“Heroine of FDA Keeps Bad Drug Off Market”
That is the title of a front page article on the July 15th, 1962 issue of The Washington Post. We recently marked the passing of that heroine, Dr. Frances Oldham Kelsey, who lived to an impressive 101 and died at her daughter’s home in London, Ontario on Aug. 7th. A recipient of the Distinguished Civilian Federal Service medal and inductee into the National Women’s Hall of Fame, she was not only a pioneer for women in the STEM fields but also instrumental in the creation of our current drug safety regulations and, through this, the prevention of potentially thousands of deaths.
Born in 1914, Kelsey’s fascination with the inner workings of the natural world started at a very young age as she roamed the countryside of her native Vancouver Island, British Columbia. She graduated high school at 15 and earned a Bsc and Msc from McGill University in 1934 and 1935, respectively. Upon graduating, she applied for a research assistant position with Professor Eugene Geiling of the University of Chicago and was accepted, sight unseen. In his offer letter, Dr. Geiling addressed her as “Mr. Oldham.” Kelsey expressed some hesitation at accepting the position under accidental false pretenses but a McGill professor advised her, “Don’t be stupid. Accept the position, sign your name and put ‘Miss’ in brackets afterward.” And so she did.
While Kelsey was in Chicago, the FDA asked Dr. Geiling and his team to look into a series of deaths relating to the use of Elixir Sulfanilamide, a drug that had killed 107 people, many of them children. The mixture was an alternative form of sulfanilamide, a medicine that was extremely effective in fighting bacterial infections. Patients, however, disliked the taste of the pills in which the drug was administered. S.E. Massengill, the company that manufactured the pills, looked for a way to address this problem. Their chief chemist found that sulfanilamide did not dissolve in water or alcohol but it did dissolve in diethylene glycol, a chemical currently used in anti-freeze. Massengill added pink dye and cherry flavoring to the mixture and began distribution without a thorough investigation of its safety.
This was all perfectly legal. The main law regulating the sale of pharmaceuticals at the time had been passed in 1906. While it prevented “the manufacture, sale, or transportation of adulterated or misbranded or poisonous or deleterious foods, drugs, medicines, and liquors”, it did not require manufacturers to prove that their products were safe before selling them. Instead, the onus was on the federal government to find and reveal these harmful substances.
After the discovery of diethylene glycol’s deadly properties, S.E. Massengill was fined $26,100 for a technicality of branding, since they broke no law in their failure to properly test the effects of diethylene glycol. This changed with the passage of the Federal Food, Drug, and Cosmetic Act of 1938, which mandated that companies demonstrate the safety of their product before they were permitted to market it.
While a great step forward, the law still had its weaknesses. One of these was the ease with which companies could gain FDA approval for new pharmaceuticals. Under the 1938 legislation, all new drugs had to be submitted to the FDA for approval. The FDA then had 60 days to evaluate the product’s safety and either approve the submission or ask for further information. If the FDA did not respond within 60 days, then the drug could be sold.
That was still the policy when Kelsey joined the FDA in 1960 as one of seven full time experts assigned to review any and all drug applications. After completing medical school (during which time she married and had two daughters), Kelsey had worked in South Dakota before taking up a post in Washington, DC. William S. Merrell’s application to market the drug thalidomide (under the brand name Kevadon) was her first assignment.
It should have been a simple one. The drug had been widely used across Europe to treat insomnia, nervousness, and morning sickness in the first trimester of pregnancy. In Germany, it was considered so safe that it was sold over the counter. Merrell wanted in on the game. They had already distributed samples to 1,200 doctors across the country (a practice allowed under the 1938 law). Kelsey, however, was concerned over lackadaisical records regarding tests on the drug’s safety, including a complete lack of information on its effects on pregnant women. While testing anti-malarial agencies during WWII, Kelsey had found evidence of drugs transferring from mother to fetus, though this ran contrary to the generally accepted view that the placenta protected a fetus from such substances.
Kelsey asked Merrell for more information. In so doing, she activated a useful loophole in regulations, since a request for information restarted the 60-day timer on drug applications. Merrell dutifully supplied more records. These proved to be little help in answering Kelsey’s concerns and those of her supervisors, who supported her as she asked, again and again, for more evidence. Merrell’s representatives, meanwhile, began running out of patience. They complained to her superiors, calling her a “bureaucratic nitpicker” and “unreasonable”. At one point, they admitted that they were pushing for the drug to be approved before the Christmas season, since the winter holidays were a prime sales period for sedatives like thalidomide.
Thalidomide was not approved in time for Christmas and Kelsey continued to block its approval through into 1961, when reports started flooding in from Europe, reports of deformed fetuses and babies born dead or with malformations of the arms and legs, eyes, and internal organs. The drug was pulled from shelves in Germany. Merrell withdrew their application the following year. Even so, at least 17 babies were born with serious defects as a result of their distribution of Kevadon samples.
Kesley’s actions were lauded in an article written by Washington Post reporter Morton Minz, helping to turn the spotlight on the dangerous practices of pharmaceutical manufacturers and the desperate need for better regulations. In 1962, Congress passed the Kefauver-Harris Amendment to the 1938 Food, Drug, and Cosmetic Act. The amendment required companies to prove both the safety and the effectiveness of a proposed drug, based on evidence from well control clinical studies. The FDA now had 180 days to review applications and approval would no longer be assumed if time ran out. The agency was also empowered with the authority to set manufacturing regulations and run inspections to make sure the rules were being followed. These regulations still govern the development and sale of drugs in the United States today.
Kesley was given charge of the FDA’s new investigational branch before becoming director of the Office of Scientific Investigations. She remained at the post until 1995 and then worked another further decade with the FDA’s Center for Drug Evaluation and Research. She finally retired at 90.
Thalidomide is still used to treat a limited number of conditions, including some cancers, but only under the strictest regulations. Even so, Kelsey remained concerned about its use, saying at one point, “We need to take precautions because people forget very soon.”
We here at IVAL honor Dr. Kelsey’s trailblazing work for both toxicology and women in the STEM fields. We strive to uphold her legacy through our own efforts to investigate the effects of experimental compounds on the human body and ensure that all pharmaceuticals are as safe and effective as possible.
Sources and Further Reading:
FDA article highlighting Dr. Kelsey’s work, based on an interview with her
Posthumous article from The Washington Post
The Washington Post Front Page, July 15th, 1962
The Food, Drug, and Cosmetic Act of 1096
The Food, Drug, and Cosmetic Act of 1938
The Kefauver-Harris Amendment of 1962
Thalidomide Today
The Dangers of Diethylene Glycol
In Vitro ADMET Laboratories, LLC 