Frances Oldham Kelsey
Frances Kelsey receiving the President’s Distinguished Federal Civilian Service Award from President John F. Kennedy in 1962. Courtesy FDA History Office, Rockville, Maryland.
It is estimated that 10,000 children worldwide have been born deformed because of the use of the sedative thalidomide during pregnancy. This tragic situation inspired the 1962 Kefauver-Harris Amendment, strengthening drug regulation by forcing companies to disclose side effects and prove efficacy. Today thalidomide is being investigated for use in a variety of conditions, including inflammation, severe canker sores in AIDS patients, several forms of cancer, and macular degeneration, a condition that can result in blindness. For the most part, though, thalidomide has remained off the market in the United States for almost 40 years, owing primarily to the tenacity of one FDA medical officer, Frances Oldham Kelsey (1914−2015).
Kelsey was born in Cobble Hill, British Columbia. She was educated in Canada, receiving her B.Sc. from McGill University in 1934 and her M.Sc. from the same institution a year later. She moved to the United States to continue her education at the University of Chicago, earning her Ph.D. in pharmacology in 1938 and her M.D. in 1950. While in graduate school, Kelsey worked on some of the experiments that helped to identify diethylene glycol as the toxic agent in the elixir of sulfanilamide that killed 107 people in 1937 (see Walter G. Campbell). She taught at both the University of Chicago and the University of South Dakota before becoming a general practitioner in Vermillion, South Dakota.
Kelsey joined the U.S. Food and Drug Administration (FDA) in August 1960. A month later she became a reviewing medical officer in the Bureau of Medicine, with the task of reviewing new drug applications. The first application she received was from the Cincinnati-based William S. Merrell Company (now Aventis Pharma) for thalidomide.
Developed in the 1950s by the German company Chemie Grünenthal, thalidomide was considered to be an unusually safe sedative with few side effects and low toxicity. It was soon found to reduce the nausea and vomiting associated with pregnancy. Beginning in 1956, it was marketed under the trade name Contergan and became widely used in Europe. Grünenthal, wishing to capitalize on the drug’s success, began to license the manufacture and distribution of thalidomide to companies in other countries. The American licensee was the Merrell Company.
The Merrell Company submitted its application for FDA approval of thalidomide (under the brand name Kevadon) in September 1960. Under law at that time the FDA had 60 days to decide whether a drug was safe—no provisions for determining or testing efficacy were made. The applications were reviewed by three individuals: a chemist, a pharmacologist, and a medical officer. If the FDA did not respond within 60 days, the drug manufacturer could assume it was approved and could then market the medication.
When Kelsey and the other two FDA officials reviewed the thalidomide application, they quickly developed questions about the drug. For example, the pharmacologist on the team, Oyam Jiro, felt that the company’s toxicity tests had not been sufficient. The chemist, Lee Geismar, questioned the company’s manufacturing controls. Kelsey herself felt that the safety data were inconclusive and questioned why large amounts of the drug—ostensibly a sedative—could be given to animals without producing drowsiness.
As a result Kelsey sent the Merrell Company a letter within 60 days stating that their application was incomplete. In mid-January the company resubmitted their application, but questions remained about the drug’s metabolism, excretion and absorption levels, and toxicity. At the end of February, Kelsey read a letter by A. Leslie Florence in the British Medical Journal that noted a connection between thalidomide use and the development of peripheral neuritis—a condition characterized by inflammation of nerves, particularly in the arms and legs, causing pain, muscle weakness, and a decrease in reflexes. Although the European producers of thalidomide had discovered this connection earlier, the American company was not required to submit such information in their FDA application.
This British Medical Journal article also led Kelsey to suspect that thalidomide could damage nerves in a fetus. She had an interest in teratogens—drugs that can create malformations in fetuses—and the FDA and the American Academy of Pediatrics had been concerned about the effects of drugs taken during pregnancy. In November 1961 the first case of phocomelia was reported and linked to thalidomide use. Phocomelia is a severe birth defect that causes the malformation of the fetus’s limbs. Subsequent findings showed that phocomelia was most likely to occur in cases in which the mother took thalidomide during the first trimester of her pregnancy, when the limb buds of the fetus are forming.
Clinical testing of the drug ceased (except for clinical studies on its possible use in cancer), and the Merrell Company withdrew their thalidomide application from the FDA. Given the potential danger of the medication, the FDA tracked down the remaining samples in the United States. During this search the FDA found a few cases of phocomelia that had resulted from clinical trials in the United States.
These discoveries had little press coverage until the Washington Post reporter Morton Mintz broke the story in July 1962. This publicity led to increased public support for stronger drug regulation. The result was the Kefauver-Harris Amendment, passed in October 1962. This amendment required that companies demonstrate the effectiveness of new drugs, that companies send adverse reaction reports to the FDA, and that patients participating in clinical studies give consent. The provision for efficacy was retroactively applied to 1938, when the Food, Drug, and Cosmetic Act was passed. In order to test the effectiveness of drugs that had been approved on the basis of safety between 1938 and 1962, the FDA contracted with the National Academy of Sciences and the National Research Council.
In 1962 Kelsey received the President’s Distinguished Federal Civilian Service Award from President John F. Kennedy. She remained at the FDA and in 1995 at the age of 81 received yet another appointment there as deputy for scientific and medical affairs in the Office of Compliance of the FDA’s Center for Drug Evaluation and Research. The FDA named one of their annual awards after her in 2005, the year of her retirement.