Although the Food and Drug Act of 1906 was relatively clear about drug standards, misbranding of drugs became a source of considerable controversy in drug regulation, leading to a growing number of untested drugs or drugs labeled with false therapeutic claims intended to defraud consumers, by the early 1930s it was recognized that ‘1906’ was obsolete. There was, however, bitter disagreement as to how to replace it.
With the election of Franklin D. Roosevelt in 1932, work began to replace the old law, legally mandated quality and identity standards. The new law required that drugs should be labeled with adequate directions for safe use and mandated pre-market approval of all new drugs, requiring manufacturers to prove that a drug was safe before it could be marketed.
However, it took a therapeutic disaster and the death of over 100 people, many of them children, before Congress acted by replacing the 1906 law.[1]
The disaster was caused by a Tennessee-based drug company, S.E. Massengill Co., which marketed a new formulation of sulfanilamide*, a drug used to treat streptococcal infections and had been shown to have dramatic curative effects. The drug had been used safely for some time in tablet and powder form. However, following up on information from his sales manager, Dr. Samual Evans Massengill, the company’s founder and owner, was convinced that a new liquid formulation would appeal more to pediatric patients.
In developing the new formulation, the company’s chief chemist and pharmacist, Harold Cole Watkins, experimented and found that sulfanilamide would nicely dissolve in diethylene glycol (DEG, a cheap solvent), a highly toxic chemical analogue of antifreeze. The company tested the new drug for its flavor, appearance and fragrance, but not for toxicity. Without further pharmacological studies the new liquid drug formulation was found to be ‘satisfactory’ for marketing, after which the company immediately compounded it for distribution. Marketed as Elixir Sulfanilamide, the toxic drug was shipped all over the United States.
S.E. Massengill Co.’s Elixir Sulfanilamide, was used to treat adults and children for sore throats caused by Streptococcus. Patients treated with the miracle elixir quickly developed headaches, dizziness, malaise, back and abdominal pain, vomiting, stupor, convulsions and anorexia. The majority developed anuric renal failure, characterized by the absence of urine production, experienced seizures, lapsed into coma, and suffered from intense and unrelenting pain. Without a known antidote or treatment for diethylene glycol poisoning, most patients died
The disaster could have been avoided if the manufacturer had performed a simple test on experimental animals. This would have demonstrated the deadly properties of Elixir Sulfanilamide. And while the link between diethylene glycol and liver, neurological, and renal toxicity of DEG was poorly understood, a quick review of the available medical literature at the time would also have shown that diethylene glycol was indeed toxic and could cause kidney damage or failure, leading to death.
Remarkable as it may seem, in 1937 there was no law prohibiting the marketing, sale and distribution of dangerous, untested, or poisonous drugs, a fact that well known by the company’s owner Dr. Samual Evans Massengill.
In a statement, Massengill criticized all those who complained about the lethal results of Elixir Sulfanilamide and stated that while he and his “chemists… deeply regret the fatal results, …there was no error in the manufacture of the product. We have been supplying a legitimate professional demand and not once could have foreseen the unlooked-for results.” Massengill did not feel that there was any responsibility on his part. However, after learning of the deadly effects of his concoction, Harold Cole Watkins, the company’s chief chemist and pharmacist, committed suicide.**
The public outcry that followed this therapeutic disaster, without a doubt one of the most consequential mass poisonings of the 20th century, not only reshaped the drug provisions of the new law to prevent such an event from happening again, but it also shaped our current attitudes to drug safety and, after 5 years of delays, it propelled the bill through Congress. Franklin D. Roosevelt signed the Food, Drug, and Cosmetic Act on June 25, 1938.
The new legislation changed regulation and oversight of pre-market testing, development, and licensing of pharmaceutical drugs in the United States and became a model for adoption by other countries.
Between 1938 and 1962 more than 13,000 drug applications were submitted to the FDA. In that year following the Thalidomide-disaster, a new drug law, the Kefauver-Harris Amendments, derived from hearings held by Senator Estes Kefauver, resulted in a much stricter law that not only required proof of safety for new drugs, but also required substantial evidence of efficacy based on adequate and well-controlled clinical studies. In the years that followed, strict regulations for the ethical conduct of clinical research and the rules to protect study participants were adopted.
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Note: * In 1932 Gerhard Domagk, German chemist and pathologist, discovered the antibacterial properties of sulfanilamide. He won the Nobel Prize for this achievement.
** S.E. Massengill Co continued to operate as a family-owned pharmaceutical firm until it was acquired in 1971 by Beecham plc., itself later merged into SmithKline Beecham in 1989 and in 2000 with GlaxoSmithKline.
Reference
[1] History of Modern Clinical Toxicology Edited by: Alan D. Woolf; Chapter 2.1 – Sulfanilamide (diethylene glycol) disaster—United States, 1937 2022, Pages 139-148; ISBN: 978-0-12-822218-8; DOI: 10.1016/C2019-0-03597-2
[2] Bennett PN. Detecting adverse reactions to drugs. Hum Toxicol. 1988 Sep;7(5):465-7. doi: 10.1177/096032718800700514. PMID: 3056843.
