Similarly to drugs, manufacturers of medical devices in the United States are required to conduct clinical trials for  premarket approval . [ 14 ]  Device trials may compare a new device to an established therapy, or may compare similar devices to each other. An example of the former in the field of  vascular surgery  is the Open versus Endovascular Repair (OVER trial) for the treatment of  abdominal aortic aneurysm , which compared the older  open aortic repair  technique to the newer  endovascular aneurysm repair  device. [ 15 ]  An example of the latter are clinical trials on mechanical devices used in the management of adult female  urinary incontinence . [ 16 ]


Similarly to drugs, medical or surgical procedures may be subjected to clinical trials, [ 17 ]  such as comparing different surgical approaches in treatment of  fibroids  for  subfertility . [ 18 ]  However, when clinical trials are unethical or logistically impossible in the surgical setting,  case-controlled studies  will be replaced. [ 19 ]


Besides being participants in a clinical trial, members of the public can be actively collaborate with researchers in designing and conducting  clinical research . This is known as  patient and public involvement  (PPI). Public involvement involves a working partnership between patients, caregivers, people with lived experience, and researchers to shape and influence what is researcher and how. [ 20 ]  PPI can improve the quality of research and make it more relevant and accessible. People with current or past experience of illness can provide a different perspective than professionals and compliment their knowledge. Through their personal knowledge they can identify research topics that are relevant and important to those living with an illness or using a service. They can also help to make the research more grounded in the needs of the specific communities they are part of. Public contributors can also ensure that the research is presented in  plain language  that is clear to the wider society and the specific groups it is most relevant for. [ 21 ]


Although early medical experimentation was performed often, the use of a  control group  to provide an accurate comparison for the demonstration of the intervention's efficacy was generally lacking. For instance,  Lady Mary Wortley Montagu , who campaigned for the introduction of  inoculation  (then called variolation) to prevent  smallpox , arranged for seven prisoners who had been sentenced to death to undergo variolation in exchange for their life. Although they survived and did not contract smallpox, there was no control group to assess whether this result was due to the inoculation or some other factor. Similar experiments performed by  Edward Jenner  over his  smallpox vaccine  were equally conceptually flawed. [ 22 ]


The first proper clinical trial was conducted by the Scottish physician  James Lind . [ 23 ]  The disease  scurvy , now known to be caused by a  Vitamin C  deficiency, would often have terrible effects on the welfare of the crew of long-distance ocean voyages. In 1740, the catastrophic result of  Anson 's  circumnavigation  attracted much attention in Europe; out of 1900 men, 1400 had died, most of them allegedly from having contracted scurvy. [ 24 ]   John Woodall , an English military surgeon of the  British East India Company , had recommended the consumption of  citrus fruit  from the 17th century, but their use did not become widespread. [ 25 ]


Lind conducted the first systematic  clinical trial  in 1747. [ 26 ]  He included a dietary supplement of an acidic quality in the experiment after two months at sea, when the ship was already afflicted with scurvy. He divided twelve scorbutic sailors into six groups of two. They all received the same diet but, in addition, group one was given a quart of  cider  daily, group two twenty-five drops of elixir of  vitriol  ( sulfuric acid ), group three six spoonfuls of  vinegar , group four half a pint of seawater, group five received two  oranges  and one  lemon , and the last group a spicy paste plus a drink of  barley water . The treatment of group five stopped after six days when they ran out of fruit, but by then one sailor was fit for duty while the other had almost recovered. Apart from that, only group one also showed some effect of its treatment. [ 27 ]  Each year, May 20 is celebrated as Clinical Trials Day in honor of Lind's research. [ 28 ]


After 1750 the discipline began to take its modern shape. [ 29 ] [ 30 ]  The English doctor  John Haygarth  demonstrated the importance of a control group for the correct identification of the  placebo effect  in his celebrated study of the ineffective remedy called  Perkin's tractors . Further work in that direction was carried out by the eminent physician  Sir William Gull, 1st Baronet  in the 1860s. [ 22 ]


Frederick Akbar Mahomed  (d. 1884), who worked at  Guy's Hospital  in  London , made substantial contributions to the process of clinical trials, where "he separated chronic  nephritis  with  secondary hypertension  from what we now term  essential hypertension . He also founded the Collective Investigation Record for the  British Medical Association ; this organization collected data from physicians practicing outside the hospital setting and was the precursor of modern collaborative clinical trials." [ 31 ]


Ideas of Sir  Ronald A. Fisher  still play a role in clinical trials. While working for the  Rothamsted experimental station  in the field of agriculture, Fisher developed his  Principles of experimental design  in the 1920s as an accurate methodology for the proper design of experiments. Among his major ideas include the importance of  randomization —the random assignment of individuals to different groups for the experiment; [ 32 ]   replication —to reduce  uncertainty , measurements should be repeated and experiments replicated to identify sources of variation; [ 33 ]   blocking —to arrange experimental units into groups of units that are similar to each other, and thus reducing irrelevant sources of variation; use of  factorial experiments —efficient at evaluating the effects and possible  interactions  of several independent factors. [ 22 ]  Of these, blocking and factorial design are seldom applied in clinical trials, because the experimental units are human subjects and there is typically only one independent intervention: the treatment. [ citation needed ]


The  British Medical Research Council  officially recognized the importance of clinical trials from the 1930s. The council established the  Therapeutic Trials Committee  to advise and assist in the arrangement of properly controlled clinical trials on new products that seem likely on experimental grounds to have value in the treatment of disease. [ 22 ]


The first randomised curative trial was carried out at the MRC Tuberculosis Research Unit by Sir Geoffrey Marshall (1887–1982). The trial, carried out between 1946 and 1947, aimed to test the efficacy of the chemical  streptomycin  for curing  pulmonary tuberculosis . The trial was both  double-blind  and  placebo-controlled . [ 34 ]


The methodology of clinical trials was further developed by Sir  Austin Bradford Hill , who had been involved in the streptomycin trials. From the 1920s, Hill applied  statistics  to medicine, attending the lectures of renowned mathematician  Karl Pearson , among others. He became famous for a landmark study carried out in collaboration with  Richard Doll  on the correlation between  smoking  and  lung cancer . They carried out a  case-control study  in 1950, which compared lung cancer patients with matched control and also began a sustained  long-term prospective study  into the broader issue of smoking and health, which involved  studying the smoking habits and health of more than 30,000 doctors  over a period of several years. His certificate for election to the  Royal Society  called him "...   the leader in the development in medicine of the precise experimental methods now used nationally and internationally in the evaluation of new therapeutic and  prophylactic agents ."


International clinical trials day is celebrated on 20 May. [ 35 ]


The acronyms used in the  titling of clinical trials  are often contrived, and have been the subject of derision. [ 36 ]


Clinical trials are classified by the research objective created by the investigators. [ 12 ]


Trials are classified by their purpose. After approval for human research is granted to the trial sponsor, the U.S.  Food and Drug Administration  (FDA) organizes and monitors the results of trials according to type: [ 12 ]


Clinical trials are conducted typically in four phases, with each phase using different numbers of subjects and having a different purpose to construct focus on identifying a specific effect. [ 12 ]


Clinical trials involving new drugs are commonly classified into five phases. Each phase of the drug approval process is treated as a separate clinical trial. The  drug development  process will normally proceed through phases I–IV over many years, frequently involving a  decade  or longer. If the drug successfully passes through phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. [ 12 ]  Phase IV trials are performed after the newly approved drug, diagnostic or device is marketed, providing assessment about risks, benefits, or best uses. [ 12 ]


A fundamental distinction in  evidence-based practice  is between  observational studies  and  randomized controlled trials . [ 45 ]  Types of observational studies in  epidemiology , such as the  cohort study  and the  case-control study , provide less compelling evidence than the randomized controlled trial. [ 45 ]  In observational studies, the investigators retrospectively assess associations between the treatments given to participants and their health status, with potential for considerable errors in design and interpretation. [ 46 ]


A randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health. [ 45 ]


Some Phase II and most Phase III drug trials are designed as randomized,  double-blind , and  placebo -controlled. [ citation needed ]


Clinical studies having small numbers of subjects may be "sponsored" by single researchers or a small group of researchers, and are designed to test simple questions or feasibility to expand the research for a more comprehensive randomized controlled trial. [ 47 ]


Clinical studies can be "sponsored"  (financed and organized) by academic institutions, pharmaceutical companies, government entities and even private groups. Trials are conducted for new drugs, biotechnology, diagnostic assays or medical devices to determine their safety and efficacy  prior to being submitted for regulatory review that would determine market approval. [ citation needed ]


In cases where giving a placebo to a person suffering from a disease may be unethical, "active comparator" (also known as "active control") trials may be conducted instead. [ 48 ]  In trials with an active control group, subjects are given either the experimental treatment or a previously approved treatment with known effectiveness. In other cases, sponsors may conduct an active comparator trial to establish an efficacy claim relative to the active comparator instead of the placebo in  labeling . [ citation needed ]


A master protocol includes multiple substudies, which may have different objectives and involve coordinated efforts to evaluate one or more medical products in one or more diseases or conditions within the overall study structure. Trials that could develop a master protocol include the umbrella trial (multiple medical products for a single disease),  platform trial  (multiple products for a single disease entering and leaving the platform), and basket trial (one medical product for multiple diseases or disease subtypes). [ 49 ]


Genetic testing  enables researchers to group patients according to their genetic profile, deliver drugs based on that profile to that group and compare the results. Multiple companies can participate, each bringing a different drug. The first such approach targets  squamous cell cancer , which includes varying genetic disruptions from patient to patient. Amgen, AstraZeneca and Pfizer are involved, the first time they have worked together in a late-stage trial. Patients whose genomic profiles do not match any of the trial drugs receive a drug designed to stimulate the immune system to attack cancer. [ 50 ]


A  clinical trial protocol  is a document used to define and manage the trial. It is prepared by a panel of experts. All study investigators are expected to strictly observe the protocol. [ citation needed ]


The protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations and organization of the planned trial. Details of the trial are provided in documents referenced in the protocol, such as an  investigator's brochure . [ citation needed ]


The protocol contains a precise study plan to assure safety and health of the trial subjects and to provide an exact template for trial conduct by investigators. This allows data to be combined across all investigators/sites. The protocol also informs the study administrators (often a  contract research organization ). [ citation needed ]


The format and content of clinical trial protocols sponsored by pharmaceutical, biotechnology or medical device companies in the United States, European Union, or Japan have been standardized to follow Good Clinical Practice guidance [ 51 ]  issued by the  International Conference on Harmonisation  (ICH). [ 52 ]  Regulatory authorities in  Canada ,  China ,  South Korea , and  the UK  also follow ICH guidelines. Journals such as  Trials , encourage investigators to publish their protocols.


Clinical trials recruit study subjects to sign a document representing their " informed consent ". [ 53 ]  The document includes details such as its purpose, duration, required procedures, risks, potential benefits, key contacts and institutional requirements. [ 54 ]  The participant then decides whether to sign the document. The document is not a contract, as the participant can withdraw at any time without penalty. [ citation needed ]


Informed consent is a legal process in which a recruit is instructed about key facts before deciding whether to participate. [ 53 ]  Researchers explain the details of the study in terms the subject can understand. The information is presented in the subject's native language. Generally, children cannot autonomously provide informed consent, but depending on their age and other factors, may be required to provide informed assent. [ citation needed ]


In any clinical trial, the number of subjects, also called the sample size, has a large impact on the ability to reliably detect and measure the effects of the intervention. This ability is described as its " power ", which must be calculated before initiating a study to figure out if the study is worth its costs. [ 55 ]  In general, a larger sample size increases the statistical power, also the cost.


The statistical power estimates the ability of a trial to detect a difference of a particular size (or larger) between the treatment and control groups. For example, a trial of a  lipid -lowering drug versus placebo with 100 patients in each group might have a power of 0.90 to detect a difference between placebo and trial groups receiving dosage of 10 mg/dL or more, but only 0.70 to detect a difference of 6 mg/dL. [ citation needed ]


Merely giving a treatment can have nonspecific effects. These are controlled for by the inclusion of patients who receive only a placebo. Subjects are assigned  randomly  without informing them to which group they belonged. Many trials are doubled-blinded so that researchers do not know to which group a subject is assigned.


Assigning a subject to a placebo group can pose an ethical problem if it violates his or her right to receive the best available treatment. The  Declaration of Helsinki  provides guidelines on this issue.


Clinical trials are only a small part of the research that goes into developing a new treatment. Potential drugs, for example, first have to be discovered, purified, characterized, and tested in labs (in cell and animal studies) before ever undergoing clinical trials. In all, about 1,000 potential drugs are tested before just one reaches the point of being tested in a clinical trial. [ 56 ]  For example, a new cancer drug has, on average, six years of research behind it before it even makes it to clinical trials. But the major holdup in making new cancer drugs available is the time it takes to complete clinical trials themselves. On average, about eight years pass from the time a cancer drug enters clinical trials until it receives approval from regulatory agencies for sale to the public. [ 57 ]  Drugs for other diseases have similar timelines.


Some reasons a clinical trial might last several years:


A clinical trial might also include an extended post-study follow-up period from months to years for people who have participated in the trial, a so-called "extension phase", which aims to identify long-term impact of the treatment. [ 58 ]


The biggest barrier to completing studies is the shortage of people who take part. All drug and many device trials target a subset of the population, meaning not everyone can participate. Some drug trials require patients to have unusual combinations of disease characteristics. It is a challenge to find the appropriate patients and obtain their consent, especially when they may receive no direct benefit (because they are not paid, the study drug is not yet proven to work, or the patient may receive a placebo). In the case of cancer patients, fewer than 5% of adults with cancer will participate in drug trials. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), about 400 cancer medicines were being tested in clinical trials in 2005. Not all of these will prove to be useful, but those that are may be delayed in getting approved because the number of participants is so low. [ 59 ]


For clinical trials involving potential for seasonal influences (such as  airborne allergies ,  seasonal affective disorder ,  influenza , and  skin diseases ), the study may be done during a limited part of the year (such as spring for pollen allergies), when the drug can be tested. [ 60 ] [ 61 ]


Clinical trials that do not involve a new drug usually have a much shorter duration. (Exceptions are epidemiological studies, such as the  Nurses' Health Study ).


Clinical trials designed by a local investigator, and (in the US) federally funded clinical trials, are almost always administered by the researcher who designed the study and applied for the grant. Small-scale device studies may be administered by the sponsoring company. Clinical trials of new drugs are usually administered by a  contract research organization  (CRO) hired by the sponsoring company. The sponsor provides the drug and medical oversight. A CRO is contracted to perform all the administrative work on a clinical trial. For Phases   II–IV the CRO recruits participating researchers, trains them, provides them with supplies, coordinates study administration and  data collection , sets up meetings, monitors the sites for compliance with the clinical protocol, and ensures the sponsor receives data from every site. Specialist  site management organizations  can also be hired to coordinate with the CRO to ensure rapid IRB/IEC approval and faster site initiation and patient recruitment. Phase   I clinical trials of new medicines are often conducted in a specialist clinical trial clinic, with dedicated pharmacologists, where the subjects can be observed by full-time staff. These clinics are often run by a CRO which specialises in these studies.


At a participating site, one or more research assistants (often nurses) do most of the work in conducting the clinical trial. The research assistant's job can include some or all of the following: providing the local  institutional review board  (IRB) with the documentation necessary to obtain its permission to conduct the study, assisting with study start-up, identifying eligible patients, obtaining consent from them or their families, administering study treatment(s), collecting and statistically analyzing data, maintaining and updating data files during followup, and communicating with the IRB, as well as the sponsor and CRO.


In the context of a clinical trial, quality typically refers to the absence of errors which can impact decision making, both during the conduct of the trial and in use of the trial results. [ 62 ]


An Interactional Justice Model may be used to test the effects of willingness to talk with a doctor about clinical trial enrollment. [ 63 ]  Results found that potential clinical trial candidates were less likely to enroll in clinical trials if the patient is more willing to talk with their doctor. The reasoning behind this discovery may be patients are happy with their current care. Another reason for the negative relationship between perceived fairness and clinical trial enrollment is the lack of independence from the care provider. Results found that there is a positive relationship between a lack of willingness to talk with their doctor and clinical trial enrollment. Lack of willingness to talk about clinical trials with current care providers may be due to patients' independence from the doctor. Patients who are less likely to talk about clinical trials are more willing to use other sources of information to gain a better insight of alternative treatments. Clinical trial enrollment should be motivated to utilize websites and television advertising to inform the public about clinical trial enrollment.


The last decade has seen a proliferation of  information technology  use in the planning and conduct of clinical trials.  Clinical trial management systems  are often used by research sponsors or CROs to help plan and manage the operational aspects of a clinical trial, particularly with respect to investigational sites. Advanced analytics for identifying researchers and research sites with expertise in a given area utilize public and private information about ongoing research. [ 64 ]  Web-based  electronic data capture  (EDC) and  clinical data management systems  are used in a majority of clinical trials [ 65 ]  to collect case report data from sites, manage its quality and prepare it for analysis.  Interactive voice response  systems are used by sites to register the enrollment of patients using a phone and to allocate patients to a particular treatment arm (although phones are being increasingly replaced with web-based (IWRS) tools which are sometimes part of the EDC system). While  patient-reported outcome  were often paper based in the past, measurements are increasingly being collected using web portals or hand-held  ePRO  (or eDiary) devices, sometimes wireless. [ 66 ]   Statistical software  is used to analyze the collected data and prepare them for regulatory submission. Access to many of these applications are increasingly aggregated in web-based  clinical trial portals . In 2011, the FDA approved a Phase   I trial that used telemonitoring, also known as remote patient monitoring, to collect biometric data in patients' homes and transmit it electronically to the trial database. This technology provides many more data points and is far more convenient for patients, because they have fewer visits to trial sites. As noted below, decentralized clinical trials are those that do not require patients' physical presence at a site, and instead rely largely on digital health data collection, digital informed consent processes, and so on.


A clinical trial produces data that could reveal quantitative differences between two or more interventions;  statistical analyses  are used to determine whether such differences are true, result from chance, or are the same as no treatment (placebo). [ 67 ] [ 68 ]  Data from a clinical trial accumulate gradually over the trial duration, extending from months to years. [ 53 ]  Accordingly, results for participants recruited early in the study become available for analysis while subjects are still being assigned to treatment groups in the trial. Early analysis may allow the emerging evidence to assist decisions about whether to stop the study, or to reassign participants to the more successful segment of the trial. [ 67 ]  Investigators may also want to stop a trial when data analysis shows no treatment effect. [ 68 ]


Clinical trials are closely supervised by appropriate regulatory authorities. All studies involving a medical or therapeutic intervention on patients must be approved by a supervising ethics committee before permission is granted to run the trial. The local ethics committee has discretion on how it will supervise noninterventional studies (observational studies or those using already collected data). In the US, this body is called the  Institutional Review Board  (IRB); in the EU, they are called  Ethics committees . Most IRBs are located at the local investigator's hospital or institution, but some sponsors allow the use of a central (independent/for profit) IRB for investigators who work at smaller institutions.


To be ethical, researchers must obtain the full and  informed consent  of participating human subjects. (One of the IRB's main functions is to ensure potential patients are adequately informed about the clinical trial.) If the patient is unable to consent for him/herself, researchers can seek consent from the patient's legally authorized representative. In addition, the clinical trial participants must be made aware that they can withdraw from the clinical trial at any time without any adverse action taken against them. [ 69 ]  In  California , the state has prioritized the individuals who can serve as the legally authorized representative. [ 70 ]


In some US locations, the local IRB must certify researchers and their staff before they can conduct clinical trials. They must understand the federal patient privacy ( HIPAA ) law and good clinical practice. The International Conference of Harmonisation Guidelines for Good Clinical Practice is a set of standards used internationally for the conduct of clinical trials. The guidelines aim to ensure the "rights, safety and well being of trial subjects are protected".


The notion of informed consent of participating human subjects exists in many countries but its precise definition may still vary.


Informed consent is clearly a 'necessary' condition for ethical conduct but does not 'ensure' ethical conduct. In  compassionate use  trials the latter becomes a particularly difficult problem. The final objective is to serve the community of patients or future patients in a best-possible and most responsible way. See also  Expanded access . However, it may be hard to turn this objective into a well-defined, quantified, objective function. In some cases this can be done, however, for instance, for questions of when to stop sequential treatments (see  Odds algorithm ), and then quantified methods may play an important role.


Additional ethical concerns are present when conducting  clinical trials on children  ( pediatrics ), and in emergency or epidemic situations. [ 71 ] [ 72 ]


Ethically balancing the rights of multiple stakeholders may be difficult. For example, when drug trials fail, the sponsors may have a duty to tell current and potential investors immediately, which means both the research staff and the enrolled participants may first hear about the end of a trial through public  business news . [ 73 ]


In response to specific cases in which unfavorable data from pharmaceutical company-sponsored research were not published, the  Pharmaceutical Research and Manufacturers of America  published new guidelines urging companies to report all findings and limit the financial involvement in drug companies by researchers. [ 74 ]  The  US Congress  signed into law a bill which requires Phase   II and Phase   III clinical trials to be registered by the sponsor on the  clinicaltrials.gov  website compiled by the  National Institutes of Health . [ 75 ]


Drug researchers not directly employed by pharmaceutical companies often seek grants from manufacturers, and manufacturers often look to academic researchers to conduct studies within networks of universities and their hospitals, e.g., for  translational  cancer research. Similarly, competition for tenured academic positions, government grants and prestige create conflicts of interest among academic scientists. [ 76 ]  According to one study, approximately 75% of articles retracted for misconduct-related reasons have no declared industry financial support. [ 77 ]   Seeding trials  are particularly controversial. [ 78 ]


In the United States, all clinical trials submitted to the FDA as part of a drug approval process are independently assessed by clinical experts within the Food and Drug Administration, [ 79 ]  including inspections of primary data collection at selected clinical trial sites. [ 80 ]


In 2001, the editors of 12 major journals issued a joint editorial, published in each journal, on the control over clinical trials exerted by sponsors, particularly targeting the use of contracts which allow sponsors to review the studies prior to publication and withhold publication. They strengthened editorial restrictions to counter the effect. The editorial noted that  contract research organizations  had, by 2000, received 60% of the grants from  pharmaceutical companies  in the US. Researchers may be restricted from contributing to the trial design, accessing the raw data, and interpreting the results. [ 81 ]


Despite explicit recommendations  by stakeholders of measures to improve the standards of industry-sponsored medical research, [ 82 ]    in 2013,  Tohen  warned of the persistence of a gap in the credibility of conclusions arising from industry-funded clinical trials, and called for ensuring strict adherence to ethical standards in industrial collaborations with academia, in order to avoid further erosion of the public's trust. [ 83 ]  Issues referred for attention in this respect include potential observation bias, duration of the observation time for maintenance studies, the selection of the patient populations, factors that affect placebo response, and funding sources. [ 84 ] [ 85 ] [ 86 ]


Conducting clinical trials of vaccines during epidemics and pandemics is subject to ethical concerns. For diseases with high mortality rates like Ebola, assigning individuals to a placebo or control group can be viewed as a death sentence. In response to ethical concerns regarding clinical research during epidemics, the  National Academy of Medicine  authored a report identifying seven ethical and scientific considerations. These considerations are: [ 87 ]


Pregnant women and children are typically excluded from clinical trials as vulnerable populations, though the data to support excluding them is not robust. By excluding them from clinical trials, information about the safety and effectiveness of therapies for these populations is often lacking. During the early history of the  HIV/AIDS  epidemic, a scientist noted that by excluding these groups from potentially life-saving treatment, they were being "protected to death". Projects such as  Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) have advocated for the ethical inclusion of pregnant women in vaccine trials. Inclusion of children in clinical trials has additional moral considerations, as children lack decision-making autonomy. Trials in the past had been criticized for using hospitalized children or orphans; these ethical concerns effectively stopped future research. In efforts to maintain effective pediatric care, several European countries and the US have policies to entice or compel pharmaceutical companies to conduct pediatric trials. International guidance recommends ethical pediatric trials by limiting harm, considering varied risks, and taking into account the complexities of pediatric care. [ 87 ]


Responsibility for the safety of the subjects in a clinical trial is shared between the sponsor, the local site investigators (if different from the sponsor), the various IRBs that supervise the study, and (in some cases, if the study involves a marketable drug or device), the regulatory agency for the country where the drug or device will be sold.


A systematic concurrent safety review is frequently employed to assure research participant safety. The conduct and on-going review is designed to be proportional to the risk of the trial. Typically this role is filled by a  Data and Safety Committee , an externally appointed Medical Safety Monitor, [ 88 ]  an  Independent Safety Officer , or for small or low-risk studies the principal investigator. [ 89 ]


For safety reasons, many clinical trials of drugs [ 90 ]  are designed to exclude women of childbearing age, pregnant women, or women who become pregnant during the study. In some cases, the male partners of these women are also excluded or required to take birth control measures.


Throughout the clinical trial, the sponsor is responsible for accurately informing the local site investigators of the true historical safety record of the drug, device or other medical treatments to be tested, and of any potential interactions of the study treatment(s) with already approved treatments. This allows the local investigators to make an informed judgment on whether to participate in the study or not. The sponsor is also responsible for  monitoring  the results of the study as they come in from the various sites as the trial proceeds. In larger clinical trials, a sponsor will use the services of a  data monitoring committee  (DMC, known in the US as a data safety monitoring board). This independent group of clinicians and statisticians meets periodically to review the  unblinded  data the sponsor has received so far. The DMC has the power to recommend termination of the study based on their review, for example if the study treatment is causing more deaths than the standard treatment, or seems to be causing unexpected and study-related serious  adverse events . The sponsor is responsible for collecting  adverse event  reports from all site investigators in the study, and for informing all the investigators of the sponsor's judgment as to whether these adverse events were related or not related to the study treatment.


The sponsor and the local site investigators are jointly responsible for writing a site-specific  informed consent  that accurately informs the potential subjects of the true risks and potential benefits of participating in the study, while at the same time presenting the material as briefly as possible and in ordinary language. FDA regulations state that participating in clinical trials is voluntary, with the subject having the right not to participate or to end participation at any time. [ 91 ]


The ethical principle of  primum non-nocere  ("first, do no harm") guides the trial, and if an investigator believes the study treatment may be harming subjects in the study, the investigator can stop participating at any time. On the other hand, investigators often have a financial interest in recruiting subjects, and could act unethically to obtain and maintain their participation.


The local investigators are responsible for conducting the study according to the study protocol, and supervising the study staff throughout the duration of the study. The local investigator or his/her study staff are also responsible for ensuring the potential subjects in the study understand the risks and potential benefits of participating in the study. In other words, they (or their legally authorized representatives) must give truly informed consent.


Local investigators are responsible for reviewing all adverse event reports sent by the sponsor. These adverse event reports contain the opinions of both the investigator (at the site where the adverse event occurred) and the sponsor, regarding the relationship of the adverse event to the study treatments. Local investigators also are responsible for making an independent judgment of these reports, and promptly informing the local IRB of all serious and study treatment-related adverse events.


When a local investigator is the sponsor, there may not be formal adverse event reports, but study staff at all locations are responsible for informing the coordinating investigator of anything unexpected. The local investigator is responsible for being truthful to the local IRB in all communications relating to the study.


Approval by an  Institutional Review Board  (IRB), or  Independent Ethics Committee  (IEC), is necessary before all but the most informal research can begin. In commercial clinical trials, the study protocol is not approved by an IRB before the sponsor recruits sites to conduct the trial. However, the study protocol and procedures have been tailored to fit generic IRB submission requirements. In this case, and where there is no independent sponsor, each local site investigator submits the study protocol, the consent(s), the data collection forms, and supporting documentation to the local IRB. Universities and most hospitals have in-house IRBs. Other researchers (such as in walk-in clinics) use independent IRBs.


The IRB scrutinizes the study both for medical safety and for protection of the patients involved in the study, before it allows the researcher to begin the study. It may require changes in study procedures or in the explanations given to the patient. A required yearly "continuing review" report from the investigator updates the IRB on the progress of the study and any new safety information related to the study.


In the US, the  FDA  can  audit  the files of local site investigators after they have finished participating in a study, to see if they were correctly following study procedures. This audit may be random, or for cause (because the investigator is suspected of fraudulent data). Avoiding an audit is an incentive for investigators to follow study procedures. A 'covered clinical study' refers to a trial submitted to the FDA as part of a marketing application (for example, as part of an  NDA  or  510(k) ), about which the FDA may require disclosure of financial interest of the  clinical investigator  in the outcome of the study. For example, the applicant must disclose whether an investigator owns equity in the sponsor, or owns proprietary interest in the product under investigation. The FDA defines a covered study as "...   any study of a drug, biological product or device in humans submitted in a marketing application or reclassification petition that the applicant or FDA relies on to establish that the product is effective (including studies that show equivalence to an effective product) or any study in which a single investigator makes a significant contribution to the demonstration of safety." [ 92 ]


Alternatively, many American pharmaceutical companies have moved some clinical trials overseas. Benefits of conducting trials abroad include lower costs (in some countries) and the ability to run larger trials in shorter timeframes, whereas a potential disadvantage exists in lower-quality trial management. [ 93 ]  Different countries have different regulatory requirements and enforcement abilities. An estimated 40% of all clinical trials now take place in Asia, Eastern Europe, and Central and South America. "There is no compulsory registration system for clinical trials in these countries and many do not follow European directives in their operations", says Jacob Sijtsma of the Netherlands-based WEMOS, an advocacy health organisation tracking clinical trials in developing countries. [ 94 ]


Beginning in the 1980s, harmonization of clinical trial protocols was shown as feasible across countries of the European Union. At the same time, coordination between Europe, Japan and the United States led to a joint regulatory-industry initiative on international harmonization named after 1990 as the  International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use  (ICH) [ 95 ]
Currently, most clinical trial programs follow ICH guidelines, aimed at "ensuring that good quality, safe and effective medicines are developed and registered in the most efficient and cost-effective manner. These activities are pursued in the interest of the consumer and public health, to prevent unnecessary duplication of clinical trials in humans and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness." [ 96 ]


Aggregating safety data across clinical trials during drug development is important because trials are generally designed to focus on determining how well the drug works. The safety data collected and aggregated across multiple trials as the drug is developed allows the sponsor, investigators and regulatory agencies to monitor the aggregate safety profile of experimental medicines as they are developed. The value of assessing aggregate safety data is: a) decisions based on aggregate safety assessment during development of the medicine can be made throughout the medicine's development and b) it sets up the sponsor and regulators well for assessing the medicine's safety after the drug is approved. [ 97 ] [ 98 ] [ 99 ] [ 100 ] [ 101 ]


Clinical trial costs vary depending on trial phase, type of trial, and disease studied. A study of clinical trials conducted in the United States from 2004 to 2012 found the average cost of Phase   I trials to be between $1.4 million and $6.6 million, depending on the type of disease. Phase II trials ranged from $7 million to $20 million, and Phase   III trials from $11 million to $53 million. [ 102 ]


The cost of a study depends on many factors, especially the number of sites conducting the study, the number of patients involved, and whether the study treatment is already approved for medical use.


The expenses incurred by a pharmaceutical company in administering a Phase III or   IV clinical trial may include, among others:


These expenses are incurred over several years.


In the US, sponsors may receive a 50 percent  tax credit  for clinical trials conducted on drugs being developed for the treatment of  orphan diseases . [ 103 ]  National health agencies, such as the US  National Institutes of Health , offer grants to investigators who design clinical trials that attempt to answer research questions of interest to the agency. In these cases, the investigator who writes the grant and administers the study acts as the sponsor, and coordinates data collection from any other sites. These other sites may or may not be paid for participating in the study, depending on the amount of the grant and the amount of effort expected from them. Using internet resources can, in some cases, reduce the economic burden. [ 104 ]


Investigators are often compensated for their work in clinical trials. These amounts can be small, just covering a partial salary for research assistants and the cost of any supplies (usually the case with national health agency studies), or be substantial and include "overhead" that allows the investigator to pay the research staff during times between clinical trials. [ citation needed ]


Participants in Phase I drug trials do not gain any direct health benefit from taking part. They are generally paid a fee for their time, with payments regulated and not related to any risk involved. Motivations of healthy volunteers is not limited to financial reward and may include other motivations such as contributing to science and others. [ 105 ]  In later phase trials, subjects may not be paid to ensure their motivation for participating with potential for a health benefit or contributing to medical knowledge. Small payments may be made for study-related expenses such as travel or as compensation for their time in providing follow-up information about their health after the trial treatment ends.


Phase 0 and Phase I drug trials seek healthy volunteers. Most other clinical trials seek patients who have a specific disease or medical condition. The diversity observed in society should be reflected in clinical trials through the appropriate inclusion of  ethnic minority  populations. [ 106 ]   Patient recruitment  or participant recruitment plays a significant role in the activities and responsibilities of sites conducting clinical trials. [ 107 ]


All volunteers being considered for a trial are required to undertake a medical screening. Requirements differ according to the trial needs, but typically volunteers would be screened in a  medical laboratory  for: [ 108 ]


It has been observed that participants in clinical trials are disproportionately white. [ 109 ] [ 110 ]  Often, minorities are not informed about clinical trials. [ 111 ]  One recent systematic review of the literature found that race/ethnicity as well as sex were not well-represented nor at times even tracked as participants in a large number of clinical trials of hearing loss management in adults. [ 112 ]  This may reduce the validity of findings in respect of non-white patients [ 113 ]  by not adequately representing the larger population s .


Depending on the kind of participants required, sponsors of clinical trials, or contract research organizations working on their behalf, try to find sites with qualified personnel as well as access to patients who could participate in the trial. Working with those sites, they may use various recruitment strategies, including patient databases, newspaper and radio advertisements, flyers, posters in places the patients might go (such as doctor's offices), and personal recruitment of patients by investigators.


Volunteers with specific conditions or diseases have additional online resources to help them locate clinical trials. For example, the Fox Trial Finder connects  Parkinson's disease  trials around the world to volunteers who have a specific set of criteria such as location, age, and symptoms. [ 114 ]  Other disease-specific services exist for volunteers to find trials related to their condition. [ 115 ]  Volunteers may search directly on  ClinicalTrials.gov  to locate trials using a registry run by the  U.S. National Institutes of Health  and  National Library of Medicine . There also is software that allows clinicians to find trial options for an individual patient based on data such as genomic data. [ 116 ]


The risk information seeking and processing (RISP) model analyzes social implications that affect attitudes and decision making pertaining to clinical trials. [ 117 ]  People who hold a higher stake or interest in the treatment provided in a clinical trial showed a greater likelihood of seeking information about clinical trials. Cancer patients reported more optimistic attitudes towards clinical trials than the general population. Having a more optimistic outlook on clinical trials also leads to greater likelihood of enrolling. [ 117 ]


Matching involves a systematic comparison of a patient's clinical and demographic information against the eligibility criteria of various trials. Methods include:


Although trials are commonly conducted at major medical centers, some participants are excluded due to the distance and expenses required for travel, leading to hardship, disadvantage, and inequity for participants, especially those in rural and underserved communities. Therefore, the concept of a "decentralized clinical trial" that minimizes or eliminates the need for patients to travel to sites, [ 122 ]  is now more widespread, a capability improved by  telehealth  and  wearable technologies . [ 123 ]


Accidental  ( CDI ), or  multiple drug intake  ( MDI ), is a cause of death by  drug overdose  from  poly drug use , often implicated in  polysubstance dependence .


People who engage in  polypharmacy  are at an elevated risk of death from CDI. Other dangers of combining drugs such as "brain damage, heart problems, seizures, stomach bleeding, liver damage/ liver failure, heatstroke, coma, suppressed breathing, and respiratory failure", along with many other complications. Disorders like depression and anxiety can also stem from polydrug use. [ 1 ]  Elderly people are at the highest risk of CDI, because of having many age-related and health problems requiring many medications combined with age-impaired judgment, leading to confusion in taking medications. [ 2 ] [ 3 ]  Elderly patients are often prescribed more than one drug within the same drug class, and doctors may treat the side effects of prescribed drugs with even more drugs, which can overwhelm the patient. [ 4 ]


In general, the simultaneous use of multiple drugs should be carefully monitored by a qualified individual such as  board certified  and  licensed   medical doctor , either an  MD  or  DO . Close association between prescribing physicians and pharmacies, along with the  computerization  of  prescriptions  and patients' medical histories, aim to avoid the occurrence of dangerous drug interactions. Lists of contraindications for a drug are usually provided with it, either in monographs, package inserts (accompanying prescribed medications), or in warning labels (for OTC drugs). CDI/MDI might also be avoided by physicians requiring their patients to return any unused prescriptions. Patients should ask their doctors and pharmacists if there are any interactions between the drugs they are taking.


In 2004, there were 3,800 deaths in the US resulting from a fatal medication error involving  alcohol , while in 1983 there were fewer than 100 such deaths. [ 5 ]  It is more of a risk for older patients. [ 3 ] [ medical citation needed ]


Alcohol  can exacerbate the symptoms and may directly contribute to increased severity of symptoms. The reasons for  toxicity  vary depending on the mixture of drugs. Usually, most victims die after using two or more drugs in combination that suppress breathing, and the low blood  oxygen  level causes  brain death . [ 6 ]


The  Commission on Human Medicines  ( CHM ) is a committee of the UK's  Medicines and Healthcare products Regulatory Agency .  It was formed in October 2005, and assumed the responsibilities of the  Medicines Commission  and the  Committee on Safety of Medicines . Membership in this various and extensive body is listed on  a governmental website .


The CHM's responsibilities include advising the UK government ministers on matters relating to regulation of human medicinal products, giving advice in relation to the safety, quality and efficacy of human medicinal products, and promoting the collection and investigation of information relating to adverse reactions for human  medicines .


The Medicines and Healthcare products Regulatory Agency undertook a public consultation on proposals to amend the advisory body structure laid down in the  Medicines Act 1968  in February 2005. Ministers agreed to a new structure with the establishment of the Commission that amalgamated the responsibilities of the Medicines Commission and the Committee on Safety of Medicines. The commission was established under Section 2 of the Medicines Act 1968 (SI 2005 No. 1094).


The work done by the CHM is parcelled out to  Expert Advisory Groups  (EAGs), which in effect constitute a subcommittee structure. The EAG chairs and members are also required to follow the  NHS Code of Practice . Three statutory EAGs [ citation needed ]  - namely Pharmacovigilance; Chemistry, Pharmacy and Standards; and Biologicals/Vaccines - are appointed by the  NHS Appointments Commission  because they are also standing members of the commission.


A list of all EAGs, as they were on 16 May 2011:


The duties of the Commission which came into being on 30 October 2005 are set out in Section 3 of the Medicines Act 1968, as amended by the Medicines (Advisory Bodies) Regulations 2005 and include the following:


The first Chairman of the Committee on Safety of Medicines was Sir  Derrick Dunlop . [ 1 ]  Other Chairmen are listed at  Committee on Safety of Medicines .


The chairs of the Commission on Human Medicines have been


The term “dormant therapy” refers to a new drug or a new biological product which was made the subject of a request for designation in compliance with the Dormant Therapies Act. [ 1 ]   According to the legislation, the assignment of dormant therapy is given to a drug or new biological product that has been determined to have insufficient  patent  protection and meets an unmet medical need, improves outcomes, or reduces risks compared to an existing treatment. [ 2 ]


Many drugs may be abandoned due to their failure to meet a  clinical endpoint . Over time, manufacturers wanting to re-investigate the abandoned drug will not because the  patent  for the drug has expired or will expire prior to the completion of research and the federal approval process. Weak or no patent protection is a disincentive for drug development as it hinders a manufacturer’s ability to recoup the investment in expensive  clinical trials . This disincentive is even more pronounced for treatments for more complex conditions such as  Alzheimer’s , which require more clinical data than conditions which currently have existing treatments.


In  medicine , a  drug eruption  is an  adverse drug reaction  of the  skin . Most drug-induced cutaneous reactions are mild and disappear when the offending drug is withdrawn. [ 1 ]  These are called "simple" drug eruptions. However, more serious drug eruptions may be associated with organ injury such as liver or kidney damage and are categorized as "complex". [ 2 ]  Drugs can also cause  hair  and  nail  changes, affect the  mucous membranes , or cause  itching  without outward skin changes. [ 3 ]


The use of synthetic pharmaceuticals and  biopharmaceuticals  in medicine has revolutionized human health, allowing us to live longer lives. Consequently, the average human adult is exposed to many drugs over longer treatment periods throughout a lifetime. [ 4 ]  This unprecedented rise in pharmaceutical use has led to an increasing number of observed adverse drug reactions. [ 4 ]


There are two broad categories of adverse drug reactions.  Type A  reactions are known side effects of a drug that are largely predictable and are called,  pharmatoxicologic. [ 5 ]  Whereas  Type B  or  hypersensitivity  reactions, are often immune-mediated and reproducible with repeated exposure to normal dosages of a given drug. [ 5 ]  Unlike type A reactions, the mechanism of type B or hypersensitivity drug reactions is not fully elucidated. However, there is a complex interplay between a patient's inherited genetics, the pharmacotoxicology of the drug and the immune response that ultimately give rise to the manifestation of a drug eruption. [ 5 ]


Because the manifestation of a drug eruption is complex and highly individual, there are many subfields in medicine that are studying this phenomenon. For example, the field of  pharmacogenomics  aims to prevent the occurrence of severe adverse drug reactions by analyzing a person's inherited genetic risk. [ 6 ]  As such, there are clinical examples of inherited genetic  alleles  that are known to predict drug hypersensitivities and for which diagnostic testing is available. [ 6 ]


Some of the most severe and life-threatening examples of drug eruptions are  erythema multiforme ,  Stevens–Johnson syndrome  (SJS),  toxic epidermal necrolysis  (TEN),  hypersensitivity vasculitis ,  drug induced hypersensitivity syndrome  (DIHS),  erythroderma  and  acute generalized exanthematous pustulosis  (AGEP). [ 4 ]  These severe cutaneous drug eruptions are categorized as hypersensitivity reactions and are immune-mediated. There are four types of hypersensitivity reactions and many drugs can induce one or more hypersensitivity reactions. [ 4 ]


basophil surface receptors


angioedema


complement-driven cell lysis


hemolytic anemia , Goodpasture's,  ANCA vasculitis


in tissues-triggers recruitment of  leukocytes


inflammation leading to tissue destruction


The most common type of eruption is a  morbilliform  (resembling  measles ) or  erythematous rash  (approximately 90% of cases). [ 7 ]  Less commonly, the appearance may also be  urticarial ,  papulosquamous ,  pustular ,  purpuric ,  bullous  (with blisters) or  lichenoid . [ 3 ]   Angioedema  can also be drug-induced (most notably, by  angiotensin converting enzyme inhibitors ).


The underlying mechanism can be immunological (such as in  drug allergies ) or non-immunological (for example, in  photodermatitis  or as a side effect of  anticoagulants ). A  fixed drug eruption  is the term for a drug eruption that occurs in the same skin area every time the person is exposed to the drug. Eruptions can occur frequently with a certain drug (for example, with  phenytoin [ 8 ] ), or be very rare (for example,  Sweet's syndrome  following the administration of  colony-stimulating factors [ 9 ] ).


The culprit can be both a  prescription drug  or an  over-the-counter medication .


Examples of common drugs causing drug eruptions are  antibiotics  and other  antimicrobial  drugs,  sulfa drugs ,  nonsteroidal anti-inflammatory drugs  (NSAIDs),  biopharmaceuticals ,  chemotherapy  agents,  anticonvulsants  and  psychotropic drugs . Common examples include photodermatitis due to local NSAIDs (such as  piroxicam ) or due to antibiotics (such as  minocycline ), fixed drug eruption due to acetaminophen or NSAIDs (Ibuprofen), and the rash following  ampicillin  in cases of  mononucleosis . [ 2 ]


Certain drugs are less likely to cause drug eruptions (rates estimated to be ≤3 per 1000 patients exposed). These include: digoxin, aluminum hydroxide, multivitamins, acetaminophen, bisacodyl, aspirin, thiamine, prednisone, atropine, codeine, hydrochlorothiazide, morphine, insulin, warfarin and spironolactone. [ 2 ]


Drug eruptions are diagnosed mainly from the  medical history  and  clinical examination . However, they can mimic various other conditions, thus delaying diagnosis (for example, in  drug-induced lupus erythematosus , or the  acne -like rash caused by  erlotinib ). A  skin biopsy ,  blood tests  or  immunological  tests can also be useful.


Drug reactions have characteristic timing. The typical amount of time it takes for a rash to appear after exposure to a drug can help categorize the type of reaction. For example,  Acute generalized exanthematous pustulosis  usually occurs within 4 days of starting the culprit drug.  Drug Reaction with Eosinophilia and Systemic Symptoms  usually occurs between 15 and 40 days after exposure.  Toxic epidermal necrolysis  and  Stevens–Johnson syndrome  typically occur 7–21 days after exposure.  Anaphylaxis occurs within minutes. Simple exanthematous eruptions occur between 4 and 14 days after exposure. [ 2 ]


TEN and SJS are severe cutaneous drug reactions that involve the skin and  mucous membranes . To accurately diagnose this condition, a detailed drug history is crucial. [ 4 ]  Often, several drugs may be causative and allergy testing may be helpful. [ 4 ]  Sulfa drugs are well known to induce TEN or SJS in certain people. For example, HIV patients have an increased incidence of SJS or TEN compared to the general population and have been found to express low levels of the drug metabolizing enzyme responsible for detoxifying sulfa drugs. [ 5 ]  Genetics plays an important role in predisposing certain populations to TEN and SJS. As such, there are some  FDA  recommended genetic screening tests available for certain drugs and ethnic populations to prevent the occurrence of a drug eruption. [ 5 ]  The most well known example is carbamezepine (an anti-convulsant used to treat seizures) hypersensitivity associated with the presence of HLA-B*5801 genetic allele in Asian populations. [ 6 ]


US African


Australian


Thai, European


Malaysian, Korean


Han


DIHS is a delayed onset drug eruption, often occurring a few weeks to 3 months after initiation of a drug. [ 2 ]  Worsening of systemic symptoms occurs 3–4 days after cessation of the offending drug. [ 5 ]  There are genetic risk alleles that are predictive of the development of DIHS for particular drugs and ethnic populations. [ 5 ]  The most important of which is abacavir (an anti-viral used in the treatment of HIV) hypersensitivity associated with the presence of the HLA-B*5701 allele in European and African population in the United States and Australians. [ 5 ]


AGEP is often caused by antimicrobial, anti-fungal or antimalarial drugs. [ 4 ]  Diagnosis is often carried out by  patch testing . This testing should be performed within one month after resolution of the rash and patch test results are interpreted at different time points: 48 hours, 72hours and even later at 96 hours and 120 hours in order to improve the sensitivity. [ 4 ]


A  drug holiday  (sometimes also called a  drug vacation ,  medication vacation ,  structured treatment interruption ,  tolerance break ,  treatment break  or  strategic treatment interruption ) is when a patient stops taking a medication(s) for a period of time; anywhere from a few days to many months or even years if the doctor or medical provider feels it is best for the patient. It is recommended not to discontinue any medication without the close supervision of the prescribing party.


Planned drug holidays are used in numerous fields of medicine. They are perhaps best known in  HIV  therapy, after a study showed that stopping medication may stimulate the  immune system  to attack the virus. [ 1 ]
Another reason for drug holidays is to permit a drug to regain  effectiveness  after a period of continuous use, and to reduce the  tolerance effect  that may require increased dosages.


In addition to drug holidays that are intended for therapeutic effect, they are sometimes used to reduce  drug side effects  so that patients may enjoy a more normal life for a period of time such as a weekend or holiday, or engage in a particular activity. For example, it is common for patients using  SSRI   anti-depressant  therapies to take a drug holiday to reduce or avoid side effects associated with  sexual dysfunction . [ 2 ]


In the treatment of mental illness, a drug holiday may be part of a progression toward treatment cessation. The holiday is also a tool to assess a drug's benefits against unwanted side effects, assuming that both will dissipate after an extended vacation. [ citation needed ]


One-day drug holidays in the lithium treatment of bipolar disorder, known as "lithium-free days", have been in use since the pioneering work of Noack and Trautner in 1951. This was found to reduce toxic buildup of the drug in some patients. [ 3 ]


Drug holidays from  L-dopa  found use in the early 1970s when Sweet et al. reported they were beneficial in terms of restoring the effectiveness of the treatment after adaptation by the brain had diminished its effectiveness. [ 4 ] [ 5 ] [ 6 ]
However, later studies revealed that such drug holidays conferred only temporary benefits to L-dopa responsiveness. Furthermore, there was an increased risk of death from associated complications, namely aspiration pneumonia, depression, and thromboembolic disease. L-dopa drug holidays are thus no longer recommended. [ 7 ]


Drug holidays from antipsychotic medication such as  chlorpromazine  have been used since the early 1980s to alleviate adverse reactions associated with long-term treatment. [ 8 ] [ 9 ]


According to Ann Mortimer, it is acknowledged that established guidelines require long-term treatment in established schizophrenia, because the vast majority of evidence from discontinuation, "drug holiday", and ultra-low-dose studies conducted over many years points to significantly higher relapse rates when compared to maintenance treatment. If  antipsychotics  cannot be avoided in the near term, there is no reason to question their long-term usefulness. The same might be said of insulin in diabetes. [ 10 ]


HIV selectively targets activated  helper T-cells . Thus, over time,  HIV  will tend to selectively destroy those helper  T-cells  most capable of fighting the HIV infection off, effectively desensitizing the immune system to the infection. The purpose of a structured treatment interruption is to create a short interval in which the virus becomes common enough to stimulate reproduction of T-cells capable of fighting the virus.


A 2006 HIV literature review noted that "two studies suggested that so-called drug holidays were of no benefit and might actually harm patients, while a third study suggested that the idea might still have value and should be revisited." [ 11 ]


In  pharmaceutical sciences ,  drug interactions  occur when a drug's  mechanism of action  is affected by the  concomitant  administration of substances such as foods, beverages, or other drugs. A popular example of drug–food interaction is the effect of  grapefruit on the metabolism of drugs .


Interactions may occur by simultaneous targeting of  receptors , directly or indirectly. For example, both  Zolpidem  and alcohol affect  GABA A  receptors , and their simultaneous consumption results in the overstimulation of the receptor, which can lead to loss of consciousness.  When two drugs affect each other, it is a  drug–drug interaction (DDI) . The risk of a DDI increases with the number of drugs used. [ 1 ]


A large share of  elderly  people regularly use five or more medications or supplements, with a significant risk of side-effects from drug–drug interactions. [ 2 ]


Drug interactions can be of three kinds:


It may be difficult to distinguish between synergistic or additive interactions, as individual effects of drugs may vary.


Direct interactions between drugs are also possible and may occur when two drugs are mixed before  intravenous injection . For example, mixing  thiopentone  and  suxamethonium  can lead to the  precipitation  of thiopentone. [ 4 ]


Pharmacodynamic  interactions are the drug–drug interactions that occur at a  biochemical  level and depend mainly on the biological processes of organisms. These interactions occur due to action on the same targets; for example, the same receptor or  signaling pathway .


Pharmacodynamic interactions can occur on protein  receptors . [ 5 ]   Two drugs can be considered to be  homodynamic , if they act on the same receptor. Homodynamic effects include drugs that act as (1) pure  agonists , if they bind to the main  locus  of the  receptor , causing a similar effect to that of the main drug, (2) partial  agonists  if, on binding to a secondary site, they have the same effect as the main drug, but with a lower intensity and (3)  antagonists , if they bind directly to the receptor's main locus but their effect is opposite to that of the main drug. These may be c ompetitive antagonists , if they compete with the main drug to bind with the receptor. or u ncompetitive antagonists,  when the antagonist binds to the receptor irreversibly. The drugs can be considered  heterodynamic  competitors, if they act on distinct receptor with similar  downstream pathways .


The interaction my also occur via signal transduction mechanisms. [ 6 ]  For example,  low blood glucose  leads to a release of  catecholamines , triggering  symptoms  that hint the organism to take action, like consuming sugary foods. If a patient is on  insulin , which reduces blood sugar, and also  beta-blockers , the body is less able to cope with an insulin overdose.


Pharmacokinetics  is the field of research studying the chemical and biochemical factors that directly affect  dosage  and the  half-life  of drugs in an organism, including absorption, transport, distribution, metabolism and excretion. Compounds may affect any of those process, ultimately interfering with the flux of drugs in the  human body , increasing or reducing drug availability.


Drugs that change intestinal motility may impact the level of other drugs taken. For example,  prokinetic agents  increase the  intestinal motility , which may cause drugs to go through the digestive system too fast, reducing absorption.  [ citation needed ]


The pharmacological modification of  pH  can affect other compounds. Drugs can be present in ionized or  non-ionized  forms depending on  pKa , and neutral compounds are usually better absorbed by membranes. [ 7 ]  Medication like  antacids  can increase pH and inhibit the absorption of other drugs such as  zalcitabine ,  tipranavir  and  amprenavir . The opposite is more common, with, for example, the antacid  cimetidine   stimulating  the absorption of  didanosine . Some resources describe that a gap of two to four hours between taking the two drugs is needed to avoid the interaction. [ 8 ]


Factors such as food with  high-fat content  may also alter the solubility of drugs and impact its absorption. This is the case for oral  anticoagulants  and  avocado . [ citation needed ]  The formation of non-absorbable complexes may occur also via  chelation , when  cations  can make certain drugs harder to absorb, for example between  tetracycline  or the  fluoroquinolones  and dairy products, due to the presence of  calcium ions . [ citation needed ]  .  Other drugs bind to proteins. Some drugs such as  sucralfate  bind to proteins, especially if they have a high  bioavailability . For this reason its administration is  contraindicated  in  enteral feeding . [ 9 ]


Some drugs also alter absorption by acting on the  P-glycoprotein  of the  enterocytes . This appears to be one of the mechanisms by which  grapefruit  juice increases the  bioavailability  of various drugs beyond its inhibitory activity on  first pass metabolism . [ 10 ]


Drugs also may affect each other by competing for transport proteins in  plasma , such as  albumin . In these cases the drug that arrives first binds with the plasma protein, leaving the other drug dissolved in the plasma, modifying its expected concentration. The organism has mechanisms to counteract these situations (by, for example, increasing  plasma clearance ), and thus they are not usually clinically relevant. They may become relevant if other problems are present, such as issues with drug excretion. [ 11 ]


Many drug interactions are due to alterations in  drug metabolism . [ 12 ]  Further, human drug-metabolizing enzymes are typically activated through the engagement of  nuclear receptors . [ 12 ]  One notable system involved in metabolic drug interactions is the enzyme system comprising the  cytochrome P450 oxidases .


Cytochrome P450  is a very large family of  haemoproteins  (hemoproteins) that are characterized by their  enzymatic  activity and their role in the metabolism of a large number of drugs. [ 13 ]  Of the various families that are present in humans, the most interesting in this respect are the 1, 2 and 3, and the most important enzymes are  CYP1A2 ,  CYP2C9 ,  CYP2C19 ,  CYP2D6 ,  CYP2E1  and  CYP3A4 . [ 14 ]
The majority of the enzymes are also involved in the metabolism of  endogenous  substances, such as  steroids  or  sex hormones , which is also important should there be interference with these substances. The function of the enzymes can either be stimulated ( enzyme induction ) or inhibited ( enzyme inhibition ).


If a drug is metabolized by a CYP450 enzyme and drug B blocks the activity of these enzymes, it can lead to pharmacokinetic alterations. A. This alteration results in drug A remaining in the bloodstream for an extended duration, and eventually increase in concentration. [ citation needed ]


In some instances, the inhibition may reduce the therapeutic effect, if instead the metabolites of the drug is responsible for the effect. [ citation needed ]


Compounds that increase the efficiency of the enzymes, on the other hand, may have the opposite effect and increase the rate of metabolism.


An example of this is shown in the following table for the  CYP1A2  enzyme, showing the substrates (drugs metabolized by this enzyme) and some inductors and inhibitors of its activity: [ 14 ]


Some foods also act as inductors or inhibitors of enzymatic activity. The following table shows the most common:


Drugs tightly bound to proteins (i.e. not in the  free fraction ) are not available for  renal excretion . [ 17 ]
Filtration depends on a number of factors including the  pH  of the urine. Drug interactions may affect those points.  [ citation needed ]


Herb-drug interactions are drug interactions that occur between  herbal medicines  and conventional drugs. [ 18 ]  These types of interactions may be more common than drug-drug interactions because herbal medicines often contain multiple pharmacologically active ingredients, while conventional drugs typically contain only one. [ 18 ]  Some such interactions are  clinically significant , [ 19 ]  although most herbal remedies are not associated with drug interactions causing serious consequences. [ 20 ]  Most catalogued herb-drug interactions are moderate in severity. [ 21 ]  The most commonly implicated conventional drugs in herb-drug interactions are  warfarin ,  insulin ,  aspirin ,  digoxin , and  ticlopidine , due to their narrow  therapeutic indices . [ 21 ] [ 22 ]  The most commonly implicated herbs involved in such interactions are those containing  St. John’s Wort , magnesium, calcium, iron, or  ginkgo . [ 21 ]


Examples of herb-drug interactions include, but are not limited to:


The mechanisms underlying most herb-drug interactions are not fully understood. [ 25 ]  Interactions between herbal medicines and anticancer drugs typically involve enzymes that metabolize  cytochrome P450 . [ 23 ]  For example, St. John's Wort has been shown to induce  CYP3A4  and  P-glycoprotein  in vitro and in vivo. [ 23 ]


The factors or conditions that predispose the appearance of interactions include factors such as  old age . [ 26 ]  This is where human physiology changing with age may affect the interaction of drugs. For example, liver metabolism, kidney function, nerve transmission, or the functioning of bone marrow all decrease with age. In addition, in old age, there is a sensory decrease that increases the chances of errors being made in the administration of drugs. [ 27 ]  The elderly are also more vulnerable to  polypharmacy , and the more drugs a patient takes, the higher is the chance of an interaction. [ 28 ]


Genetic factors  may also affect the enzymes and receptors, thus altering the possibilities of interactions.  [ citation needed ]


Patients with  hepatic  or  renal  diseases already may have difficulties metabolizing and excreting drugs, which may exacerbate the effect of interactions. [ 28 ]


Some drugs present an intrinsic increased risk for a harmful interaction, including drugs with a narrow  therapeutic index ,  where the difference between the  effective dose  and the  toxic dose  is small. [ n. 1 ]  The drug  digoxin  is an example of this type of drug. [ 29 ]


Risks are also increased when the drug presents a steep  dose-response curve , and small changes in the dosage produce large changes in the drug's concentration in the blood plasma. [ 29 ]


As of 2008, among adults in the  United States of America  older than 56, 4% were taking medication and/ or supplements that put them at risk of a major drug interaction. [ 30 ]  Potential drug-drug interactions have increased over time [ 31 ]  and are more common in the less-educated  elderly  even after controlling for age, sex, place of residence, and  comorbidity . [ 32 ]


A  drug of last resort  ( DoLR ), also known as a  heroic dose , [ 1 ]  is a  pharmaceutical drug  which is tried after all other drug options have failed to produce an adequate response in the patient.  Drug resistance , such as  antimicrobial resistance  or  antineoplastic resistance , may make the first-line drug ineffective, especially in case of  multidrug-resistant  pathogens and tumors. Such an alternative may be outside of extant regulatory requirements or medical best practices, in which case it may be viewed as  salvage therapy .


The use of a drug of last resort may be based on agreement among members of a patient's care network, including physicians and healthcare professionals across multiple specialties, or on a patient's desire to pursue a particular course of treatment and a practitioner's willingness to administer that course. Certain situations such as severe bacterial related  sepsis  or  septic shock  can more commonly lead to last resorts.


Therapies considered to be drugs of last resort may at times be used earlier in the event that an agent would likely show the most immediate  dose-response  related efficacy in time-critical situations such as high mortality circumstances. Many of the drugs considered last resorts fall into one or more of the categories of  antibiotics ,  antivirals , and  chemotherapy  agents. These agents often exhibit what are considered to be among the most efficient dose-response related effects, or are drugs for which few or no resistant strains are known.


With regard to antibiotics, antivirals, and other agents indicated for treatment of infectious pathological disease, drugs of last resort are commonly withheld from administration until after the trial and failure of more commonly used treatment options to prevent the development of drug resistance. One of the most commonly known examples of both antimicrobial resistance and the relationship to the classification of a drug of last resort is the emergence of  Staphylococcus aureus  (MRSA) (sometimes also referred to as multiple-drug resistant  S. aureus  due to resistance to non-penicillin antibiotics that some strains of  S. aureus  have shown to exhibit). In cases presenting with suspected  S. aureus , it is suggested by many public health institutions (including the  World Health Organization  (WHO) and the  Centers for Disease Control and Prevention  (CDC) in the United States) to treat first with empirical therapies for  S. aureus , with an emphasis on evaluating the response to initial treatment and laboratory diagnostic techniques to isolate cases of drug resistance.


Due to the possibility of potential severe or fatal consequences of resistant strains, initial treatment often includes concomitant administration of multiple antimicrobial agents that are not known to show cross-resistance, so as to reduce the possibility of a resistant strain remaining inadequately treated by a single agent during the evaluation of drug response. Once a specific resistance profile has been isolated via clinical laboratory findings, treatment is often modified as indicated.


Vancomycin  has long been considered a drug of last resort, due to its efficiency in treating multiple drug-resistant infectious agents and the requirement for  intravenous  administration. Recently, resistance to even vancomycin has been shown in some strains of  S. aureus  (sometimes referred to as  vancomycin resistant  S. aureus  (VRSA) or vancomycin intermediate-resistance  S. aureus  (VISA)) often coinciding with methicillin/penicillin resistance, prompting the inclusion of newer antibiotics (such as  linezolid ) that have shown efficacy in highly drug-resistant strains. There are also strains of enterococci that have developed resistance to vancomycin referred to as  vancomycin resistant enterococcus  (VRE).


Agents classified as fourth-line (or greater) treatments or experimental therapies could be considered by default to be drugs of last resort due to their low placement in the treatment hierarchy. Such placement may result from a multitude of considerations, including greater efficacy of other agents, socioeconomic considerations, availability issues,  unpleasant side effects  or similar issues relating to patient tolerance. Some experimental therapies might also be called drugs of last resort when administered following the failure of all other currently accepted treatments.


Although most of the notable drugs of last resort are antibiotics or antivirals, other drugs are sometimes considered drugs of last resort, such as  cisapride . [ 2 ]


Drug reaction testing  uses a  genetic test  to predict how a particular person will respond to various prescription and non-prescription  medications .  It checks for genes that code for specific  liver   enzymes  which activate, deactivate, or are influenced by various drugs.


There are currently four  genetic markers  commonly tested for:  2D6 ,  2C9 ,  2C19 , and  1A2 .


This testing has been done for some time by drug companies working on new drugs, but is relatively newly available to the general public.   Strattera  is the first drug to mention the test in the official documentation, although it doesn't specifically recommend that patients get the test before taking the medication.


There are four possible categories for each marker:  poor metabolizer ,  intermediate metabolizer ,  extensive metabolizer , or  ultra-extensive metabolizer .  Different testing companies may call these by different names.  Extensive metabolizers (that is, people who are extensive metabolizers of a given type) are the most common, and are the type of people for which drugs are designed.  Up to 7% of Caucasians are poor metabolizers of drugs metabolized by the  CYP2D6  enzyme. [ 1 ] [ 2 ]


People who cannot  metabolize  a drug will require a much lower dose than is recommended by the manufacturer, and those who metabolize it quickly may require a higher dose.  Some drugs, such as  codeine , will not be effective in people without the requisite enzymes to activate them.


People who are poor metabolizers of a drug may overdose while taking less than the recommended dose.


Drug-induced amnesia  is  amnesia  caused by drugs.  Amnesia may be therapeutic for medical treatment or for medical procedures, or it may be a side-effect of a drug, such as  alcohol , or certain medications for psychiatric disorders, such as  benzodiazepines . [ 1 ]  It is seen also with slow acting parenteral general anaesthetics. [ citation needed ]


Amnesia is desirable during surgery, so  general anaesthesia  procedures are designed to induce it for the duration of the operation. Sedatives such as benzodiazepines, which are commonly used for anxiety disorders, can reduce the encoding of new memories, particularly in high doses (for example, prior to surgery in order for a person not to recall the surgery). [ 2 ]  Amnestic drugs can be used to induce a  coma  for a child breathing using mechanical ventilation, or to help reduce intracranial pressure after  head trauma . [ 3 ] [ failed verification ]


Researchers are currently experimenting with drugs which induce amnesia in order to improve understanding of human memory, and develop better drugs to treat psychiatric disorders and memory-related disorders. People with  Alzheimer's disease  and other forms of  dementia  are likely to benefit. By understanding the ways in which amnesia-inducing drugs interact with the brain, researchers hope to better understand the ways in which  neurotransmitters  aid in the formation of memory. By stimulating rather than depressing these neurotransmitters, memory may improve. [ 1 ]


Holmes et al. (2010) [ 4 ]  commented that the media misrepresented two recent studies as research on "erasing" traumatic memories, but showed the fear response associated with stressful memory could be greatly reduced whilst the factual memory of the trauma remained intact. Similarly, Brunet et al. (2008) found that the people with chronic  posttraumatic stress disorder  who were treated with  propranolol  for a single day had a reduced response to existing trauma while retaining memory of the trauma. [ 5 ]  In the process of remembering, the memory needs to be restored in the brain. By introducing an amnesia-inducing drug during this process, the memory can be disrupted. While the memory remains intact, the emotional reaction is damped, making the memory less overwhelming. Researchers believe this drug will help patients with post-traumatic stress disorder be able to better process the trauma without reliving the trauma emotionally. [ citation needed ]  This has raised legal and ethical concerns should drugs be found to have altered the memory of traumatic events that occur in victims of crimes (e.g. murder attempt), and whether it is therapeutically desirable to do so. [ 4 ] [ 6 ]


Amnesia can result from a side-effect of prescription or non-prescription drugs. Both  substance use  and alcohol can cause both long-term and short-term memory loss, resulting in  blackouts .


The most commonly used group of prescription drugs which can produce amnesia are benzodiazepines, especially if combined with alcohol, however, in limited quantities,  triazolam  (Halcion) is not associated with amnesia or memory impairment. [ 7 ]


Nepenthe , literally named anti-sorrow, is a substance mentioned in the  Odyssey  given to  Helen of Troy , said to originate from  Egypt . Consumption causes sorrowful memories to be forgotten. [ 12 ] [ 13 ]


In  pharmacology , an  effective dose  ( ED ) or  effective concentration  ( EC ) is the  dose  or  concentration  of a  drug  that produces a biological response. [ 1 ] [ 2 ]  The term "effective dose" is used when measurements are taken  in vivo ,  while "effective concentration" is used when the measurements are taken  in vitro . [ 3 ]


It has been stated  that any substance can be toxic at a high enough dose. This concept was exemplified in 2007 when a California woman died of  water intoxication  in  a contest sanctioned by a radio station . [ 4 ]  The line between efficacy and toxicity is dependent upon the particular patient, although the dose administered by a physician should fall into the predetermined  therapeutic window  of the drug.


The importance of determining the therapeutic range of a drug cannot be overstated. This is generally defined by the range between the  minimum effective dose  (MED) and the  maximum tolerated dose  (MTD). The MED is defined as the lowest dose level of a pharmaceutical product that provides a clinically significant response in average efficacy, which is also statistically significantly superior to the response provided by the placebo. [ 5 ]  Similarly, the MTD is the highest possible but still tolerable dose level with respect to a pre-specified clinical limiting toxicity. [ 5 ]  In general, these limits refer to the average patient population. For instances in which there is a large difference between the MED and MTD, it is stated that the drug has a large therapeutic window. Conversely, if the range is relatively small, or if the MTD is less than the MED, then the pharmaceutical product will have little to no practical value. [ 5 ]


The  median effective dose  is the dose that produces a quantal effect (all or nothing) in 50%  of the population that takes it (median referring to the 50% population base). [ 6 ]  It is also sometimes abbreviated as the ED 50 , meaning "effective dose for 50% of the population". The ED50 is commonly used as a measure of the reasonable expectancy of a drug effect, but does not necessarily represent the dose that a clinician might use. This depends on the need for the effect, and also the toxicity. The toxicity and even the lethality of a drug can be quantified by the TD 50  and LD 50  respectively. Ideally, the effective dose would be substantially less than either the toxic or lethal dose for a drug to be therapeutically relevant.


The  ED 95  is the dose required to achieve the desired effect in 95% of the population.


In anaesthesia, the term ED 95  is also used when referring to the pharmacology of neuromuscular blocking drugs. In this context, it is the dose which will cause 95% depression of the height of a single muscle twitch, in half of the population. Put another way, it is the ED 50  for 95% reduction in twitch height. [ 7 ]  The single twitch response occurs when a nerve stimulator is used to stimulate the ulnar nerve, and the degree of twitch of the adductor pollicus muscle is measured. A more accurate nomenclature when used in this way would be "ED 50 95".


An  equianalgesic  chart is a  conversion chart  that lists equivalent doses of  analgesics  (drugs used to relieve pain). Equianalgesic charts are used for calculation of an equivalent dose (a dose which would offer an equal amount of  analgesia ) between different analgesics. [ 1 ]  Tables of this general type are also available for  NSAIDs ,  benzodiazepines ,  depressants ,  stimulants ,  anticholinergics  and others.


Equianalgesic tables are available in different formats, such as pocket-sized cards for ease of reference. [ 1 ]  A frequently-seen format has the drug names in the left column, the route of administration in the center columns and any notes in the right column. [ 2 ] [ 3 ]


There are several reasons for switching a patient to a different pain medication. These include practical considerations such as lower cost or unavailability of a drug at the patient's preferred pharmacy, or medical reasons such as lack of effectiveness of the current drug or to minimize adverse effects. Some patients request to be switched to a different narcotic due to stigma associated with a particular drug (e.g. a patient refusing  methadone  due to its association with  opioid   addiction treatment ). [ 4 ]  Equianalgesic charts are also used when calculating an equivalent dosage of the same drug, but with a different  route of administration . [ citation needed ]


An equianalgesic chart can be a useful tool, but the user must take care to correct for all relevant variables such as route of administration,  cross tolerance ,  half-life  and the  bioavailability  of a drug. [ 5 ]  For example, the narcotic  levorphanol  is 4–8 times  stronger  than  morphine , but also has a much longer half-life. Simply switching the patient from 40 mg of morphine to 10 mg of levorphanol would be dangerous due to dose accumulation, and hence frequency of administration should also be taken into account.


There are other concerns about equianalgesic charts. Many charts derive their data from studies conducted on opioid-naive patients. Patients with  chronic  (rather than acute) pain may respond to analgesia differently. Repeated administration of a medication is also different from single dosing, as many drugs have active metabolites that can build up in the body. [ 6 ]  Patient variables such as sex, age, and organ function may also influence the effect of the drug on the system. These variables are rarely included in equianalgesic charts. [ 7 ] [ 3 ] [ 8 ]


Opioids  are a class of compounds that elicit  analgesic  (pain killing) effects in humans and animals by binding to the  μ-opioid receptor  within the  central nervous system . The following table lists opioid and non-opioid analgesic drugs and their relative  potencies . Values for the potencies represent opioids taken orally unless another  route of administration  is provided. As such, their  bioavailabilities  differ, and they may be more potent when taken  intravenously . [ citation needed ]


This chart measures pain relief versus mass of medication. Not all medications have a fixed relationship on this scale.  Methadone  is different from most opioids because its potency can vary depending on how long it is taken. Acute use (1–3 days) yields a potency about 1.5× stronger than that of  morphine  and chronic use (7 days+) yields a potency about 2.5 to 5× that of morphine. Similarly, the effect of  tramadol  increases after consecutive dosing due to the accumulation of its active metabolite and an increase of the oral bioavailability in chronic use. [ citation needed ]


300 mg ( PO )


Unknown (researches are still being made)


( IV / IM ) or other parental administrations apart from spinal administration


IV / IM ) or other parental administrations apart from spinal administration [ 28 ]


2–2.5  (insufflated) [ 29 ]


(morphine  prodrug ) [ 30 ]


( IV , IM )


Buccal: 28%
Sublingual: 37.5%
Intranasal: 43%
IV, IM & IT: 100%


2–6 hours parenteral


Explanatory notes


Citations


Bibliography


Expanded access  or  compassionate use  is the use of an unapproved drug or medical device under special forms of  investigational new drug applications  (IND) or  IDE application  for devices, outside of a  clinical trial , by people with serious or life-threatening conditions who do not meet the enrollment criteria for the clinical trial in progress.


These programs go under various names, including  early access ,  special access , or  managed access program ,  compassionate use ,  compassionate access ,  named-patient access ,  temporary authorization for use ,  cohort access , and  pre-approval access . [ 1 ] [ 2 ] [ 3 ]


In general the person and their doctor must apply for access to the investigational product, the company has to choose to cooperate, and the medicine's regulatory agency needs to agree that the risks and possible benefits of the drug or device are understood well enough to determine if putting the person at risk has sufficient potential benefit.  In some countries the government will pay for the drug or device, but in many countries the person must pay for the drug or device, as well as medical services necessary to receive it.


In the US, compassionate use started with the provision of investigational medicine to certain patients in the late 1970s, and a formal program was established in 1987 in response to HIV/AIDS patients requesting access to drugs in development. An important legal case was  Abigail Alliance v. von Eschenbach , in which the Abigail Alliance, a group that advocates for access to investigational drugs for people who are terminally ill, tried to establish such access as a legal right. The Supreme Court declined to hear the case, effectively upholding previous cases that have maintained that there is not a constitutional right to unapproved medical products.


As of 2016, [update]  regulation of access to pharmaceuticals that were not approved for marketing was handled on a country by country basis, including in the European Union, where the  European Medicines Agency  issued guidelines for national regulatory agencies to follow. In the US, Europe, and the EU, no company could be compelled to provide a drug or device that it was  developing . [ 1 ]


Companies sometimes provide drugs under these programs to people who were in clinical trials and who responded to the drug, after the clinical trial ends. [ 2 ] [ 3 ]


In the US as of 2018, people could try obtain unapproved drugs or medical devices that were in development under specific conditions. [ 4 ] [ 5 ]


These conditions were: [ 5 ]


Drugs can be made available to individuals, small groups, or large groups. [ 5 ]


In the US, actual provision of the drug depends on the manufacturer's willingness to provide it, as well as the person's ability to pay for it; it is the company's decision whether to require payment or to provide the drug or device for free. [ 1 ]   The manufacturer can only charge  direct costs  for individual INDs; it can add some but not all  indirect costs  for small group or larger expanded access programs. [ 6 ]  To the extent that a doctor or clinic is required for use of the drug or device, they too may require payment. [ 1 ]


In some cases, it may be in the manufacturer's commercial interest to provide access under an EA program; this is a way, for example, for a company to make money before the drug or device is approved.  Companies must provide data collected from people getting the drug or device under EA programs to the FDA annually; this data may be helpful with regard to getting the drug or device approved, or may be harmful, should unexpected adverse events occur.  The manufacturer remains legally liable as well. If the manufacturer chooses to charge for the investigational product, that price influences later discussions about the price if the product is approved for marketing. [ 1 ]


As of February 2019 [update] , 41 states have passed  right-to-try laws  that permit manufacturers to provide experimental medicines to terminally ill people without US FDA authorization. [ 7 ]   Legal, medical, and bioethics scholars, including Jonathan Darrow and Arthur Caplan, have argued that these state laws have little practical significance because people can already obtain pre-approval access through the FDA's expanded access program, and because the FDA is generally not the limiting factor in obtaining pre-approval access. [ 8 ] [ 9 ]


In Europe, the  European Medicines Agency  issued guidelines that members may follow. Each country has its own regulations, and they vary. In the UK, for example, the program is called "early access to medicine scheme" or EAMS and was established in 2014. If a company that wants to provide a drug under EAMS, it must submit its Phase I data to the  Medicines and Healthcare products Regulatory Agency  and apply for what is called a "promising innovative medicine" (PIM) designation. If that designation is approved, the data is reviewed, if that review is positive, the  National Health Service  is obligated to pay for people who fit the criteria to have access to the drug. As of 2016, governments also paid for early access to drugs in Austria, Germany, Greece, and Spain. [ 1 ]  Since 2021, France has a system of early and expanded access separated in two systems: AAC and AAP. [ 10 ]


Companies sometimes make use of expanded programs in Europe even after they receive EMA approval to market a drug, because drugs also must go through regulatory processes in each member state, and in some countries this process can take nearly a year; companies can start making sales earlier under these programs. [ 1 ]


In the Philippines, the usage of unregistered drugs may be allowed through a doctor, a specialist, or health institution or society obtaining a specific compassionate use permit (CSP) from the country's  Food and Drug Administration  for the treatment of their terminally or seriously ill patients. The issuance of CSP is stated under  Department of Health  Administrative Order No. 4 of 1992. [ 11 ]


Those seeking CSP are required to provide the following information; estimated amount of the unregistered drug the patient, the "licensed drug/device establishment through which the unregistered drug may be procured", and "the names and address of the specialists qualified and authorized to use the product." A CSP may also be obtained for processed  medical cannabis  despite cannabis in general being illegal in the Philippines. [ 11 ] [ 12 ]


In the US, one of the earliest expanded access programs was a compassionate use IND that was established in 1978, which allowed a limited number of people to use  medical cannabis  grown at the  University of Mississippi , under the direction of Marijuana Research Project Director Dr.  Mahmoud ElSohly .  It is administered by the  National Institute on Drug Abuse . [ citation needed ]