"kind":"string","value":"882a321cadbd78d1547a9154f19ea1c3a8cbd229"},"source":{"kind":"string","value":"nice"},"text":{"kind":"string","value":"Urinary incontinence and pelvic organ prolapse in women: management\n\nThis guideline covers assessing and managing urinary incontinence and pelvic organ prolapse in women aged 18 and over. It also covers complications associated with mesh surgery for these conditions.\n\n# Recommendations\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Organisation of specialist services\n\n## Local multidisciplinary teams\nLocal multidisciplinary teams (MDTs) for women with primary stress urinary incontinence, overactive bladder or primary prolapse should:\nreview the proposed treatment for all women offered invasive procedures for primary stress urinary incontinence, overactive bladder or primary prolapse\nreview the proposed management for women with primary stress urinary incontinence, overactive bladder or primary prolapse if input from a wider range of healthcare professionals is needed\nwork within an established clinical network that has access to a regional MDT. Note: In 2018, NHS England consulted on specialised gynaecology surgery and complex urogynaecology conditions service specifications.\nLocal MDTs for women with primary stress urinary incontinence, overactive bladder or primary prolapse should include:\nconsultants with expertise in managing urinary incontinence in women and/or pelvic organ prolapse\na urogynaecology, urology or continence specialist nurse\na pelvic floor specialist physiotherapistand may also include:\na member of the care of the elderly team\nan occupational therapist\na colorectal surgeon. \nMembers of the local MDT (listed in recommendation 1.1.2) should attend all local MDT meetings. \n\n## Regional multidisciplinary teams\nRegional MDTs that deal with complex pelvic floor dysfunction and mesh-related problems should review the proposed treatment for women if:\nthey are having repeat continence surgery\nthey are having repeat, same-site prolapse surgery\ntheir preferred treatment option is not available in the referring hospital\nthey have coexisting bowel problems that may need additional colorectal intervention\nvaginal mesh for prolapse is a treatment option for them\nthey have mesh complications or unexplained symptoms after mesh surgery for urinary incontinence or prolapse\nthey are considering surgery and may wish to have children in the future. \nRegional MDTs that deal with complex pelvic floor dysfunction and mesh-related problems should include:\na subspecialist in urogynaecology\na urologist with expertise in female urology\na urogynaecology, urology or continence specialist nurse\na pelvic floor specialist physiotherapist\na radiologist with expertise in pelvic floor imaging\na colorectal surgeon with expertise in pelvic floor problems\na pain specialist with expertise in managing pelvic painand may also include:\na healthcare professional trained in bowel biofeedback and trans-anal irrigation\na clinical psychologist\na member of the care of the elderly team\nan occupational therapist\na surgeon skilled at operating in the obturator region\na plastic surgeon. \nRegional MDTs that deal with complex pelvic floor dysfunction and mesh-related problems should have ready access to the following services:\npsychology\npsychosexual counselling\nchronic pain management\nbowel symptom management\nneurology. \nMembers of the regional MDT (listed in recommendation 1.1.5) should attend regional MDT meetings when their specific expertise is needed. \nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on organisation of specialist services .\nFull details of the evidence and the committee's discussion are in evidence review F: effectiveness of multidisciplinary teams for the assessment and management of urinary incontinence or pelvic organ prolapse.\nLoading. Please wait.\n\n# Collecting data on surgery and surgical complications\nAsk women having surgery for stress urinary incontinence or pelvic organ prolapse, or who have experienced complications related to these types of surgery, for their consent to enter the data listed in recommendation 1.2.2 in a national registry. Give each woman a copy of her data. \nProviders must ensure that the following data are recorded in a national registry of surgery for urinary incontinence and pelvic organ prolapse in women:\nthe woman's NHS number\nhospital and consultant identifiers\ndate and details of the procedure\nfor procedures involving mesh, the mesh material, manufacturer, product unique identification code and type of sutures used\nfor procedures involving colposuspension, the type of sutures used\nfor procedures involving bulking agent, the bulking material, manufacturer and product unique identification code\ndate and details of any investigation for complications\ndate and details of any surgical or non-surgical intervention for complications. \nThe national registry of surgery for urinary incontinence and pelvic organ prolapse in women must ensure that follow‑up data are collected on key short- and long-term (at least 5 years) outcomes, including:\nvalidated relevant outcome measures\nadverse events including pain\nsuspected and confirmed mesh-related complications. \nThe national registry of surgery for urinary incontinence and pelvic organ prolapse in women should report annually and be quality assured. \nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on collecting data on surgery and surgical complications .\nFull details of the evidence and the committee's discussion are in evidence review E: surgical and physical management of stress urinary incontinence and evidence review I: surgical management of pelvic organ prolapse.\nLoading. Please wait.\n\n# Assessing urinary incontinence\n\n## History taking and physical examination\nAt the initial clinical assessment, categorise the woman's urinary incontinence as stress urinary incontinence, mixed urinary incontinence or urgency urinary incontinence/overactive bladder. Start initial treatment on this basis. In mixed urinary incontinence, direct treatment towards the predominant symptom. \nIf stress incontinence is the predominant symptom in mixed urinary incontinence, discuss with the woman the benefit of non-surgical management and medicines for overactive bladder before offering surgery. \nDuring the clinical assessment seek to identify relevant predisposing and precipitating factors and other diagnoses that may require referral for additional investigation and treatment. \n\n## Assessing pelvic floor muscles\nUndertake routine digital assessment to confirm pelvic floor muscle contraction before the use of supervised pelvic floor muscle training for the treatment of urinary incontinence. \n\n## Urine testing\nUndertake a urine dipstick test in all women presenting with urinary incontinence to detect the presence of blood, glucose, protein, leucocytes and nitrites in the urine. \nIf women have symptoms of urinary tract infection (UTI) and their urine tests positive for both leucocytes and nitrites, send a midstream urine specimen for culture and analysis of antibiotic sensitivities. Prescribe an appropriate course of antibiotic treatment pending culture results. See the NICE guideline on urinary tract infection (lower): antimicrobial prescribing for more information. \nIf women have symptoms of UTI and their urine tests negative for either leucocytes or nitrites, send a midstream urine specimen for culture and analysis of antibiotic sensitivities. Consider the prescription of antibiotics pending culture results. \nIf women do not have symptoms of UTI, but their urine tests positive for both leucocytes and nitrites, do not offer antibiotics without the results of midstream urine culture. \nIf a woman does not have symptoms of UTI and her urine tests negative for either leucocytes or nitrites, do not send a urine sample for culture because she is unlikely to have UTI. \n\n## Assessing residual urine\nMeasure post-void residual volume by bladder scan or catheterisation in women with symptoms suggestive of voiding dysfunction or recurrent UTI. \nUse a bladder scan in preference to catheterisation on the grounds of acceptability and lower incidence of adverse events. \n\n## Symptom scoring and quality-of-life assessment\nUse a validated urinary incontinence-specific symptom and quality-of-life questionnaire when therapies are being evaluated. \n\n## Bladder diaries\nUse bladder diaries in the initial assessment of women with urinary incontinence or overactive bladder. Encourage women to complete a minimum of 3 days of the diary covering variations in their usual activities, such as both working and leisure days. \n\n## Pad testing\nDo not use pad tests in the routine assessment of women with urinary incontinence. \n\n## Urodynamic testing\nDo not perform multichannel filling and voiding cystometry before primary surgery if stress urinary incontinence or stress-predominant mixed urinary incontinence is diagnosed based on a detailed clinical history and demonstrated stress urinary incontinence at examination. \nAfter undertaking a detailed clinical history and examination, perform multichannel filling and voiding cystometry before surgery for stress urinary incontinence in women who have any of the following:\nurge-predominant mixed urinary incontinence or urinary incontinence in which the type is unclear\nsymptoms suggestive of voiding dysfunction\nanterior or apical prolapse\na history of previous surgery for stress urinary incontinence. \nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on urodynamic testing .\nFull details of the evidence and the committee's discussion are in evidence review A: urodynamic assessment prior to primary surgery for stress urinary incontinence.\nLoading. Please wait.\n\n## Other tests of urethral competence\nDo not use the Q‑tip, Bonney, Marshall and Fluid-Bridge tests in the assessment of women with urinary incontinence. \n\n## Cystoscopy\nDo not use cystoscopy in the initial assessment of women with urinary incontinence alone. \n\n## Imaging\nDo not use imaging (MRI, CT, X‑ray) for the routine assessment of women with urinary incontinence. Do not use ultrasound other than for the assessment of residual urine volume. \n\n## Indications for referral to a specialist service\nIn women with urinary incontinence, indications for consideration for referral to a specialist service include:\npersisting bladder or urethral pain\npalpable bladder on bimanual or abdominal examination after voiding\nclinically benign pelvic masses\nassociated faecal incontinence\nsuspected neurological disease\nsymptoms of voiding difficulty\nsuspected urogenital fistulae\nprevious continence surgery\nprevious pelvic cancer surgery\nprevious pelvic radiation therapy. \nFollow the recommendations on referral for urinary tract cancer in the NICE guideline on suspected cancer, for women with haematuria or recurrent or persistent unexplained UTI. \n\n# Non-surgical management of urinary incontinence\n\n## Lifestyle interventions\nRecommend a trial of caffeine reduction to women with overactive bladder. \nConsider advising women with urinary incontinence or overactive bladder and a high or low fluid intake to modify their fluid intake. \nAdvise women with urinary incontinence or overactive bladder who have a BMI greater than 30 to lose weight. \n\n## Physical therapies\nOffer a trial of supervised pelvic floor muscle training of at least 3 months' duration as first-line treatment to women with stress or mixed urinary incontinence. \nPelvic floor muscle training programmes should comprise at least 8 contractions performed 3 times per day. \nDo not use perineometry or pelvic floor electromyography as biofeedback as a routine part of pelvic floor muscle training. \nContinue an exercise programme if pelvic floor muscle training is beneficial. \nFor a short explanation of why the committee made the 2019 recommendation and how it might affect practice, see the rationale and impact section on pelvic floor muscle training .\nFull details of the evidence and the committee's discussion are in evidence review H: lifestyle and conservative management options for pelvic organ prolapse.\nLoading. Please wait.\nDo not routinely use electrical stimulation in the treatment of women with overactive bladder. \nDo not routinely use electrical stimulation in combination with pelvic floor muscle training. \nElectrical stimulation and/or biofeedback should be considered for women who cannot actively contract pelvic floor muscles to aid motivation and adherence to therapy. \n\n## Behavioural therapies\nOffer bladder training lasting for a minimum of 6 weeks as first-line treatment to women with urgency or mixed urinary incontinence. \nIf women do not achieve satisfactory benefit from bladder training programmes, the combination of an overactive bladder medicine with bladder training should be considered if frequency is a troublesome symptom. \n\n## Neurostimulation\nDo not offer transcutaneous sacral nerve stimulation (surface electrodes placed above the sacrum, often known as transcutaneous electrical nerve stimulation ) to treat overactive bladder in women. \nDo not offer transcutaneous posterior tibial nerve stimulation for overactive bladder. \nDo not offer percutaneous posterior tibial nerve stimulation (needles inserted close to the posterior tibial nerve) for overactive bladder unless:\nthere has been a local MDT review and\nnon-surgical management including overactive bladder medicine treatment has not worked adequately and\nthe woman does not want botulinum toxin type A or percutaneous sacral nerve stimulation. In April 2019, most botulinum toxin type A preparations were off label for this indication. Evidence was only available for the licensed botulinum toxin type A preparation (BOTOX, Allergan).\n\n## Absorbent containment products, urinals and toileting aids\nDo not offer absorbent containment products, hand-held urinals or toileting aids to treat urinary incontinence. Offer them only:\nas a coping strategy pending definitive treatment\nas an adjunct to ongoing therapy\nfor long-term management of urinary incontinence only after treatment options have been explored. \nOffer a review at least once a year to women who are using absorbent containment products for long-term management of urinary incontinence. The review should cover:\nroutine assessment of continence\nassessment of skin integrity\nchanges to symptoms, comorbidities, lifestyle, mobility, medication, BMI, and social and environmental factors\nthe suitability of alternative treatment options\nthe efficacy of the absorbent containment product the woman is currently using and the quantities used. \nReviews for women who are using absorbent containment products for long-term management of urinary incontinence should be carried out by either:\na registered healthcare professional who is trained in assessing continence and making referrals to specialist services or\na non-registered healthcare worker, under the supervision of a registered healthcare professional who is trained in assessing continence and making referrals to specialist services. See indications for referral to a specialist service in this guideline. \nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on absorbent containment products .\nFull details of the evidence and the committee's discussion are in evidence review B: treatment options for women using absorbent containment products.\nLoading. Please wait.\n\n## Catheters\nBladder catheterisation (intermittent or indwelling urethral or suprapubic) should be considered for women in whom persistent urinary retention is causing incontinence, symptomatic infections or renal dysfunction, and in whom this cannot otherwise be corrected. Healthcare professionals should be aware, and explain to women, that the use of indwelling catheters in urgency urinary incontinence may not result in continence. \nOffer intermittent urethral catheterisation to women with urinary retention who can be taught to self-catheterise or who have a carer who can perform the technique. \nGive careful consideration to the impact of long-term indwelling urethral catheterisation. Discuss the practicalities, benefits and risks with the woman or, if appropriate, her carer. Indications for the use of long-term indwelling urethral catheters for women with urinary incontinence include:\nchronic urinary retention in women who are unable to manage intermittent self-catheterisation\nskin wounds, pressure ulcers or irritations that are being contaminated by urine\ndistress or disruption caused by bed and clothing changes\nwhere a woman expresses a preference for this form of management. \nIndwelling suprapubic catheters should be considered as an alternative to long-term urethral catheters. Be aware, and explain to women, that they may be associated with lower rates of symptomatic UTI, 'bypassing', and urethral complications than indwelling urethral catheters. \n\n## Products to prevent leakage\nDo not use intravaginal and intraurethral devices for the routine management of urinary incontinence in women. Do not advise women to consider such devices other than for occasional use when necessary to prevent leakage, for example during physical exercise. \n\n## Complementary therapies\nDo not recommend complementary therapies for the treatment of urinary incontinence or overactive bladder. \n\n## Medicines for overactive bladder\nBefore starting treatment with a medicine for overactive bladder, explain to the woman:\nthe likelihood of the medicine being successful\nthe common adverse effects associated with the medicine\nthat some adverse effects of anticholinergic medicines, such as dry mouth and constipation, may indicate that the medicine is starting to have an effect\nthat she may not see substantial benefits until she has been taking the medicine for at least 4 weeks and that her symptoms may continue to improve over time\nthat the long-term effects of anticholinergic medicines for overactive bladder on cognitive function are uncertain. \nWhen offering anticholinergic medicines to treat overactive bladder, take account of the woman's:\ncoexisting conditions (such as poor bladder emptying, cognitive impairment or dementia)\ncurrent use of other medicines that affect total anticholinergic load\nrisk of adverse effects, including cognitive impairment. \nFor women who have a diagnosis of dementia and for whom anticholinergic medicines are an option, follow the recommendations on medicines that may cause cognitive impairment in the NICE guideline on dementia. \nDo not offer women flavoxate, propantheline or imipramine to treat urinary incontinence or overactive bladder. \nDo not offer oxybutynin (immediate release) to older women who may be at higher risk of a sudden deterioration in their physical or mental health. \nOffer the anticholinergic medicine with the lowest acquisition cost to treat overactive bladder or mixed urinary incontinence in women. \nIf the first medicine for overactive bladder or mixed urinary incontinence is not effective or well-tolerated, offer another medicine with a low acquisition cost (see additional information). \nOffer a transdermal overactive bladder treatment to women unable to tolerate oral medicines. \nFor guidance on mirabegron, see the NICE technology appraisal guidance on mirabegron for treating symptoms of overactive bladder. \nThe use of desmopressin may be considered specifically to reduce nocturia in women with urinary incontinence or overactive bladder who find it a troublesome symptom. Use particular caution in women with cystic fibrosis and avoid in those over 65 years with cardiovascular disease or hypertension. \nDo not use duloxetine as a first-line treatment for women with predominant stress urinary incontinence. Do not routinely offer duloxetine as a second-line treatment for women with stress urinary incontinence, although it may be offered as second-line therapy if women prefer pharmacological to surgical treatment or are not suitable for surgical treatment. If duloxetine is prescribed, counsel women about its adverse effects. For guidance on safe prescribing of antidepressants (such as duloxetine) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\nDo not offer systemic hormone replacement therapy to treat urinary incontinence. \nOffer intravaginal oestrogens to treat overactive bladder symptoms in postmenopausal women with vaginal atrophy. \nOffer a face-to-face or telephone review 4 weeks after starting a new medicine for overactive bladder. Ask the woman if she is satisfied with the treatment and:\nif improvement is optimal, continue treatment\nif there is no or suboptimal improvement, or intolerable adverse effects, change the dose or try an alternative medicine for overactive bladder (see the recommendations for when the first medicine is not effective and offering a transdermal patch in the section on choosing medicines), and review again 4 weeks later. \nOffer a review before 4 weeks if the adverse events of a medicine for overactive bladder are intolerable. \nRefer women who have tried taking medicine for overactive bladder, but for whom it has not been successful or tolerated, to secondary care to consider further treatment. \nOffer a further face-to-face or telephone review if a medicine for overactive bladder or urinary incontinence stops working after an initial successful 4‑week review. \nOffer a review in primary care to women who remain on long-term medicine for overactive bladder or urinary incontinence every 12 months, or every 6 months if they are aged over 75. \nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on medicines for overactive bladder .\nFull details of the evidence and the committee's discussion are in evidence review C: the risks to cognitive function for women taking anticholinergic drugs for overactive bladder.\nLoading. Please wait.\n\n## Invasive procedures for overactive bladder\nFor women with overactive bladder that has not responded to non-surgical management or treatment with medicine and who wish to discuss further treatment options:\n-ffer urodynamic investigation to determine whether detrusor overactivity is causing her overactive bladder symptoms and\nif detrusor overactivity is causing her overactive bladder symptoms, offer an invasive procedure in line with the recommendation on bladder wall injection in the section on botulinum toxin type A and the recommendation in the section on urinary diversionor\nif there is no detrusor overactivity, seek advice on further management from the local MDT in line with the recommendation on considering treatment with botulinum toxin type A in the section on botulinum toxin type A. \nSee additional information on prescribing botulinum toxin type A.\nAfter a local MDT review, offer bladder wall injection with botulinum toxin type A to women with overactive bladder caused by detrusor overactivity that has not responded to non-surgical management, including pharmacological treatments. \nConsider treatment with botulinum toxin type A after a local MDT review for women with symptoms of overactive bladder in whom urodynamic investigation has not demonstrated detrusor overactivity, if the symptoms have not responded to non-surgical management and the woman does not wish to have other invasive treatments. \nAfter a local MDT review, discuss the benefits and risks of treatment with botulinum toxin type A with the woman and explain:\nthe likelihood of complete or partial symptom relief\nthe process of clean intermittent catheterisation, the risks, and how long it might need to be continued\nthe risk of adverse effects, including an increased risk of urinary tract infection\nthat there is not much evidence about how long the injections work for, how well they work in the long term and their long-term risks. \nStart treatment with botulinum toxin type A only if the woman is willing, in the event of developing significant voiding dysfunction:\nto perform clean intermittent catheterisation on a regular basis for as long as needed or\nto accept a temporary indwelling catheter if she is unable to perform clean intermittent catheterisation. \nUse 100 units as the initial dose of botulinum toxin type A to treat overactive bladder in women. \nOffer a face-to-face or telephone review within 12 weeks of the first treatment with botulinum toxin type A to assess the response to treatment and adverse effects, and:\nif there is good symptom relief, tell the woman how to self-refer for prompt specialist review if symptoms return, and offer repeat treatment as necessary\nif there is inadequate symptom relief, consider increasing subsequent doses of botulinum toxin type A to 200 units and review within 12 weeks\nif there was no effect, discuss with the local MDT. \nIf symptom relief has been adequate after injection of 100 units of botulinum toxin type A but has lasted for less than 6 months, consider increasing subsequent doses of botulinum toxin type A to 200 units and review within 12 weeks. \nDo not offer botulinum toxin type B to women with overactive bladder. \nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on botulinum toxin type A injection .\nFull details of the evidence and the committee's discussion are in evidence review D: management of overactive bladder.\nLoading. Please wait.\nOffer percutaneous sacral nerve stimulation to women after local or regional MDT review if their overactive bladder has not responded to non-surgical management including medicines and:\ntheir symptoms have not responded to botulinum toxin type A or\nthey are not prepared to accept the risks of needing catheterisation associated with botulinum toxin type A. \nDiscuss the long-term implications of percutaneous sacral nerve stimulation with women including:\nthe need for test stimulation and probability of the test's success\nthe risk of failure\nthe long-term commitment\nthe need for surgical revision\nthe adverse effects. \nTell women how to self-refer for prompt specialist review if symptoms return following a percutaneous sacral nerve stimulation procedure. \nRestrict augmentation cystoplasty for the management of idiopathic detrusor overactivity to women whose condition has not responded to non-surgical management and who are willing and able to self-catheterise. Preoperative counselling for the woman or her carer should include common and serious complications: bowel disturbance, metabolic acidosis, mucus production and/or retention in the bladder, UTI and urinary retention. Discuss the small risk of malignancy occurring in the augmented bladder. Provide life-long follow‑up. \nUrinary diversion should be considered for a woman with overactive bladder only when non-surgical management has failed, and if botulinum toxin type A, percutaneous sacral nerve stimulation and augmentation cystoplasty are not appropriate or are unacceptable to her. Provide life-long follow‑up. In April 2019, most botulinum toxin type A preparations were off label for this indication. Evidence was only available for the licensed botulinum toxin type A preparation (BOTOX, Allergan).\n\n# Surgical management of stress urinary incontinence\nThere is public concern about the use of mesh procedures. For all of the procedures recommended in this section, including mesh procedures, there is evidence of benefit but limited evidence on the long-term adverse effects. In particular, the true prevalence of long-term complications is unknown.\nIf a woman is thinking about a surgical procedure for stress urinary incontinence, use the NICE patient decision aid on surgery for stress urinary incontinence to promote informed preference and shared decision making. Discussion with the woman should include:\nthe benefits and risks of all surgical treatment options for stress urinary incontinence that NICE recommends, whether or not they are available locally\nthe uncertainties about the long-term adverse effects for all procedures, particularly those involving the implantation of mesh materials\ndifferences between procedures in the type of anaesthesia, expected length of hospital stay, surgical incisions and expected recovery period\nany social or psychological factors that may affect the woman's decision. \nIf non-surgical management for stress urinary incontinence has failed, and the woman wishes to think about a surgical procedure, offer her the choice of:\ncolposuspension (open or laparoscopic) or\nan autologous rectus fascial sling.Also include the option of a retropubic mid-urethral mesh sling in this choice but see the recommendations in the section on mid-urethral mesh sling procedures for additional guidance on the use of mid-urethral mesh sling procedures for stress urinary incontinence. \nConsider intramural bulking agents to manage stress urinary incontinence if alternative surgical procedures are not suitable for or acceptable to the woman. Explain to the woman that:\nthese are permanent injectable materials\nrepeat injections may be needed to achieve effectiveness\nlimited evidence suggests that they are less effective than the surgical procedures listed in recommendation 1.5.2 and the effects wear off over time\nthere is limited evidence on long-term effectiveness and adverse events. \nIf an intramural bulking agent is injected, give the woman written information about the bulking agent, including its name, manufacturer, date of injection, and the injecting surgeon's name and contact details. \nIf the woman's chosen procedure for stress urinary incontinence is not available from the consulting surgeon, refer her to an alternative surgeon. \nProviders must ensure that data on surgical procedures for stress urinary incontinence are recorded in a national registry, as outlined in the section on collecting data on surgery and surgical complications in this guideline. \n\n## Mid-urethral mesh sling procedures\nWhen offering a retropubic mid-urethral mesh sling, advise the woman that it is a permanent implant and complete removal might not be possible. \nIf a retropubic mid-urethral mesh sling is inserted, give the woman written information about the implant, including its name, manufacturer, date of insertion, and the implanting surgeon's name and contact details. \nWhen planning a retropubic mid-urethral mesh sling procedure, surgeons should:\nuse a device manufactured from type 1 macroporous polypropylene mesh\nconsider using a retropubic mid-urethral mesh sling coloured for high visibility, for ease of insertion and revision. \nDo not offer a transobturator approach unless there are specific clinical circumstances (for example, previous pelvic procedures) in which the retropubic approach should be avoided. \nDo not use the 'top‑down' retropubic mid-urethral mesh sling approach or single-incision sub-urethral short mesh sling insertion except as part of a clinical trial. \n\n## Artificial urinary sphincters\nDo not offer women an artificial urinary sphincter to manage stress urinary incontinence unless previous surgery has failed. \nFor women who have had an artificial urinary sphincter inserted:\n-ffer postoperative follow‑up and\nensure access to review if needed. \n\n## Procedures that should not be offered\nDo not offer women the following procedures to treat stress urinary incontinence:\nanterior colporrhaphy\nneedle suspension\nparavaginal defect repair\nporcine dermis sling\nthe Marshall–Marchetti–Krantz procedure. \n\n## Follow-up after surgery\nOffer a follow‑up appointment within 6 months to all women who have had a surgical procedure to treat stress urinary incontinence. \nFor women who have had retropubic mid-urethral mesh sling surgery, the follow‑up appointment should include a vaginal examination to check for exposure or extrusion of the mesh sling. \nProviders should ensure that women who have had surgery for stress urinary incontinence have access to further referral if they have recurrent symptoms or suspected complications. See also assessing complications associated with mesh surgery in this guideline. \nFor women whose primary surgical procedure for stress urinary incontinence has failed (including women whose symptoms have returned):\nseek advice on assessment and management from a regional MDT that deals with complex pelvic floor dysfunction or\n-ffer the woman advice about managing urinary symptoms if she does not wish to have another surgical procedure, and explain that she can ask for a referral if she changes her mind. \nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on surgical management of stress urinary incontinence .\nFull details of the evidence and the committee's discussion are in evidence review E: surgical and physical management of stress urinary incontinence.\nLoading. Please wait.\n\n# Assessing pelvic organ prolapse\nFor women presenting in primary care with symptoms or an incidental finding of vaginal prolapse:\ntake a history to include symptoms of prolapse, urinary, bowel and sexual function\ndo an examination to rule out a pelvic mass or other pathology and to document the presence of prolapse (see the recommendations in the NICE guideline on suspected cancer about ovarian cancer and bladder cancer)\ndiscuss the woman's treatment preferences with her, and refer if needed. \nFor women referred to secondary care for an unrelated condition who have incidental symptoms or an incidental finding of vaginal prolapse, consider referral to a clinician with expertise in prolapse. \nFor women who are referred for specialist evaluation of vaginal prolapse, perform an examination to:\nassess and record the presence and degree of prolapse of the anterior, central and posterior vaginal compartments of the pelvic floor, using the POP‑Q (Pelvic Organ Prolapse Quantification) system\nassess the activity of the pelvic floor muscles\nassess for vaginal atrophy\nrule out a pelvic mass or other pathology. \nFor women with pelvic organ prolapse, consider using a validated pelvic floor symptom questionnaire to aid assessment and decision making. \nDo not routinely perform imaging to document the presence of vaginal prolapse if a prolapse is detected by physical examination. \nIf the woman has symptoms of prolapse that are not explained by findings from a physical examination, consider repeating the examination with the woman standing or squatting, or at a different time. \nConsider investigating the following symptoms in women with pelvic organ prolapse:\nurinary symptoms that are bothersome and for which surgical intervention is an option\nsymptoms of obstructed defaecation or faecal incontinence (see the recommendations for baseline assessment of faecal incontinence in the NICE guideline on faecal incontinence in adults)\npain\nsymptoms that are not explained by examination findings. \nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on assessing pelvic organ prolapse .\nFull details of the evidence and the committee's discussion are in evidence review G: assessing pelvic organ prolapse.\nLoading. Please wait.\n\n# Non-surgical management of pelvic organ prolapse\nDiscuss management options with women who have pelvic organ prolapse, including no treatment, non-surgical treatment and surgical options, taking into account:\nthe woman's preferences\nsite of prolapse\nlifestyle factors\ncomorbidities, including cognitive or physical impairments\nage\ndesire for childbearing\nprevious abdominal or pelvic floor surgery\nbenefits and risks of individual procedures. \n\n## Lifestyle modification\nConsider giving advice on lifestyle to women with pelvic organ prolapse, including information on:\nlosing weight, if the woman has a BMI greater than 30 kg/m2\nminimising heavy lifting\npreventing or treating constipation. \n\n## Topical oestrogen\nConsider vaginal oestrogen for women with pelvic organ prolapse and signs of vaginal atrophy. For managing urogenital atrophy, see the recommendations in managing short-term menopausal symptoms in the NICE guideline on menopause. \nConsider an oestrogen-releasing ring for women with pelvic organ prolapse and signs of vaginal atrophy who have cognitive or physical impairments that might make vaginal oestrogen pessaries or creams difficult to use. \n\n## Pelvic floor muscle training\nConsider a programme of supervised pelvic floor muscle training for at least 16 weeks as a first option for women with symptomatic POP‑Q (Pelvic Organ Prolapse Quantification) stage 1 or stage 2 pelvic organ prolapse. If the programme is beneficial, advise women to continue pelvic floor muscle training afterwards. \n\n## Pessaries\nConsider a vaginal pessary for women with symptomatic pelvic organ prolapse, alone or in conjunction with supervised pelvic floor muscle training. \nRefer women who have chosen a pessary to a urogynaecology service if pessary care is not available locally. \nBefore starting pessary treatment:\nconsider treating vaginal atrophy with topical oestrogen\nexplain that more than 1 pessary fitting may be needed to find a suitable pessary\ndiscuss the effect of different types of pessary on sexual intercourse\ndescribe complications including vaginal discharge, bleeding, difficulty removing pessary and pessary expulsion\nexplain that the pessary should be removed at least once every 6 months to prevent serious pessary complications. \nOffer women using pessaries an appointment in a pessary clinic every 6 months if they are at risk of complications, for example because of a physical or cognitive impairment that might make it difficult for them to manage their ongoing pessary care. \nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on non-surgical management of pelvic organ prolapse .\nFull details of the evidence and the committee's discussion are in evidence review H: lifestyle and conservative management options for pelvic organ prolapse.\nLoading. Please wait.\n\n# Surgical management of pelvic organ prolapse\nThere is public concern about the use of mesh procedures. For all of the procedures recommended in this section, including mesh procedures, there is some evidence of benefit, but limited evidence on long-term effectiveness and adverse effects. In particular, the true prevalence of long-term complications is unknown.\nOffer surgery for pelvic organ prolapse to women whose symptoms have not improved with or who have declined non-surgical treatment. \nIf a woman is thinking about a surgical procedure for pelvic organ prolapse, use a decision aid (use the NICE patient decision aids on surgery for uterine prolapse and surgery for vaginal vault prolapse where they apply) to promote informed preference and shared decision making. Discussion with the woman should include:\nthe different treatment options for pelvic organ prolapse, including no treatment or continued non-surgical management\nthe benefits and risks of each surgical procedure, including changes in urinary, bowel and sexual function\nthe risk of recurrent prolapse\nthe uncertainties about the long-term adverse effects for all procedures, particularly those involving the implantation of mesh materials\ndifferences between procedures in the type of anaesthesia, expected length of hospital stay, surgical incisions and expected recovery period\nthe role of intraoperative prolapse assessment in deciding the most appropriate surgical procedure. \nDo not offer surgery to prevent incontinence in women having surgery for prolapse who do not have incontinence. \nExplain to women considering surgery for anterior or apical prolapse who do not have incontinence that there is a risk of developing postoperative urinary incontinence and further treatment may be needed. \nIf the woman's chosen procedure for pelvic organ prolapse is not available from the consulting surgeon, refer her to an alternative surgeon. \nIf mesh is to be used in prolapse surgery:\nexplain to the woman about the type of mesh that will be used and whether or not it is permanent\nensure that details of the procedure and its subsequent short- and long-term outcomes are recorded in a national registry (see the section on collecting data on surgery and surgical complications in this guideline)\ngive the woman written information about the implant, including its name, manufacturer, date of insertion, and the implanting surgeon's name and contact details. \nProviders must ensure that data on surgical procedures for pelvic organ prolapse are recorded in a national registry, as outlined in the section on collecting data on surgery and surgical complications in this guideline. \n\n## Surgery for uterine prolapse\nDiscuss the options for treatment (see recommendation 1.8.2 on using a decision aid), including non-surgical options, hysterectomy and surgery that will preserve the uterus, with women who have uterine prolapse. \nFor women considering surgery for uterine prolapse:\ndiscuss the possible complications and the lack of long-term evidence on the effectiveness of the procedures\nuse the NICE patient decision aid on surgery for uterine prolapse to discuss the benefits and risks of treatment, including non-surgical options. \nFor women with uterine prolapse who have no preference about preserving their uterus, offer a choice of:\nvaginal hysterectomy, with or without vaginal sacrospinous fixation with sutures or\nvaginal sacrospinous hysteropexy with sutures or\nManchester repair. Also include the option of sacro-hysteropexy with mesh (abdominal or laparoscopic) in this choice but see recommendation 1.8.6 for specific guidance on the use of mesh in prolapse surgery. \nFor women with uterine prolapse who wish to preserve their uterus, offer a choice of:\nvaginal sacrospinous hysteropexy with sutures or\nManchester repair, unless the woman may wish to have children in the future. Also include the option of sacro-hysteropexy with mesh (abdominal or laparoscopic) in this choice but see recommendation 1.8.6 for specific guidance on the use of mesh in prolapse surgery. \nIf a synthetic polypropylene mesh is inserted, the details of the procedure and its subsequent short- and long-term outcomes must be collected in a national registry (see the section on collecting data on surgery and surgical complications in this guideline). \nEnsure the proposed treatment is reviewed by a regional MDT (see the recommendation on MDTs reviewing proposed treatment in the section on regional multidisciplinary teams) if the woman wishes to have children in the future. \n\n## Surgery for vault prolapse\nDiscuss the options for treatment (see recommendation 1.8.2 on using a decision aid), including non-surgical and surgical options, with women who have vault prolapse. \nFor women considering surgery for vault prolapse:\ndiscuss the possible complications and the lack of long-term evidence on the effectiveness of the procedures\nuse the NICE patient decision aid on surgery for vaginal vault prolapse to discuss the benefits and risks of treatment, including non-surgical options. \nOffer women with vault prolapse a choice of:\nvaginal sacrospinous fixation with sutures or\nsacrocolpopexy (abdominal or laparoscopic) with mesh. See recommendation 1.8.6 for specific guidance on the use of mesh in prolapse surgery. \nIf a synthetic polypropylene mesh is inserted, the details of the procedure and its subsequent short- and long-term outcomes must be collected in a national registry (see the section on collecting data on surgery and surgical complications in this guideline). \n\n## Colpocleisis for vault or uterine prolapse\nConsider colpocleisis for women with vault or uterine prolapse who do not intend to have penetrative vaginal sex and who have a physical condition that may put them at increased risk of operative and postoperative complications. \n\n## Surgery for anterior prolapse\nDiscuss the options for treatment (see recommendation 1.8.2 on using a decision aid), including non-surgical and surgical options, with women who have anterior prolapse. \nOffer anterior repair without mesh to women with anterior vaginal wall prolapse. \nRecommendation withdrawn in June 2019.\nRecommendation withdrawn in June 2019.\nJune 2019: Recommendations 1.8.21 and 1.8.22, which related to the use of synthetic polypropylene or biological mesh insertion for women with recurrent anterior vaginal wall prolapse, have been withdrawn. Instead, please see NICE interventional procedures guidance 599 on transvaginal mesh repair of anterior or posterior vaginal wall prolapse, which says:\n'1.1 Current evidence on the safety of transvaginal mesh repair of anterior or posterior vaginal wall prolapse shows there are serious but well-recognised safety concerns. Evidence of long-term efficacy is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research.\n'1.2 All adverse events involving the medical devices (including the mesh) used in this procedure should be reported to the Medicines and Healthcare products Regulatory Agency.\n'1.3 Further research should include details of patient selection, long-term outcomes including complications, type of mesh used and method of fixation, and quality of life.'\nThe replacement of the guideline recommendation with a cross-reference to IPG599 is to provide clarity regarding the relation of NG123 and IPG599 and to take account of a material change since publication in the availability of products CE-marked for the indication which was referred to in the guideline recommendations.\n\n## Surgery for posterior prolapse\nOffer posterior vaginal repair without mesh to women with a posterior vaginal wall prolapse. \n\n## Follow-up after surgery\nOffer women a review 6 months after surgery for pelvic organ prolapse. Ensure that the review includes a vaginal examination and, if mesh was used, check for mesh exposure. \nProviders should ensure that women who have had surgery for pelvic organ prolapse have access to further referral if they have recurrent symptoms or suspected complications. Also see the section on assessing complications associated with mesh surgery in this guideline. \nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on surgical management of pelvic organ prolapse .\nFull details of the evidence and the committee's discussion are in evidence review I: surgical management of pelvic organ prolapse.\nLoading. Please wait.\n\n# Surgery for women with both stress urinary incontinence and pelvic organ prolapse\nConsider concurrent surgery for stress urinary incontinence and pelvic organ prolapse in women with anterior and/or apical prolapse and stress urinary incontinence. \nWhen considering concurrent surgery for stress urinary incontinence and pelvic organ prolapse, discuss the options for treatment (see the recommendation on using the NICE decision aid in the section on surgical management of stress incontinence and in the section on surgical management of pelvic organ prolapse) and explain to the woman:\nthat there is uncertainty about whether the combined procedure is effective for treating stress urinary incontinence beyond 1 year, and that stress urinary incontinence might persist despite surgery\nthe risk of complications related to having surgery for stress urinary incontinence at the same time as prolapse surgery compared with the risk of complications related to having sequential surgery. \nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on surgery for women with both stress urinary incontinence and pelvic organ prolapse .\nFull details of the evidence and the committee's discussion are in evidence review J: surgical management of pelvic organ prolapse and stress urinary incontinence.\nLoading. Please wait.\n\n# Assessing complications associated with mesh surgery\nFor women who report new-onset symptoms after having mesh surgery for urinary incontinence or pelvic organ prolapse, evaluate whether the symptoms might be caused by a mesh-related complication. These symptoms could include:\npain or sensory change in the back, abdomen, vagina, pelvis, leg, groin or perineum that is:\neither unprovoked, or provoked by movement or sexual activity and\neither generalised, or in the distribution of a specific nerve, such as the obturator nerve\nvaginal problems including discharge, bleeding, painful sexual intercourse, or penile trauma or pain in sexual partners\nurinary problems including recurrent infection, incontinence, retention, or difficulty or pain during voiding\nbowel problems including difficulty or pain on defaecation, faecal incontinence, rectal bleeding or passage of mucus\nsymptoms of infection, either alone or in combination with any of the symptoms outlined above. \nRefer women with a suspected mesh-related complication to a urogynaecologist, urologist or colorectal surgeon for specialist assessment. \nFor women who are referred for specialist evaluation of a suspected mesh complication:\ntake a history of all past surgical procedures for prolapse or incontinence using mesh, including the dates, type of mesh and site of mesh placement and the relationship of the symptoms to the surgical procedure(s)\nconsider using a validated pelvic floor symptom questionnaire and a pain questionnaire to aid assessment and decision making\nperform a vaginal examination to:\nassess whether mesh is palpable, exposed or extruded\nlocalise pain and its anatomical relationship to mesh\nconsider performing a rectal examination, if indicated, to assess for the presence of mesh perforation or fistula\nconsider performing a neurological assessment to assess the distribution of pain, if present, sensory alteration or muscle weakness. \nFor women with a confirmed mesh-related complication or unexplained symptoms after a mesh procedure:\nrefer to a consultant at a regional centre specialising in the diagnosis and management of mesh-related complications or\nif the woman has a vaginal exposure of mesh that is smaller than 1 cm2 and no other symptoms, follow the recommendations on discussing topical oestrogen cream treatment and a follow-up appointment for those having topical oestrogen cream in the section on managing vaginal complications. \nThe responsible consultant should develop an individualised investigation plan for each woman with suspected or confirmed mesh-related complications, involving other members of the regional MDT if needed, and use table 1 in this guideline to inform decisions on possible investigations. \nThe responsible consultant must ensure that details of any confirmed mesh-related complications are:\nrecorded in a national registry (see the section on collecting data on surgery and surgical complications in this guideline) and\nreported to the Medicines and Healthcare products Regulatory Agency (MHRA). \nInvestigation\nType of mesh\nIndications\nBenefits\nRisks\nExamination under anaesthesia\nAll types of mesh\nPain or suspected:\nvaginal or rectal exposure or extrusion\nsinus tract, urinary or bowel fistula\nAllows diagnosis when not revealed by awake examination or when an awake, examination is not tolerated\nAnaesthetic risk\nCystourethro-scopy\nAll types of mesh\nSuspected:\nurethral perforation\nbladder perforation\nfistula\ncalculus on suture or mesh material\nAllows diagnosis by direct visualisation\nAids management planning\nAnaesthetic risk and risk of urinary tract infection\nSigmoidoscopy\nAbdominally, laparo-scopically or vaginally placed mesh for pelvic organ prolapse\nSuspected bowel perforation by mesh\nAllows diagnosis by direct visualisation\nAids management planning\nAnaesthetic risk if carried out under anaesthesia\nRisk of bowel perforation\nLaparoscopy\nAbdominally or laparo-scopically placed mesh for pelvic organ prolapse\nPain\nSuspected bowel entrapment around mesh\nSuspected adhesions secondary to mesh placement\nAllows diagnosis by direct visualisation\nAids management planning\nAnaesthetic risk\nRisks of laparoscopy, including bowel injury\nMRI, protocolled and reported by a clinician with experience in interpreting mesh complications\nAll types of mesh\nSuspected mesh infection\nAnatomical mapping of suspected fistula\nAnatomical mapping and mesh localisation to guide further surgery\nBack pain following abdominal mesh placement with mesh attachment to sacral promontory\nIdentification of discitis or osteomyelitis\nShows implanted material and complications nearby\nShows location of mesh in relation to the vaginal wall and sacrum\nGenerally regarded as safe, with a low risk of short- and long-term harms. Risk of contrast media injection\nUltrasound scan (transperineal, transvaginal or translabial, or 3D), performed and reported by a clinician with experience in interpreting mesh complications\nVaginally placed mesh to treat incontinence\nPain\nVoiding dysfunction\nSuspected infection\nSuspected urethral mesh perforation\nAnatomical mapping to guide excision surgery\nShows implanted material and local complications\nIdentifies mid-urethral slings\nShows location of mesh in relation to the vaginal wall and urethra\nDiscomfort\nCT\nAll types of mesh, although CT is not commonly used to show implanted material\nSuspected:\nurinary tract injury\nbowel injury\nbowel obstruction\nMay be useful in assessing for urinary fistulae or bowel injury\nPotential radiation-related harms and risk of contrast media injection\nFluoroscopic studies (cystography or contrast enema). Perform with water-soluble contrast media\nFluoroscopic studies and CT may be used according to local preference and expertise\nAll types of mesh\nSuspected urinary or bowel fistula\nAids management planning\nPotential radiation-related harms\nUrinary flow studies and post-void residual volume assessment or cystometry\nAll types of mesh\nVoiding dysfunction\nUrinary incontinence\nAids management planning\nUrinary tract infection and radiation risks if fluoroscopy is used\nNeuro-physiology, including nerve conduction studies\nAll types of mesh\nSuspected nerve injury\nAllows diagnosis of impaired nerve function\nNerve conduction studies are difficult to perform and can induce more pain\nNote: Individualised investigation plans may include, but are not limited to, 1 or more of these investigations.\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on assessing complications associated with mesh surgery .\nFull details of the evidence and the committee's discussion are in evidence review K: assessing mesh complications after pelvic floor mesh surgery.\nLoading. Please wait.\n\n# Managing complications associated with mesh surgery\n\n## General considerations before removing mesh\nIf a woman who has had a mesh procedure to treat urinary incontinence or pelvic organ prolapse is thinking about having the mesh removed, discuss the decision with her and with a regional MDT. \nWhen discussing surgery to remove mesh, explain to the woman that:\nthere is limited evidence on the benefits of partial or complete removal compared with no mesh removal\nsurgery to remove mesh can have significant complications including organ injury, worsening pain, and urinary, bowel and sexual dysfunction\nit is not certain that removing the mesh will relieve symptoms\nit might not be possible to remove all of the mesh\nremoving only part of the mesh might be just as effective at improving symptoms as removing all of it\nurinary incontinence or prolapse can recur after the mesh has been removed. \n\n## Managing vaginal complications\nDiscuss non-surgical treatment with topical oestrogen cream with women who have a single area of vaginal mesh exposure that is smaller than 1 cm2. \nOffer a follow‑up appointment within 3 months to women with vaginal mesh exposure who choose treatment with topical oestrogen cream. \nConsider partial or complete surgical removal of the vaginal portion of mesh for women:\nwho do not wish to have treatment with topical oestrogen or\nif the area of vaginal mesh sling exposure is 1 cm2 or larger or\nif there is vaginal mesh extrusion or\nif there has been no response to non-surgical treatment after a period of 3 months. \nOffer imaging and further treatment to women who have signs of infection in addition to vaginal mesh exposure or extrusion. \nDiscuss with women who have vaginal complications after mesh sling surgery for stress urinary incontinence that:\ncomplete removal of the vaginal portion of mesh sling is associated with a greater risk of recurrence of stress urinary incontinence than partial removal\npartial removal is associated with a higher rate of further mesh sling extrusion\ncomplete removal might not be possible. \nExplain to women who have vaginal complications after vaginally placed mesh for pelvic organ prolapse that:\ncomplete removal might not be possible\ncomplete removal has a higher risk of urinary tract or bowel injury than partial removal\nthere may be a risk of recurrent prolapse. \nExplain to women who have vaginal complications after abdominally placed mesh for pelvic organ prolapse that:\nremoval is associated with a risk of urinary tract and bowel injury\nthere is a risk of recurrent prolapse\nthey might need abdominal surgery to remove the mesh\ncomplete removal might not be possible. \nFor women who have pain or painful sexual intercourse suspected to be related to previous mesh surgery:\nif specialist assessment indicates a mesh-related complication, seek advice from a regional MDT\nif assessment and investigation do not show a mesh abnormality such as vaginal extrusion or exposure, or an infection, consider non-surgical treatments such as pain management, vaginal oestrogen, dilators, counselling (including psychosexual counselling) and physiotherapy\nif pain does not respond to initial management, seek advice from a regional MDT. \n\n## Managing urinary complications\nRefer women who have mesh perforating the lower urinary tract to a centre for mesh complications for further assessment or management. \nFor women with urinary symptoms after mesh surgery for stress urinary incontinence or pelvic organ prolapse who are considering mesh removal surgery, explain that:\nurinary symptoms might not improve and new symptoms might occur after complete or partial removal of the mesh\nstress urinary incontinence might recur after mesh removal, and the risk of this happening is higher with complete than with partial mesh removal\ncomplete removal of the mesh might not be possible\nfurther treatment might be needed for mesh complications, or recurrent or persistent urinary symptoms\nthere is a risk of adverse events such as urinary tract fistula. \nDiscuss division of mesh sling with women who have voiding difficulty after mesh sling surgery. \nRefer women considering excision of mesh sling for persistent voiding dysfunction to a centre specialising in the diagnosis and management of mesh-related complications for assessment and management. \nFor women considering surgery to alleviate voiding symptoms caused by mesh surgery, explain that:\nthe risk of recurrent stress urinary incontinence is higher after mesh excision than mesh division\nfurther surgery might be needed. \n\n## Managing bowel symptoms\nFor women who present with functional bowel disorders after mesh surgery for pelvic organ prolapse, follow the recommendations in the NICE guideline on faecal incontinence in adults for women with faecal incontinence or locally agreed protocols for women with obstructed defecation. \nFor women with bowel complications that are directly related to mesh placement, such as erosion, stricture or fistula, discuss treatment with a regional MDT that has expertise in complex pelvic floor dysfunction and mesh-related problems. Use this discussion to formulate an individualised treatment plan with the woman. \nExplain to women with bowel complications directly related to mesh placement that:\ncomplete removal might not be possible\nbowel symptoms might persist or recur after mesh removal\nthey might need a temporary or permanent stoma after mesh removal. \nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on managing complications associated with mesh surgery .\nFull details of the evidence and the committee's discussion are in evidence review L: management of mesh complications.\nLoading. Please wait.\n\n# Terms used in this guideline\nThis section defines some of the terms that are used in this guideline. For other definitions, see the NICE glossary.\n\n## Anticholinergic medicine\nA type of medicine used to treat overactive bladder. It reduces the activity of the bladder muscle by blocking chemical messengers to the nerves that control muscle movements.\n\n## Augmentation cystoplasty\nA procedure to treat overactive bladder. The bladder is made larger by adding a piece of tissue from the intestines to the bladder wall.\n\n## Autologous rectus fascial sling\nA type of sling used to treat stress urinary incontinence. It is made out of tissue from the woman's abdomen. The sling supports the tube that carries urine out of the body (the urethra).\n\n## Botulinum toxin type A\nA treatment used for overactive bladder. It is injected into the wall of the bladder.\n\n## Colpocleisis\nAn operation to treat pelvic organ prolapse by closing the vagina.\n\n## Colposuspension\nA type of surgery used to treat stress urinary incontinence. The neck of the bladder is lifted up and stitched in this position.\n\n## Detrusor overactivity\nInvoluntary bladder contractions seen during a cystometry test. They can be the cause of overactive bladder symptoms.\n\n## Intramural bulking agents\nMaterials used to treat stress urinary incontinence. They are injected into the sides of the tube that carries urine out of the body (the urethra). This helps it remain closed so that urine is less likely to leak out.\n\n## Manchester repair\nAn operation used to treat uterine prolapse. The neck of the womb (the cervix) is shortened. It involves shortening the cervix (neck of the womb) and supporting the womb in its natural position.\n\n## Mesh procedure\nAn operation to insert plastic mesh to support tissues. Mesh procedures are used to treat stress urinary incontinence and pelvic organ prolapse in women.\n\n## Percutaneous sacral nerve stimulation\nA procedure used to treat overactive bladder. A device is implanted in the back to stimulate the nerves at the base of the spine. These nerves affect the bladder and surrounding muscles.\n\n## Percutaneous posterior tibial nerve stimulation\nA procedure used to treat overactive bladder. A mild electric current is passed through a fine needle to stimulate a nerve in the leg. This nerve controls bladder function.\n\n## Retropubic mid-urethral mesh sling\nA type of sling used to treat stress urinary incontinence. A strip of plastic is placed behind the tube that carries urine out of the body (the urethra) to support it in a sling.\n\n## Sacrocolpopexy\nA type of surgery used to treat vaginal vault prolapse. Plastic mesh is used to attach the vagina to a bone at the bottom of the spine.\n\n## Sacro-hysteropexy\nAn operation to treat uterine prolapse. Plastic mesh is used to attach the womb (the uterus) to a bone at the bottom of the spine.\n\n## Urinary diversion\nA type of surgery used to treat stress urinary incontinence. It causes urine to flow through an opening in the abdomen into an external bag, instead of into the bladder.\n\n## Vaginal sacrospinous fixation\nA type of surgery used to treat vaginal vault or uterine prolapse. The top of the vagina is stitched to a ligament in the pelvis. It is done through a cut on the inside of the vagina.\n\n## Vaginal sacrospinous hysteropexy\nAn operation used to treat uterine prolapse. The cervix is stitched to a ligament in the pelvis. It is done through a cut on the inside of the vagina.\n\n# Additional information\n\n## Recommendation 1.4.31\nThis could be any medicine with the lowest acquisition cost from any of the medicines reviewed in 2013. The evidence review considered the following medicines: darifenacin, fesoterodine, oxybutynin (immediate release), oxybutynin (extended release), oxybutynin (transdermal), oxybutynin (topical gel), propiverine, propiverine (extended release), solifenacin, tolterodine (immediate release), tolterodine (extended release), trospium and trospium (extended release). See chapter 6 of the 2013 full guideline.\n\n## Recommendations 1.4.44 to 1.4.50\nIn April 2019, only 1 preparation of botulinum toxin type A (BOTOX, Allergan) had a UK marketing authorisation for overactive bladder. The licensed dose was 100 units.\nOne preparation of botulinum toxin type A (BOTOX, Allergan) had a UK marketing authorisation for use at a dose of 200 units, for treating neurogenic detrusor overactivity with urinary incontinence due to subcervical spinal cord injury (traumatic or non-traumatic) or multiple sclerosis.\nNote that units of botulinum toxin type A are not interchangeable between preparations. If prescribing outside the marketing authorisation ('off label'), see NICE's information on prescribing medicines.# Recommendations for research\nThe guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Anticholinergic medicines\nWhat is the effectiveness and safety of anticholinergic medicines for overactive bladder in older women? \nFor a short explanation of why the committee made the recommendation for research, see the rationale on medicines for overactive bladder .\nFull details of the evidence and the committee's discussion are in evidence review C: the risks to cognitive function for women taking anticholinergic drugs for overactive bladder.\nLoading. Please wait.\n\n## Colpocleisis compared with sacrospinous fixation for pelvic organ prolapse\nWhat is the effectiveness of colpocleisis compared with sacrospinous fixation for pelvic organ prolapse in elderly women? \nFor a short explanation of why the committee made the recommendation for research, see the rationale on surgical management of pelvic organ prolapse .\nFull details of the evidence and the committee's discussion are in evidence review I: surgical management of pelvic organ prolapse.\nLoading. Please wait.\n\n## Assessing complications associated with mesh surgery\nWhat is the effectiveness of ultrasound-guided visualisation compared with clinical assessment to identify complications after mesh surgery for stress urinary incontinence or pelvic organ prolapse in women? \nFor a short explanation of why the committee made the recommendation for research, see the rationale on assessing complications associated with mesh surgery .\nFull details of the evidence and the committee's discussion are in evidence review K: assessing mesh complications after pelvic floor mesh surgery.\nLoading. Please wait.\n\n## Pessaries or surgery for pelvic organ prolapse\nWhat are the long-term outcomes, including patient satisfaction, from the use of pessaries compared with surgery for pelvic organ prolapse in women? \nFor a short explanation of why the committee made the recommendation for research, see the rationale on non-surgical management of pelvic organ prolapse .\nFull details of the evidence and the committee's discussion are in evidence review H: lifestyle and conservative management options for pelvic organ prolapse.\nLoading. Please wait.\n\n## Long-term risks of surgery with and without mesh\nWhat are the long-term risks of mesh surgery compared with non-mesh surgery for stress urinary incontinence and pelvic organ prolapse in women? \nFor a short explanation of why the committee made the recommendation for research, see the rationale on surgical management of stress urinary incontinence and surgical management of pelvic organ prolapse .\nFull details of the evidence and the committee's discussion are in:\nevidence review E: surgical and physical management of stress urinary incontinence\nevidence review I: surgical management of pelvic organ prolapse.\nLoading. Please wait.\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Long-term effectiveness of botulinum toxin type A for overactive bladder\nWhat is the long-term effectiveness of bladder wall injection with botulinum toxin type A for overactive bladder in women? \nFor a short explanation of why the committee made the recommendation for research, see the rationale on botulinum toxin type A injection .\nFull details of the evidence and the committee's discussion are in evidence review D: management of overactive bladder.\nLoading. Please wait.\n\n## Surgery for stress urinary incontinence and pelvic organ prolapse\nWhat is the most effective surgical management for women with both stress urinary incontinence and pelvic organ prolapse, including the sequence of interventions? \nFor a short explanation of why the committee made the recommendation for research, see the rationale on surgery for women with both stress urinary incontinence and pelvic organ prolapse .\nFull details of the evidence and the committee's discussion are in evidence review J: surgical management of pelvic organ prolapse and stress urinary incontinence.\nLoading. Please wait.\n\n## Pain management after mesh surgery\nWhat is the effectiveness of pain management for women who present with chronic pain 3 months after mesh surgery for stress urinary incontinence or pelvic organ prolapse? \nFor a short explanation of why the committee made the recommendation for research, see the rationale on managing complications associated with mesh surgery .\nFull details of the evidence and the committee's discussion are in evidence review L: management of mesh complications.\nLoading. Please wait.# Rationale and impact\nThese sections briefly explain why the committee made the 2019 recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Organisation of specialist services\nRecommendations 1.1.1 to 1.1.7\n\n## Why the committee made the 2019 recommendations\nThe committee agreed, based on their experience, that women with stress urinary incontinence, overactive bladder or primary prolapse would benefit from the broad range of expertise provided by a local multidisciplinary team (MDT). They agreed that a local MDT working within a regional clinical network could refer women to other services within the network for treatments that are not available locally, thus providing a broader choice of treatments.\nThe committee thought that women with complications related to mesh surgery, or with complex pelvic floor problems, should have access to a specialist MDT working at the regional level. The regional MDT could provide expert assessment and ensure that women are offered all available treatment options.\nThe committee acknowledged that membership of local and regional MDTs needs to be flexible and will vary in line with local and regional arrangements.\n\n## How the recommendations might affect practice\nThe recommendations on the different levels of MDTs, their composition, and how they should work together might affect how local and regional MDTs are commissioned and how services are currently organised.\nReturn to recommendations\n\n# Collecting data on surgery and surgical complications\nRecommendations 1.2.1 to 1.2.4\n\n## Why the committee made the 2019 recommendations\nThe committee were concerned about the lack of reliable evidence on adverse events after surgery for urinary incontinence and pelvic organ prolapse, especially those that occur 2 years or more after surgery. They were also aware of the widespread public concern about the use of synthetic mesh to treat these conditions in women. The wording of the recommendations reflects the committee's strong support for the collection of data in a national registry of surgery for urinary incontinence and pelvic organ prolapse in women.\nThe committee agreed that it would be helpful to provide a broad indication of the types of information that should be included in the registry, rather than specifying this in detail. The data in the registry will be analysed in the future to provide more reliable evidence than is available currently on the use of the various procedures in England and Wales and their long-term effects. This could be used to inform future guidance. The recommendations support the findings of the Mesh Oversight Group Report on reporting procedures in a national database.\nThe committee also agreed to highlight the importance of obtaining consent from women to include their data in the registry, and giving women a copy of their own data.\n\n## How the recommendations might affect practice\nThe recommendations are likely to have an impact on healthcare professionals and providers who are not already doing this because additional time and resource will be needed to report data to the registry and because of the cost of maintaining the registry and analysing the data.\nReturn to recommendations\n\n# Urodynamic testing\nRecommendations 1.3.15 and 1.3.16\n\n## Why the committee made the 2019 recommendations\nThe evidence did not show any benefit from urodynamic testing to assess stress urinary incontinence or stress-predominant mixed urinary incontinence in women who have demonstrable stress urinary incontinence before primary surgery. The committee concluded that urodynamic testing is not necessary for most women in this situation.\nHowever, based on their experience the committee agreed that urodynamic testing can be beneficial if the diagnosis is unclear or if the woman has symptoms of voiding dysfunction, anterior or apical prolapse, or a history of surgery for stress urinary incontinence.\n\n## How the recommendations might affect practice\nThe recommendations are likely to reduce variation in practice, which is largely caused by uncertainty about the clinical value of urodynamic testing before surgery. They are also expected to reduce the number of women having urodynamic testing before surgery, and avoid unnecessary use of a procedure that some women find unpleasant.\nReturn to recommendations\n\n# Pelvic floor muscle training\nRecommendation 1.4.4\n\n## Why the committee made the 2019 recommendation\nAlthough there was some good evidence showing that surgery is more effective than pelvic floor muscle training to manage stress urinary incontinence, the committee also took into account the risks associated with surgery and the absence of side effects from pelvic floor muscle training. They noted that the 2006 guideline committee had recommended pelvic floor muscle training, and had looked at evidence on both stress urinary incontinence and mixed urinary incontinence. The 2019 committee looked at evidence on stress urinary incontinence alone. The evidence showed that pelvic floor muscle training is just as effective as surgery for around half of women with stress urinary incontinence. The committee therefore decided to retain the 2006 recommendation for pelvic floor muscle training as a first-line treatment for stress urinary incontinence.\n\n## How the recommendation might affect practice\nThe 2019 recommendation is unchanged from 2006 and so should not lead to changes in clinical practice in most services. However, there might still be services in which pelvic floor muscle training is not routinely offered, so the recommendation might lead to a change in practice in those areas.\nReturn to recommendations\n\n# Absorbent containment products\nRecommendations 1.4.16 to 1.4.18\n\n## Why the committee made the 2019 recommendations\nThere was no evidence available on the use of absorbent containment products to manage urinary incontinence. In the committee's experience, these products are often used for long-term management, with no review of their ongoing suitability or discussion of other possible management options. The committee were particularly concerned about the effect that long-term use of these products can have on skin integrity if urine absorption is not adequate, noting that breakdown of vulval skin is uncomfortable and distressing. They agreed that a review of absorbent containment products should be done at least once a year to ensure that problems are identified more promptly and management can be tailored to women's changing clinical and lifestyle needs.\nThe committee noted that standard medical reviews often do not include absorbent containment product use, and therefore agreed that reviews of absorbent containment products should be conducted or overseen by a continence-trained healthcare professional. They thought this would ensure that reviews are consistent and thorough, and offer women a full range of management options, including referral to specialist services if needed.\n\n## How the recommendations might affect practice\nThe recommendations will result in an increase in reviews for women using absorbent containment products. This might reduce the overall use of these products and lead to more referrals for alternative treatment. Although short‑term costs might rise, long-term costs can be expected to fall through reduction in the use of absorbent containment products.\nReturn to recommendations\n\n# Medicines for overactive bladder\nRecommendations 1.4.25 to 1.4.27 and 1.4.30\n\n## Why the committee made the 2019 recommendations\nThe committee noted that there is very little evidence about how anticholinergic medicines prescribed for overactive bladder affect cognitive function in women. They were aware that some anticholinergic medicines have been associated with dementia and Alzheimer's disease. They also noted that large numbers of women are prescribed anticholinergic medicines, with some estimates suggesting that one‑third of women aged over 65 have some degree of incontinence. Because the long-term effects of anticholinergic medicines are uncertain, the committee stressed the importance of a full discussion with the woman, taking account of the woman's total anticholinergic load and carrying out regular reviews. They also decided to make a research recommendation on anticholinergic medicines to inform future guidance.\nThe effectiveness of anticholinergic and other medicines for overactive bladder was not reviewed in this guideline update.\n\n## How the recommendations might affect practice\nThe recommendations might raise awareness of the potential adverse effects of anticholinergic medicines, especially on cognitive function, and result in women being able to make better informed choices about managing their overactive bladder. The recommendations should also ensure that healthcare professionals regularly review women who remain on long-term medication.\nReturn to recommendations\n\n# Botulinum toxin type A injection\nRecommendations 1.4.44 to 1.4.51\n\n## Why the committee made the 2019 recommendations\nThe evidence on botulinum toxin type A injections for overactive bladder was limited, especially on the long-term effectiveness, dosage and frequency of injections, and the risks of adverse effects. The committee decided to make a research recommendation on the long-term effectiveness of botulinum toxin type A to inform future guidance.\nThe committee discussed starting doses and agreed that there was not enough evidence on the benefits and risks to recommend starting treatment with a higher dose than 100 units. The committee were aware from their own experience that there may be an increased risk of self-catheterisation with 200 units and that women usually wish to avoid this if possible. Although starting with the lower dose (100 units) may result in some women needing more injections, the committee agreed that there was not enough evidence to support starting at the higher dose.\nDespite the limited evidence, the committee agreed that increasing the dose to 200 units might be effective for women who have not had a satisfactory response to 100 units. The committee also agreed that an increase in dose to 200 units should be considered for women who had a response to 100 units that lasted less than 6 months. These recommendations were based on the committee's clinical experience.\nThe committee discussed follow‑up in clinical practice. They noted that the 2013 guideline recommended follow‑up at 6 months, or sooner if symptoms return. However, based on their experience, the committee agreed that 6 months might be too late for some women, and recommended a telephone call or a clinic appointment within 12 weeks of their first injection.\n\n## How the recommendations might affect practice\nThe recommendations are expected to reduce variation in practice by giving clear guidance on the initial dose of botulinum toxin A for treating women with idiopathic overactive bladder.\nChanges in practice are unlikely because services are already in place to support botulinum toxin type A treatment. There will be a cost saving by having a starting dose of 100 units. There may also be savings because the recommendations no longer specify that women need training in self-catheterisation before treatment.\nReturn to recommendations\n\n# Surgical management of stress urinary incontinence\nRecommendations 1.5.1 to 1.5.18\n\n## Why the committee made the 2019 recommendations\nThe evidence showed that there were no important differences in the short- and medium-term effectiveness of colposuspension, retropubic mid-urethral mesh slings and autologous rectus fascial slings, so the committee agreed that women should be offered a choice of these 3 procedures.\nHowever, they emphasised that there is substantial uncertainty about the long-term complications associated with each procedure, and agreed that women should be made aware of this when choosing a procedure. They also made a research recommendation on the long-term risks of surgery with and without mesh to help inform future guidance.\nThe committee acknowledged the public concern about the risks of these procedures, especially those involving the insertion of mesh products. However, they agreed that women should not be denied effective surgical options. Instead, women should be fully informed and supported by their doctor to make the right decision about their treatment, taking into account the benefits and risks of all the options as well as any individual social or psychological factors that might affect their decision. The committee agreed that a patient decision aid could help women better understand the different surgical options and promote shared decision making.\nThe committee also noted variation in the amount of information and level of detail given to women before surgery and agreed that key information should be included in the recommendations, with more detailed information provided in the patient decision aid. The committee noted the importance of giving women full information about the benefits and risks of these procedures.\nEvidence showed that open and laparoscopic colposuspension were equally effective procedures. Although there is a slightly increased risk of bladder injury with the laparoscopic approach, the committee thought this risk was not sufficient to exclude this option.\nThe committee recommended the retropubic, rather than the transobturator, route because the evidence showed that retropubic mesh slings are more likely to cure incontinence in the short term and less likely to cause complications in the medium and short term. In addition, the committee agreed that the retropubic mesh slings are easier to remove if complications do occur. However, there is evidence of a greater risk of bladder injury and need for temporary catheterisation with a retropubic procedure.\nThe committee agreed that porcine dermis slings should not be offered because they are less likely to result in a cure and more likely to lead to repeat surgery than a retropubic mesh sling.\nThe committee noted the lack of evidence on the long-term use of intramural bulking agents and uncertainty about the risks. However, in the committee's experience, some women, particularly those who are older or frail, find them beneficial. The committee agreed that intramural bulking agents should be considered if other surgery is unsuitable for, or unacceptable to, the woman. They emphasised that women who choose an intramural bulking agent should be fully advised of the risks, the lack of evidence for long-term effectiveness and adverse events, and that other surgical procedures may be more effective.\n\n## How the recommendations might affect practice\nMore thorough and detailed discussion with women before they have surgery for stress urinary incontinence is likely to moderately increase the time spent in consultations.\nSynthetic mesh slings, colposuspension, autologous rectus fascial slings and intramural bulking agents are offered in current practice. However, all surgical options are not available at every hospital and women may require referral to another centre (regional centre) if they choose to have a procedure that is not available locally. Regional centres may require extra resources to meet this need. There might also be an increase in the number of colposuspensions and autologous rectus fascial sling procedures carried out.\nReturn to recommendations\n\n# Assessing pelvic organ prolapse\nRecommendations 1.6.1 to 1.6.7\n\n## Why the committee made the 2019 recommendations\nThe evidence indicated that self-reported symptoms can accurately identify pelvic organ prolapse, although the committee noted that prolapse is often an incidental finding. They agreed, based on the evidence and their clinical experience, that accurate assessment of suspected pelvic organ prolapse depends on a thorough clinical history and examination.\nThe committee thought that secondary care clinicians who suspect or identify vaginal prolapse could consider referral to a clinician with expertise in prolapse.\nEvidence showed that the POP‑Q (Pelvic Organ Prolapse Quantification) system produces an accurate assessment of pelvic organ prolapse, and the committee agreed that it provides an objective and standardised measure that will ensure consistency of assessment.\nBased on their experience, the committee agreed that it is important to assess pelvic floor muscles and vaginal atrophy, and to rule out a pelvic mass or other pathology. They also agreed that a validated pelvic floor symptom questionnaire could aid assessment.\nThe committee noted evidence showing that imaging does not provide any additional benefit in the assessment of vaginal prolapse diagnosed by physical examination. They agreed that imaging would delay management, and should not be routinely carried out in this situation.\nBased on their experience, the committee agreed that symptoms of pelvic floor prolapse can become more prominent when the woman is straining or changes her position. They concluded that repeating the physical examination with the woman in a different position could be helpful if her symptoms are not explained by the physical examination. They also agreed, based on their experience, that other pelvic floor symptoms, including symptoms that remain unexplained after physical examination, should also be investigated.\n\n## How the recommendations might affect practice\nThe recommendations reflect current good practice, so the committee agreed there should be little change in practice.\nReturn to recommendations\n\n# Non-surgical management of pelvic organ prolapse\nRecommendations 1.7.1 to 1.7.9\n\n## Why the committee made the 2019 recommendations\nBased on their experience, the committee agreed that there should be an initial discussion of the management options with women who have pelvic organ prolapse, including no treatment, non-surgical treatment and all surgical options.\nThere was no evidence available on lifestyle modification to manage pelvic organ prolapse, so the committee used their knowledge and clinical experience to make this recommendation. They thought that advice on aspects of lifestyle that directly affect the pelvic organs is most useful for women with pelvic organ prolapse. The committee agreed that obesity, heavy lifting and constipation all exacerbate the symptoms of pelvic organ prolapse by increasing intra-abdominal pressure.\nThere was no evidence available on topical oestrogen to manage pelvic organ prolapse. In the committee's experience, women with urogenital atrophy have more pronounced symptoms of pelvic organ prolapse. Treatment with a vaginal oestrogen reduces the effect of the atrophy and improves symptoms. The committee noted that vaginal oestrogen is available in a pessary, a cream or an oestrogen-releasing ring.\nA small amount of evidence suggests that pelvic floor muscle training is beneficial for women with pelvic organ prolapse.\nLimited evidence suggests that pessaries are an important alternative to surgical intervention for women with all stages of prolapse including advanced prolapse. The committee agreed that pessaries are an easily available option for women and that many women prefer them as an alternative to surgery. However, there is little evidence so the committee made a research recommendation on pessaries or surgery for pelvic organ prolapse to inform future practice.\nThe committee discussed the complications that can develop with pessary use and agreed that women should be advised of these, and of the importance of the pessary being removed at regular intervals. Serious complications such as pessary incarceration necessitating removal under anaesthetic, or the development of fistulae, can occur if pessaries are not changed regularly. The committee noted that women who have difficulty managing long-term pessary care because of physical or cognitive impairments are at higher risk of these complications. They therefore recommended regular appointments for these women.\n\n## How the recommendations might affect practice\nThe recommendation generally reflects current practice, so the committee agreed there should be no major impact on practice.\nThe committee concluded that these recommendations can be expected to increase the use of vaginal oestrogen, especially in primary care, and decrease the number of referrals for specialist advice and use of other interventions.\nThe recommendation is current practice in some services but not all, and the committee suspects that the recommendation may result in the need for some increase in resources.\nThe recommendations are current practice in some services and the committee does not expect it to result in significant resource increases.\nReturn to recommendations\n\n# Surgical management of pelvic organ prolapse\nRecommendations 1.8.1 to 1.8.25\n\n## Why the committee made the 2019 recommendations\nThe evidence on surgery for pelvic organ prolapse was limited, making it difficult for the committee to draw definite conclusions about the benefits and risks of the different types of surgery. In particular, they noted a lack of long-term evidence on the effectiveness of different types of mesh surgery. In view of this, the committee agreed that it is important to give women information on all the treatment options, including no treatment, physiotherapy, pessaries and the range of surgical options, so that they can decide which is their preferred treatment.\nThe committee emphasised that there is substantial uncertainty about the long-term success and complications associated with each procedure, and agreed that women should be made aware of this when choosing a procedure. They also made a research recommendation on the long-term risks of surgery with and without mesh to help inform future guidance.\nThe committee acknowledged the public concern about the risks of procedures involving the insertion of mesh products. However, they agreed that women should not be denied effective surgical options. Instead, they should be fully informed and supported by their doctor to make the right decision about their treatment. They agreed that a patient decision aid could help women better understand the benefits and risks of the different treatment options and promote shared decision making.\nThe committee agreed informed choice is of great importance in making decisions about surgery, and that a woman should be provided with information on all her potential options for management. The committee were aware that multiple factors (for example, comorbidities and lifestyle) affect the choice of treatment, many of which were not captured by the evidence, and that these should be taken into account when discussing surgery with women.\nThe committee also noted variation in the amount of information and level of detail given to women before surgery and agreed that key information should be included in the recommendations, with more detailed information provided in the NICE patient decision aids. The committee noted the importance of providing full information about the benefits and risks of these procedures.\nThe committee noted that for some women, the full extent of prolapse in all compartments can only be evaluated during surgery. Therefore it is important to discuss with women the surgical plan if prolapse is found to be more severe than anticipated from clinic examination.\nThe committee agreed that surgical options, including surgery that will preserve the uterus, should be discussed with the woman.\nBased on their clinical experience, they agreed that women who wish to preserve their uterus should be offered a choice of 3 types of surgery. There was no evidence available that compared these 3 procedures.\nFor women who have no preference about preserving their uterus, the committee used their clinical experience to agree that women should be offered a choice of 4 surgical options. There was a very small amount of evidence showing that vaginal hysterectomy might be slightly better than sacrospinous hysteropexy, but there was not enough evidence to justify a preference for any of the 4 options.\nThe committee noted that the evidence showed no difference in cure and quality of life between sacrocolpopexy and sacrospinous fixation. Based on the evidence and their clinical experience, the committee agreed that women with vault prolapse should be offered a choice of 2 types of surgery. The committee noted that sacrocolpopexy can be performed either as open surgery or laparoscopically.\nBased on their clinical experience, the committee agreed that colpocleisis should be considered a potential surgical option for managing symptoms of vault or uterine prolapse in some groups of women. There was no evidence comparing colpocleisis with other management options. However, the committee thought that colpocleisis should be considered for women who have no other surgical options or for whom the other procedures would carry a higher risk of a serious complication. They made a research recommendation on colpocleisis compared with sacrospinous fixation for pelvic organ prolapse to help inform future guidance.\nThe evidence suggested that mesh surgery has higher cure rates, fewer repeat surgeries for pelvic organ prolapse, and lower recurrence rates compared with anterior colporrhaphy. However, the committee were aware of the potential complications associated with mesh exposure and erosion, and that these may increase over time. This is particularly relevant for younger women having surgery, but there was no evidence specifically for these women. Based on the evidence of risks associated with mesh surgery, the committee agreed that anterior repair without mesh should be offered.\nThey agreed that mesh surgery could be considered, but only for recurrent prolapse in a very limited number of women for whom there is no alternative treatment. The committee noted that evidence supports the effectiveness of mesh placement for anterior prolapse. They discussed the balance between the risks associated with mesh surgery and the potential harms of no treatment, which include persistent prolapse, problems with bladder emptying, ulceration of vaginal skin, recurrent urinary tract infections, pain and discomfort, sexual dysfunction, and problems with working and social life. The committee agreed that some women with recurrent prolapse after a non-mesh repair might be prepared to accept the risks associated with mesh surgery, and that these women should have the option to make an informed choice.\nThere was no evidence showing that mesh surgery is better than non-mesh surgery for posterior prolapse, and mesh surgery is associated with an increased risk of complications. The committee therefore agreed that vaginal repair without mesh should be offered to women with posterior prolapse.\nBased on their experience, the committee agreed that a review 6 months after any type of surgery for prolapse will help to establish the effectiveness and rate of short-term complications. In view of the concern regarding long-term complications, the committee considered that it was important that women should be referred for specialist advice if they experience recurrent symptoms or complications after 6 months.\n\n## How the recommendations might affect practice\nMore thorough and detailed discussion with women before they have surgery for pelvic organ prolapse is likely to moderately increase time spent in consultations. Sacro-hysteropexy with mesh is not available at all centres so this might increase referrals between centres. However, because fewer women are choosing mesh surgery, the increase in this type of referral is likely to be negligible. Similarly, there could be a small increase in referrals for laparoscopic sacrocolpopexy and colpocleisis, but this is not expected to have a significant impact on practice.\nReturn to recommendations\n\n# Surgery for women with both stress urinary incontinence and pelvic organ prolapse\nRecommendations 1.9.1 and 1.9.2\n\n## Why the committee made the 2019 recommendations\nThe evidence did not show any clear benefits for concurrent surgery for stress urinary incontinence and pelvic organ prolapse, but the committee agreed that it should be considered in women with anterior and/or apical prolapse and stress urinary incontinence. They agreed that women should be told about the uncertainty of the benefits and risks of concurrent surgery compared with sequential surgery, to ensure that they are equipped to make an informed decision. The committee made a research recommendation on the most effective surgical management for women with both stress urinary incontinence and pelvic organ prolapse.\n\n## How the recommendations might affect practice\nThe committee expect these recommendations to reduce variations in care and improve the information women are given when choosing between sequential and concurrent surgery for stress urinary incontinence and pelvic organ prolapse.\nReturn to recommendations\n\n# Assessing complications associated with mesh surgery\nRecommendations 1.10.1 to 1.10.6\n\n## Why the committee made the 2019 recommendations\nThe committee noted, based on their experience, that there can be delays in the diagnosis of mesh-related complications. They therefore highlighted the importance of considering mesh as a possible cause of pain, vaginal problems, or urinary or bowel problems in women who have had mesh inserted.\nThe committee were unable to make generalised recommendations on assessing possible mesh-related complications because of the wide variety of procedures and implanted materials used, and the many different complications that might result from these. They therefore agreed that women with suspected mesh-related complications should be referred to a specialist centre unless they have an uncomplicated, small mesh exposure that can be treated with topical oestrogen.\nThere was little evidence available on the use of specific investigations to assess suspected mesh-related complications, so the committee decided to outline a range of possible investigations. They also made a research recommendation on assessing complications associated with mesh surgery to inform future guidance.\n\n## How the recommendations might affect practice\nThe recommendations reflect current good practice and the committee did not expect them to result in changes in practice.\nReturn to recommendations\n\n# Managing complications associated with mesh surgery\nRecommendations 1.11.1 to 1.11.18\n\n## Why the committee made the 2019 recommendations\nThe available evidence was very limited and so the committee made recommendations based on their experience. They noted that women often have multiple complications from mesh surgery and that these complications can be long lasting. They also noted that the success of mesh removal varies widely depending on the specific mesh-related complication. In addition, some women who have complete mesh removal will have further complications and recurrence of stress urinary incontinence, pelvic organ prolapse, or both. The committee therefore agreed that healthcare professionals should have a full discussion with women who are considering having partial or complete mesh removal. They also agreed that mesh should be removed only after a review by the regional MDT.\nBased on their experience, the committee agreed that topical oestrogen is only likely to be effective for small exposures of mesh and should be discussed with the woman as an option that could be tried before surgery is considered. They noted that some women who present with mesh exposure or extrusion with vaginal discharge may have a mesh infection, and imaging should be considered to assist in the diagnosis.\nThe committee acknowledged the impact that mesh perforation in the lower urinary tract has on women's quality of life, and agreed that women with this complication should be referred for further assessment. Similarly, women who have pain or painful sexual intercourse should be offered specialist assessment. The committee reiterated the need to tell women about the possible benefits and risks of mesh removal surgery. The committee also noted the lack of evidence in this area and made a recommendation for research on pain management after mesh surgery.\n\n## How the recommendations might affect practice\nThe committee thought that these recommendations will reduce delays in treatment for mesh-related complications, although they might increase the number of referrals.\nReturn to recommendations# Context\nUrinary incontinence is a common symptom that can affect women of all ages, with a wide range of severity and nature. Although it is rarely life-threatening, urinary incontinence can be very detrimental to the physical, psychological and social wellbeing of the women it affects. The impact on families and carers can also be profound, and the resource implications for the health service are considerable. Urinary incontinence is defined by the International Continence Society as 'the complaint of any involuntary leakage of urine'.\nUrinary incontinence can be a result of functional abnormalities in the lower urinary tract or of illnesses. Stress urinary incontinence is involuntary urine leakage on effort, exertion, sneezing or coughing. Urgency urinary incontinence is involuntary urine leakage accompanied or immediately preceded by urgency (a sudden compelling desire to urinate that is difficult to delay). Mixed urinary incontinence is involuntary urine leakage associated with both urgency and exertion, effort, sneezing or coughing. Overactive bladder (OAB) is defined as urgency that occurs with or without urgency urinary incontinence and usually with frequency and nocturia. OAB that occurs with incontinence is known as 'OAB wet'. OAB that occurs without incontinence is known as 'OAB dry'. These combinations of symptoms are suggestive of the urodynamic finding of detrusor overactivity, but can be the result of other forms of urethrovesical dysfunction.\nPelvic organ prolapse is defined as symptomatic descent of 1 or more of: the anterior vaginal wall, the posterior vaginal wall, the cervix or uterus, or the apex of the vagina (vault or cuff). Symptoms include a vaginal bulge or sensation of something coming down, urinary, bowel and sexual symptoms, and pelvic and back pain. These symptoms affect women's quality of life.\nThe prevalence of pelvic organ prolapse is high; in primary care in the UK, 8.4% of women reported vaginal bulge or lump, and on examination prolapse is present in up to 50% of women. One in 10 women will need at least 1 surgical procedure, and the rate of re‑operation is as high as 19%. There is likely to be an increasing need for surgery for urinary incontinence and pelvic organ prolapse because of the ageing population.\nThe NHS England Mesh Working Group report published in December 2015 raised a number of concerns about the safety and efficacy of surgery for stress urinary incontinence and pelvic organ prolapse using mesh devices. The report made the following recommendations for NICE:\nto produce a clinical guideline that describes, holistically, care for women with pelvic organ prolapse\nto review the 2013 NICE guideline on urinary incontinence in women (CG171)\nto review evidence on complications arising from surgery for stress urinary incontinence and pelvic organ prolapse.\nNICE accepted these recommendations and has reviewed the evidence on complications arising from surgery for stress urinary incontinence and managing pelvic organ prolapse and updated this guideline.# Finding more information and resources\nTo find NICE guidance on related topics, including guidance in development, see the NICE topic pages on gynaecological conditions and urological conditions.\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting our guidelines into practice, see resources to help you put NICE guidance into practice."}}}],"truncated":false,"partial":false},"paginationData":{"pageIndex":0,"numItemsPerPage":100,"numTotalItems":241,"offset":0,"length":100}},"jwt":"eyJhbGciOiJFZERTQSJ9.eyJyZWFkIjp0cnVlLCJwZXJtaXNzaW9ucyI6eyJyZXBvLmNvbnRlbnQucmVhZCI6dHJ1ZX0sImlhdCI6MTc3NzQxNDM0MSwic3ViIjoiL2RhdGFzZXRzL2Nob25raWUtYWkvcnlva3VjaGEiLCJleHAiOjE3Nzc0MTc5NDEsImlzcyI6Imh0dHBzOi8vaHVnZ2luZ2ZhY2UuY28ifQ.GBCgC7eriU6B7y0PUJ-Bc_l-CHMV_2ehRSMWcNSkIhYNcZbjo9707jd8BcuvaSqDd0O39COCwaa6dZqp7AIzBw","displayUrls":true,"splitSizeSummaries":[{"config":"corpus","split":"train","numRows":241,"numBytesParquet":13465549},{"config":"questions","split":"train","numRows":1351,"numBytesParquet":225130}]},"discussionsStats":{"closed":0,"open":0,"total":0},"fullWidth":true,"hasGatedAccess":true,"hasFullAccess":true,"isEmbedded":false,"savedQueries":{"community":[],"user":[]}}">
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f1a4a2ea235620f166f9e333bb46d628f80f7e30 | cdc | This report updates the 2000 recommendations by the Advisory Committee on Immunization Practices (ACIP) on the use of influenza vaccine and antiviral agents (MMWR 2000;49:1-38). The 2001 recommendations include new or updated information regarding a) the cost-effectiveness of influenza vaccination; b) the influenza vac... |
2387dc1c8f7bb149a9d50339fcbee1428efbb3b2 | cdc | However, the benefits are well worth the effort. Compared to maintaining the current rate of decline, eliminating tuberculosis by 2035 would result in 253,000 fewer tuberculosis cases 15,200 fewer tuberculosis-related deaths $1.3 billion less in treatment costs in 2006 dollars 7 Each case of tuberculosis represen... |
e90d041308d141d1d24badb45089f30000f755a9 | who | Web annex: Development of updated guidance for the third edition (www.who.int/reproductivehealth/ publications/family_planning/SPR-3/en/) The World Health Organization (WHO) would like to thank the members of the Guideline Development Group (GDG) and the Evidence Secretariat for their contributions throughout the devel... |
e606c38c9f95cda69ae98ca25a40fa7a41f3ce24 | cdc | CDC, our planners, and our content experts wish to disclose that they have no financial interests or other relationships with the manufacturers of commerical products, suppliers of commercial services, or commercial supporters. This report will not include any discussion of the unlabeled use of a product or a product u... |
56948141c8ac6666cc22065f580c8df761b48284 | nice | Advocacy services for adults with health and social care needs
This guideline covers advocacy for people using health and social care services in all adult settings (including young people under 18 using adult services). It describes how to commission and deliver effective advocacy, as well as identifying who should b... |
9b1a630de8fc139787b80fd16bd248c425dc7e57 | nice | Suspected neurological conditions: recognition and referral
This guideline covers the initial assessment of symptoms and signs that might indicate a neurological condition. It helps non-specialist healthcare professionals to identify people who should be offered referral for specialist investigation.
# Recommendation... |
2ffee6aeb1c637f860b32371a6dd48b0361c5477 | who | Introduction Introduction 12
The reorganized chapter is: Chapter 5: Screening and treatment of cervical pre-cancer. Chapter 5 now consolidates information from what were two chapters: screening for cervical precancer and treatment for cervical pre-cancer. This consolidation was done because screening without treatment ... |
206253872ec53313c6e65cc859fb525d115fe2c1 | cdc | M ention o f the name o f any company or product does not constitute endorsement by the N ational Institute for Occupational Safety and Health. This document is in the public domain and may b e freely copied or reprinted. C opies o f this and other NIOSH docum ents are available from Publications D issem ination, DSDTT... |
5ac83530381bb8273a3aa36b573cd6fe553b29a7 | cdc | This report compiles and summarizes all recommendations from CDC's Advisory Committee on Immunization Practices (ACIP) regarding prevention and control of tetanus, diphtheria, and pertussis in the United States. As a comprehensive summary of previously published recommendations, this report does not contain any new rec... |
2ec6411fd8434d453399e8f52f9d1cbf5cb17788 | cdc | Health Resources and Services Administration (HRSA), are pleased to announce the publication of Recommendations for Case Management Collaboration and Coordination in Federally Funded HIV/AIDS Programs. These new recommendations were developed jointly by CDC and HRSA with the assistance of the Federal Interagency HIV/AI... |
24f7b3ef063e71fcf24f61d85b0392fa597aafb5 | cdc | depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction
Epidemics of influenza typically occur during the winter months in temperate regions and have been... |
ceb53016631748ec4177fea37488fd5455b9a68f | cdc | depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction
In the United States, epidemics of influenza typically occur during the winter months and have bee... |
c7f6a8b5cc2ba151699a4e0fee4fd32a0be889d8 | who | Lead exposure is confirmed by measurement of a venous blood lead concentration (see section 5). An elevated blood lead concentration may be due to a single acute exposure or to continuing exposure. Termination of lead exposure is an overarching principle of this guideline, as, without this action, lead will continue to... |
09ff2a5a76f3c2c26cd8a3a7498d1771bd193cdb | nice | Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor
Evidence-based recommendations on adalimumab (Humira), etanercept (Enbrel), infliximab (Remicade), rituximab (MabThera) and abatacept (Orencia). These drugs are for adults with sev... |
3424d85ae3115438cd0ffe331bdc670a09c1d91e | who | # INTRODUCTION Background
Malaria continues to cause unacceptably high levels of disease and death, as documented in successive editions of the World malaria report. According to the latest report, there were an estimated 247 million cases and 619 000 deaths globally in 2021. Malaria is preventable and treatable, and t... |
7dab888ce97cfa52a2b07164f462a7d9bd7f1420 | cdc | # List of Tables, Figures, and Boxes
# Summary
Preexposure Prophylaxis for HIV Prevention in the United States -2017 Update: A Clinical Practice Guideline provides comprehensive information for the use of daily oral antiretroviral preexposure prophylaxis (PrEP) to reduce the risk of acquiring HIV infection in adults. ... |
becda314f626192776ec1603430f38926c13ee47 | nice | Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management
This guideline covers diagnosing and managing myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS) in children, young people and adults. It aims to improve awareness and understanding about ME/CF... |
eb819145d75ee7033720a18b9905026b2844010f | nice | Prasugrel with percutaneous coronary intervention for treating acute coronary syndromes
Evidence-based recommendations on prasugrel (Efient) with percutaneous coronary intervention for treating acute coronary syndromes in adults.
# Guidance
This guidance replaces NICE technology appraisal guidance 182 issued in Octob... |
6ea68cb11741fa0ccfe3f0300ed679c050b1ea68 | nice | Rifaximin for preventing episodes of overt hepatic encephalopathy
Evidence-based recommendations on rifaximin (Targaxan) for preventing episodes of hepatic encephalopathy in adults.
# Guidance
Rifaximin is recommended, within its marketing authorisation, as an option for reducing the recurrence of episodes of overt h... |
a8543fa68e6702299a58a7a5bc1d8648b7283783 | who | The World Health Organization (WHO) would like to thank the many individuals who contributed to these guidelines, 1 especially Hanan Balkhy, Peter Collignon, John Conly, Cindy Friedman, Aidan Hollis, Samuel Kariuki, Hyo-Sun Kwak, Scott McEwen, Gérard Moulin, Antoinette Ngandjio, Bernard Rollin, Flavia Rossi, and David ... |
25629bb57077b675ba61b02f3677d2ee20e15fcf | cdc | This report updates the 2008 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccine for the prevention and control of seasonal influenza (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices . MMWR 2008... |
2357f725d301b847df0733ea2d0a91ed10d322ee | nice | Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy
Evidence-based recommendations on infliximab (Remicade, Inflectra or Remsima), adalimumab (Humira) and golimumab (Simponi) for treating moderate to severe ulcerative colitis in a... |
7811eddbaf1b9f70f81570b43f85b57674105245 | who | # INTRODUCTION Introduction
Action on the guidance in these guidelines requires a strategy appropriate to the local context. Planning, decision-making and monitoring are parts of an ongoing process. Once a plan is developed and implemented, it must be monitored and evaluated. The resulting findings then inform revision... |
d62da547ebe9b64a685b0dfe48bda04aeca61a9b | who | The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers... |
36e444de4e5c7efa526f7c847f4196d2ce6e4516 | cdc | This version annotates information that has changed from the 2011 version of the VSP Construction Guidelines using a yellow highlight and a vertical rule.Seal SEAMS greater than 0.8 millimeters (1/32 inch), but less than 3 millimeters (1/8 inch), with an appropriate SEALANT or appropriate profile strips.#
VSP would lik... |
654d7e20573aba7015704c709ced7dde86b3460a | nice | Alcohol-use disorders: prevention
This guideline covers alcohol problems among people over 10. It aims to prevent and identify such problems as early as possible using a mix of policy and practice.
# Introduction
The Department of Health asked NICE to produce public health guidance on the prevention and early identif... |
da06ffd685c40151bd4abd3a54b2b40cd452ff02 | cdc | Concerned by reports that the precast concrete products industry (SIC 3272) has an injury incidence rate which is consistently at least twice that of the national average, the National Institute for Occupational Safety and Health (NIOSH) began developing this document with the intent of providing recommendations aimed ... |
928a795091e668132593eedbc167c3bfca7b463f | nice | Oral health: local authorities and partners
This guideline covers improving oral health by developing and implementing a strategy that meets the needs of people in the local community. It aims to promote and protect people’s oral health by improving their diet and oral hygiene, and by encouraging them to visit the den... |
cc5ad33d3b2873dd0bc37fc84235387bdc89dadb | cdc | The views expressed and conclusions reached in this document, together with the recommendations for a standard, are those of NIOSH, after review of the evidence and consideration of the comments of reviewers. These views and conclusions are not necessarily those of the consultants, other federal agencies, and professio... |
67bb54a24ecaef2340b2541520a823c4684e3622 | cdc | As the nation's prevention agency, CDC strives to accomplish its vision of "Healthy People in a Healthy World...Through Prevention." For women, this involves working to better understand the health issues that have an adverse impact on women, disproportionately affect women, occur only in women, or have an impact on in... |
9bae8fda2975a32b200162434422954d517122a0 | nice | Chronic kidney disease: assessment and management
This guideline covers care and treatment for people with, or at risk of, chronic kidney disease (CKD). It aims to prevent or delay the progression, and reduce the risk of complications and cardiovascular disease. It also covers managing anaemia and hyperphosphataemia a... |
57ba64cc0b4eec0efef84e52bdc032445c03a8f2 | cdc | NIOSH recommends the procedures set forth in the following sections as a means of protecting the health, and significantly reducing accidental injury and death associated with entering, working in, and exiting from confined spaces. The standard is designed not only to make the confined space safe for the worker, but al... |
fb9b204d46065588de0b6ef2c89846cea8aa4fad | cdc | This document will not include any discussion of the unlabeled use of a product or a product under investigational use, with the exception that some of the recommendations in this document might be inconsistent with package labeling.# Introduction
Approximately 45% of all pregnancies that occur in the United States are... |
9d747a8573ef58c9dca620c2bd609be549abb0f4 | who | Antiretroviral (ARV) drug: the medicine used to treat HIV infection. Antiretroviral therapy (ART): the use of a combination of three or more ARV drugs for treating HIV infection. ART involves lifelong treatment. ARV drugs for HIV prevention: ARV drugs for the prevention of HIV transmission and includes ARV drugs given ... |
5ca670a394bc20386d4dbcfadf76287f0362e759 | cdc | health and safety concerns associated with its use. It is the responsibility of the user of this document to establish appropriate health and safety practices and determine the applicability of regulatory limitations prior to each use.#
Indoor / Outdoor Environment 111 5.6.1
Lighting 111 5.6.2 A Indoor Aquatic Facility... |
7419f776406ce1fca8ddeb54f33dad174d54cc7a | cdc | These guidelines update previous CDC recommendations for the diagnosis, treatment, and prevention of tuberculosis (TB) among adults and children coinfected with human immunodeficiency virus (HIV) in the United States. The most notable changes in these guidelines reflect both the findings of clinical trials that evaluat... |
4207fa4c52bc7fe54b9a3b191f5935ba653d08c5 | cdc | † National Nosocomial Infection Surveillance definition: a nonhuman-derived implantable foreign body (e.g., prosthetic heart valve, nonhuman vascular graft, mechanical heart, or hip prosthesis) that is permanently placed in a patient during surgery. ‡ If the area around a stab wound becomes infected, it is not an SSI. ... |
d1541cb9e33fcd7eb8055aad4a56b8a68bc20efc | who | # INTRODUCTION Objectives
This guideline provides global, evidence-informed recommendations on preventive chemotherapy, as a public health intervention in areas endemic for soil-transmitted helminths, to decrease the worm burden of soil-transmitted helminth infections in children, adolescent girls, women of reproductiv... |
9bd8bdb8f4d24329683e484f9f1b94c61342b294 | nice | Abatacept, adalimumab, etanercept and tocilizumab for treating juvenile idiopathic arthritis
Evidence-based recommendations on abatacept (Orencia), adalimumab (Humira), etanercept (Enbrel) and tocilizumab (RoActemra) for treating juvenile idiopathic arthritis in children, young people and adults.
# Guidance
This guid... |
29ec5ccca4b411224edd33b7621f491735c6d1bf | cdc | It is anticipated that FDA will review and may approve cabotegravir injections for PrEP within 2-3 months after the publication of this guideline. We will then post a revised version of this guideline that replaces references to pending FDA approval with statements indicating that approval has been given.All material i... |
fa4463070a66ca04f3afe2e08a46f4204f49d836 | cdc | Brown MJ, McLaine P, Dixon S, Simon P. A randomized community-based trial of home visiting to reduce blood lead levels in children. Pediatrics. In press 2005. Moel DI, Sachs HK, Drayton MA. Slow and natural reduction in blood lead level after chelation therapy for lead poisoning in childhood.# Table of Contents Preface... |
55e4da313e87cdd076e76602a856ee75d73dcc02 | nice | Diabetes (type 1 and type 2) in children and young people: diagnosis and management
This guideline covers the diagnosis and management of type 1 and type 2 diabetes in children and young people aged under 18. The guideline recommends how to support children and young people and their families and carers to maintain ti... |
dd5eebb1be3e3330d7c353a1cfa69a889055a0e7 | nice | Bortezomib for induction therapy in multiple myeloma before high-dose chemotherapy and autologous stem cell transplantation
Evidence-based recommendations on bortezomib (Velcade) for treating multiple myeloma before chemotherapy and stem cell transplant in adults.
# Guidance
Bortezomib is recommended as an option wit... |
d4d7cfb6c3c3af8aedab5ecca8b484290da0c9ac | nice | Abortion care
This guideline covers care for women of any age (including girls and young women under 18) who request an abortion. It aims to improve the organisation of services and make them easier for women to access. Detailed recommendations on conducting abortions at different gestational stages are also included,... |
9a777264e66db5bab94932f17234550509bdf664 | nice | Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for treating recurrent ovarian cancer
Evidence-based recommendations on topotecan, pegylated liposomal doxorubicin hydrochloride (Caelyx; PLDH), paclitaxel, trabectedin (Yondelis) and gemcitabine. These drugs are for peop... |
0089c9767b80e023257a34feccd23fe8de3e030c | cdc | These recommendations are an expansion of previous recommendations for the prevention of hepatitis C virus (HCV) infection that focused on screening and followup of blood, plasma, organ, tissue, and semen donors (CDC. Public Health Service inter-agency guidelines for screening donors of blood, plasma, organs, tissues, ... |
20d83c400b031feead37471826c783d7065b7abb | nice | Self-harm: assessment, management and preventing recurrence
This guideline covers assessment, management and preventing recurrence for children, young people and adults who have self-harmed. It includes those with a mental health problem, neurodevelopmental disorder or learning disability and applies to all sectors th... |
8dd026219544d2f0421312a55788a8545b6d76c7 | nice | Sapropterin for treating hyperphenylalaninaemia in phenylketonuria
Evidence-based recommendations on sapropterin for treating hyperphenylalaninaemia in phenylketonuria.
# Recommendations
Sapropterin is recommended as an option for treating hyperphenylalaninaemia that responds to sapropterin (response as defined in th... |
b8703a640a18ad9f824ebc75b85bda4d6dc3196e | nice | Antenatal care
This guideline covers the routine antenatal care that women and their babies should receive. It aims to ensure that pregnant women are offered regular check‑ups, information and support. We have also published a guideline on postnatal care, which covers the topics of emotional attachment and baby feedin... |
b24211a1e1e994c7cc1677c1d0763645d1c4bc52 | cdc | Front cover photos: Top row, left to right: colorimetric biotinidase assay; thin layer chromatography analysis for mucopolysaccharidoses, a group of lysosomal disorders; laboratorian using tandem mass spectrometry. Second row, left to right: sleeping newborn; acylcarnitine profile indicating elevated C8, a biochemical ... |
0717b3d55365abffb2e93c5faaa342a98a1cf93b | cdc | These recommendations update the February 4, 2002, guidelines developed by the Public Health Service for the use of zidovudine (ZDV) to reduce the risk for perinatal human immunodeficiency virus type 1 (HIV-1) transmission. This report provides healthcare providers with information for discussion with HIV-1-infected pr... |
3eb537a0fc6c347a99aa71d96ede214efae38b70 | cdc | Vol. 47 / No. RR-4 MMWR iThese guidelines were developed by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children convened by the National Pediatric# INTRODUCTION
In 1993, the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, composed of speci... |
2c9464d282046ba0c25ab57109068aa88f660253 | cdc | ACIP is chartered as a federal advisory committee to provide expert external advice and guidance to the Director of the Centers for Disease Control and Prevention (CDC) on use of vaccines and related agents for the control of vaccine-preventable diseases in the civilian population of the United States. Recommendations ... |
252b74fbf04db676b7680669a972c34e2b37a9d2 | who | Acute symptomatic seizure: seizures that occur in close temporal relation to a brain insult such as trauma, infection or metabolic or structural abnormalities Coma: unconscious state as defined on the AVPU scale: Alert (A), responds to your Voice (V), responds to Pain (P), Unresponsive (U) Convulsion: see "Seizure" Cri... |
f586a4930ffcd2d7f70cb92c800b5962d327faee | cdc | Routine annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications. For the 2016-17 influenza season, inactivated influenza vaccines (IIVs) will be available in both trivalent (IIV3) and quadrivalent (IIV4) formulations. Recombinant influenza vaccine (RIV) will be avail... |
b89c379ce202e95912b85a0f60211cfeefe170ab | who | WHO guidelines for the treatment of visceral leishmaniasis in HIV co-infected patients in East Africa and South-East Asia #
The leishmaniases are a group of diseases caused by Leishmania spp. transmitted by the bites of female phlebotomine sandflies. The clinical manifestations include cutaneous leishmaniasis, mucocut... |
51e6137c9f9b5d17359d3b7fdaf9e6fbad99580b | nice | Social work with adults experiencing complex needs
This guideline covers the planning, delivery and review of social work interventions for adults who have complex needs. It promotes ways for social work professionals, other care staff and people with complex needs to work together to make decisions about care and sup... |
1be8b645ef1a848509fb10e4d2f445706019e46c | cdc | Tickborne rickettsial diseases (TBRD) continue to cause severe illness and death in otherwise healthy adults and children, despite the availability of low cost, effective antimicrobial therapy. The greatest challenge to clinicians is the difficult diagnostic dilemma posed by these infections early in their clinical cou... |
39baa8b6e9feea2021ca376619c2de33e0e7129b | cdc | Seal all openings where piping and other items penetrate through the deck.#
VSP would like to acknowledge the following organizations and companies for their cooperative efforts in the revisions of the VSP 2011 Construction Guidelines. The cover art was designed by Carrie Green.
# Background and Purpose
The Centers fo... |
359372cac27db7a1bb1c4741811a6bc9fb1f23ad | cdc | # II. Recommendations for prevention of infections in health care
. Summary of suggested work restrictions for health care personnel exposed to or infected with infectious diseases of importance in health care settings, in the absence of state and local regulations 299 Table 4. Recommendation for postexposure prophylax... |
6abc3d7ff2ef9b8b500161e876a3c5f9bf0c3f38 | nice | Social and emotional wellbeing: early years
This guideline covers supporting the social and emotional wellbeing of vulnerable children under 5 through home visiting, childcare and early education. It aims to optimise care for young children who need extra support because they have or are at risk of social or emotional... |
3d232ef3940e160e3ed6b9d509901457106bfc42 | nice | Type 2 diabetes prevention: population and community-level interventions
This guideline covers preventing type 2 diabetes in adult populations and communities who are at high risk. It aims to promote a healthy diet and physical activity at community and population level, and recommends how to tailor services for peopl... |
0e10cb29f06067e66ff5bfe93a94ad90e190cf37 | cdc | data are insufficient to recommend use of the FDA-approved single-use rapid HIV-1/HIV-2 antigen/antibody combination immunoassay as the initial assay in the algorithm.# Laboratory Testing for the Diagnosis of HIV Infection: Updated Recommendations
# A. Executive Summary
This document updates recommendations for HIV te... |
8c7aebd6d064f2b8dd4487b7182a2d1f24ab2a79 | nice | Enzalutamide for metastatic hormone‑relapsed prostate cancer previously treated with a docetaxel‑containing regimen
Evidence-based recommendations on enzalutamide (Xtandi) for treating metastatic hormone-relapsed prostate cancer in adults who have had treatment with docetaxel-containing chemotherapy.
# Guidance
Enzal... |
4143d23cad078ded4ceff392e174606a0c851ca8 | nice | Intrapartum care for healthy women and babies
This guideline covers the care of healthy women and their babies, during labour and immediately after the birth. It focuses on women who give birth between 37 and 42 weeks of pregnancy (‘term’). The guideline helps women to make an informed choice about where to have their... |
54529de143cdd9a528e6f0c7360ccc7dbbd2b871 | cdc | Morbidity and Mortality Weekly Report depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction
Epidemics of influenza typically occur during the winter mon... |
c22b456e5f6d0ce078dfa666e8011f230630c14f | who | The Global Tuberculosis Programme also thanks the Guideline Review Committee and its WHO secretariat for their review and approval of the guidelines.
Screening test, examination or procedure for tuberculosis disease: A test, examination, or other procedure used to distinguish people with a high likelihood of having TB ... |
8fec99add089cdd8b3d4e84b8efe45ec519f9ae4 | nice | Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed
Evidence-based recommendations on adalimumab (Humira), etanercept (Enbrel), infliximab (Remicade, Remsima, Inflectra), c... |
4e4e518dd0f130a6df6e2f0176cf8f35e12ff2e3 | cdc | Acute hepatitis B Newly acquired symptomatic hepatitis B virus (HBV) infection. Acute hepatitis C Newly acquired symptomatic hepatitis C virus (HCV) infection. ALT Alanine aminotransferase, previously called SGPT. Anti-HBc Antibody to hepatitis B core antigen. Anti-HBe Antibody to hepatitis B e antigen. Anti-HBs Antibo... |
6f5bacb5f640dd689037c405a41a925d9cc3b144 | cdc | Today, B. anthracis is considered one of the most serious biowarfare or bioterrorism agents because of the ability of the spores to persist in the environment, the ability of the aerosolized spores to readily cause infection via respiratory (inhalation) exposure, and the high mortality of resulting inhalation anthrax (... |
6d65b2f97d0616b72be99122e18b953f865f7c7b | nice | Suspected cancer: recognition and referral
This guideline covers identifying children, young people and adults with symptoms that could be caused by cancer. It outlines appropriate investigations in primary care, and selection of people to refer for a specialist opinion. It aims to help people understand what to expec... |
ac7803c45c6482a1bc631f7f762e6c086965b664 | cdc | An estimated one third of the world's population is infected with Mycobacterium tuberculosis, and nearly 9 million persons develop disease caused by M. tuberculosis each year. Although tuberculosis (TB) occurs predominantly in resource-limited countries, it also occurs in the United States. During 1985-1992, the Unite... |
25c2b022642f2e4ccdfee9afb88aefece0604c89 | cdc | Ceftriaxone 1 g, IM or IV, every 24 hours or Ceftizoxime 1 g, IV, every 8 hours or Cefotaxime 1 g, IV, every 8 hours. Patients who are allergic to (3-lactam drugs should be treated with spectinomycin 2 g IM every 12 hours. "Erythromycin stearate 500 mg or erythromycin ethylsuccinate 800 mg or equivalent may be substitu... |
0b698e0e189e28d0bd9597fafb6eb34f799adea1 | cdc | Disclosure of Relationship CDC, our planners, and our content experts wish to disclose they have no financial interest or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. Planners have reviewed content to ensure there is no bias. This documen... |
43d6613bdc6b0b195aeb380da81f6d211ba47543 | cdc | The recommendations outline how to provide quality family planning services, which include contraceptive services, pregnancy testing and counseling, helping clients achieve pregnancy, basic infertility services, preconception health services, and sexually transmitted disease services. The primary audience for this repo... |
9a3971baff0365943f4a68822259e6f709ee349d | nice | Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease
Evidence-based recommendations on donepezil (Aricept), galantamine (Reminyl), rivastigmine (Exelon) and memantine (Ebixa) for treating Alzheimer's disease in adults.
# Guidance
This guidance has been partially updated by the N... |
2d209d694c5f2920d20f848237d8b91a9a88af97 | cdc | CDC, our planners, and our content experts disclose that they have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. Presentations will not include any discussion of the unlabeled use of a product or a product under i... |
05349a5df55abfe48d1bd7fd6d939fea88440196 | nice | Supporting adult carers
This guideline covers support for adults (aged 18 and over) who provide unpaid care for anyone aged 16 or over with health or social care needs. It aims to improve the lives of carers by helping health and social care practitioners identify people who are caring for someone and give them the ri... |
efd0ed5ee5abf83d32b6615ec10c90fe464507bd | who | # Introduction 1.Breastfeeding matters
Breastfeeding is the biological norm for all mammals, including humans. Breastfeeding is critical for achieving global goals on nutrition, health and survival, economic growth and environmental sustainability. WHO and the United Nations Children's Fund (UNICEF) recommend that brea... |
81f6294dd11f8bbd56d14f123071c3cfcf2c45ae | who | WHO recommendation on uterine balloon tamponade for the treatment of postpartum haemorrhage# Introduction vii
Postpartum haemorrhage (PPH) is commonly defined as a blood loss of at least 500 mL within 24 hours after birth and affects about 5% of all women giving birth around the world. Globally, nearly one quarter of a... |
dd7041541f9c0070451b79f6ed2d027a11c9a8fd | nice | Pelvic floor dysfunction: prevention and non-surgical management
This guideline covers the prevention, assessment and non-surgical management of pelvic floor dysfunction in women aged 12 and over. It aims to raise awareness and help women to reduce their risk of pelvic floor dysfunction. For women who have pelvic floo... |
72bfb9678d27e5037245b5402c73ce90ee315f1f | cdc | will be glad to provide the latest information on any changes made to the text, plans for new editions, and reprints and translations already available.# Chikungunya Virus
There is no specific treatment for CHIKV infection, nor any commercially available vaccine to prevent it. Pending the development of a new vaccine, ... |
30bfde21e4cbd38f27cc786eb8e3c3f8711156aa | nice | Vortioxetine for treating major depressive episodes
Evidence-based recommendations on vortioxetine (Brintellix) for treating major depressive episodes in adults.
# Guidance
Vortioxetine is recommended as an option for treating major depressive episodes in adults whose condition has responded inadequately to 2 antidep... |
6e724c0b3c9be4d66e7ed99cac367b20eb8bace6 | who | - 1 Background 1
- 2 Scope and purpose 3 1.3 Objectives 5
- 4 Target audience 5
# How this guideline was developed 6
- 1 Contributors to guideline development 6
- 2 Guideline development process 7
- 3 Management of conflicts of interest 11
# Summary of evidence
Evidence on the nature, extent and impact of food market... |
ac465c8454d457f8dd8ca38e2fe172d64ba29494 | nice | Physical activity: walking and cycling
This guideline covers encouraging people to increase the amount they walk or cycle for travel or recreation purposes.
# What is this guidance about?
This guidance aims to set out how people can be encouraged to increase the amount they walk or cycle for travel or recreation purp... |
85a80f631bb21eb38c62adf0ca5d1519f413085d | nice | Tuberculosis
This guideline covers preventing, identifying and managing latent and active tuberculosis (TB) in children, young people and adults. It aims to improve ways of finding people who have TB in the community and recommends that everyone under 65 with latent TB should be treated. It describes how TB services s... |
65a0ea6ad84ab7b2c5b58c63d2a46a1f98af1d80 | cdc | On May 14, 1796, Edward Jenner, an English physician, inoculated James Phipps, age 8, with material from a cowpox lesion on the hand of a milkmaid. Jenner subsequently demonstrated that the child was protected against smallpox. This procedure became known as vaccination, which resulted in the global eradication of smal... |
1003f78bb49085934bf4795be1683424e01a6e82 | who | HIV refers to the human immunodeficiency virus. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of HIV infections globally.The following definitions for adults, adolescents, children and infants are used to ensure consistency within these guidelines. Other agencies may use differ... |
4c242a21b896c6a43a4b3ea7829b80f33a8ae2f3 | cdc | Through the Act, Congress charged NIOSH with recommending occupational safety and health standards and describing exposure levels that are safe for various periods of employment, including but not limited to the exposures at which no worker will suffer diminished health, functional capacity, or life expectancy because ... |
214aec5355b6d9cda5a9e03f854dbb3b04e40600 | nice | Ranibizumab for treating visual impairment caused by macular oedema secondary to retinal vein occlusion
# Guidance
Ranibizumab is recommended as an option for treating visual impairment caused by macular oedema:
following central retinal vein occlusion or
following branch retinal vein occlusion only if treatment with... |
7bfbf3d1b5d4b21cfbf987ae9d33dd91e6e4826b | who | Fortification of industrially processed flour, when appropriately designed and implemented, is an efficient, simple and inexpensive strategy for supplying vitamins and minerals to the diets of large segments of the population. Wheat is cultivated and consumed in many parts of the world and its domestication contributed... |
2f85d6ec392675d75b60506cc999bf8e19e39343 | nice | Pixantrone monotherapy for treating multiply relapsed or refractory aggressive non-Hodgkin's B‑cell lymphoma
Evidence-based recommendations on pixantrone (Pixuvri) for treating relapsed or refractory aggressive non-Hodgkin's B-cell lymphoma in adults.
# Guidance
Pixantrone monotherapy is recommended as an option for ... |
2a8ce388e7d1c0bf619852c859fd1f7a3d18bce2 | nice | Mannitol dry powder for inhalation for treating cystic fibrosis
# Guidance
Mannitol dry powder for inhalation is recommended as an option for treating cystic fibrosis in adults:
who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase and
whose lung function is rapidly declining (... |
ec1de4cfafd8784038ec92328c7180ec7d49fe86 | nice | Sofosbuvir for treating chronic hepatitis C
# Guidance
Sofosbuvir is recommended as an option for treating chronic hepatitis C in adults, as specified in table 1.
# Table 1 Sofosbuvir for treating adults with chronic hepatitis C
Sofosbuvir in combination with peginterferon alfa and ribavirin
Sofosbuvir in combination... |
5c8f362ae74d53be86095ea31ca56c71d7d429a1 | cdc | This report is a revision o f the General Recomm endations on Im m unization a?id updates the 2 0 0 6 statement by the Advisory Committee on Im m unization Practices (ACIP) (CDC. General recommendations on im m unization: recommendations o f the Advisory Committee on Im m unization Practices , M M W R 2006;55, M M W R ... |
6f54b2765652e9c1ce06057c1089f86ea5ec3a8e | cdc | The Occupational Safety and Health Act of 1970 (Public Law 91-596) states that the purpose of Congress expressed in the Act is "to assure so far as possible every working man and woman in the Nation safe and healthful working conditions and to preserve our human resources...by," among other things, "providing for rese... |
956e47509e52886649a7f807db121067a1d8cd75 | nice | Integrated health and social care for people experiencing homelessness
This guideline covers providing integrated health and social care services for people experiencing homelessness. It aims to improve access to and engagement with health and social care, and ensure care is coordinated across different services.
# C... |
5393c6d6c50e5551d8774a44490402fd149d8ab6 | nice | Babies, children and young people's experience of healthcare
This guideline describes good patient experience for babies, children and young people, and makes recommendations on how it can be delivered. It aims to make sure that all babies, children and young people using NHS services have the best possible experience... |
9cb75b1f551a384f6e1fcdc552a322b78e4c2de5 | nice | Brain tumours (primary) and brain metastases in over 16s
This guideline covers diagnosing, monitoring and managing any type of primary brain tumour or brain metastases in people aged 16 or over. It aims to improve diagnosis and care, including standardising the care people have, how information and support are provide... |
882a321cadbd78d1547a9154f19ea1c3a8cbd229 | nice | Urinary incontinence and pelvic organ prolapse in women: management
This guideline covers assessing and managing urinary incontinence and pelvic organ prolapse in women aged 18 and over. It also covers complications associated with mesh surgery for these conditions.
# Recommendations
People have the right to be invol... |
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