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The pharmaceutical industry discovers, develops, produces, and markets
drugs or pharmaceutical drugs for use as
medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...
s to be administered to
patient
A patient is any recipient of health care services that are performed by healthcare professionals. The patient is most often ill or injured and in need of treatment by a physician, nurse, optometrist, dentist, veterinarian, or other hea ...
s (or self-administered), with the aim to
cure them,
vaccinate them, or alleviate
symptoms.
Pharmaceutical companies
The pharmaceutical industry discovers, develops, produces, and markets drugs or pharmaceutical drugs for use as medications to be administered to patients (or self-administered), with the aim to cure them, vaccinate them, or alleviate symptoms. ...
may deal in
generic or
brand
A brand is a name, term, design, symbol or any other feature that distinguishes one seller's good or service from those of other sellers. Brands are used in business, marketing, and advertising for recognition and, importantly, to create ...
medications and medical devices. They are subject to a
variety of laws and regulations that govern the
patent
A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A ...
ing, testing, safety, efficacy using drug testing and
marketing of drugs. The global pharmaceuticals market produced treatments worth $1,228.45 billion in 2020 and showed a compound annual growth rate (CAGR) of 1.8%.
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
morphine
Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...
and
quinine
Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to '' Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal le ...
to wholesale manufacture in the mid-1800s, and from discoveries resulting from applied research. Intentional
drug discovery from plants began with the isolation between 1803 and 1805 of
morphine
Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...
- an analgesic and sleep-inducing agent - from opium by the German apothecary assistant
Friedrich Sertürner
Friedrich Wilhelm Adam Sertürner (19 June 1783 – 20 February 1841) was a German pharmacist and a pioneer of alkaloid chemistry. He is best known for his discovery of morphine in 1804.
Biography
Friedrich Wilhelm Adam Sertürner was born to J ...
, who named this compound after the Greek god of dreams,
Morpheus
Morpheus ('Fashioner', derived from the grc, μορφή meaning 'form, shape') is a god associated with sleep and dreams. In Ovid's ''Metamorphoses'' he is the son of Somnus and appears in dreams in human form. From the Middle Ages, the name b ...
. By the late 1880s, German dye manufacturers had perfected the purification of individual
organic compounds
In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The s ...
from tar and other mineral sources and had also established rudimentary methods in
organic chemical synthesis. 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.
Epinephrine, norepinephrine, and amphetamine
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 signalling 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
An antihemorrhagic (antihæmorrhagic) agent is a substance that promotes hemostasis (stops bleeding). It may also be known as a hemostatic (also spelled haemostatic) agent.
Antihemorrhagic agents used in medicine have various mechanisms of action: ...
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
John Abel (1578/79 – January 1675) was an English carpenter and mason, granted the title of 'King's Carpenter', who was responsible for several notable structures in the ornamented Half-timbered construction typical of the West Midlands.
Jo ...
of
Johns Hopkins University
Johns Hopkins University (Johns Hopkins, Hopkins, or JHU) is a private research university in Baltimore, Maryland. Founded in 1876, Johns Hopkins is the oldest research university in the United States and in the western hemisphere. It consi ...
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
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...
attacks, and an inhaled version was sold in the United States until 2011 (
Primatene Mist).
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 and orally active derivatives were sought. A structurally similar compound,
ephedrine
Ephedrine is a central nervous system (CNS) stimulant that is often used to prevent low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred treatment. It is of unclear benefit in ...
, was identified by Japanese chemists in the ''Ma Huang'' plant and marketed by
Eli Lilly
Eli Lilly (July 8, 1838 – June 6, 1898) was an American soldier, pharmacist, chemist, and businessman who founded the Eli Lilly and Company pharmaceutical corporation. Lilly enlisted in the Union Army during the American Civil War and ...
as an oral treatment for asthma. Following the work of
Henry Dale and
George Barger
George Barger FRS FRSE FCS LLD (4 April 1878 – 5 January 1939) was a British chemist.
Life
He was born to an English mother, Eleanor Higginbotham, and Gerrit Barger, a Dutch engineer in Manchester, England.
He was educated at Utrecht and ...
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
Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affect ...
,
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
The American Medical Association (AMA) is a professional association and lobbying group of physicians and medical students. Founded in 1847, it is headquartered in Chicago, Illinois. Membership was approximately 240,000 in 2016.
The AMA's sta ...
for these uses in 1937, and remained in common use for depression until the development of
tricyclic antidepressants
Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and wer ...
in the 1960s.
Discovery and development of the barbiturates
![Veronal](https://upload.wikimedia.org/wikipedia/commons/3/30/Veronal.jpg)
In 1903,
Hermann Emil Fischer and
Joseph von Mering disclosed their discovery that diethylbarbituric acid, formed from the reaction of 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
Barbital (or barbitone), marketed under the brand names Veronal for the pure acid and Medinal for the sodium salt, was the first commercially available barbiturate. It was used as a sleeping aid (hypnotic) from 1903 until the mid-1950s. The chemic ...
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
Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of ep ...
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
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrica ...
through the 1970s, and as of 2014, remains on the World Health Organizations list of essential medications. 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
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrica ...
.
In 1958,
Leo Sternbach discovered the first
benzodiazepine,
chlordiazepoxide
Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol and other drugs.
Chlordiazepoxide has a medium t ...
(Librium). Dozens of other benzodiazepines have been developed and are in use, some of the more popular drugs being
diazepam
Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, ...
(Valium),
alprazolam
Alprazolam, sold under the brand name Xanax, among others, is a fast-acting, potent tranquilizer of medium duration in the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring. It is most commonly u ...
(Xanax),
clonazepam
Clonazepam, sold under the brand names Klonopin and Rivotril, is a medication used to prevent and treat seizures, panic disorder, anxiety disorders, and the movement disorder known as akathisia. It is a tranquilizer of the benzodiazepine class ...
(Klonopin), and
lorazepam
Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety disorders, trouble sleeping, severe agitation, active seizures including status epilepticus, alcohol withdrawal, and c ...
(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
Heather Ashton (11 July 1929 – 15 September 2019) was a British psychopharmacologist and physician. She is best known for her clinical and research work on benzodiazepine dependence.
Biography
Chrystal Heather Champion was born in Dehradu ...
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
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
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.
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%.
In 1911
arsphenamine
Arsphenamine, also known as Salvarsan or compound 606, is a drug that was introduced at the beginning of the 1910s as the first effective treatment for syphilis, relapsing fever, and African trypanosomiasis.
This organoarsenic compound was the f ...
, the first synthetic anti-infective drug, was developed by
Paul Ehrlich
Paul Ehrlich (; 14 March 1854 – 20 August 1915) was a Nobel Prize-winning German physician and scientist who worked in the fields of hematology, immunology, and antimicrobial chemotherapy. Among his foremost achievements were finding a cure ...
and chemist Alfred Bertheim of the Institute of Experimental Therapy in Berlin. The drug was given the commercial name Salvarsan. Ehrlich, noting both the general toxicity of
arsenic
Arsenic is a chemical element with the symbol As and atomic number 33. Arsenic occurs in many minerals, usually in combination with sulfur and metals, but also as a pure elemental crystal. Arsenic is a metalloid. It has various allotropes, ...
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 found to exhibit partially selective toxicity. Arsphenamine proved to be the first effective treatment for
syphilis, a disease which prior to that time was incurable and led inexorably to severe skin ulceration, neurological damage, and death.
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
Gerhard Johannes Paul Domagk (; 30 October 1895 – 24 April 1964) was a German pathologist and bacteriologist. He is credited with the discovery of sulfonamidochrysoidine (KL730) as an antibiotic for which he received the 1939 Nobel Prize in Phy ...
. This work, also based in the testing of compounds available from the German dye industry, led to the development of
Prontosil
Prontosil is an antibacterial drug of the sulfonamide group. It has a relatively broad effect against gram-positive cocci but not against enterobacteria. One of the earliest antimicrobial drugs, it was widely used in the mid-20th century but is ...
, the first representative of the
sulfonamide class of
antibiotics
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention o ...
. 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. In 1939, Domagk received the
Nobel Prize in Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, according ...
for this discovery. Nonetheless, the dramatic decrease in deaths from infectious diseases that occurred prior to
World War II
World War II or the Second World War, often abbreviated as WWII or WW2, was a world war that lasted from 1939 to 1945. It involved the vast majority of the world's countries—including all of the great powers—forming two opposing ...
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.
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 Second World War.
Early progress toward the development of vaccines occurred 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 rabies vaccine is a vaccine used to prevent rabies. There are a number of rabies vaccines available that are both safe and effective. They can be used to prevent rabies before, and, for a period of time, after exposure to the rabies virus, ...
. The first
diphtheria vaccines were produced in 1914 from a mixture of
diphtheria toxin and
antitoxin
An antitoxin is an antibody with the ability to neutralize a specific toxin. Antitoxins are produced by certain animals, plants, and bacteria in response to toxin exposure. Although they are most effective in neutralizing toxins, they can also ...
(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
Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section ...
. In 1944,
Maurice Hilleman
Maurice Ralph Hilleman (August 30, 1919 – April 11, 2005) was a leading American microbiologist who specialized in vaccinology and developed over 40 vaccines, an unparalleled record of productivity. According to one estimate, his vaccines ...
of Squibb Pharmaceuticals developed the first
vaccine against Japanese Encephalitis. Hilleman would later move to
Merck where he would play a key role in the development of vaccines against
measles,
mumps,
chickenpox,
rubella,
hepatitis A,
hepatitis B
Hepatitis B is an infectious disease caused by the '' Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection.
Many people have no symptoms during an initial infection. ...
, and
meningitis.
Unsafe drugs and early industry regulation
![Elixir Sulfanilamide](https://upload.wikimedia.org/wikipedia/commons/4/40/Elixir_Sulfanilamide.jpg)
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. 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.
In 1937 over 100 people died after ingesting "
Elixir Sulfanilamide
Elixir sulfanilamide was an improperly prepared sulfonamide antibiotic that caused mass poisoning in the United States in 1937. It is believed to have killed more than 100 people. The public outcry caused by this incident and other similar disast ...
" manufactured by S.E. Massengill Company of Tennessee. The product was formulated in
diethylene glycol
Diethylene glycol (DEG) is an organic compound with the formula (HOCH2CH2)2O. It is a colorless, practically odorless, and hygroscopic liquid with a sweetish taste. It is a four carbon dimer of ethylene glycol. It is miscible in water, alcohol, ...
, a highly toxic solvent that is now widely used as antifreeze. 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.
The post-war years, 1945–1970
Further advances in anti-infective research
The aftermath of
World War II
World War II or the Second World War, often abbreviated as WWII or WW2, was a world war that lasted from 1939 to 1945. It involved the vast majority of the world's countries—including all of the great powers—forming two opposing ...
saw an explosion in the discovery of new classes of antibacterial drugs including the
cephalosporins
The cephalosporins (sg. ) are a class of β-lactam antibiotics originally derived from the fungus ''Acremonium'', which was previously known as ''Cephalosporium''.
Together with cephamycins, they constitute a subgroup of β-lactam antibiotics ...
(developed by Eli Lilly based on the seminal work of
Giuseppe Brotzu and
Edward Abraham),
streptomycin
Streptomycin is an antibiotic medication used to treat a number of bacterial infections, including tuberculosis, ''Mycobacterium avium'' complex, endocarditis, brucellosis, ''Burkholderia'' infection, plague, tularemia, and rat bite fever. F ...
(discovered during a Merck-funded research program in Selman Waksman's laboratory
), the tetracyclines (discovered at Lederle Laboratories, now a part of
Pfizer
Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...
), erythromycin (discovered at Eli Lilly and Co.) 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.
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. Notable among these was a 75% decline in deaths due to tuberculosis.
![Measles US 1938-2019](https://upload.wikimedia.org/wikipedia/commons/3/3f/Measles_US_1938-2019.png)
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.
Vaccine development continued to accelerate, with the most notable achievement of the period being
Jonas Salk
Jonas Edward Salk (; born Jonas Salk; October 28, 1914June 23, 1995) was an American virologist and medical researcher who developed one of the first successful polio vaccines. He was born in New York City and attended the City College of New ...
'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
Merck & Co., Inc. is an American multinational pharmaceutical company headquartered in Rahway, New Jersey, and is named for Merck Group, founded in Germany in 1668, of whom it was once the American arm. The company does business as Merck Sharp ...
identified the
SV40
SV40 is an abbreviation for simian vacuolating virus 40 or simian virus 40, a polyomavirus that is found in both monkeys and humans. Like other polyomaviruses, SV40 is a DNA virus that has the potential to cause tumors in animals, but most often ...
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. The contamination appears to have originated both in the original cell stock and in monkey tissue used for production. In 2004 the United States Cancer Institute announced that it had concluded that SV40 is not associated with cancer in people.
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) The United States incidences of rubella, congenital rubella syndrome, measles, and mumps all fell by >95% in the immediate aftermath of widespread vaccination. 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
Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signifi ...
, and 5,200 deaths.
Development and marketing of antihypertensive drugs
Hypertension is a risk factor for atherosclerosis,
heart failure,
coronary artery disease,
stroke,
renal disease,
and
peripheral arterial disease,
and is the most important
risk factor
In epidemiology, a risk factor or determinant is a variable associated with an increased risk of disease or infection.
Due to a lack of harmonization across disciplines, determinant, in its more widely accepted scientific meaning, is often ...
for
cardiovascular
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
morbidity
A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
and
mortality, in
industrialized countries.
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.
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. A major shortcoming of hydralazine monotherapy was that it lost its effectiveness over time (
tachyphylaxis Tachyphylaxis (Greek ταχύς, ''tachys'', "rapid", and φύλαξις, ''phylaxis'', "protection") is a medical term describing an acute, sudden decrease in response to a drug after its administration; i.e. a rapid and short-term onset of drug to ...
). 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
Chlorothiazide, sold under the brand name Diuril among others, is an organic compound used as a diuretic and as an antihypertensive.
It is used both within the hospital setting or for personal use to manage excess fluid associated with congestive ...
, which remains the most widely used antihypertensive drug today. This development was associated with a substantial decline in the mortality rate among people with hypertension. The inventors were recognized by a Public Health
Lasker Award
The Lasker Awards have been awarded annually since 1945 to living persons who have made major contributions to medical science or who have performed public service on behalf of medicine. They are administered by the Lasker Foundation, which was ...
in 1975 for "the saving of untold thousands of lives and the alleviation of the suffering of millions of victims of hypertension".
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. 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),
beta blockers
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack after a first heart attack ( secondary prevention). They are ...
(
ICI Pharmaceuticals, 1964)
ACE inhibitors
Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease in blood volume ...
, and
angiotensin receptor blockers
Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals tha ...
. ACE inhibitors reduce the risk of new onset kidney disease
R 0.71and death
R 0.84in diabetic patients, irrespective of whether they have hypertension.
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
Comstock laws
The Comstock laws were a set of federal acts passed by the United States Congress under the Grant administration along with related state laws.Dennett p.9 The "parent" act (Sect. 211) was passed on March 3, 1873, as the Act for the Suppression of ...
. 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
Mary Coffin Ware Dennett (April 4, 1872 – July 25, 1947) was an American women's rights activist, pacifist, homeopathic advocate, and pioneer in the areas of birth control, sex education, and women's suffrage. She co-founded the National ...
, 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 E.D. Searle and 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. 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.
Thalidomide and the Kefauver-Harris Amendments
![NCP14053](https://upload.wikimedia.org/wikipedia/commons/a/a5/NCP14053.jpg)
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
Thalidomide, sold under the brand names Contergan and Thalomid among others, is a medication used to treat a number of cancers (including multiple myeloma), graft-versus-host disease, and a number of skin conditions including complications o ...
), 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.
The
thalidomide
Thalidomide, sold under the brand names Contergan and Thalomid among others, is a medication used to treat a number of cancers (including multiple myeloma), graft-versus-host disease, and a number of skin conditions including complications o ...
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 advertising of prescription drugs and to establish
good manufacturing practices
Current good manufacturing practices (cGMP) are those conforming to the guidelines recommended by relevant agencies. Those agencies control the authorization and licensing of the manufacture and sale of food and beverages, cosmetics, pharmaceutica ...
. The law required that all drugs introduced between 1938 and 1962 had to be effective. An FDA - National Academy of Sciences collaborative study showed that nearly 40 percent of these products were not effective. A similarly comprehensive study of over-the-counter products began ten years later.
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 trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...
s, 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
Pindaros Roy Vagelos (born October 8, 1929, in Westfield, New Jersey), better known as P. Roy Vagelos or Roy Vagelos, is an American physician and business executive, who was president and chief executive officer (1985) and chairman (1986) of t ...
, 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
Lovastatin, sold under the brand name Mevacor among others, is a statin medication, to treat high blood cholesterol and reduce the risk of cardiovascular disease. Its use is recommended together with lifestyle changes. It is taken by mouth.
...
(mevinolin, MK803) from the fungus ''
Aspergillus terreus
''Aspergillus terreus'', also known as ''Aspergillus terrestris'', is a fungus (mold) found worldwide in soil. Although thought to be strictly asexual until recently, ''A. terreus'' is now known to be capable of sexual reproduction. This saprotr ...
'', first marketed in 1987 as Mevacor.
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%.
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
Lasker-DeBakey Clinical Medical Research Award is one of four annual awards presented by the Lasker Foundation. The Lasker-DeBakey award is given to honor outstanding work for the understanding, diagnosis, prevention, treatment, and cure of diseas ...
in 2008. For his "pioneering research into a new class of molecules" for "lowering cholesterol,"
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.
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).
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
Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast canc ...
and
Humira
Adalimumab, sold under the brand name Humira, among others, is a monoclonal antibody used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativ ...
.
Research and development
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
Biotechnology is the integration of natural sciences and engineering sciences in order to achieve the application of organisms, cells, parts thereof and molecular analogues for products and services. The term ''biotechnology'' was first used ...
often focuses on understanding the
metabolic pathway
In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...
s related to a
disease
A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
state or
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
, and manipulating these pathways using
molecular biology
Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
or
biochemistry
Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...
. 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
Dosing generally applies to feeding chemicals or medicines when used in small quantities.
For medicines the term '' dose'' is generally used. In the case of inanimate objects the word dosing is typical. The term dose titration, referring to stepw ...
, as well as to establish
safety
Safety is the state of being "safe", the condition of being protected from harm or other danger. Safety can also refer to risk management, the control of recognized hazards in order to achieve an acceptable level of risk.
Meanings
There are ...
. Research in these areas generally includes a combination of ''
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'' studies, ''
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
'' studies, and
clinical trials
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
. The cost of late stage development has meant it is usually done by the larger pharmaceutical companies. 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.
Often, large multinational corporations exhibit
vertical integration
In microeconomics, management and international political economy, vertical integration is a term that describes the arrangement in which the supply chain of a company is integrated and owned by that company. Usually each member of the suppl ...
, 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 organization In the life sciences, a contract research organization (CRO) is a company that provides support to the pharmaceutical, biotechnology, and medical device industries in the form of research services outsourced on a contract basis. A CRO may provid ...
s to manage drug development.
The cost of innovation
Drug
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...
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
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...
before they can be marketed in those countries. In 2010 18 NMEs (New Molecular Entities) were approved and three
biologics
A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, th ...
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.
This approval comes only after heavy investment in
pre-clinical development
In drug development, preclinical development, also termed preclinical studies or nonclinical studies, is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug ...
and
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...
s, as well as a commitment to ongoing
safety monitoring
Clinical monitoring is the oversight and administrative efforts that monitor a participant's health and efficacy of the treatment during a clinical trial. Both independent and government-run grant-funding agencies, such as the National Institutes o ...
. 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 A new chemical entity (NCE) is, according to the U.S. Food and Drug Administration, a novel, small, chemical molecule drug that is undergoing clinical trials or has received a first approval (not a new use) by the FDA in any other application submi ...
, or NCE), has been estimated at US$1.3 billion (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.
Industry-wide research and investment reached a record $65.3 billion in 2009.
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).
A study by the consulting firm
Bain & Company
Bain & Company is an American management consulting company headquartered in Boston, Massachusetts. The firm provides advice to public, private, and non-profit organizations. One of the Big Three management consultancies, Bain & Company was fou ...
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. According to Forbes, by 2010 development costs were between $4 billion to $11 billion per drug.
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
The time value of money is the widely accepted conjecture that there is greater benefit to receiving a sum of money now rather than an identical sum later. It may be seen as an implication of the later-developed concept of time preference.
The ...
). 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. Some approved drugs, such as those based on re-formulation of an existing
active ingredient
An active ingredient is any ingredient that provides biologically active or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of humans or animals. The ...
(also referred to as Line-extensions) are much less expensive to develop.
Product approval
In the United States, new pharmaceutical products must be approved by the
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) as being both safe and effective. This process generally involves submission of an
Investigational New Drug 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
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...
using healthy volunteers. Phase II can include
pharmacokinetics
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
and
dosing
Dosing generally applies to feeding chemicals or medicines when used in small quantities.
For medicines the term '' dose'' is generally used. In the case of inanimate objects the word dosing is typical. The term dose titration, referring to stepw ...
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.
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 Postmarketing surveillance (PMS), also known as post market surveillance, is the practice of monitoring the safety of a pharmaceutical drug or medical device after it has been released on the market and is an important part of the science of phar ...
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.
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
The National Institute for Health and Care Excellence (NICE) is an executive non-departmental public body of the Department of Health and Social Care in England that publishes guidelines in four areas:
* the use of health technologies withi ...
(NICE), for England and Wales, who decides if and how the
National Health Service
The National Health Service (NHS) is the umbrella term for the publicly funded healthcare systems of the United Kingdom (UK). Since 1948, they have been funded out of general taxation. There are three systems which are referred to using the " ...
(NHS) will allow (in the sense of paying for) their use. The
British National Formulary
The ''British National Formulary'' (BNF) is a United Kingdom (UK) pharmaceutical reference book that contains a wide spectrum of information and advice on prescribing and pharmacology, along with specific facts and details about many medicine ...
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
The quality-adjusted life year (QALY) is a generic measure of disease burden, including both the quality and the quantity of life lived. It is used in economic evaluation to assess the value of medical interventions. One QALY equates to one year i ...
) 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
Healthcare Improvement Scotland (HIS) is the national healthcare improvement organisation for Scotland. It is a public body which is part of the Scottish National Health Service, created in April 2011.
History
NHS Quality Improvement Scotland ( ...
in Scotland, and the
Pharmaceutical Benefits Advisory Committee
The Pharmaceutical Benefits Scheme (PBS) is a program of the Australian Government that subsidises prescription medication for Australian citizens and permanent residents, as well as international visitors covered by a reciprocal health care ag ...
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.
Orphan drugs
There are Orphan Drug Act, 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. 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.
Global sales
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. Emerging markets such as China, Russia, South Korea and Mexico outpaced that market, growing a huge 81 percent.
The top ten best-selling drugs of 2013 totaled $75.6 billion in sales, with the anti-inflammatory drug
Humira
Adalimumab, sold under the brand name Humira, among others, is a monoclonal antibody used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativ ...
being the best-selling drug worldwide at $10.7 billion in sales. The second and third best selling were Enbrel and Remicade, respectively. 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). The best-selling drug ever, Atorvastatin, 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.
Patents and generics
Depending on a number of considerations, a company may apply for and be granted a chemical patent, patent for the drug, or the process of producing the drug, granting exclusivity rights typically for about 20 years. 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. Patent protection enables the owner of the patent to recover the costs of research and development through high profit margins for the
brand
A brand is a name, term, design, symbol or any other feature that distinguishes one seller's good or service from those of other sellers. Brands are used in business, marketing, and advertising for recognition and, importantly, to create ...
ed 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. 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.
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. Annual pharmaceutical drug sales, 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.
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, pharmaceutical lobby, pharmaceutical companies also employ lobbyists to influence politicians. Marketing of prescription drugs in the US is regulated by the federal Prescription Drug Marketing Act (PDMA), Prescription Drug Marketing Act of 1987. Th
pharmaceuticalmarketing plan incorporates the spending plans, channels, and thoughts which will take the drug association, and its items and administrations, forward in the current scene.
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.
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; 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); sponsorship of medical schools or nurse training; sponsorship of continuing educational events, with influence on the curriculum; and hiring physicians as paid consultants on medical advisory boards.
Some advocacy groups, such as No Free Lunch (organization), 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.
There have been related accusations of disease mongering (over-medicalising) to expand the market for medications. An inaugural conference on that subject took place in Australia in 2006. 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.
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. 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. 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.
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.
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.
Medication pricing
It has been argued that 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.
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.
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.
Pharmaceutical fraud
Pharmaceutical fraud involves deceptions which bring financial gain to a pharmaceutical company. It affects individuals and public health insurance, public and private health insurance, private insurers. There are several different schemes
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.
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
Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles 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).
Every major company selling atypical antipsychotics—Bristol-Myers Squibb, Eli Lilly and Company,
Pfizer
Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles 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.
On 2 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. The settlement is related to the company's illegal promotion of prescription drugs, its failure to report safety data, 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 (bribery), kickback scheme.
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 fraud, Medicare and Medicaid fraud, Off-label use, off-label promotion, and inadequate manufacturing practices.
Physician roles
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.
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. The Wall Street Journal ran an editorial calling for this achievement to be recognized with a Nobel Peace Prize.
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.
[
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.]
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, 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.
American pharmaceutical company Gilead Sciences, Gilead sought and obtained Orphan Drug Act of 1983, 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.[ 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.][ Remdesivir was developed by Gilead with over $79 million in U.S. government funding.] In May 2020, Gilead announced that it would provide the first 940,000 doses of remdesivir to the federal government free of charge. After facing strong public reactions, Gilead gave up the "orphan drug" status for remdesivir on 25 March. Gilead retains 20-year remdesivir patents in more than 70 countries. 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.
Developing world
Patents
Patents have been criticized in the developing world, as they are thought to reduce access to existing medicines. Reconciling patents and universal access to medicine would require an efficient international policy of Price discrimination#International price discrimination, 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.
In March 2001, 40 multi-national pharmaceutical companies brought litigation against South Africa for its Medicines and Related Substances Control Amendment Act, 1997, Medicines Act, which allowed the generic production of antiretroviral drugs (ARVs) for treating HIV, despite the fact that these drugs were on-patent. 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.
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. 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.
Charitable programs and drug discovery & development efforts by pharmaceutical companies include:
* "Merck & Co., Merck's Gift", wherein billions of river blindness drugs were donated in Africa
* Pfizer
Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...
's gift of free/discounted fluconazole and other drugs for AIDS in South Africa
* GlaxoSmithKline, GSK's commitment to give free albendazole tablets to the WHO for, and until, the elimination of lymphatic filariasis worldwide.
* In 2006, Novartis committed US$755 million in corporate citizenship initiatives around the world, particularly focusing on improving access to medicines in the developing world through its Access to Medicine projects, including donations of medicines to patients affected by leprosy, tuberculosis, and malaria; Glivec patient assistance programs; and relief to support major humanitarian organisations with emergency medical needs.
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Pharmaceutical industry,
Pharmacology
Pharmacy
Industries (economics)