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  1. FDA History Exhibits

Drug Therapeutics & Regulation in the U.S.

assorted pharmaceutical artifacts

Drug therapeutics from the late 19th century to the present evolved as a function of changes in science, medicine, public health concerns, and market forces, among other factors. Beginning with the passage of the 1906 Pure Food and Drugs Act and through subsequent legislation overseen by the FDA and its predecessors, regulation was increasingly integrated into this evolution. Accurate labeling, mandatory standards of identity and quality, safety grounded in rigorous evidence, proof of efficacy derived from the latest clinical research methodology, and other key requirements placed the patient’s well-being front and center.

The drugs in this exhibit are a representative rather than comprehensive glimpse into these developments. A long-time family practitioner and indefatigable collector recognized their importance in documenting medical history. Arthur E. Lewis, M. D. (1936-2016), was an avid collector before, during, and after his four-decade career practicing medicine in Burbank, California. These drugs are now part of the FDA’s broad collection of artifacts documenting the history of the agency, its work, and those who served. Many at FDA today today were involved in the introduction of a number of the drugs exhibited.

Lewis Collection Artifacts

introduced c. 1886


Discovered in 1886 by French scientists Arnold Cahn and Paul Hepp, acetanilide became the first drug product with both analgesic and antipyretic properties commercially available.  Marketed as Antifebrin by the German pharmaceutical firm Kalle & Co., acetanilide filled a void in the therapeutic marketplace that in the late-19th century was limited to opiates, alcohol and chloroform for pain relief and botanicals like willow bark or meadowsweet to reduce fevers.  However, initial enthusiasm for this much needed product was tempered by early reports of poisoning, cyanosis, methemoglobinemia and liver and kidney damage resulting from its significant toxicity.  

Due to the lack of drug regulation at the time, there were no requirements that the product be labeled with directions for use, dosing, or contraindications, let alone explicit warnings about risks or even active ingredients.  And at a time when patients relied heavily on self-care and could easily access drugs without a prescription, there was a considerable risk of toxic exposure due to improper dosing.  The commercialization of acetaminophen by von Mering in 1893 provided a safer combined pain reliever and fever reducer and decreased the therapeutic need for acetanilide.


Aminopterin sodium
approved 1951


The discovery of one wonder drug's mechanism of action helped lead to other unrelated drugs, including the first clinically tested antimetabolite to offer some hope for a childhood scourge.  By 1940 British researcher Donald Woods revealed that sulfanilamide interfered with the access of bacteria to a key metabolic component in their synthesis of folic acid-para-aminobenzoic  acid (PABA)-based on structural similarity.  

Drawing in part on the work of Mt. Sinai Hospital surgeon Richard Lewisohn and his studies of a folic acid conjugate in adenocarcinoma in mice, Sidney Farber and his colleagues in Boston investigated Lewisohn's drug and other folic acid conjugates prepared by Lederle Laboratories and Calco Chemical.  The Farber group proceeded to a therapeutic test of a new folic acid antagonist, Aminopterin, structurally similar to the other conjugates but more potent.

Their study from 1947 to 1948 involving 16 children suffering acute leukemia included the astounding observation that "10 showed clinical, hematological and pathological evidence of improvement of important nature of three months' duration."  They recognized that some had toxic reactions necessitating temporary suspension of therapy, acknowledged the temporary nature of the remissions, and explicitly stated there was nothing to suggest a cure.  However, these results provided a therapeutic pathway toward improved treatments for acute leukemia and other diseases.  A similar antimetabolite prepared shortly after Aminopterin, Methotrexate, surpassed its predecessor's toxicity profile and efficacy.   Methotrexate remains eight decades later an important therapeutic asset for many.

introduced 1910


The introduction of Salvarsan-known as arsphenamine in the U. S.-marked the birth of modern chemotherapy.  Beginning with his 1878 dissertation on histological staining, it was the result of German scientist Paul Ehrlich's interest in selective affinities of certain dyes for certain cells, his investigations of the relationship between chemical structure and pharmacological action, and his work in immunology.  He aimed to create a drug with one chemical group that would bind to a parasite (the receptor theory of drug action), kill the parasite with another chemical group, and act with much more specificity for the pathogen than the cells of the host.  With co-worker Sacachiro Hata, Ehrlich announced the discovery of Salvarsan as an effective syphilis treatment in 1910.

By 1917, and with the U. S. having earlier entered WWI, the U. S. Public Health Service Hygienic Laboratory, which had oversight of biological medicines since 1902, developed rules and standards for the manufacture and testing of arsphenamine and soon began issuing licenses for its production and sale.  Arsphenamine's toxicity prompted the development of many modifications since the 1910s, but it maintained a central role in the treatment of syphilis until the arrival of penicillin and the antibiotics in the 1940s.

Benzedrine (amphetamine)
Smith Kline & French
introduced 1934


Chemist Gordon Alles-and Smith Kline & French independently-discovered a powerful central nervous system stimulant, amphetamine sulfate, in 1929 while searching for structural analogues of the asthma drug, ephedrine.  SKF introduced the Benzedrine decongestant inhaler in 1934, and oral dosage forms later;  its early clinical indications included narcolepsy, depressive states, and weight reduction.  FDA approved nearly 30 different NDAs for amphetamine and congeners in the decade after the patent expired.  Many had multiple congeners and ingredients to counteract some amphetamine effects.

Amphetamine's habituation or addiction and other untoward effects were noted early on, as was its abuse potential.  The widespread illicit distribution of these prescription drugs was the focus of frequent compliance actions by FDA;  amphetamines along with barbiturates probably occupied more enforcement time than all other drugs from the 1940s to the 1960s.

In the 1970s, and facing some confusion and disagreement over efficacy data on amphetamines,  FDA launched a study of 200 trials involving 10,000 patients from recent years.  FDA determined that amphetamines and their congeners were effective in obesity, but labels would indicate short-term use only and carry an addiction warning.  

Cascara Sagrada
Sharpe and Dohme
legacy use

Cascara Sagrada

For centuries, the dried bark of the Frangula Pershiana shrub, native to western North America, was used as a traditional botanical remedy by Native American communities to treat constipation and other digestive ailments.  By the late-19th century, cascara sagrada was widely recognized for its usefulness as a laxative and was an active ingredient in a variety of patent medicines.  

Before the passage of the 1906 Pure Food and Drugs Act nostrums and other drugs were not required to label any ingredients and after its passage were only required to indicate the inclusion of 11 dangerous or habit-forming substances (not including cascara sagrada).  As a result, consumers had no way of knowing whether they were taking a product that contained cascara sagrada, nor the potency, and might inadvertently take far too much of this powerful laxative.  

In 1972, FDA began a review of all over-the-counter drug products to evaluate their safety and efficacy.  In order to efficiently establish clear guidelines for the hundreds of thousands of OTC products on the market, FDA developed a monograph, or rulebook, for certain classes of products.  This process resulted in a 2002 final rule announcing that cascara sagrada is generally not recognized as safe and effective in stimulant laxative OTC drug products and any such products would be considered misbranded.


Chloromycetin (chloramphenicol)
approved 1949


Chloramphenicol, like many early post-penicillin antibiotics, derived from a broad search for signs of activity through soils samples and other sources around the world.  Its source was isolated in a Venezuelan soil sample.  It was among the earliest broad spectrum antibiotics, effective against rickettsial infections such as Rocky Mountain spotted fever as well as streptococcal and staphylococcal diseases, Bordatella pertussis, Hemophilus influenzae, Pasteurella, Salmonella, Shigella, Brucella, Bacillus anthracis, Clostridium, Listeria, and many others.  Chloramphenicol also was the first antibiotic to be manufactured primarily by synthetic means-realizing an effort that began with penicillin production during WWII.

However, chloramphenicol also manifested a range of adverse reactions, the most concerning of which became known by the early 1950s-fatal aplastic anemia that occurred as frequently as about 1 in 20,000 patients.  FDA warned prescribers through label modifications but its inappropriate use continued.  In 1961 the agency ordered a  boxed warning for chloramphenicol-the first of its kind and an important tool for future risk communication to health practitioners.  It still took time to rein in inappropriate use of this important but dangerous medicine, which remains a part of the therapeutic arsenal as a drug of last resort.


DBI-TD (phenformin hydrochloride)
U. S. Vitamin and Pharmaceutical
approved 1959


Phenformin, approved for use in adult-onset diabetes, became part of the University Group Diabetes Program (UGDP) in the 1960s, a large, randomized, placebo-controlled clinical trial sponsored by NIH that considered hypoglycemics, insulin, and dietary control.  In 1971 the study dropped phenformin, having shown indicators of a link to cardiovascular fatalities;  stricter labeling followed.  One reaction involving phenformin, lactic acidosis-a rare but serious side effect with a mortality rate of about 50 percent-had already prompted a label change in 1964.

By 1976, when reports of possible  phenformin-linked lactic acidosis had grown to nearly 200, FDA consulted its Endocrinology and Metabolism Advisory Committee, which concluded there was a clear and unequivocal link between the drug and the adverse event, and not all of the 400,000 taking phentermine who might be at risk could be identified.  In July 1977, two months after a public hearing, Secretary of Health, Education, and Welfare Joseph A. Califano, Jr. invoked the imminent hazard provision under the 1962 Drug Amendments since this represented such a threat to the public health.  This action immediately suspended its new drug application and ordered its market withdrawal within 90 days, the first and only time this provision has been employed.  

Dicumarol                                   Coumadin (warfarin sodium)
Squibb                           &           Endo       
approved 1944                            approved 1954  

Dicumarol Coumadin

What began as an investigation into hemorrhaging livestock in the 1920s turned into a medicine that nearly 90 years later was taken by two million new patients per year to prevent disastrous cardiovascular events.  Two veterinarians traced the 1920s incident to incorrectly cured sweet clover hay that disrupted blood clotting.  A farmer brought a similar problem to the attention of University of Wisconsin biochemist Karl Paul Link in 1933;  six years later his lab isolated from the hay a substance they confirmed as the hemorrhagic agent in sweet clover.  Following clinical investigations of the responsible chemical FDA approved several applications for this drug, dicumarol, in the mid-1940s.

Scores of dicumarol congeners followed, one of which Link's lab developed and introduced in 1948 as an efficient rodenticide, warfarin, named after the Wisconsin Alumni Research Foundation.  Link encouraged clinical study of warfarin, which bettered dicumarol in potency, speed, and dosage form variety.  Coumadin (warfarin sodium), approved by FDA in 1954, became the dominant oral anticoagulant.  When Pres. Eisenhower suffered a myocardial infarction in 1955 his physicians turned to Coumadin.

Individualizing doses has always been important in dicumarol-type therapy considering the narrow margin of error.  Adverse reactions linked to anticoagulants such as Coumadin are among those that most commonly lead patients to seek emergency care.  In 2007 FDA cleared a new genetic test to help in the assessment of a patient's sensitivity to warfarin based on variants of two genes.

approved 1941


A synthetic estrogen discovered in 1938 and commercially introduced in 1941, diethylstilbestrol or DES, was prescribed to treat a variety of reproductive issues in women.  It was often administered as a prophylactic against preterm labor, miscarriage and other pregnancy complications, but was also used to treat vaginitis, to increase birth weight, to alleviate menopausal symptoms, and to halt lactation.  Though initially it was recommended for the treatment of high-risk pregnancies, it became increasingly commonly used for routine pregnancies by the late-1950s.  

However, even as DES was gaining popularity in treating a myriad of conditions, concerns emerged regarding its safety.  Since the late-1930s a number of studies had shown that DES caused tumors in animal studies, and by the early 1960s there was mounting evidence that DES caused cervical cancer in the daughters of women who took it while pregnant.  This was confirmed in 1971 by clinicians at Massachusetts General Hospital who documented eight cases of the rare vaginal cancer adenocarcinoma in women under 20 -- all of whom had been exposed to DES in utero.  FDA quickly issued a drug alert to all U.S. doctors warning against treating pregnant women with DES.  

legacy use


Though medical use of purple foxglove, or Digitalis purpurea, dates 500 years earlier in Wales,  its modern use began in 1775 with Birmingham physician William Withering.  He investigated digitalis in over 150 cases of dropsy, alerted by possible folk medical success in treating this condition of generalized accumulation of fluids in the tissues.  He observed that the heart was in some way affected, and noted as well that many benefited, though he attributed that principally to diuresis rather than the cardiac stimulation that subsequent workers soon came to understand.  Withering's An Account of the Foxglove and Some of Its Medical Uses (1785) included his results, information about dosage of this famously violent drug, and different preparations.

The 19th century witnessed indiscriminate use of digitalis, but 20th century research helped refocus this as a valuable specific therapy for congestive heart failure.  Discoveries of cardiac glycosides in digitalis species, including digitoxin (1870s) and digoxin (1920s), were key.

The clinical significance and narrow therapeutic index of digitalis and its glycosides drove much of FDA's scientific and regulatory work throughout the 20th century:  assay improvements, seizures of products substantially variant from stated potency, and the launch of a voluntary certification program in the 1970s to address rampant poor quality.  These drugs nonetheless remained an anchor in cardiac care for a long time. 

Enovid (mestranol/norethynodrel)
approved 1960


G.D. Searle's 1960 introduction of Enovid, the first birth control pill, has been heralded both as a therapeutic and a social revolution.  For the first time in history, it became possible for women to prevent pregnancy by chemically controlling their menstrual cycle, enabling women greater power over their own bodies and capacity for family planning.  Because Enovid was a prescription medication that was taken over long periods of time, it transformed women's relationships with their doctors and the nature of reproductive healthcare. But that's not all.

The effort to develop Enovid, a formulation of 19-nor progestin, was a decade long collaboration between biologist Gregory Pincus and gynecologist John Rock with support from Planned Parenthood founder Margaret Sanger and her benefactor Katherine McCormick, involving clinical trials that enrolled thousands of women around the world and employed methodology and vulnerable populations that would later be invoked to call for major reforms in the conduct of clinical trials.  

Shortly after Enovid was first marketed, the drug was linked to an increased risk for venous thrombosis.  However, because the pill offered significant benefits, particularly in treating menstrual disorders, endometriosis and alleviating the dangers of delivering babies, FDA required the product to include a Patient Package Insert educating patients about the drug's risks–becoming the second product ever to bear this requirement.  

Iletin (U-80 Lente insulin)
introduced 1922


The 1921 discovery that insulin is effective in treating diabetes, made by Canadian researchers Frederick Banting, Charles Best, J. J. R. Macleod and James B. Collip, was one of the most significant therapeutic revolutions of the 20th century.  Not only did insulin offer life-saving treatment to millions of diabetes patients whose only prior therapeutic options were near starvation no-carbohydrate diets, but it also ignited interest in developing other hormonal therapies and transformed the relationship between academic researchers and private pharmaceutical firms.

To meet the vast demand for insulin, in 1923 the University of Toronto (which held the patent for insulin) permitted Eli Lilly to develop and distribute the drug under the trade name Iletin in the United States.  Even as other firms gained rights to market their own insulin products, Lilly remained the dominant supplier for decades.  By 1941, when millions of Americans depended on insulin treatment, Congress deemed this drug so essential to public health it passed an amendment to the Food, Drug, & Cosmetic Act requiring FDA to certify batches of insulin for safety, potency and identity to ensure patients had access to high quality products.  The program was so successful in safeguarding the quality of insulin that by the 1990s it was no longer necessary to elevate industry practices, and it ended under the Food and Drug Administration Modernization Act of 1997.

Inderal (propranolol)
approved 1967


In 1964 Scottish pharmacologist and head of biological research at Smith, Kline and French, Sir James Black, discovered a drug that would prove indispensable in the treatment of cardiovascular disease for the rest of the 20th century.  Black was trying to find a drug that would alleviate the pain of angina pectoris by decreasing the heart's demand for blood oxygen, but clinical applications showed it was actually effective in alleviating heart attacks, arrhythmia and hypertension.  This discovery would earn Black a knighthood in 1981 and the 1988 Nobel Prize in Medicine.

Propranolol, marketed by Ayerst as Inderal, was approved by the FDA in 1967 and became the first non-selective beta-blocker, a class of drugs that can reduce the work of the heart, thereby reducing the risk of adverse cardiac events. Propranolol quickly became crucial for managing ischemic heart disease, arrhythmias, and myocardial infarction.  However, in time it also proved useful in treating noncardiovascular conditions that are also exacerbated by adrenaline binding, such as migraines, essential tremors and anxiety disorders.  However, because propranolol can induce chemical dependency, in 2010 FDA required it be labeled with a boxed warning advising against abruptly discontinuing use.

Accutane (isotretinoin)
approved 1982


Hoffman-LaRoche introduced its prescription isotretinoin product, Accutane, in 1982 as a treatment for cystic acne.  The drug proved to be remarkably effective in treating this disfiguring and emotionally distressing disease and was celebrated by doctors and a vast population of patients.  However, even before beginning clinical trials, animals studies had revealed the drug's teratogenic effects, so FDA's approval required that the drug be labeled with an explicit warning that it should not be used by pregnant women.  Yet, despite this precaution and an added 1984 requirement that patients take a pregnancy test prior to initiating isotretinoin treatment, by 1987 an alarming number of birth defects were linked to the drug.  

FDA's Dermatologic Drugs Advisory Committee recommended specific labeling changes targeted to both patients and practitioners, and the agency worked with the manufacturer to develop strategies to more impactfully educate patients about the potential risks, including extensive pregnancy prevention materials and the 2005 launch of the iPLEDGE program.  These efforts signified a complex and sophisticated approach to mitigating risks of useful drugs that can have dangerous side effects if not properly used, and presaged the formalization of the FDA's Risk Evaluation and Mitigation Strategies program in 2007.  

MER/29 (triparanol)
approved 1960


Researchers had long linked cholesterol to heart disease when the William S. Merrell Company developed triparanol, or MER/29, the first drug designed to intervene in the biosynthetic pathway of cholesterol production as a means of reducing the risk of heart disease.  FDA approved the drug in April 1960 and it sold briskly, but questions remained.  Many were concerned with the unknown metabolic effects of an accumulating intermediate from cleaved cholesterol generation.  Reports of those effects appeared increasingly in 1961, including bilateral cataracts, hair loss, and scaling and other effects on the skin.

Following a November FDA-authorized warning Merrell withdrew triparanol from the market in April 1962, with more problems imminent.  A company whistleblower turned over to FDA evidence of falsified laboratory results in the new drug application.  In December 1963 a federal grand jury indicted the firm and three of its research scientists for withholding information and filing false statements with the FDA.  The defendants pleaded no contest and suffered both the penalties of their criminal actions and the losses from many subsequent civil suits.  The company's much better known experience with thalidomide certainly left a more lasting impression, but MER/29 registered its own unique and damaging impact.

Mercurochrome (merbromin)
Hyson, Westcott & Dunning
introduced 1919


Merbromin is an organic mercurial germicide and fluorescein used both as an antiseptic and a dye for microscopy.  It was discovered in 1918 by Johns Hopkins urologist, Hugh Hampton Young, who conducted extensive research on the compound's intravenous use for treating genitourological diseases.  Merbromin proved to be useful in treating a number of bacteriological diseases, including pneumonia and meningitis, but it is perhaps most widely recognized as a topical antibacterial ointment.  

By the mid-20th century, merbromin products such as Mercurochrome were commonly found in household first aid kits and used to treat the minor scrapes and cuts of countless children.  However, due to its fluorescein nature, merbromin ointments would stain the skin bright red, obscuring the conspicuous warning signs of infection and inflammation.  

By the end of the 20th-century, concerns about the toxicity of mercury led to disuse in many developed countries, and in 1998 the U.S. Food and Drug Administration issued a final rule withdrawing the generally recognized as safe classification for merbromin, which prohibited its sale as an over-the-counter drug.  It is still widely used in many underdeveloped countries because it is so inexpensive to produce.

Miltown (meprobamate)                   Equanil (meprobamate)    
Wallace                                  &          Wyeth
approved 1955                                   approved 1955

Miltown Equanil

The first blockbuster minor tranquilizer, meprobamate, derived from the keen observations of Frank Berger.  His WWII studies of possible adjuvants to broaden penicillin's activity led him to mephenesin, which to Berger's surprise produced a loss of muscle control in conscious animals.  Smaller doses lacked the paralytic result but quieted stressed and nervous animals-a "tranquilization" effect according to Berger.  At Wallace Laboratories in New Jersey, Berger found a longer lasting version of mephenesin in 1950, meprobamate.  It safely relieved symptoms of anxiety over a long duration in the vast majority of patients.  Approved in April 1955, Wallace named the drug Miltown after a nearby village;  its licensee, Wyeth Laboratories, marketed it as Equanil.

Early enthusiasm for meprobamate in the entertainment industry launched a frenzy that reached into most areas of American society.  Miltown sales grew to more than $2 million by the end of the 1955, and Equanil outsold Miltown by a substantial margin. FDA investigated the possibility that its intense and spontaneous publicity created an illicit market, though that did not pan out.  But as quickly as meprobamate introduced America to the culture of tranquilization, by the early 1960s its standing was usurped by the rise of the benzodiazepines.


Pentothal sodium (thiopental sodium)
introduced 1934

Pentothal Sodium

Until the early-20th century, patients requiring surgery were commonly anesthetized with ether or chloroform, both dangerous sedatives that could easily be fatal if the dosage was not properly calculated.  In 1923 Abbott Laboratories Chief Chemist Ernest Volwiler developed an alcohol-sodium based barbituric acid sedative marketed as Nembutal (pentobarbital), which offered a much safer option for anesthesia, but took longer to induce unconsciousness and up to 3 days to be eliminated from a patients' system.  

In 1934 Abbott introduced a new barbiturate anesthetic, Pentothal sodium (thiopental sodium), which took effect in 3-5 minutes and was excreted from the kidneys in under 12 hours.  Use of sodium pentothal as an induction anesthetic revolutionized combat surgery during the Second World War, and also proved beneficial as a sedative in the psychoanalytical treatment of war neuroses.  One study estimates that between 1934-1955 sodium pentothal was used in 94% of all intravenous anesthesia injections.  

After the war, it was increasingly popular for off-label uses in criminology as a "truth serum" and for the lethal injection of convicts.  The introduction of propofol in the 1980s eclipsed sodium pentothal's usefulness as an anesthetic, and its bioethically questionable uses led to a major decline in demand that eliminated its domestic production in the United States.

Nicorette (nicotine polacrilex)
Marion Merrell Dow
approved 1984


Following the publication of the 1964 Surgeon General's Report on Smoking, increasing evidence linking cigarette smoking to lung cancer and emphysema inspired the development of new methods to help smokers quit the habit.  Nicotine replacement therapy (NRT), first developed in 1971 by Ove Fernö at the Swiss firm AB Leo, sought to support smoking cessation by enabling smokers to gradually reduce their addiction to nicotine without inhaling the tars and other harmful ingredients in cigarettes.  Fernö's innovation was to develop a means of controlled release of nicotine over time, which he achieved by binding nicotine to an ion-exchange resin (polacrilex).  

In 1984, after almost 3 years of review, Nicorette gum became the first NRT product approved by the FDA.  Concerns about excess nicotine intake prompted a requirement that the product be labeled with a warning cautioning against the use of Nicorette in concurrence with continued cigarette smoking.  Contraindications in cardiovascular and cerebrovascular diseases, pregnancy, and lactation were subsequently added to the required warnings.  

In 1991 the NicoDerm CQ patch was introduced, and since then the field of NRT products has grown to include lozenges, oral sprays, nasal sprays, inhalers and sublingual tablets.  After the passage of the 2009 Family Smoking Prevention and Tobacco Control Act officially authorized the FDA to regulate tobacco products, the newly created Center for Tobacco Products removed original contraindications for use while smoking and revised the pregnancy warning.


Oraflex (benoxaprofen)
approved 1982


Benoxaprofen was born of an industry-wide interest in potent, longer lasting non-steroidal anti-inflammatory drugs as alternatives to corticosteroids for arthritis and other diseases.  An English Eli Lilly research facility prepared this drug in 1966, and Lilly filed an IND in June 1974 and an NDA in January 1980.  The company had received frequent reports of unusual dermatological and other reactions, delaying FDA approval.  Eventually the agency's Arthritis Advisory Committee unanimously recommended approval, and in April 1982 FDA approved benoxaprofen.

But over the next month the agency learned from British officials of 27 cases of fatal gastrointestinal, hepatic, and renal disorders in the U. K. associated with the drug, where it had been marketed since March 1980.  FDA mandated labeling changes in July, and in early August Lilly suspended all sales of benoxaprofen worldwide;  more than 40 deaths were linked to the drug in the U. S. alone.  An investigation-including company insider reports-preceded legal action resulting in a guilty plea to multiple counts of failing to report foreign adverse events and misbranding for absent label disclosures.  Senior company officials were fined as well.  The case of benoxaprofen informed future policies on reporting adverse events in drug applications and illuminated the need for greater communication between international regulators.

Ovarian substance

Ovarian Capsules

The 1962 Drug Amendments was not the first time efficacy per se appeared in federal law.  A number of earlier statutes explicitly required effectiveness for several specific drugs.  In addition, as early as 1939 FDA began to raise regulatory concerns with certain types of drugs that lacked efficacy yet allegedly contained therapeutically active ingredients.  In December 1939 FDA advised the industry that some oral preparations of ovary extracts lacked any ingredients that would have estrogenic or progestational activity. In such cases the article would be deemed adulterated and misbranded.

However, one year later the agency backed off a bit; if some physicians wanted to employ harmless and inert products such as oral ovarian extracts, the 1938 act would not stand in their way. Nevertheless, the law required material facts on the label, and in this case the agency considered the lack of therapeutic effect, based on scientific evidence, material. Thus, in 1941 FDA advised manufacturers that oral or otherwise inert ovary, suprarenal, pituitary, prostate, pineal, and mammary extracts should be labeled with the statement that such an article "does not contain any known therapeutically useful constituent of the glands mentioned."

Panalba (tetracycline and novobiocin)
approved 1957


Panalba combined tetracycline hydrochloride, a broad spectrum antibiotic, and novobiocin, another antibiotic.  Many in academic medicine questioned this approach, but such combinations flooded the market and were lucrative.  The 1962 Drug Amendments required drug effectiveness based on substantial evidence derived from adequate and well-controlled clinical studies.  So, in the late 1960s FDA contracted with therapeutic experts for an external study of the effectiveness of all pre-1962 drugs based on published or other evidence from industry.

One-quarter of more than 4000 drugs evaluated were fixed combination antibiotics.  The experts determined that if the combined therapeutic effect of the drug were no greater than one of its parts, it would be considered "ineffective as a fixed combination," a combination that also exposed the patient to unnecessary risk. The experts deemed Panalba ineffective, and in 1968 Commissioner Herbert Ley moved to revoke Panalba's certification:  "The use of two or more active ingredients in the treatment of a patient who can be cured by one is irrational therapy."  Upjohn challenged the decision but the Supreme Court declined to hear Upjohn's appeal of the Circuit court ruling in FDA's favor, clearing a path for FDA's future actions against ineffective fixed combination antibiotics. 



In 1928 Alexander Fleming discovered that a mold, Penicillium, had contaminated-and surprisingly lysed-his cultures of pathogens through a mold filtrate he called "penicillin."  But it was Howard Florey and his colleagues at Oxford who uncovered the drug's chemotherapeutic potential.  They showed the drug was safe and, with sufficient penicillin available, patients survived severe staphylococcal and streptococcal infections.  The drug was difficult to purify and defied production in sufficient quantities.  With the British industry otherwise focused on the war effort the Oxford team turned to government and private officials in the U. S. in July 1941 for assistance in producing more penicillin to further test the drug.

The Americans contributed crucial changes in the Penicillium mold and its cultivation, they advanced the chemical understanding of the filtrate, and 21 penicillin production plants came on line.  These efforts improved penicillin yield and purity 100 and 85 fold, respectively, and larger trials confirmed Florey's promising results.  By 1943 penicillin made its way to the battlefield.

First, though, war planning leadership asked FDA to certify every lot prior to release to the troops.  The agency checked samples for potency, absence of fever-producing contaminants, toxicity, sterility, and optimum moisture.  The Penicillin Amendment of 1945 codified FDA's wartime certification work-a responsibility that continued for nearly four decades.

Rezulin (troglitazone)
approved 1997


The first new group of oral antidiabetic drugs since the 1950s derived from research in Japan and elsewhere into a new class of compounds, the glitazones.  Troglitazone (Rezulin), synthesized by Sankyo in 1988 and licensed to Parke-Davis, was the first of its kind to be approved by FDA in January 1997 for type II diabetes patients inadequately controlled by insulin.  As a priority review because of the unmet need among patients with type II diabetes, the agency reviewed troglitazone in six months, which was approximately twice as fast as the typical review period at the time.  

However, by the end of the year reports of about 150 cases of hepatotoxicity, including three deaths and a liver transplant, led FDA to recommend more frequent liver monitoring. As seen in the ensuing months many patients were not abiding by the monitoring protocol;  some patients died despite monitoring their liver enzymes; there was strong disagreement among some FDA staff about Rezulin's possible withdrawal;  and many clinicians and diabetic patients still firmly believed Rezulin had an important place in diabetes therapy.  

After an advisory committee meeting on Rezulin, in June 1999 FDA revised the labeling again to contraindicate Rezulin as a monotherapy or first-line therapy.  In March 2000 Parke-Davis withdrew Rezulin at FDA's request upon the agency's review of troglitazone, rosiglitazone (Avandia), and pioglitazone (Actos), confirming that the latter two 1999 approvals provided the expected clinical benefit of the drug class without the liver toxicity of the pioneer drug.  

Ritalin (methylphenidate)
approved 1955


In 1944, Ciba chemist Leandro Pannizon synthesized the amphetamine derivative methylphenidate, named Ritalin after his wife Marguerite (aka, Rita) who used the drug to manage her low blood pressure.  However, within a decade, it was recognized as therapeutically useful in the treatment of a variety of psychological and neuropsychiatric conditions.  

In 1955 Ritalin was approved by the FDA for treatment of narcolepsy, depression, lethargy, chronic fatigue, and barbiturate-induced coma, as well as senility and memory deficits in the elderly.  Since the late-1930s, psychologist Charles Bradley had conducted research on the use of psychostimulants, particularly Benzedrine, to treat attention deficit and hyperactivity in children.  

As Ritalin was believed to be a safer alternative to these powerful amphetamines, in 1962 Ciba received FDA approval to market the drug to children.  However, this was not widely done until the 1980 publication of the 3rd edition of the Diagnostic and Statistical Manual which recognized Attention Deficit Disorder (ADD) as an official psychiatric diagnosis (revised in 1987 to Attention Deficit Hyperactivity Disorder, or ADHD).  The creation of a diagnostic category for childhood hyperactivity and attention problems led to a vast increase in the use of Ritalin to treat these conditions, so that by 2019 it was the 51st most prescribed drug in the United States.

Seldane (terfenadine)
Merrell Dow
approved 1985


The history of antihistamines, dating back to the 1940s, witnessed such a variety of choices that the esteemed Goodman and Gilman's The Pharmacological Basis of Therapeutics characterized them as a "needlessly large number of antihistamines, and little distinction can be made between them on the basis of efficacy . . . ."  However, they all shared a problem that was overcome in the 1980s.  Researchers at Merrell Dow prepared terfenadine in the early 1970s as a possible tranquilizer.  However, not only did it surprisingly arrest common allergic reactions;  it did so with a unique property that spelled its failure as a tranquilizer:  it did not sedate the patient and thus lacked the common corollary of all preceding antihistamines.  

FDA approved terfenadine (Seldane) in 1985, but in 1990 the agency relabeled the drug and the firm issued a Dear Doctor letter, warning that patients were at risk of life-threatening cardiac arrhythmias due to drug interactions between Seldane and an antifungal or certain antibiotics or if the patient had liver disease.  In 1992, when over five dozen cases had been reported, FDA mandated a boxed warning on Seldane for the same problems.  The company again contacted hundreds of thousands of health professionals to alert them of the risk.  

In 1996 FDA approved fexofenadine (Allegra), the active metabolite of terfenadine introduced by Seldane's manufacturer, which had the therapeutic merits of terfenadine without its dangerous side effects.  FDA no longer believed terfenadine's benefits outweighed its risks given the safer alternative, and the firm withdrew Seldane by early 1998. 

introduced c. 1936


When Austrian chemist Paul Josef Jakob Gelmo first discovered sulfanilamide as a doctoral student in 1908, he inadvertently initiated a revolution in the treatment of bacterial infections that would contribute significantly to a steadily rising increase in life expectancy.  Within the next two decades, sulfanilamide powder and tablets would enable hundreds of thousands of people to treat infections that might otherwise have escalated to become more severe.  

In 1935 Gerhard Domagk of I.G. Farbenindustrie's Bayer Laboratories published the results of a five-year study of the antibacterial properties of azo dyes that revealed the chemotherapeutic effect of the prodrug, Prontosil.  Subsequent researchers showed this to be metabolized into the active component, sulfanilamide.  The following year, Leonard Colebrook of Queen Charlotte' Hospital in London proved Prontosil effective in treating puerperal sepsis, a condition that was often fatal in postpartum mothers. And in December 1936, President Franklin Roosevelt's adult son made a miraculous recovery from a streptococcal throat infection thanks to Prontosil (when only a decade earlier a strep infection had killed former President Calvin Coolidge's son).  

Sadly, enthusiasm about this wonder drug was blunted in the Fall of 1937 by the tragic mass poisoning caused by a toxic oral preparation of the drug, Elixir Sulfanilamide, which rallied a call for reform that led to the passage of the 1938 Food, Drug, and Cosmetics Act requiring that henceforth any drug marketed in the United States would first be required to demonstrate evidence of safety.  And while the discovery of penicillin and other antibiotics during and after the Second World War would quickly overshadow sulfanilamide, sulfa drugs remain medically useful in treating a variety of infections. 

Tamiflu (oseltamivir)
approved 1999


In 1999, Roche's Tamiflu (oseltamivir) became the first antiviral product approved in the United States for the prophylaxis of seasonal flu.  A neuraminidase inhibitor, it works by blocking an infected host cell from releasing progeny virus and thereby prevents the spread of infection to other cells.  However, since the peak of viral replication occurs between 24-72 hours after infection, these drugs work best when administered as close as possible to infection, which may be difficult due to late onset of symptoms.  

Due to its low toxicity and the lack of adverse events reported from clinical trial data, the drug's approval created hope that oseltamivir could be used for pandemic preparedness, and therefore led to national stockpiling.  This theory was tested during the 2009 H1N1 influenza pandemic, when the drug was administered on a large scale to ameliorate flu symptoms.  However, this experience revealed that increased use of the drug carried risks of cardiac arrhythmia, convulsions and encephalitis, as well as worrisome neuropsychiatric adverse events, including panic, delirium, hallucination, and self-injury, all of which occurred more commonly in children than adults.  

These concerns ignited a scientific debate about the risks and benefits of Tamiflu that scrutinized the original clinical trial data, as well as post-market real world evidence, and ultimately led to the World Health Organization down-grading the drug from "core" to "complimentary" on the essential medicines list.

Tylenol (acetaminophen)
approved 1955


Though it was initially discovered in 1878, acetaminophen was not used therapeutically until the early 1950s, shortly after researchers at Yale and New York University had revealed it to be a safer alternative to acetanilide and aspirin that possessed the same analgesic and antipyretic properties.  By the mid-1950s, several firms had introduced acetaminophen products, but it was the Philadelphia family drug firm McNeil Laboratories' vision to take advantage of acetaminophen's solubility to market the drug as a liquid children's pain reliever that promoted wider spread use of the drug.  

In 1955 FDA approved McNeil's NDA for Tylenol Elixir for Children (derived from the drug's chemical name, N-aceTYL-p-aminophENOL, or APAP) and the firm began exclusively producing this drug "for little hotheads."  By 1959 the product was so successful that Johnson & Johnson acquired McNeil and continued to market Tylenol as a mild pain reliever suitable for children.  However, seeking to boost sales, in 1975 Johnson & Johnson shifted their marketing strategy to emphasize the "extra strength" of Tylenol's 500 mg dose, compared to aspirin's 325mg.  By the early 1980s, Tylenol sales were believed to more than triple those of the other four leading over-the-counter pain relievers.

Veronal (barbital)
introduced 1903


The introduction of the first synthetic hypnotic in 1869, chloral hydrate, led many to search for improvements.  Most significant was the work of German chemists Emil Fisher and Josef von Mering, who modified barbituric acid-long known but neglected-to produce the first barbiturate, a central nervous system depressant marketed in 1903 as Veronal (barbital).  Fisher and a colleague prepared another barbiturate the following year, phenobarbital, which had several advantages over barbital;  Bayer introduced it in 1912 as Luminal.  Researchers prepared over 2500 barbiturates in ensuing decades, and about 50 were marketed.

Barbiturate abuse appeared early on, and surveys of American hospitals indicated a doubling of acute barbiturate toxicity cases from the 1930s to the 1940s.  The 1938 Act mandated labeling barbiturates with a warning of possible habit formation, and they required a prescription to be dispensed.  The agency initially dealt with illicit distribution by focusing on over-the-counter sales by pharmacists.  However, other outlets, especially in the trucking industry, increased in the 1950s and 1960s and attracted more of the agency's attention.  By the early 1970s FDA retained authority over approval and other aspects of the medical and scientific use of controlled substances such as barbiturates, while the Justice Department was charged to oversee their diversion and other aspects.

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