Pharmaceutical industry
The pharmaceutical industry is an industry in
History
Mid-1800s – 1945: From botanicals to the first synthetic drugs
The modern era of pharmaceutical industry began with local apothecaries that expanded from their traditional role of distributing botanical drugs such as
Epinephrine, norepinephrine, and amphetamine
By the 1890s, the profound effect of
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[
Discovery and development of the barbiturates
In 1903,
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.
Insulin
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.[13]
Early anti-infective research: Salvarsan, Prontosil, Penicillin and vaccines
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%.[14][15][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.[16] 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.[17]
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
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.[23]
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,
Unsafe drugs and early industry regulation
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.
In 1937 over 100 people died after ingesting "
The post-war years, 1945–1970
Further advances in anti-infective research
The aftermath of
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.[37] Notable among these was a 75% decline in deaths due to tuberculosis.[38]
During the years 1940–1955, the rate of decline in the U.S.
Other notable new vaccines of the period include those for measles (1962,
Development and marketing of antihypertensive drugs
Hypertension is a risk factor for atherosclerosis,
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,
A 2009 Cochrane review concluded that thiazide antihypertensive drugs reduce the risk of death (
Oral Contraceptives
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
Thalidomide and the Kefauver-Harris Amendments
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 (
The
1970–1990s
Statins
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.
In April 1994, the results of a Merck-sponsored study, the
21st Century
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.[78]
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.[79] 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".[80] 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.[80]
Impact of Mergers and Acquisitions
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).
Research and development
Drug discovery is the process by which potential
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
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.[84]
The cost of innovation
Industry-wide research and investment reached a record $65.3 billion in 2009.[88] 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).[87]
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.[89] According to Forbes, by 2010 development costs were between $4 billion to $11 billion per drug.[90]
Some of these estimates also take into account the
Product approval
In the United States, new pharmaceutical products must be approved by the
A fourth phase of post-approval surveillance is also often required due to the fact that even the largest clinical trials cannot effectively predict the prevalence of rare side-effects. Postmarketing surveillance ensures that after marketing the safety of a drug is monitored closely. In certain instances, its indication may need to be limited to particular patient groups, and in others the substance is withdrawn from the market completely.
The FDA provides information about approved drugs at the Orange Book site.[93]
In the UK, the Medicines and Healthcare products Regulatory Agency approves and evaluates drugs for use. Normally an approval in the UK and other European countries comes later than one in the USA. Then it is the National Institute for Health and Care Excellence (NICE), for England and Wales, who decides if and how the National Health Service (NHS) will allow (in the sense of paying for) their use. The British National Formulary is the core guide for pharmacists and clinicians.
In many non-US western countries, a 'fourth hurdle' of
Orphan drugs
There are
Global sales
Company | Pharma revenue ($ million) |
---|---|
Pfizer | 100,330 |
Johnson & Johnson | 94,940 |
66,260 | |
59,280 | |
58,050 | |
Novartis | 50,540 |
Bristol Myers Squibb | 46,160 |
Sanofi | 45,220 |
AstraZeneca / | 44,350 |
GSK | 36,150 |
Takeda | 30,000 |
Eli Lilly and Company | 28,550 |
Gilead Sciences | 27,280 |
Bayer | 26,640 |
Amgen | 26,320 |
Boehringer Ingelheim | 25,280 |
Novo Nordisk | 25,000 |
Moderna | 19,260 |
19,160 | |
BioNTech | 18,200 |
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.[96] Emerging markets such as China, Russia, South Korea and Mexico outpaced that market, growing a huge 81 percent.[97][98]
The top ten best-selling drugs of 2013 totaled $75.6 billion in sales, with the anti-inflammatory drug
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.[101]
Patents and generics
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.[102] 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.[103] 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.[104] 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.[105]
Prescriptions
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.[106]
Marketing
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,
To healthcare professionals
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.[107]
Direct to consumer advertising
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.
Controversies
Drug marketing and lobbying
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;[108] 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[109]); sponsorship of medical schools or nurse training; sponsorship of continuing educational events, with influence on the curriculum;[110] 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.[111]
There have been related accusations of
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.[115][116][117] 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.[118] 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.[119]
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.[120]
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.[121]
Medication pricing
The pricing of pharmaceuticals is becoming a major challenge for health systems.
Regulatory issues
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.[124] 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.[124]
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.[125]
Pharmaceutical fraud
The examples and perspective in this section deal primarily with the United States and do not represent a worldwide view of the subject. (August 2015) |
Every major company selling atypical antipsychotics—
On 2 July 2012,
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.[135][136]
Company | Settlement | Violation(s) | Year | Product(s) | Laws allegedly violated (if applicable) |
---|---|---|---|---|---|
GlaxoSmithKline[137] |
$3 billion | Off-label promotion/ failure to disclose safety data |
2012 | Avandia/Wellbutrin/Paxil | False Claims Act/FDCA
|
Pfizer[138] | $2.3 billion | Off-label promotion/kickbacks | 2009 | Bextra/Geodon/ Zyvox/Lyrica |
False Claims Act/FDCA |
Abbott Laboratories[139] | $1.5 billion | Off-label promotion | 2012 | Depakote |
False Claims Act/FDCA |
Eli Lilly[140] | $1.4 billion | Off-label promotion | 2009 | Zyprexa | False Claims Act/FDCA |
Physician roles
In May 2015, the
Response to COVID-19
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.[143] The Wall Street Journal ran an editorial calling for this achievement to be recognized with a Nobel Peace Prize.[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.[146]
In the United States the government signed agreements in which research and development and/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,[147] 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.[148]
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.[149][150] 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.[149][150] Remdesivir was developed by Gilead with over $79 million in U.S. government funding.[150] In May 2020, Gilead announced that it would provide the first 940,000 doses of remdesivir to the federal government free of charge.[151] After facing strong public reactions, Gilead gave up the "orphan drug" status for remdesivir on 25 March.[152] Gilead retains 20-year remdesivir patents in more than 70 countries.[145] 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.[153]
Developing world
Patents
Patents have been criticized in the developing world, as they are thought[
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.[156] 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.[157]
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.[158] GlaxoSmithKline published a list of 50 countries they would no longer hold patents in, affecting one billion people worldwide.
Charitable programs
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.[159]
Charitable programs and drug discovery & development efforts by pharmaceutical companies include:
- "river blindness drugs were donated in Africa[160]
- AIDS in South Africa[161]
- GSK's commitment to give free albendazole tablets to the WHO for, and until, the elimination of lymphatic filariasisworldwide.
- In 2006, Glivec patient assistance programs; and relief to support major humanitarian organisations with emergency medical needs.[162]
See also
- List of industrial complexes– Economic concept
- Big Pharma conspiracy theory– Conspiracy theories about the pharmaceutical industry
- Clinical trial – Phase of clinical research in medicine
- Drug development – Process of bringing a new pharmaceutical drug to the market
- Drug discovery – Pharmaceutical procedure
- Legal drug trade – manufacture and sale of pharmaceutical drugs
- List of pharmaceutical companies
- Licensed production – Production under license of technology developed elsewhere
- Outsourcing – Contracting formerly internal tasks to an external organization
- Pharmaceutical marketing – Advertising by pharmaceutical companies
- Pharmacy – Clinical health science
- Pharmacy benefit management – Administration of prescription drug programs in the United States
- Unitaid – Global health initiative
- Valuation (finance) § Valuation of intangible assets
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External links
- Quotations related to Pharmaceutical industry at Wikiquote
- "Global Medicines Use in 2020". IMS Institute for Healthcare Informatics. November 2015.
- "The pharmaceutical industry and global health – Facts & figures 2017" (PDF). International Federation of Pharmaceutical Manufacturers & Associations. February 2017.
- "Licensing Agreements in the Pharmaceutical Industry".
- "The Pharmaceutical Industry in Figures – Key Data 2018" (PDF). European Federation of Pharmaceutical Industries and Associations.