More recently it has been argued that  genetic exceptionalism  is past its expiration date as we move into a blended genomic/big data era of medicine, yet exceptionalism practices continue to permeate clinical healthcare today. [ 58 ] [ 59 ]  Garrison et al. recently relayed a call to action to update verbiage from genetic exceptionalism to genomic contextualism in that we recognize a fundamental duality of genetic information. [ 60 ]  This allows room in the argument for different types of genetic information to be handled differently while acknowledging that genomic information is similar and yet distinct from other health-related information. [ 60 ]  Genomic contextualism would allow for a case-by-case analysis of the technology and the context of its use (e.g., clinical practice, research, secondary findings).


Others argue that genetic information is indeed distinct from other health-related information but not to the extent of requiring legal/regulatory protections, similar to other sensitive health-related data such as HIV status. [ 61 ]  Additionally, Evans et al. argue that the EHR has sufficient privacy standards to hold other sensitive information such as social security numbers and that the fundamental nature of an EHR is to house highly personal information. [ 58 ]  Similarly, a systematic review reported that the public had concern over privacy of genetic information, with 60% agreeing that maintaining privacy was not possible; however, 96% agreed that a direct-to-consumer testing company had protected their privacy, with 74% saying their information would be similarly or better protected in an EHR. With increasing technological capabilities in EHRs, it is possible to mask or hide genetic data from subsets of providers and there is not consensus on how, when, or from whom genetic information should be masked. [ 55 ] [ 62 ]   Rigorous protection and masking of genetic information is argued to impede further scientific progress and clinical translation into routine clinical practices. [ 63 ]


Pharmacogenomics was first recognized by  Pythagoras  around 510 BC when he made a connection between the dangers of  fava bean  ingestion with  hemolytic anemia  and  oxidative stress . In the  1950s , this identification was validated and attributed to deficiency of  G6PD  and is called  favism . [ 64 ] [ 65 ]  Although the first official publication was not until 1961, [ 66 ]  the unofficial beginnings of this science were around the 1950s. Reports of prolonged paralysis and fatal reactions linked to genetic variants in patients who lacked  butyrylcholinesterase  ('pseudocholinesterase') following succinylcholine injection during anesthesia were first reported in 1956. [ 2 ] [ 67 ]  The term pharmacogenetics was first coined in 1959 by  Friedrich Vogel  of  Heidelberg ,  Germany  (although some papers suggest it was 1957 or 1958). [ 68 ]  In the late 1960s,  twin studies  supported the inference of genetic involvement in drug metabolism, with identical twins sharing remarkable similarities in drug response compared to fraternal twins. [ 69 ]  The term pharmacogenomics first began appearing around the 1990s. [ 64 ]


The first FDA approval of a pharmacogenetic test was in 2005 [ 9 ]  (for  alleles  in  CYP2D6  and  CYP2C19 )


Computational advances have enabled cheaper and faster sequencing. [ 70 ]  Research has focused on  combinatorial chemistry , [ 71 ]  genomic mining, omic technologies, and  high throughput screening .


As the cost per genetic test decreases, the development of personalized drug therapies will increase. [ 72 ]  Technology now allows for genetic analysis of hundreds of target genes involved in medication metabolism and response in less than 24 hours for under $1,000.  This a huge step towards bringing pharmacogenetic technology into everyday medical decisions. Likewise, companies like  deCODE genetics , MD Labs Pharmacogenetics,  Navigenics  and  23andMe  offer genome scans. The companies use the same  genotyping  chips that are used in GWAS studies and provide customers with a write-up of individual risk for various traits and diseases and testing for 500,000 known SNPs. Costs range from $995 to $2500 and include updates with new data from studies as they become available. The more expensive packages even included a telephone session with a genetics counselor to discuss the results. [ 73 ]


Pharmacogenetics has become a controversial issue in the area of  bioethics . Privacy and confidentiality are major concerns. [ 74 ]  The evidence of benefit or risk from a genetic test may only be suggestive, which could cause dilemmas for providers. [ 74 ] : 145   Drug development may be affected, with rare genetic variants possibly receiving less research. [ 74 ]  Access and patient autonomy are also open to discussion. [ 75 ] : 680


Journals:


Cytochrome P450 1A2  (abbreviated  CYP1A2 ), a member of the  cytochrome P450  mixed-function oxidase system, is involved in the metabolism of  xenobiotics  in the human body. [ 5 ]  In humans, the CYP1A2 enzyme is encoded by the  CYP1A2   gene . [ 6 ]


CYP1A2 is a member of the  cytochrome P450  superfamily of enzymes. The cytochrome P450 proteins are  monooxygenases  which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. CYP1A2 localizes to the  endoplasmic reticulum  and its expression is induced by some  polycyclic aromatic hydrocarbons  (PAHs), some of which are found in cigarette smoke. The enzyme's endogenous substrate is unknown; however, it is able to metabolize some PAHs to carcinogenic intermediates. Other xenobiotic substrates for this enzyme include  caffeine , aflatoxin B1, and  paracetamol  (acetaminophen). The transcript from this gene contains four Alu sequences flanked by direct repeats in the 3' untranslated region. [ 7 ]


CYP1A2 also metabolizes  polyunsaturated fatty acids  into signaling molecules that have physiological as well as pathological activities. It has monoxygenase activity for certain of these fatty acids in that it metabolizes  arachidonic acid  to 19-hydroxyeicosatetraenoic acid (19-HETE) (see  20-Hydroxyeicosatetraenoic acid ) but also has  epoxygenase  activity in that it metabolizes  docosahexaenoic acid  to  epoxides , primarily 19 R ,20 S -epoxyeicosapentaenoic acid and 19 S ,20 R -epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and similarly metabolizes  eicosapentaenoic acid  to epoxides, primarily 17 R ,18 S - eicosatetraenoic acid  and 17 S ,18 R -eicosatetraenoic acid isomers (termed 17,18-EEQ). [ 8 ]


19-HETE is an inhibitor of  20-HETE , a broadly active signaling molecule, e.g., it constricts  arterioles , elevates blood pressure, promotes  inflammation  responses, and stimulates the growth of various types of tumor cells; however the in vivo ability and significance of 19-HETE in inhibiting 20-HETE has not been demonstrated. The EDP ( epoxydocosapentaenoic acid ) and EEQ ( epoxyeicosatetraenoic acid ) metabolites have a broad range of activities. In various animal models and in vitro studies on animal and human tissues, they decrease hypertension and pain perception; suppress inflammation; inhibit  angiogenesis , endothelial cell migration and endothelial cell proliferation; and inhibit the growth and metastasis of human breast and prostate cancer cell lines. [ 9 ] [ 10 ] [ 11 ] [ 12 ]  It is suggested that the EDP and EEQ metabolites function in humans as they do in animal models and that, as products of the  omega-3 fatty acids , docosahexaenoic acid and eicosapentaenoic acid, the EDP and EEQ metabolites contribute to many of the beneficial effects attributed to dietary omega-3 fatty acids. [ 9 ] [ 12 ] [ 13 ]   EDP and EEQ metabolites are short-lived, being inactivated within seconds or minutes of formation by  epoxide hydrolases , particularly  soluble epoxide hydrolase , and therefore act locally.


CYP1A2 is not regarded as being a major contributor to forming the aforementioned epoxides [ 12 ]  but could act locally in certain tissues to do so.


The authoritative list of star  allele  nomenclature for CYP1A2 along with activity scores is kept by PharmVar. [ 14 ]


Expression of CYP1A2 appears to be induced by various dietary constituents. [ 15 ]  Vegetables such as cabbages, cauliflower and broccoli are known to increase levels of CYP1A2. Lower activity of CYP1A2 in South Asians appears to be due to cooking these vegetables in curries using ingredients such as  cumin  and  turmeric , ingredients known to inhibit the enzyme. [ 16 ]


A single 2006 paper found CYP1A2 to be involved in the metabolization of  caffeine , and the presence of alleles that make this metabolization slow have been associated with an increased risk of nonfatal  myocardial infarction  for those who drink a lot of  coffee  (4 or more cups per day). [ 17 ]


Following is a table of selected  substrates ,  inducers  and  inhibitors  of CYP1A2.


Inhibitors of CYP1A2 can be classified by their  potency , such as:


Moderate


Weak


Unspecified potency :


Moderate inducers: [ 20 ]


Unspecified potency:


2F9Q ,  3QM4 ,  3TBG ,  3TDA ,  4WNT ,  4WNU ,  4WNV ,  4WNW ,  4XRY ,  4XRZ


NM_000106 NM_001025161


NM_001163472 NM_019823


NP_000097 NP_001020332


NP_001156944 NP_062797


Cytochrome P450 2D6  ( CYP2D6 ) is an  enzyme  that in humans is encoded by the  CYP2D6   gene .  CYP2D6  is primarily expressed in the  liver . It is also highly expressed in areas of the  central nervous system , including the  substantia nigra .


CYP2D6, a member of the  cytochrome P450  mixed-function oxidase system, is one of the most important enzymes involved in the  metabolism  of  xenobiotics  in the body. In particular, CYP2D6 is responsible for the metabolism and  elimination  of approximately 25% of clinically used drugs, via the addition or removal of certain  functional groups  – specifically,  hydroxylation ,  demethylation , and  dealkylation . [ 5 ]   CYP2D6 also activates some  prodrugs . This enzyme also metabolizes several endogenous substances, such as  N,N-Dimethyltryptamine ,  hydroxytryptamines ,  neurosteroids , and both  m -tyramine  and  p -tyramine  which CYP2D6 metabolizes into  dopamine  in the brain and liver. [ 5 ] [ 6 ] [ 7 ]


Considerable variation exists in the efficiency and amount of CYP2D6 enzyme produced between individuals. Hence, for drugs that are metabolized by CYP2D6 (that is, are CYP2D6  substrates ), certain individuals will eliminate these drugs quickly (ultrarapid metabolizers) while others slowly (poor metabolizers).  If a drug is metabolized too quickly, it may decrease the drug's  efficacy  while if the drug is metabolized too slowly, toxicity may result. [ 8 ]   So, the dose of the drug may have to be adjusted to take into account of the speed at which it is metabolized by CYP2D6. [ 9 ]  Individuals who exhibit an ultrarapid metabolizer phenotype, metabolize  prodrugs , such as  codeine  or  tramadol , more rapidly, leading to higher than therapeutic levels. [ 10 ] [ 11 ]  A case study of the death of an infant breastfed by an ultrarapid metabolizer mother taking codeine impacted postnatal pain relief clinical practices, but was later debunked. [ 12 ]  These drugs may also cause serious toxicity in ultrarapid metabolizer patients when used to treat other post-operative pain, such as after  tonsillectomy . [ 13 ] [ 14 ] [ 15 ]  Other drugs may function as  inhibitors  of CYP2D6 activity or  inducers  of CYP2D6 enzyme expression that will lead to decreased or increased CYP2D6 activity respectively.  If such a drug is taken at the same time as a second drug that is a CYP2D6 substrate, the first drug may affect the elimination rate of the second through what is known as a  drug-drug interaction . [ 8 ]


The gene is located on  chromosome 22q 13.1. near two cytochrome P450  pseudogenes  (CYP2D7P and CYP2D8P). [ 16 ]  Among them, CYP2D7P originated from CYP2D6 in a stem lineage of great apes and humans, [ 17 ]  the CYP2D8P originated from CYP2D6 in a stem lineage of  Catarrhine  and  New World monkeys ' stem lineage. [ 18 ]   Alternatively spliced  transcript variants encoding different  isoforms  have been found for this gene. [ 19 ]


CYP2D6 shows the largest  phenotypical  variability among the CYPs, largely due to  genetic   polymorphism . The  genotype  accounts for normal, reduced, and non-existent CYP2D6 function in subjects. Pharmacogenomic tests are now available to identify patients with variations in the CYP2D6 allele and have been shown to have widespread use in clinical practice. [ 20 ]
The CYP2D6 function in any particular subject may be described as one of the following: [ 21 ]


A patient's CYP2D6 phenotype is often clinically determined via the administration of  debrisoquine  (a selective CYP2D6 substrate) and subsequent plasma concentration assay of the debrisoquine  metabolite  (4-hydroxydebrisoquine). [ 22 ]


The type of CYP2D6 function of an individual may influence the person's response to different doses of drugs that CYP2D6 metabolizes. The nature of the effect on the drug response depends not only on the type of CYP2D6 function, but also on the extent to which processing of the drug by CYP2D6 results in a chemical that has an effect that is similar, stronger, or weaker than the original drug, or no effect at all. For example, if CYP2D6 converts a drug that has a strong effect into a substance that has a weaker effect, then poor metabolizers (weak CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects; conversely, if CYP2D6 converts a different drug into a substance that has a greater effect than its parent chemical, then ultrarapid metabolizers (strong CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects. [ 23 ]  Information about how human genetic variation of CYP2D6 affects response to medications can be found in databases such PharmGKB, [ 24 ]  Clinical Pharmacogenetics Implementation Consortium (CPIC). [ 25 ]


The variability in metabolism is due to multiple different  polymorphisms  of the  CYP2D6   allele , located on  chromosome 22 . Subjects possessing certain allelic variants will show normal, decreased, or no CYP2D6 function, depending on the allele. Pharmacogenomic tests are now available to identify patients with variations in the CYP2D6 allele and have been shown to have widespread use in clinical practice. [ 20 ]  The current known alleles of CYP2D6 and their clinical function can be found in databases such as PharmVar. [ 26 ]


Ethnicity is a factor in the occurrence of CYP2D6 variability. The reduction of the liver cytochrome CYP2D6 enzyme occurs approximately in 7–10% in  white  populations, and is lower in most other ethnic groups such as  Asians  and  African-Americans  at 2% each. A complete lack of CYP2D6 enzyme activity, wherein the individual has two copies of the polymorphisms that result in no CYP2D6 activity at all, is said to be about 1-2% of the population. [ 27 ]  The occurrence of CYP2D6 ultrarapid metabolizers appears to be greater among  Middle Eastern  and  North African  populations. [ 28 ] [ 29 ]  In  Ethiopia , a particularly high percentage (30%) of the population are ultrametabolizers. As a result, the analgesic codeine is banned in Ethiopia due to the high rate of adverse events associated with ultrarapid metabolism of codeine in this population.  [ 30 ]


Caucasians with European descent predominantly (around 71%) have the functional group of CYP2D6 alleles, producing extensive metabolism, while functional alleles represent only around 50% of the allele frequency in populations of Asian descent. [ 31 ]


This variability is accounted for by the differences in the prevalence of various  CYP2D6  alleles among the populations–approximately 10% of whites are intermediate metabolizers, due to decreased CYP2D6 function, because they appear to have the one ( heterozygous ) non-functional  CYP2D6*4  allele, [ 32 ]  while approximately 50% of Asians possess the decreased functioning  CYP2D6*10  allele. [ 32 ]


Following is a table of selected  substrates ,  inducers  and  inhibitors  of CYP2D6. Where classes of agents are listed, there may be exceptions within the class.


Inhibitors of CYP2D6 can be classified by their  potency , such as:


Strong


Unspecified potency


In  enzymology , a  dihydropyrimidine dehydrogenase (NADP+)  ( EC   1.3.1.2 ) is an  enzyme  that  catalyzes  the  chemical reaction


Thus, the two  substrates  of this enzyme are  5,6-dihydrouracil  and  NADP + , whereas its 3  products  are  uracil ,  NADPH , and  H + .


In humans the enzyme is encoded by the  DPYD   gene . [ 1 ] [ 2 ]  It is the initial and rate-limiting step in pyrimidine catabolism. [ citation needed ]  It catalyzes the reduction of  uracil  and  thymine . [ 3 ]  It is also involved in the degradation of the chemotherapeutic drugs  5-fluorouracil  and  tegafur . [ 4 ]  It also participates in  beta-alanine metabolism  and  pantothenate and coa biosynthesis .


The  systematic name  of this enzyme class is  5,6-dihydrouracil:NADP+ 5-oxidoreductase .  Other names in common use include:


As of late 2007, 5  structures  have been solved for this class of enzymes, with  PDB  accession codes  1GT8 ,  1GTE ,  1GTH ,  1H7W , and  1H7X .


The protein is a  pyrimidine  catabolic enzyme and the initial and rate-limiting factor in the pathway of  uracil  and  thymidine   catabolism . Genetic deficiency of this enzyme results in an error in pyrimidine metabolism associated with thymine-uraciluria and an increased risk of toxicity in cancer patients receiving  5-fluorouracil  chemotherapy. [ 2 ]


Click on genes, proteins and metabolites below to link to respective articles. [ § 1 ]


This  EC 1.3   enzyme -related article is a  stub . You can help Wikipedia by  expanding it .


The following is a list of countries by  pharmaceutical   exports .


Global sales from exported drugs and medicines by country total US$371.3 billion in 2018. Overall the value of drugs and medicine exports grew by an average 5.80% for all exporting countries since 2014 when drugs and medicines shipments were valued at $344.1 billion. Year over year, there was a 7.9% uptick from 2017 to 2018.


Among continents, European countries sold the highest dollar value worth of exported drugs and medicines during 2018 with shipments from Europe totaling $295.8 billion or 79.70% of the global total. In second place were Asian pharmaceutical exporters at 10.70% while 8.10% of worldwide drugs and medicine shipments originated from North America.


Smaller percentages came from drugs and medicines suppliers in Latin America (0.7%) excluding Mexico but including the Caribbean, Oceania (0.5%) led by Australia and New Zealand, then Africa (0.2%).


The 4-digit Harmonized Tariff System code prefixes for drugs and medicines are:


Below are the 15 countries that exported the highest dollar value worth of drugs and medicines during 2021.


By value, the listed 15 countries shipped 85.3% of all exported drugs and medicine for 2021.


Among the above countries, the fastest-growing exporters of drugs and medicines from 2019 to 2020 were: Slovenia (up 42.2%), Ireland (up 28.8%), India (up 13.5%) and Italy (up 11.2%).


Those countries that posted the slowest gains year over year were: Switzerland (up 0.7%), Canada (up 1.6%), United Kingdom (up 1.6%), United States (up 1.8%) and Germany (up 6.5%). [ 1 ]


Data is for 2014, in billions of  United States dollars , as reported by  The Observatory of Economic Complexity . Currently the top ten countries are listed, which account for more than 75% of the total market value, estimated to be $US 354 billions.


Note: The total was calculated excluding the figures for individual member states (for this purpose these include the UK) in order to avoid double-counting.


These are Wikipedia lists about the  pharmaceutical industry . The pharmaceutical industry develops, produces, and markets  drugs  or  pharmaceuticals   licensed  for use as  medications .  Pharmaceutical companies  are allowed to deal in  generic  or  brand  medications and medical devices. They are subject to a  variety of laws  and regulations regarding the production, testing, and  marketing of drugs .


The  pharmaceutical industry  is a  medical  industry that discovers, develops, produces and markets pharmaceutical  goods  such as  medications  and  medical devices . Medications are then administered to (or  self-administered  by)  patients  for  curing  or  prevention  of  disease , as well as alleviating  symptoms  of illness or  injury . [ 1 ] [ 2 ]


Pharmaceutical companies  may deal in  generic ,  branded , or both, within different contexts. Generic materials are without the involvement of  intellectual property , whereas branded materials are protected by  chemical patents . The industry's various subdivisions include distinct areas, such as manufacturing  biologics  or  total synthesis . The industry is subject to a  variety of laws and regulations  that govern the  patenting , efficacy testing,  safety evaluation , and  marketing  of these drugs. The global pharmaceutical market produced treatments worth a total of $1,228.45 billion in 2020. The sector showed a  compound annual growth rate  (CAGR) of 1.8% in 2021, including the effects of the  COVID-19 pandemic . [ 3 ]


In historical terms, the pharmaceutical industry as an intellectual  concept  arose in the middle to late 1800s in  nation-states  with  developed economies  such as  Germany ,  Switzerland , and the  United States . Some  businesses  engaging in synthetic  organic chemistry , such as several firms generating  dyestuffs  derived from  coal tar  on a large scale, were seeking out new applications of their artificial  materials  in terms of human  health . This trend to increased  capital investment  occurred in tandem with the scholarly study of  pathology  as a  field  advancing significantly, and a variety of businesses set up cooperative relationships with  academic   laboratories  evaluating human injury and disease. Examples of industrial companies with a pharmaceutical focus that have endured to this day after such distant beginnings include  Bayer  (based out of Germany) and  Pfizer  (based out of the U.S.). [ 4 ]


The modern era of the pharmaceutical industry began with local  apothecaries  that expanded their traditional role of distributing  botanical drugs  such as  morphine  and  quinine  to wholesale manufacture in the mid-1800s. Intentional  drug discovery  from plants began with the extraction of  morphine  – an  analgesic  and sleep-inducing agent – from  opium  by the German apothecary assistant  Friedrich Sertürner  somewhere between 1803 and 1805.  Sertürner later named this compound after the Greek god of dreams,  Morpheus . Multinational corporations including  Merck ,  Hoffman-La Roche , Burroughs-Wellcome (now part of  Glaxo Smith Kline ),  Abbott Laboratories ,  Eli Lilly  and  Upjohn  (now part of  Pfizer ) began as local apothecary shops in the mid-1800s. By the late 1880s, German dye manufacturers had perfected the purification of individual  organic compounds  from  tar  and other mineral sources and had also established rudimentary methods in  organic chemical synthesis . [ 4 ]  The development of synthetic chemical methods allowed scientists to systematically vary the structure of chemical substances, and growth in the emerging science of  pharmacology  expanded their ability to evaluate the biological effects of these structural changes. [ citation needed ]


By the 1890s, the profound effect of  adrenal  extracts on many different tissue types had been discovered, setting off a search both for the mechanism of chemical signaling and efforts to exploit these observations for the development of new drugs. The blood pressure raising and vasoconstrictive effects of adrenal extracts were of particular interest to surgeons as  hemostatic  agents and as treatment for shock, and a number of companies developed products based on adrenal extracts containing varying purities of the active substance. In 1897,  John Abel  at the  Johns Hopkins University  identified the active principle as  epinephrine , which he isolated in an impure state as the sulfate salt. Industrial chemist  Jōkichi Takamine  later developed a method for obtaining epinephrine in a pure state, and licensed the technology to  Parke-Davis . Parke-Davis marketed epinephrine under the trade name  Adrenalin . Injected epinephrine proved to be especially efficacious for the acute treatment of  asthma  attacks, and an inhaled version was sold in the United States until 2011 ( Primatene Mist ). [ 5 ] [ 6 ]  By 1929 epinephrine had been formulated into an inhaler for use in the treatment of nasal congestion.


While highly effective, the requirement for injection limited the use of epinephrine [ clarification needed ]  and orally active derivatives were sought. A structurally similar compound,  ephedrine , was identified by Japanese chemists in the  Ma Huang  plant and marketed by  Eli Lilly  as an oral treatment for asthma. Following the work of  Henry Dale  and  George Barger  at  Burroughs-Wellcome , academic chemist  Gordon Alles  synthesized  amphetamine  and tested it in asthma patients in 1929. The drug proved to have only modest anti-asthma effects but produced sensations of exhilaration and palpitations. Amphetamine was developed by  Smith, Kline and French  as a nasal decongestant under the trade name  Benzedrine Inhaler.  Amphetamine was eventually developed for the treatment of  narcolepsy ,  post-encephalitic parkinsonism , and mood elevation in depression and other psychiatric indications. It received approval as a New and Nonofficial Remedy from the  American Medical Association  for these uses in 1937, [ 7 ]  and remained in common use for depression until the development of  tricyclic antidepressants  in the 1960s. [ 6 ]


In 1903,  Hermann Emil Fischer  and  Joseph von Mering  disclosed their discovery that diethylbarbituric acid, formed from the reaction of diethylmalonic acid, phosphorus oxychloride and urea, induces sleep in dogs. The discovery was patented and licensed to  Bayer pharmaceuticals , which marketed the compound under the trade name  Veronal  as a sleep aid beginning in 1904. Systematic investigations of the effect of structural changes on potency and duration of action led to the discovery of  phenobarbital  at Bayer in 1911 and the discovery of its potent anti-epileptic activity in 1912. Phenobarbital was among the most widely used drugs for the treatment of  epilepsy  through the 1970s, and as of 2014, remains on the World Health Organizations list of essential medications. [ 8 ] [ 9 ]  The 1950s and 1960s saw increased awareness of the addictive properties and abuse potential of barbiturates and amphetamines and led to increasing restrictions on their use and growing government oversight of prescribers. Today, amphetamine is largely restricted to use in the treatment of  attention deficit disorder  and phenobarbital in the treatment of  epilepsy . [ 10 ] [ 11 ]


In 1958,  Leo Sternbach  discovered the first  benzodiazepine ,  chlordiazepoxide  (Librium). Dozens of other benzodiazepines have been developed and are in use, some of the more popular drugs being  diazepam  (Valium),  alprazolam  (Xanax),  clonazepam  (Klonopin), and  lorazepam  (Ativan). Due to their far superior safety and therapeutic properties, benzodiazepines have largely replaced the use of barbiturates in medicine, except in certain special cases. When it was later discovered that benzodiazepines, like barbiturates, significantly lose their effectiveness and can have serious side effects when taken long-term,  Heather Ashton  researched benzodiazepine dependence and developed a protocol to discontinue their use. [ citation needed ]


A series of experiments performed from the late 1800s to the early 1900s revealed that  diabetes  is caused by the absence of a substance normally produced by the pancreas. In 1869,  Oskar Minkowski  and  Joseph von Mering  found that diabetes could be induced in dogs by surgical removal of the pancreas. In 1921, Canadian professor  Frederick Banting  and his student Charles Best repeated this study and found that injections of pancreatic extract reversed the symptoms produced by pancreas removal. Soon, the extract was demonstrated to work in people, but development of insulin therapy as a routine medical procedure was delayed by difficulties in producing the material in sufficient quantity and with reproducible purity. The researchers sought assistance from industrial collaborators at Eli Lilly and Co. based on the company's experience with large scale purification of biological materials. Chemist  George B. Walden  of Eli Lilly and Company found that careful adjustment of the pH of the extract allowed a relatively pure grade of insulin to be produced. Under pressure from Toronto University and a potential patent challenge by academic scientists who had independently developed a similar purification method, an agreement was reached for non-exclusive production of insulin by multiple companies. Prior to the discovery and widespread availability of insulin therapy the life expectancy of diabetics was only a few months. [ 12 ]


The development of drugs for the treatment of infectious diseases was a major focus of early research and development efforts; in 1900, pneumonia, tuberculosis, and diarrhea were the three leading causes of death in the United States and mortality in the first year of life exceeded 10%. [ 13 ] [ 14 ] [ failed verification ]


In 1911  arsphenamine , the first synthetic anti-infective drug, was developed by  Paul Ehrlich  and chemist  Alfred Bertheim  of the Institute of Experimental Therapy in Berlin. The drug was given the commercial name Salvarsan. [ 15 ]  Ehrlich, noting both the general toxicity of  arsenic  and the selective absorption of certain dyes by bacteria, hypothesized that an arsenic-containing dye with similar selective absorption properties could be used to treat bacterial infections. Arsphenamine was prepared as part of a campaign to synthesize a series of such compounds, and was found to exhibit partially selective toxicity. Arsphenamine proved to be the first effective treatment for  syphilis , a disease untl then had been incurable and led inexorably to severe skin ulceration, neurological damage, and death. [ 16 ]


Ehrlich's approach of systematically varying the chemical structure of synthetic compounds and measuring the effects of these changes on biological activity was pursued broadly by industrial scientists, including  Bayer  scientists Josef Klarer, Fritz Mietzsch, and  Gerhard Domagk . This work, also based on the testing of compounds available from the German dye industry, led to the development of  Prontosil , the first representative of the  sulfonamide  class of  antibiotics . Compared to arsphenamine, the sulfonamides had a broader spectrum of activity and were far less toxic, rendering them useful for infections caused by pathogens such as  streptococci . [ 17 ]  In 1939, Domagk received the  Nobel Prize in Medicine  for this discovery. [ 18 ] [ 19 ]  Nonetheless, the dramatic decrease in deaths from infectious diseases that occurred prior to  World War II  was primarily the result of improved public health measures such as clean water and less crowded housing, and the impact of anti-infective drugs and vaccines was significant mainly after World War II. [ 20 ] [ 21 ]


In 1928,  Alexander Fleming  discovered the antibacterial effects of  penicillin , but its exploitation for the treatment of human disease awaited the development of methods for its large scale production and purification. These were developed by a U.S. and British government-led consortium of pharmaceutical companies during the world war. [ 22 ]


There was early progress toward the development of vaccines throughout this period, primarily in the form of academic and government-funded basic research directed toward the identification of the pathogens responsible for common communicable diseases. In 1885,  Louis Pasteur  and  Pierre Paul Émile Roux  created the first  rabies vaccine . The first  diphtheria vaccines  were produced in 1914 from a mixture of  diphtheria toxin  and  antitoxin  (produced from the serum of an inoculated animal), but the safety of the inoculation was marginal and it was not widely used. The United States recorded 206,000 cases of diphtheria in 1921, resulting in 15,520 deaths. In 1923, parallel efforts by  Gaston Ramon  at the Pasteur Institute and  Alexander Glenny  at the Wellcome Research Laboratories (later part of  GlaxoSmithKline ) led to the discovery that a safer vaccine could be produced by treating diphtheria toxin with  formaldehyde . [ 23 ]  In 1944,  Maurice Hilleman  of Squibb Pharmaceuticals developed the first  vaccine against Japanese Encephalitis . [ 24 ]  Hilleman later moved to  Merck , where he played a key role in the development of vaccines against  measles ,  mumps ,  chickenpox ,  rubella ,  hepatitis A ,  hepatitis B , and  meningitis .


Prior to the 20th century, drugs were generally produced by small scale manufacturers with little regulatory control over manufacturing or claims of safety and efficacy. To the extent that such laws did exist, enforcement was lax. In the United States, increased regulation of vaccines and other biological drugs was spurred by tetanus outbreaks and deaths caused by the distribution of contaminated smallpox vaccine and diphtheria antitoxin. [ 25 ]  The Biologics Control Act of 1902 required that federal government grant premarket approval for every biological drug and for the process and facility producing such drugs. This was followed in 1906 by the  Pure Food and Drugs Act , which forbade the interstate distribution of adulterated or misbranded foods and drugs. A drug was considered misbranded if it contained alcohol, morphine, opium, cocaine, or any of several other potentially dangerous or addictive drugs, and if its label failed to indicate the quantity or proportion of such drugs. The government's attempts to use the law to prosecute manufacturers for making unsupported claims of efficacy were undercut by a Supreme Court ruling restricting the federal government's enforcement powers to cases of incorrect specification of the drug's ingredients. [ 26 ]


In 1937 over 100 people died after ingesting " Elixir Sulfanilamide " manufactured by S.E. Massengill Company of Tennessee. The product was formulated in  diethylene glycol , a highly toxic solvent that is now widely used as antifreeze. [ 27 ]  Under the laws extant at that time, prosecution of the manufacturer was possible only under the technicality that the product had been called an "elixir", which literally implied a solution in ethanol. In response to this episode, the U.S. Congress passed  the Federal Food, Drug, and Cosmetic Act of 1938 , which for the first time required pre-market demonstration of safety before a drug could be sold, and explicitly prohibited false therapeutic claims. [ 28 ]


The aftermath of  World War II  saw an explosion in the discovery of new classes of antibacterial drugs [ 29 ]  including the  cephalosporins  (developed by Eli Lilly based on the seminal work of  Giuseppe Brotzu  and  Edward Abraham ), [ 30 ] [ 31 ]   streptomycin  (discovered during a Merck-funded research program in Selman Waksman's laboratory [ 32 ] ), the tetracyclines [ 33 ]  (discovered at Lederle Laboratories, now a part of  Pfizer ), erythromycin (discovered at Eli Lilly and Co.) [ 34 ]  and their extension to an increasingly wide range of bacterial pathogens. Streptomycin, discovered during a Merck-funded research program in Selman Waksman's laboratory at Rutgers in 1943, became the first effective treatment for tuberculosis. At the time of its discovery, sanitoriums for the isolation of tuberculosis-infected people were an ubiquitous feature of cities in developed countries, with 50% dying within 5 years of admission. [ 32 ] [ 35 ]


A  Federal Trade Commission  report issued in 1958 attempted to quantify the effect of antibiotic development on American public health. The report found that over the period 1946–1955, there was a 42% drop in the incidence of diseases for which antibiotics were effective and only a 20% drop in those for which antibiotics were not effective. The report concluded that "it appears that the use of antibiotics, early diagnosis, and other factors have limited the epidemic spread and thus the number of these diseases which have occurred". The study further examined mortality rates for eight common diseases for which antibiotics offered effective therapy (syphilis, tuberculosis, dysentery, scarlet fever, whooping cough, meningococcal infections, and pneumonia), and found a 56% decline over the same period. [ 36 ]  Notable among these was a 75% decline in deaths due to tuberculosis. [ 37 ]


During the years 1940–1955, the rate of decline in the U.S.  death rate  accelerated from 2% per year to 8% per year, then returned to the historical rate of 2% per year. The dramatic decline in the immediate post-war years has been attributed to the rapid development of new treatments and vaccines for infectious disease that occurred during these years. [ 39 ] [ 21 ]
Vaccine development continued to accelerate, with the most notable achievement of the period being  Jonas Salk 's 1954 development of the polio vaccine under the funding of the non-profit  National Foundation for Infantile Paralysis . The vaccine process was never patented but was instead given to pharmaceutical companies to manufacture as a low-cost  generic . In 1960 Maurice Hilleman of  Merck Sharp & Dohme  identified the  SV40  virus, which was later shown to cause tumors in many mammalian species. It was later determined that SV40 was present as a contaminant in polio vaccine lots that had been administered to 90% of the children in the United States. [ 40 ] [ 41 ]  The contamination appears to have originated both in the original cell stock and in monkey tissue used for production. In 2004 the  National Cancer Institute  announced that it had concluded that SV40 is not associated with cancer in people. [ 42 ]


Other notable new vaccines of the period include those for measles (1962,  John Franklin Enders  of Children's Medical Center Boston, later refined by Maurice Hilleman at Merck), Rubella (1969, Hilleman, Merck) and mumps (1967, Hilleman, Merck) [ 43 ]  The United States incidences of rubella, congenital rubella syndrome, measles, and mumps all fell by >95% in the immediate aftermath of widespread vaccination. [ 44 ]  The first 20 years of licensed  measles vaccination  in the U.S. prevented an estimated 52 million cases of the disease, 17,400 cases of  mental retardation , and 5,200 deaths. [ 45 ]


Hypertension is a risk factor for atherosclerosis, [ 46 ]   heart failure , [ 47 ]   coronary artery disease , [ 48 ] [ 49 ]   stroke , [ 50 ]   renal disease , [ 51 ] [ 52 ]  and  peripheral arterial disease , [ 53 ] [ 54 ]  and is the most important  risk factor  for  cardiovascular   morbidity  and  mortality , in  industrialized countries . [ 55 ]  Prior to 1940 approximately 23% of all deaths among persons over age 50 were attributed to hypertension. Severe cases of hypertension were treated by surgery. [ 56 ]


Early developments in the field of treating hypertension included quaternary ammonium ion sympathetic nervous system blocking agents, but these compounds were never widely used due to their severe side effects, because the long-term health consequences of high blood pressure had not yet been established, and because they had to be administered by injection.


In 1952 researchers at Ciba discovered the first orally available vasodilator,  hydralazine . [ 57 ]  A major shortcoming of hydralazine monotherapy was that it lost its effectiveness over time ( tachyphylaxis ). In the mid-1950s Karl H. Beyer, James M. Sprague, John E. Baer, and Frederick C. Novello of  Merck and Co.  discovered and developed  chlorothiazide , which remains the most widely used antihypertensive drug today. [ 58 ]  This development was associated with a substantial decline in the mortality rate among people with hypertension. [ 59 ]  The inventors were recognized by a Public Health  Lasker Award  in 1975 for "the saving of untold thousands of lives and the alleviation of the suffering of millions of victims of hypertension". [ 60 ]


A 2009 Cochrane review concluded that thiazide antihypertensive drugs reduce the risk of death ( RR  0.89), stroke (RR 0.63), coronary heart disease (RR 0.84), and cardiovascular events (RR 0.70) in people with high blood pressure. [ 61 ]  In the ensuring years other classes of antihypertensive drug were developed and found wide acceptance in combination therapy, including loop diuretics (Lasix/ furosemide ,  Hoechst Pharmaceuticals , 1963), [ 62 ]   beta blockers  ( ICI Pharmaceuticals , 1964) [ 63 ]   ACE inhibitors , and  angiotensin receptor blockers . ACE inhibitors reduce the risk of new onset kidney disease [RR 0.71] and death [RR 0.84] in diabetic patients, irrespective of whether they have hypertension. [ 64 ]


Prior to the Second World war, birth control was prohibited in many countries, and in the United States even the discussion of contraceptive methods sometimes led to prosecution under  Comstock laws . The history of the development of oral contraceptives is thus closely tied to the  birth control movement  and the efforts of activists  Margaret Sanger ,  Mary Dennett , and  Emma Goldman . Based on fundamental research performed by  Gregory Pincus  and synthetic methods for progesterone developed by  Carl Djerassi  at  Syntex  and by  Frank Colton  at  G.D. Searle & Co. , the first oral contraceptive,  Enovid , was developed by G.D. Searle & Co. and approved by the FDA in 1960. The original formulation incorporated vastly excessive doses of hormones, and caused severe side effects. Nonetheless, by 1962, 1.2 million American women were on the pill, and by 1965 the number had increased to 6.5 million. [ 65 ] [ 66 ] [ 67 ] [ 68 ]  The availability of a convenient form of temporary contraceptive led to dramatic changes in social mores including expanding the range of lifestyle options available to women, reducing the reliance of women on men for contraceptive practice, encouraging the delay of marriage, and increasing pre-marital co-habitation. [ 69 ]


In the U.S., a push for revisions of the FD&C Act emerged from Congressional hearings led by Senator  Estes Kefauver  of Tennessee in 1959. The hearings covered a wide range of policy issues, including advertising abuses, questionable efficacy of drugs, and the need for greater regulation of the industry. While momentum for new legislation temporarily flagged under extended debate, a new tragedy emerged that underscored the need for more comprehensive regulation and provided the driving force for the passage of new laws.


On 12 September 1960, an American licensee, the William S. Merrell Company of Cincinnati, submitted a new drug application for Kevadon ( thalidomide ), a  sedative  that had been marketed in Europe since 1956. The FDA medical officer in charge of reviewing the compound,  Frances Kelsey , believed that the data supporting the safety of thalidomide was incomplete. The firm continued to pressure Kelsey and the FDA to approve the application until November 1961, when the drug was pulled off the German market because of its association with grave congenital abnormalities. Several thousand newborns in Europe and elsewhere suffered the  teratogenic  effects of thalidomide. Without approval from the FDA, the firm distributed Kevadon to over 1,000 physicians there under the guise of investigational use. Over 20,000 Americans received thalidomide in this "study," including 624 pregnant patients, and about 17 known newborns suffered the effects of the drug. [ citation needed ]


The  thalidomide  tragedy resurrected Kefauver's bill to enhance drug regulation that had stalled in Congress, and the  Kefauver-Harris Amendment  became law on 10 October 1962. Manufacturers henceforth had to prove to FDA that their drugs were effective as well as safe before they could go on the US market. The FDA received authority to regulate the advertising of prescription drugs and to establish  good manufacturing practices . The law required that all drugs introduced between 1938 and 1962 had to be effective. A collaborative study by the U.S. Food and Drug Administration and the National Academy of Sciences showed that nearly 40 percent of these products were not effective. A similarly comprehensive study of over-the-counter products began ten years later. [ 70 ]


In 1971,  Akira Endo , a Japanese biochemist working for the pharmaceutical company Sankyo, identified  mevastatin  (ML-236B), a molecule produced by the fungus  Penicillium citrinum , as an inhibitor of HMG-CoA reductase, a critical enzyme used by the body to produce cholesterol.  Animal trials  showed very good inhibitory effect as in  clinical trials , however a long-term study in dogs found toxic effects at higher doses and as a result mevastatin was believed to be too toxic for human use. Mevastatin was never marketed, because of its adverse effects of tumors, muscle deterioration, and sometimes death in laboratory dogs.


P. Roy Vagelos , chief scientist and later CEO of  Merck & Co , was interested, and made several trips to Japan starting in 1975. By 1978, Merck had isolated  lovastatin  (mevinolin, MK803) from the fungus  Aspergillus terreus , first marketed in 1987 as Mevacor. [ 71 ] [ 72 ] [ 73 ]


In April 1994, the results of a Merck-sponsored study, the  Scandinavian Simvastatin Survival Study , were announced. Researchers tested  simvastatin , later sold by Merck as Zocor, on 4,444 patients with high cholesterol and heart disease. After five years, the study concluded the patients saw a 35% reduction in their cholesterol, and their chances of dying of a heart attack were reduced by 42%. [ 74 ]  In 1995, Zocor and Mevacor both made Merck over US$1 billion. Endo was awarded the 2006  Japan Prize , and the  Lasker-DeBakey Clinical Medical Research Award  in 2008. For his "pioneering research into a new class of molecules" for "lowering cholesterol," [ sentence fragment ] [ 75 ] [ 76 ]


Since several decades, biologics have been rising in importance in comparison with small molecules treatments. The  biotech  subsector, animal health and the Chinese pharmaceutical sector have also grown substantially. On the organisational side, big international pharma corporations have experienced a substantial decline of their value share. Also, the core generic sector (substitutions for off-patent brands) has been downvalued due to competition. [ 77 ]


Torreya estimated the pharmaceutical industry to have a market valuation of US$7.03 trillion by February 2021 from which US$6.1 trillion is the value of the publicly traded companies. Small Molecules modality had 58.2% of the valuation share down from 84.6% in 2003. Biologics was up at 30.5% from 14.5%. The valuation share of Chinese Pharma grew from 2003 to 2021 from 1% to 12% overtaking Switzerland who is now ranked number 3 with 7.7%. The United States had still by far the most valued pharmaceutical industry with 40% of global valuation. [ 78 ]  2023 was a year of layoffs for at least 10,000 people across 129 public biotech firms globally, albeit most small firms; this was a significant increase in reductions versus 2022 was in part due to worsening global financial conditions and a reduction in investment by "generalist investors". [ 79 ]  Private firms also saw a significant reduction in  venture capital  investment in 2023, continuing a downward trend started in 2021, which also led to a reduction in  initial public offerings  being floated. [ 79 ]


A 2022 article articulated this notion succinctly by saying "In the business of drug development, deals can be just as important as scientific breakthroughs", typically referred to as pharmaceutical M&A (for mergers and acquisitions). [ 80 ]  It highlighted that some of the most impactful of the remedies of the early 21st Century were only made possible through M&A activities, specifically noting  Keytruda  and  Humira . [ 80 ]


Drug discovery  is the process by which potential  drugs  are discovered or designed. In the past, most drugs have been discovered either by isolating the active ingredient from traditional remedies or by  serendipitous  discovery. Modern  biotechnology  often focuses on understanding the  metabolic pathways  related to a  disease  state or  pathogen , and manipulating these pathways using  molecular biology  or  biochemistry . A great deal of early-stage drug discovery has traditionally been carried out by universities and research institutions.


Drug development  refers to activities undertaken after a compound is identified as a potential drug in order to establish its suitability as a medication. Objectives of drug development are to determine appropriate  formulation  and  dosing , as well as to establish  safety . Research in these areas generally includes a combination of  in vitro  studies,  in vivo  studies, and  clinical trials . The cost of late stage development has meant it is usually done by the larger pharmaceutical companies. [ 81 ]  The pharmaceuticals and biotechnology industry spends more than 15% of its net sales for Research & Development which is in comparison with other industries by far the highest share. [ 82 ]


Often, large multinational corporations exhibit  vertical integration , participating in a broad range of drug discovery and development, manufacturing and quality control, marketing, sales, and distribution. Smaller organizations, on the other hand, often focus on a specific aspect such as discovering drug candidates or developing formulations. Often, collaborative agreements between research organizations and large pharmaceutical companies are formed to explore the potential of new drug substances. More recently, multi-nationals are increasingly relying on  contract research organizations  to manage drug development. [ 83 ]


Drug  discovery and development are very expensive; of all compounds investigated for use in humans only a small fraction are eventually  approved  in most nations by government-appointed medical institutions or boards, who have to approve new  drugs  before they can be marketed in those countries. In 2010 18 NMEs (New Molecular Entities) were approved and three  biologics  by the FDA, or 21 in total, which is down from 26 in 2009 and 24 in 2008. On the other hand, there were only 18 approvals in total in 2007 and 22 back in 2006. Since 2001, the Center for Drug Evaluation and Research has averaged 22.9 approvals a year. [ 84 ]
This approval comes only after heavy investment in  pre-clinical development  and  clinical trials , as well as a commitment to ongoing  safety monitoring . Drugs which fail part-way through this process often incur large costs, while generating no revenue in return. If the cost of these failed drugs is taken into account, the cost of developing a successful new drug ( new chemical entity , or NCE), has been estimated at US$1.3 billion [ 85 ]  (not including  marketing expenses ). Professors Light and Lexchin reported in 2012, however, that the rate of approval for new drugs has been a relatively stable average rate of 15 to 25 for decades. [ 86 ]


Industry-wide research and investment reached a record $65.3 billion in 2009. [ 87 ]  While the cost of research in the U.S. was about $34.2 billion between 1995 and 2010, revenues rose faster (revenues rose by $200.4 billion in that time). [ 86 ]


A study by the consulting firm  Bain & Company  reported that the cost for discovering, developing and launching (which factored in marketing and other business expenses) a new drug (along with the prospective drugs that fail) rose over a five-year period to nearly $1.7 billion in 2003. [ 88 ]  According to Forbes, by 2010 development costs were between $4 billion to $11 billion per drug. [ 89 ]


Some of these estimates also take into account the  opportunity cost  of investing capital many years before revenues are realized (see  Time-value of money ). Because of the very long time needed for discovery, development, and approval of pharmaceuticals, these costs can accumulate to nearly half the total expense. A direct consequence within the pharmaceutical industry value chain is that major pharmaceutical multinationals tend to increasingly outsource risks related to fundamental research, which somewhat reshapes the industry ecosystem with biotechnology companies playing an increasingly important role, and overall strategies being redefined accordingly. [ 90 ]  Some approved drugs, such as those based on re-formulation of an existing  active ingredient  (also referred to as Line-extensions) are much less expensive to develop.


In the United States, new pharmaceutical products must be approved by the  Food and Drug Administration  (FDA) as being both safe and effective. This process generally involves submission of an  Investigational New Drug  (IND) filing with sufficient pre-clinical data to support proceeding with human trials. Following IND approval,  three phases  of progressively larger human clinical trials may be conducted.  Phase I  generally studies  toxicity  using healthy volunteers.  Phase II  can include  pharmacokinetics  and  dosing  in patients, and  Phase III  is a very large study of efficacy in the intended patient population. Following the successful completion of Phase III testing, a  New Drug Application  is submitted to the FDA. The FDA reviews the data and if the product is seen as having a positive benefit-risk assessment, approval to market the product in the US is granted. [ 91 ]


A fourth phase of post-approval surveillance is also often required due to the fact that even the largest clinical trials cannot effectively predict the prevalence of rare side-effects.  Postmarketing surveillance  ensures that after marketing the safety of a drug is monitored closely. In certain instances, its indication may need to be limited to particular patient groups, and in others the substance is withdrawn from the market completely.


The FDA provides information about approved drugs at the Orange Book site. [ 92 ]


In the UK, the  Medicines and Healthcare products Regulatory Agency  (MHRA) approves and evaluates drugs for use. Normally an approval in the UK and other European countries comes later than one in the USA. Then it is the  National Institute for Health and Care Excellence  (NICE), for England and Wales, who decides if and how the  National Health Service  (NHS) will allow (in the sense of paying for) their use. The  British National Formulary  is the core guide for pharmacists and clinicians.


In many non-US western countries, a 'fourth hurdle' of  cost effectiveness analysis  has developed before new technologies can be provided. This focuses on the 'efficacy price tag' (in terms of, for example, the cost per  QALY ) of the technologies in question. In England and Wales NICE decides whether and in what circumstances drugs and technologies will be made available by the NHS, whilst similar arrangements exist with the  Scottish Medicines Consortium  in Scotland, and the  Pharmaceutical Benefits Advisory Committee  in Australia. A product must pass the threshold for cost-effectiveness if it is to be approved. Treatments must represent 'value for money' and a net benefit to society.


There are  special rules  for certain rare diseases ("orphan diseases") in several major drug regulatory territories. For example, diseases involving fewer than 200,000 patients in the United States, or larger populations in certain circumstances are subject to the Orphan Drug Act. [ 93 ]  Because medical research and development of drugs to treat such diseases is financially disadvantageous, companies that do so are rewarded with tax reductions, fee waivers, and market exclusivity on that drug for a limited time (seven years), regardless of whether the drug is protected by patents.


In 2011, global spending on prescription drugs topped $954 billion, even as growth slowed somewhat in Europe and North America. The United States accounts for more than a third of the global pharmaceutical market, with $340 billion in annual sales followed by the EU and Japan. [ 95 ]  Emerging markets such as China, Russia, South Korea and Mexico outpaced that market, growing a huge 81 percent. [ 96 ] [ 97 ]


The top ten best-selling drugs of 2013 totaled $75.6 billion in sales, with the anti-inflammatory drug  Humira  being the best-selling drug worldwide at $10.7 billion in sales. The second and third best selling were Enbrel and Remicade, respectively. [ 98 ]  The top three best-selling drugs in the United States in 2013 were Abilify ($6.3 billion,) Nexium ($6 billion) and Humira ($5.4 billion). [ 99 ]  The best-selling drug ever,  Lipitor , averaged $13 billion annually and netted $141 billion total over its lifetime before Pfizer's patent expired in November 2011.


IMS Health  publishes an analysis of trends expected in the pharmaceutical industry in 2007, including increasing profits in most sectors despite loss of some patents, and new 'blockbuster' drugs on the horizon. [ 100 ]


Depending on a number of considerations, a company may apply for and be granted a  patent  for the drug, or the process of producing the drug, granting exclusivity rights typically for about 20 years. [ 101 ]  However, only after rigorous study and testing, which takes 10 to 15 years on average, will governmental authorities grant permission for the company to market and sell the drug. [ 102 ]  Patent protection enables the owner of the patent to recover the costs of research and development through high profit margins for the  branded  drug. When the patent protection for the drug expires, a  generic drug  is usually developed and sold by a competing company. The development and approval of generics is less expensive, allowing them to be sold at a lower price. Often the owner of the branded drug will introduce a generic version before the patent expires in order to get a head start in the generic market. [ 103 ]  Restructuring has therefore become routine, driven by the patent expiration of products launched during the industry's "golden era" in the 1990s and companies' failure to develop sufficient new blockbuster products to replace lost revenues. [ 104 ]


In the U.S., the value of prescriptions increased over the period of 1995 to 2005 by 3.4 billion annually, a 61 percent increase.  Retail sales of prescription drugs  jumped 250 percent from $72 billion to $250 billion, while the average price of prescriptions more than doubled from $30 to $68. [ 105 ]


Advertising is common in healthcare journals as well as through more mainstream media routes. In some countries, notably the US, they are allowed to advertise directly to the general public. Pharmaceutical companies generally employ salespeople (often called 'drug reps' or, an older term, 'detail men') to market directly and personally to physicians and other healthcare providers. In some countries, notably the US,  pharmaceutical companies also employ lobbyists  to influence politicians. Marketing of prescription drugs in the US is regulated by the federal  Prescription Drug Marketing Act of 1987 . The pharmaceutical marketing plan incorporates the spending plans, channels, and thoughts which will take the drug association, and its items and administrations, forward in the current scene.


The book  Bad Pharma  also discusses the influence of drug representatives, how ghostwriters are employed by the drug companies to write papers for academics to publish, how independent the academic journals really are, how the drug companies finance doctors' continuing education, and how patients' groups are often funded by industry. [ 106 ]


Since the 1980s, new methods of marketing for prescription drugs to consumers have become important. Direct-to-consumer media advertising was legalised in the FDA Guidance for Industry on Consumer-Directed Broadcast Advertisements.


There has been increasing controversy surrounding pharmaceutical marketing and influence. There have been accusations and findings of influence on doctors and other health professionals through drug reps including the constant provision of marketing 'gifts' and biased information to health professionals; [ 107 ]  highly prevalent advertising in journals and conferences; funding independent healthcare organizations and health promotion campaigns; lobbying physicians and politicians (more than any other industry in the US [ 108 ] ); sponsorship of  medical schools  or nurse training; sponsorship of continuing educational events, with influence on the curriculum; [ 109 ]  and hiring physicians as paid consultants on medical advisory boards.


Some advocacy groups, such as  No Free Lunch  and  AllTrials , have criticized the effect of drug marketing to physicians because they say it biases physicians to prescribe the marketed drugs even when others might be cheaper or better for the patient. [ 110 ]


There have been related accusations of  disease mongering [ 111 ]  (over-medicalising) to expand the market for medications. An inaugural conference on that subject took place in Australia in 2006. [ 112 ]  In 2009, the Government-funded  National Prescribing Service  launched the "Finding Evidence – Recognising Hype" program, aimed at educating  GPs  on methods for independent drug analysis. [ 113 ]


Meta-analyses have shown that psychiatric studies sponsored by pharmaceutical companies are several times more likely to report positive results, and if a drug company employee is involved the effect is even larger. [ 114 ] [ 115 ] [ 116 ]  Influence has also extended to the training of doctors and nurses in medical schools, which is being fought.


It has been argued that the design of the  Diagnostic and Statistical Manual of Mental Disorders  and the expansion of the criteria represents an increasing medicalization of human nature, or " disease mongering ", driven by drug company influence on psychiatry. [ 117 ]  The potential for direct  conflict of interest  has been raised, partly because roughly half the authors who selected and defined the DSM-IV psychiatric disorders had or previously had financial relationships with the pharmaceutical industry. [ 118 ]


In the US, starting in 2013, under the Physician Financial Transparency Reports (part of the Sunshine Act), the Centers for Medicare & Medicaid Services has to collect information from applicable manufacturers and group purchasing organizations in order to report information about their financial relationships with physicians and hospitals. Data are made public in the Centers for Medicare & Medicaid Services website. The expectation is that relationship between doctors and Pharmaceutical industry will become fully transparent. [ 119 ]


In a report conducted by  OpenSecrets , there were more than 1,100 lobbyists working in some capacity for the pharmaceutical business in 2017. In the first quarter of 2017, the health products and pharmaceutical industry spent $78 million on lobbying members of the United States Congress. [ 120 ]


The pricing of pharmaceuticals is becoming a major challenge for health systems. [ 121 ]  A November 2020 study by the  West Health  Policy Center stated that more than 1.1 million  senior citizens  in the U.S.  Medicare  program are expected to die prematurely over the next decade because they will be unable to afford their prescription medications, requiring an additional $17.7 billion to be spent annually on avoidable medical costs due to health complications. [ 122 ]


Ben Goldacre  has argued that regulators – such as the  Medicines and Healthcare products Regulatory Agency  (MHRA) in the UK, or the  Food and Drug Administration  (FDA) in the United States – advance the interests of the drug companies rather than the interests of the public due to revolving door exchange of employees between the regulator and the companies and friendships develop between regulator and company employees. [ 123 ]  He argues that regulators do not require that new drugs offer an improvement over what is already available, or even that they be particularly effective. [ 123 ]


Others have argued that excessive regulation suppresses therapeutic innovation and that the current cost of regulator-required clinical trials prevents the full exploitation of new genetic and biological knowledge for the treatment of human disease. A 2012 report by the President's Council of Advisors on Science and Technology made several key recommendations to reduce regulatory burdens to new drug development, including 1) expanding the FDA's use of accelerated approval processes, 2) creating an expedited approval pathway for drugs intended for use in narrowly defined populations, and 3) undertaking pilot projects designed to evaluate the feasibility of a new, adaptive drug approval process. [ 124 ]


Pharmaceutical fraud  involves deceptions which bring financial gain to a pharmaceutical company. It affects individuals and  public  and private insurers. There are several different schemes [ 125 ]  used to defraud the  health care system  which are particular to the pharmaceutical industry. These include: Good Manufacturing Practice (GMP) Violations, Off Label Marketing, Best Price Fraud, CME Fraud, Medicaid Price Reporting, and Manufactured Compound Drugs. [ 126 ]  Of this amount $2.5 billion was recovered through  False Claims Act  cases in FY 2010. Examples of fraud cases include the  GlaxoSmithKline  $3 billion settlement,  Pfizer  $2.3 billion settlement and  Merck & Co.  $650 million settlement. Damages from fraud can be recovered by use of the  False Claims Act , most commonly under the  qui tam  provisions which rewards an individual for being a " whistleblower ", or  relator (law) . [ 127 ]


Every major company selling atypical antipsychotics— Bristol-Myers Squibb ,  Eli Lilly and Company ,  Pfizer ,  AstraZeneca  and  Johnson & Johnson —has either settled recent government cases, under the False Claims Act, for hundreds of millions of dollars or is currently under investigation for possible health care fraud. Following charges of illegal marketing, two of the settlements set records in 2009 for the largest criminal fines ever imposed on corporations. One involved Eli Lilly's antipsychotic  Zyprexa , and the other involved  Bextra , an anti-inflammatory medication used for arthritis. In the Bextra case, the government also charged Pfizer with illegally marketing another antipsychotic,  Geodon ; Pfizer settled that part of the claim for $301 million, without admitting any wrongdoing. [ 128 ]


In July 2012,  GlaxoSmithKline  pleaded guilty to criminal charges and agreed to a $3 billion settlement of the largest health-care fraud case in the U.S. and the largest payment by a drug company. [ 129 ]  The settlement is related to the company's illegal promotion of prescription drugs, its failure to report safety data, [ 130 ]   bribing  doctors, and promoting medicines for uses for which they were not licensed. The drugs involved were  Paxil ,  Wellbutrin ,  Advair ,  Lamictal , and  Zofran  for off-label, non-covered uses. Those and the drugs  Imitrex ,  Lotronex ,  Flovent , and  Valtrex  were involved in the  kickback scheme . [ 131 ] [ 132 ] [ 133 ]


The following is a list of the four largest settlements reached with pharmaceutical companies from 1991 to 2012, rank ordered by the size of the total settlement. Legal claims against the pharmaceutical industry have varied widely over the past two decades, including  Medicare and Medicaid fraud ,  off-label  promotion, and inadequate manufacturing practices. [ 134 ] [ 135 ]


In May 2015, the  New England Journal of Medicine  emphasized the importance of pharmaceutical industry-physician interactions for the development of novel treatments, and argued that moral outrage over industry malfeasance had unjustifiably led many to overemphasize the problems created by financial conflicts of interest. The article noted that major healthcare organizations, such as National Center for Advancing Translational Sciences of the National Institutes of Health, the President's Council of Advisors on Science and Technology, the World Economic Forum, the Gates Foundation, the Wellcome Trust, and the Food and Drug Administration had encouraged greater interactions between physicians and industry in order to improve benefits to patients. [ 140 ] [ 141 ]


In November 2020 several pharmaceutical companies announced successful trials of COVID-19 vaccines, with efficacy
of 90 to 95% in preventing infection. Per company announcements and data reviewed by external analysts, these vaccines are priced at $3 to $37 per dose. [ 142 ]  The Wall Street Journal ran an editorial calling for this achievement to be recognized with a Nobel Peace Prize. [ 143 ]


Doctors Without Borders  warned that high prices and monopolies on medicines, tests, and vaccines would prolong the pandemic and cost lives. They urged governments to prevent profiteering, using  compulsory licenses  as needed, as had already been done by Canada, Chile, Ecuador, Germany, and Israel. [ 144 ]


On 20 February, 46 US lawmakers called for the US government not to grant monopoly rights when giving out taxpayer development money for any coronavirus vaccines and treatments, to avoid giving exclusive control of prices and availability to private manufacturers. [ 145 ]


In the United States, the government signed agreements in which research and development or the building of manufacturing plants for potential COVID-19 therapeutics was subsidized. Typically, the agreement involved the government taking ownership of a certain number of doses of the product without further payment. For example, under the auspices of Operation Warp Speed in the United States, the government subsidized research related to COVID-19 vaccines and therapeutics at Regeneron, [ 146 ]  Johnson and Johnson, Moderna, AstraZeneca, Novavax, Pfizer, and GSK. Typical terms involved research subsidies of $400 million to $2 billion, and included government ownership of the first 100 million doses of any COVID-19 vaccine successfully developed. [ 147 ]


American pharmaceutical company  Gilead  sought and obtained  orphan drug status  for  remdesivir  from the US  Food and Drug Administration  (FDA) on 23 March 2020. This provision is intended to encourage the development of drugs affecting fewer than 200,000 Americans by granting strengthened and extended legal monopoly rights to the manufacturer, along with waivers on taxes and government fees. [ 148 ] [ 149 ]  Remdesivir is a candidate for treating COVID-19; at the time the status was granted, fewer than 200,000 Americans had COVID-19, but numbers were climbing rapidly as the  COVID-19 pandemic  reached the US, and crossing the threshold soon was considered inevitable. [ 148 ] [ 149 ]  Remdesivir was developed by Gilead with over $79 million in U.S. government funding. [ 149 ]  In May 2020, Gilead announced that it would provide the first 940,000 doses of remdesivir to the federal government free of charge. [ 150 ]  After facing strong public reactions, Gilead gave up the "orphan drug" status for remdesivir on 25 March. [ 151 ]  Gilead retains 20-year remdesivir patents in more than 70 countries. [ 144 ]  In May 2020, the company further announced that it was in discussions with several generics companies to provide rights to produce remdesivir for developing countries, and with the Medicines Patent Pool to provide broader generic access. [ 152 ]


Patents have been criticized in the developing world, as they are thought [ who? ]  to reduce access to existing medicines. [ 153 ]  Reconciling patents and universal access to medicine would require an efficient international policy of  price discrimination . Moreover, under the  TRIPS  agreement of the  World Trade Organization , countries must allow pharmaceutical products to be patented. In 2001, the WTO adopted the  Doha Declaration , which indicates that the TRIPS agreement should be read with the goals of public health in mind, and allows some methods for circumventing pharmaceutical monopolies: via  compulsory licensing  or  parallel imports , even before patent expiration. [ 154 ]


In March 2001, 40 multi-national pharmaceutical companies brought litigation against  South Africa  for its  Medicines Act , which allowed the generic production of antiretroviral drugs (ARVs) for treating HIV, despite the fact that these drugs were on-patent. [ 155 ]  HIV was and is an  epidemic  in South Africa, and ARVs at the time cost between US$10,000 and US$15,000 per patient per year. This was unaffordable for most South African citizens, and so the South African government committed to providing ARVs at prices closer to what people could afford. To do so, they would need to ignore the patents on drugs and produce generics within the country (using a compulsory license), or import them from abroad. After international protest in favour of public health rights (including the collection of 250,000 signatures by  Médecins Sans Frontières ), the governments of several developed countries (including The Netherlands, Germany, France, and later the US) backed the South African government, and the case was dropped in April of that year. [ 156 ]


In 2016, GlaxoSmithKline (the world's sixth largest pharmaceutical company) announced that it would be dropping its patents in poor countries so as to allow independent companies to make and sell versions of its drugs in those areas, thereby widening the public access to them. [ 157 ]  GlaxoSmithKline published a list of 50 countries they would no longer hold patents in, affecting one billion people worldwide.


In 2011 four of the top 20 corporate charitable donations and eight of the top 30 corporate charitable donations came from pharmaceutical manufacturers. The bulk of corporate charitable donations (69% as of 2012) comes by way of non-cash charitable donations, the majority of which again were donations contributed by pharmaceutical companies. [ 158 ]


Charitable programs and drug discovery & development efforts by pharmaceutical companies include:


ADEXA  is the  German   trade union  for all pharmaceutical employees, and also for trainees and students. ADEXA negotiates the salaries and working conditions in German public pharmacies with the employers’ federations. The headquarters of the trade union is in  Hamburg .


Pharmaceutical employees being organized in this trade union are entitled to all agreed conditions of pay and contract terms such as overtime pay, bonuses and extra holiday entitlement.


For their members, ADEXA offers also legal advice and protection, lobbying, media representation and information concerning occupational politics.


In 1949, the Tarifgemeinschaft deutscher angestellter Apotheker was founded. [ 1 ]  In 1954, it was dissolved, and a new organisation, the Bundesverband der Angestellten in Apotheken, was founded as its successor. [ 2 ]  In 2004, it was renamed ADEXA. [ 3 ]  In 2012, ADEXA joined  EPhEU  (the European Association of Employed community Pharmacists in Europe. [ 4 ]  EPhEU is a network representing the interests of employed community pharmacists.


This  Hamburg -related article is a  stub . You can help Wikipedia by  expanding it .


Obi Peter Adigwe  is a Nigerian pharmacist and a doctor of pharmaceutical policy. [ 1 ]  He was appointed the Director General of the  National Institute for Pharmaceutical Research and Development  (NIPRD) with effect from 10 August 2018  [ 2 ] [ 3 ]  by the former president of the Federal Republic of Nigeria,  Muhammadu Buhari . Before his appointment as NIPRD boss, he was the Executive Secretary of the Pharmaceutical Manufacturers Group of the Manufacturers' Association of Nigeria and holds a Doctor of Pharmaceutical Policy at the  University of Leeds , United Kingdom.


Dr. Adigwe was the pioneer Head of the Health Policy Research and Development (HPRD) Unit at the  National Assembly (Nigeria) , where he formulated research and development strategies in Health Policy with a view to developing an Evidence-Based approach to Legislation and Policy formulation in Nigeria. He also developed innovative and contextual capacity-building modules for Healthcare Professionals, as well as coordinated research that contributed to Health System strengthening. He has a significant number of peer-reviewed publications including the first Knowledge Attitudes and Perceptions study on  Ebola  in  Nigeria , as well as a seminal paper on Rational Use of Medicines. While in the United Kingdom, he was the lead author of the article “Rewrite the Script for Non-medical Prescribing” which contributed to prescribing policy reforms in the  Parliament of the United Kingdom .


Throughout his career, Adigwe has pioneered a significant number of innovative research and developmental projects. He led teams that secured various high-profile grants including a Clinical Trials Grant from the  ECOWAS , an API Grant from  African Export–Import Bank , a Drug Development Mega Grant from  Tertiary Education Trust Fund  and a  European Union  /  Government of Bulgaria  Grant supporting Local Production of Vaccines in the  Nigerian  setting. Based on the NIPRD study led by Dr Adigwe, the European Union  EU  announced the award of an €18m grant to Nigeria, [ 4 ]  as a catalyst for vaccines research.


Dr. Obi Peter Adigwe has headed and served on numerous Committees and Expert Working Groups at both national and international levels, including the D8,  United Nations , World Health Organisation [WHO], The  African Union  and  ECOWAS . Dr. Adigwe was conferred with Nigeria's highest Productivity Award by the  President of Nigeria  in recognition of his hard work, productivity and excellence in National Developmental Initiatives. Adigwe is a Fellow of the Nigerian Academy of Pharmacy, as well as of the West African Institute of Public Health.


Obi Adigwe attended  University of Jos , Jos, obtaining a bachelor's degree in pharmacy in 2000. He proceeded to the  University of Edinburgh , UK and obtained MSc in Global Health and Public Policy in 2008 and a Doctorate degree (PhD) in Pharmaceutical Policy from the  University of Leeds , UK, in 2012. [ 5 ]


Obi Adigwe started his career as a pharmacist at the  National Assembly (Nigeria) 's Pharmacy Department, FCT, Abuja Nigeria, in 2005 and remained there till 2007. He proceeded to become the Senior Project Officer at the Pharmacy Department Unit at  University of Leeds , United Kingdom, from 2010 to 2012. [ 6 ]
From 2012 to 2015, he was the head of the Health Policy Research and Development Unit at the  National Assembly (Nigeria)  (NASS), FCT, Abuja, Nigeria, where he formulated research and development strategies across multiple policy areas and also authored write-ups to disseminate findings from research projects.
On 14 June 2022, Adigwe was reappointed as the Director General of  National Institute for Pharmaceutical Research and Development  (NIPRD). [ 7 ]
Adigwe has mentored over 80 PhD and MSc candidates, and 100 Pharmacists. Adigwe has more than 82 scientific presentations. He chaired and contributed to the COVID-19 pandemic response, by providing an internationally acclaimed analysis that was recognized by the Nigerian Government and positioned the country on the Madagascan Covid Organics preparation. [ 8 ]


In  pharmaceuticals , an  adverse event  ( AE ) is any untoward medical occurrence in a patient or clinical investigation subject administered a  pharmaceutical product  and which does not necessarily have a  causal relationship  with this treatment. An adverse event can therefore be any unfavourable and unintended  symptom or sign  (including an abnormal laboratory finding) or  disease  temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. [ 1 ]


AEs in patients participating in  clinical trials  must be reported to the study sponsor and if required could be reported to the local  ethics committee . Adverse events categorized as "serious" (results in death, illness requiring hospitalization, events deemed life-threatening, results in persistent or significant incapacity, a  congenital anomaly  or medically important condition) must be reported to the regulatory authorities immediately, whereas non-serious adverse events are merely documented in the annual summary sent to the regulatory authority.


The sponsor collects AE reports from the local researchers, and notifies all participating sites of the AEs at the other sites, as well as both the local investigators' and the sponsors' judgment of the seriousness of the AEs. This process allows the sponsor and all the local investigators access to a set of data that might suggest potential problems with the study treatment while the study is still ongoing.


All clinical trials have the potential to produce AEs. AEs are classified as serious or non-serious; expected or unexpected; and study-related, possibly study-related, or not study-related. [ 2 ]


For example, while a study that tests the effectiveness of a new blood pressure cuff for a period of 10 minutes might seem innocuous, the potential exists for the patient's skin to be irritated by the device. Patients in that study might also die during that 10-minute period. Both skin irritation and sudden death would be considered AEs. In this case, the skin irritation would be classified as not serious, unexpected, and possibly study-related. The death would be classified as serious and unexpected (unless the patient was already at death's door). The local researcher would use his/her medical judgment to determine whether the death could have been related to the study device.


Both the skin irritation and the death are unexpected events, and should alert the researcher to the potential existence of a problem with the device (for instance, it could have malfunctioned and shocked the patient). The researcher would report these AEs to the local  Institutional Review Board  and to the sponsor, and await direction on whether to stop the study. If the researcher feels there is an imminent danger posed by the device, he or she can use medical discretion to stop patients from participating in the study.


An adverse event can also be declared in the normal treatment of a patient which is suspected of being caused by the medication being taken or a medical device used in the treatment of the patient.


In Australia, 'Adverse EVENT' refers generically to medical errors of all kinds, surgical, medical or nursing related. The most recent available official study (1995) indicated 18,000 deaths per year are a result of hospital care. [ 3 ]  The Medical Error Action Group is lobbying for legislation to improve the reporting of AEs and through quality control, minimize the needless deaths.


Researchers participating in a clinical trial must report all adverse events to the drug regulatory authority of the respective country where the drug or device is to be registered [e.g.   Food and Drug Administration  (FDA) if it is US].  Serious AEs  must be reported immediately; minor AEs are 'bundled' by the sponsor and submitted later.


The type of method used to elicit AEs reported by individuals for evidence on likely adverse drug reactions (ADRs) influences the extent and nature of data. A 2018 review conducted found that some participants in clinical drug trials were asked simple open questions (i.e. 'how are you feeling?'), while in other trials, participants were given lengthy questionnaires about physical symptoms (i.e. 'do you experience muscle soreness or headaches?'. [ 4 ]  A 2022 review on adverse events in  Human challenge trials  found that reporting improved over time, but remains non-standardized in ways that make comparisons difficult. [ 5 ]


As there is a lack of consensus on how AEs should be assessed, there is a concern that the kinds of questions and the phrasing of questions may lead to measurement error and impede comparisons between studies and pooled analysis. However, Allen et al. [ 4 ]  concluded that the impact of the AE detected by different methods is unclear.


Clinical trial results often report the number of grade 3 and grade 4 adverse events.
Grades are defined: [ 6 ]


The FDA provides a database for reporting of adverse  medical device  events called the  Manufacturer and User Facility Device Experience Database  (MAUDE)[1]. The data consist of voluntary reports since June 1993, user facility reports since 1991, distributor reports since 1993, and manufacturer reports since August 1996, and is open for public view. Two private companies have also recently started providing access to analyzed adverse event information: Clarimed provides adverse event information for medical devices and AdverseEvents provides adverse event data for drugs.


MAUDE is incomplete.    KFF Health News  of the  Kaiser Family Foundation  reported discovering a secret set of least 1.1 million adverse events hidden in a database not known to professionals familiar MAUDE [ 7 ]  Some device AEs reported to FDA can only be found in MDR Data Files of the Device Experience Network (DEN) or in Alternative Summary Report (ASR) data received by the FDA.


Arven Pharmaceuticals  is a Turkish  pharmaceutical  corporation headquartered in  Istanbul  established as a subsidiary of Toksöz Group in 2013. Arven's primary focus is development and production of high-technology  inhaler  and  biotechnology  products. The company is specialized on difficult to make products. [ 1 ]  Arven is the first Turkish company developing biosimilars for global markets, including the US and EU. [ 2 ]


Arven has obtained a marketing authorization in 2016 for the biosimilar of  Filgrastim , marketed under Fraven, which is the first  biosimilar  drug, developed and manufactured from cell to final product in Turkey. [ 3 ] [ 4 ]


Additionally, Arven is the first Turkish company to design and develop a patented  Dry Powder Inhaler  (DPI) device under Arvohaler trademark and globally introduced Cyplos ( salmeterol/fluticasone ) product inhaled with Arvohaler device. [ 5 ]


Some of the  ministry of health   foundations have visitations to the company for the vaccine manufacturing potential during  COVID-19 pandemic  period. [ 6 ]


In 2007 the Toksöz Group launched investments to contribute to the development of biotechnological products and the advancement of the pharmaceutical field in Turkey. A Biotechnology Division was first established in the Sanovel Silivri facility within the same year, and research and development work was initiated to produce Turkey's first biosimilar product. [ 7 ] [ 8 ]


In the following years, the Toksöz Group brought together high-technology inhaler and biotechnology products under separate legal entity as“Arven İlaç San ve Tic. A.Ş.” continuing its investments, the group then decided in 2013 to build a dedicated factory for manufacturing of Arvenproducts.


As of 2020, Arven employs 200 staff in factory and R&D facility.


The factory was built in the Kırklareli Industrial Zoneclose to the western borders of Turkey and started operations by obtaining a manufacturing license from the Pharmaceutical and Medical Devices Agency of Turkey in 2017. Arven  Kırklareli  factory was constructed on a 30,000-square-meter (320,000 sq ft) area.


The R&D facility in Selimpaşa-Istanbul was established at the same time period with the manufacturing facility in Kırklareli. R&D Center certificate was granted in 2017 by the Ministry of Industry, and started to develop new products. Arven R&D Center is currently carrying out research and development activities on inhaler (respiration) medicine and biosimilar drugs.


The research and development activity on biotechnological and biosimilar drugs are divided into two main groups: microbial drugs and mammalian cell culture-based drugs. The biotechnology team at Arven R&D center comprises Microbial Manufacturing, Mammalian Production, Biotechnology R&D and Biotechnology Quality Control divisions.


Biosimilar development project generally includes following basic steps:


Characterization of the reference product,  cell line  development,  analytical  method development, process development, head-to-head  comparability  studies, manufacturing of the product at different scales for toxicology study and clinical trials, stability studies, animal studies, and phase 1 clinical trials.


The facility is utilized for  upstream  processes, including  inoculation ,  fermentation , cell disruption and harvesting; and  downstream  processes, including advanced technology filtration and  chromatographic  purification techniques, and has the capacity to manufacture bulk products in controlled,  GMP  classified areas. Following the bulk manufacture of products, the final product is obtained through syringe filling under aseptic conditions in GMP areas using validated processes. It was the first GMP certificated-biotechnology manufacturing area in Turkey. Fraven, biosimilar of Filgrastim, is the first biosimilar drug developed from cell to the finished product in Turkey and was approved by Turkish Ministry of Health in April 2016. [ 9 ]


The manufacturing protocol of the product was successfully patented before the  European Patent Office . This success has also led company to move R&D projects to more complicated biomolecules, such as  monoclonal antibodies . [ 10 ]


Arven was the first Turkish pharmaceutical company to develop a medical device and corresponding anti-asthmatic product as a dry powder inhaler (DPI) complies with international guidelines and regulations including  WHO , ICH,  FDA  and  EMA . The company has new R&D projects on other inhalable molecules on the pipeline.


Salmeterol with fluticasone propionate combined doses are manufactured as 50 mcg-500 mcg, 50 mcg-250 mcg and 50-100 mcg inhalation powder forms. [ 11 ]  Development of Cyplos Arvohaler products were started in 2006, authorization step in Turkey was completed in 2011 and the products were launched in 2012 to the Turkish market.


Product development started with design and development of a plastic inhalation device (Arvohaler) in 2006 with a 100% percent of domestic capital in Turkey. While research and design studies were conducted internally by a team of people from R&D, IP and other related departments of Arven. Development stages were completed together with a local mold and device manufacturer having a clean room in Turkey.


After the development stage today Arvohaler is a worldwide patented multi-unit dose dry powder inhalation (DPI) device developed by Arven. The device itself is protected in Turkey, EU, US and many other countries globally with a number of patent families.


Arvohaler consists of 18 components, including 16 plastic parts and 2 stainless-steel springs. Whole material selections and documentation of the development stages were performed according to international guidelines and regulations including WHO, ICH, FDA and EMA.


As a whole product; Cyplos Arvohaler is manufactured in DPI Production Unit located in Arven's GMP approved production facilities in clean room conditions. Production consists of subsequent stages.


Every stage of production and the finished product is controlled by in-process and chemical tests.


The firm's main products are:


Arven has filed 571 patent applications before the  patent  offices since its foundation. 298 of the patents belong to the inhaler device(Arvohaler) and corresponding formulation technology inventions. Arven's innovator inhaler device, Arvohaler, succeeded to obtaining patent grants from  European Patent Office ,  USPTO ,  Japan Patent Office  and Chinese State Patent Office. Additionally, the first biotechnology drug patent application in Turkey was filed by Arven Pharmaceuticals. Arven has 23 European granted patents and ranked tenth among all of the Turkish companies in terms of number of registered European patents.


Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients  is a book by the British physician and academic  Ben Goldacre  about the  pharmaceutical industry , its relationship with the medical profession, and the extent to which it controls academic research into its own products. [ 1 ]  It was published in the UK in September 2012 by the  Fourth Estate  imprint of  HarperCollins , and in the United States in February 2013 by  Faber and Faber .


Goldacre argues in the book that "the whole edifice of medicine is broken", because the evidence on which it is based is systematically distorted by the pharmaceutical industry. [ n 1 ]  He writes that the industry finances most of the  clinical trials  into its own products and much of doctors' continuing education, that clinical trials are often conducted on small groups of unrepresentative subjects and negative data is routinely withheld, and that apparently independent academic papers may be planned and even  ghostwritten  by pharmaceutical companies or their contractors, without disclosure. [ 3 ]  Describing the situation as a "murderous disaster", he makes suggestions for action by patients' groups, physicians, academics and the industry itself. [ 4 ]


Responding to the book's publication, the  Association of the British Pharmaceutical Industry  issued a statement in 2012 arguing that the examples the book offers were historical, that the concerns had been addressed, that the industry is among the most regulated in the world, and that it discloses all data in accordance with international standards. [ 5 ]


In January 2013 Goldacre joined the  Cochrane Collaboration ,  British Medical Journal  and others in setting up  AllTrials , a campaign calling for the results of all past and current clinical trials to be reported. [ 6 ]  The British House of Commons  Public Accounts Committee  expressed concern in January 2014 that drug companies were still only publishing around 50 percent of clinical-trial results. [ 7 ]


Goldacre writes in the introduction of  Bad Pharma  that he aims to defend the following:


Drugs are tested by the people who manufacture them, in poorly designed trials, on hopelessly small numbers of weird, unrepresentative patients, and analysed using techniques which are flawed by design, in such a way that they exaggerate the benefits of treatments. Unsurprisingly, these trials tend to produce results that favour the manufacturer. When trials throw up results that companies don't like, they are perfectly entitled to hide them from doctors and patients, so we only ever see a distorted picture of any drug's true effects. Regulators see most of the trial data, but only from early on in a drug's life, and even then they don't give this data to doctors or patients, or even to other parts of government. This distorted evidence is then communicated and applied in a distorted fashion.


In their forty years of practice after leaving medical school, doctors hear about what works through ad hoc oral traditions, from sales reps, colleagues or journals. But those colleagues can be in the pay of drug companies – often undisclosed – and the journals are too. And so are the patient groups. And finally, academic papers, which everyone thinks of as objective, are often covertly planned and written by people who work directly for the companies, without disclosure. Sometimes whole academic journals are even owned outright by one drug company. Aside from all this, for several of the most important and enduring problems in medicine, we have no idea what the best treatment is, because it's not in anyone's financial interest to conduct any trials at all. [ 8 ]


In "Missing Data," Goldacre argues that the clinical trials undertaken by drug companies routinely reach conclusions favourable to the company. For example, in a 2007 journal article published in  PLOS Medicine , researchers studied every published trial on  statins , drugs prescribed to reduce  cholesterol  levels. In the 192 trials they looked at, industry-funded trials were 20 times more likely to produce results that favoured the drug. [ 9 ]


He writes that these positive results are achieved in a number of ways. Sometimes the industry-sponsored studies are flawed by design (for example by comparing the new drug to an existing drug at an inadequate dose), and sometimes patients are selected to make a positive result more likely. In addition, the data are analysed as the trial progresses. If the trial seems to be producing negative data it is stopped prematurely and the results are not published, or if it is producing positive data it may be stopped early so that longer-term effects are not examined. He writes that this  publication bias , where negative results remain unpublished, is endemic within medicine and academia. As a consequence, he argues, doctors may have no idea what the effects are of the drugs they prescribe. [ 10 ]


An example he gives of the difficulty of obtaining missing data from drug companies is that of  oseltamivir  (Tamiflu), manufactured by  Roche  to reduce the complications of  bird flu . Governments spent billions of pounds stockpiling this, based in large part on a meta-analysis that was funded by the industry.  Bad Pharma  charts the efforts of independent researchers, particularly  Tom Jefferson  of the  Cochrane Collaboration  Respiratory Group, to gain access to information about the drug. [ 11 ]


In the second chapter, the book describes the process as new drugs move from  animal testing  through  phase 1  ( first-in-man study ),  phase 2 , and  phase 3  clinical trials. Phase 1 participants are referred to as volunteers, but in the US are paid $200–$400 per day, and because studies can last several weeks and subjects may volunteer several times a year, earning potential becomes the main reason for participation. [ 12 ]  Participants are usually taken from the poorest groups in society, and outsourcing increasingly means that trials may be conducted in countries with low wages by  contract research organizations  (CROs). The rate of growth for clinical trials in India is 20 percent a year, in Argentina 27 percent, and in China 47 percent, while trials in the UK have fallen by 10 percent a year and in the US by six percent. [ 13 ]


The shift to outsourcing raises issues about data integrity, regulatory oversight, language difficulties, the meaning of  informed consent  among a much poorer population, the standards of clinical care, the extent to which corruption may be regarded as routine in certain countries, and the ethical problem of raising a population's expectations for drugs that most of that population cannot afford. [ 13 ]  It also raises the question of whether the results of clinical trials using one population can invariably be applied elsewhere. There are both social and physical differences: Goldacre asks whether patients diagnosed with depression in China are really the same as patients diagnosed with depression in California, and notes that people of Asian descent metabolize drugs differently from Westerners. [ 14 ]