In 1960, America had a stroke of luck. That was when the application to begin mass-marketing the drug thalidomide in the United States landed on the desk of Frances Oldham Kelsey, a reviewer at the Food and Drug Administration. Today we know that the drug can cause a range of severe congenital deformities and even infant death when taken by pregnant women for nausea. But at the time, thalidomide’s darker effects were just becoming known.
Between 1957 and 1962, the sedative would result in thousands of infants in Canada, Great Britain and West Germany born with serious deformities, including the shortening or absence of limbs. The U.S., however, never had a crisis of thalidomide-linked deformities on that magnitude. Why not?
What stood between the drug and the health of the American public was none other than Kelsey and the FDA. As a medical reviewer, Kelsey had the power to prevent a drug from going to market if she found the application to be lacking sufficient evidence for safety. After a thorough review, Kelsey rejected the application for thalidomide on the grounds that it lacked sufficient evidence of safety through rigorous clinical trials.
Today we take it for granted that the FDA wisely spurned an unsafe drug. But in many ways, Kelsey’s education and experience up to that point made her especially well-suited for her position as a medical reviewer—and, in particular, for the thalidomide application.
After completing a master’s degree in pharmacology at McGill University in her home country of Canada, Kelsey was recommended by her graduate advisor to write to a Dr. Eugene Geiling at the University of Chicago to inquire about a research assistant position and to express her interested in obtaining a PhD. Geiling, a medical officer at the FDA known for his studies of the pituitary gland, wrote back offering Kelsey a research assistantship and a scholarship for doctoral study. In 1936, Kelsey joined Geiling at the University of Chicago.
That consequential step in Kelsey's career may been due to a fortuitous error on the part of Geiling. In her short memoir “Autobiographical Reflections,” Kelsey describes Geiling as “very conservative and old-fashioned,” noting that “he really did not hold too much with women as scientists.” This might explain why Geiling, in his response letter to Kelsey, addressed it to “Mr. Oldham”—believing her to be a man. Kelsey said she continued to wonder “if my name had been Elizabeth or Mary Jane, whether I would have gotten that first big step up.”
Kelsey was first introduced to the dangers of mass marketed unsafe pharmaceuticals in 1937, when the FDA enlisted Geiling to solve the mystery of Elixir of Sulfanilamide. Sulfanilamide effectively combated infections, but it came in a large and bitter pill that needed to be taken in large dosages. To make the drug more appealing, especially to children, manufacturers added it to a solvent with artificial raspberry flavor.
The problem was that the solvent they chose was diethylene glycol—commonly known as antifreeze. Between September and October, the drug killed 107 people.
Geiling and his lab of graduate students, including Kelsey, set out to determine what exactly in the elixir was killing people: the solvent, the flavor or the sulfanilamide. Through a series of animal studies—which at the time were not required by federal law for a drug to go to market—Geiling and his lab were able to determine that it was the diethylene glycol that was the cause of death.
The public outcry to this tragedy prompted Congress to pass the Federal Food, Drug, and Cosmetic Act of 1938, which added a New Drug section requiring manufacturers to present evidence that a drug was safe before going to market. Though this new law “provided for distribution of a new drug for testing purposes,” FDA historian John Swann says “the law did not provide in any explicit or detailed way how oversight of that testing should be conducted.” In other words, clinical trials continued to undergo little to no oversight.
Kelsey graduated from medical school in 1950, and went on to work for the Journal of the American Medical Association before starting work as a medical reviewer at the FDA in 1960. As reviewer of New Drug Applications (NDA), she was one of three people charged with determining a drug’s safety before it could be made available for public consumption. Chemists reviewed the chemical makeup of the drug and how the manufacturer could guarantee its consistency, while pharmacologists reviewed animal trials showing that the drug was safe.
Though this appears to be a rigorous and thorough process of checks and balances, Kelsey admitted to some weaknesses in her memoir, including the fact that many of the medical reviewers were part-time, underpaid and sympathetic to the pharmaceutical industry. The most troubling deficiency in the process was the 60 day window for approving or rejecting drugs: If the 60th day passed, the drug would automatically go to market. She recalls that this happened at least once.
Fortunately, drug manufacturer Richardson-Merrell’s NDA for Kevadon—the U.S. trade name for thalidomide—was only the second NDA Kelsey received, meaning she didn’t yet have a backlog of reviews to get through. For Kelsey and the other reviewers, thalidomide did not pass muster. Not only were there pharmacological problems, but Kelsey found the clinical trials to be woefully insufficient in that the physician reports were too few and they were based largely on physician testimonials rather than sound scientific study. She rejected the application.
Reports of the side effect peripheral neuritis—painful inflammation of the peripheral nerves—were published in the December 1960 issue of the British Medical Journal. This raised an even bigger red flag for Kelsey: “the peripheral neuritis did not seem the sort of side effect that should come from a simple sleeping pill.”
She asked for more information from Merrell, who responded with another application merely stating that thalidomide was at least safer than barbiturates. Kelsey then sent a letter directly to Merrell saying that she suspected they knew of the neurological toxicity that led to nerve inflammation but chose not to disclose it in their application. Merrell grew increasingly upset that Kelsey would not pass their drug, which had been used in over 40 other countries at this point.
If neurological toxicity developed in adults who took thalidomide, Kelsey wondered: What was happening to the fetus of a pregnant woman who took the drug? Her concern hit on what would be the most dangerous effect of thalidomide in other countries.
Kelsey had asked these questions before. After getting her Ph.D. in 1938, she stayed on with Geiling. During World War II, Geiling’s lab joined the widespread effort to find a treatment for malaria for soldiers in wartime. Kelsey worked on the metabolism of drugs in rabbits, particularly an enzyme in their livers that allowed them to easily break down quinine. What wasn’t clear was how this enzyme broke down quinine in pregnant rabbits and in rabbit embryos.
Kelsey found that pregnant rabbits could not as easily break down quinine and that the embryos could not break it down at all. Though there was already some work being done on the effects of pharmaceuticals on embryos, it was not yet a well-researched area.
By November of 1961, physicians in Germany and Australia had independently discovered birth defects in infants whose mothers had taken thalidomide during early pregnancy. In embryos, thalidomide could cause critical damage to organ development—even just one pill could result in infant deformities. And since many doctors prescribed thalidomide for the off-label treatment of morning sickness, 10,000 infants all over the world were affected, and countless others died in utero.
Merrell eventually withdrew the application on their own in April of 1962. But the drug had already been distributed to “more than 1200 physicians, about 15,000-20,000 patients—of whom over 600 were pregnant,” according to Swan. In the U.S., 17 cases of congenital deformities were reported, but as Swan says via email, “that could have been thousands had the FDA not insisted on the evidence of safety required under the law (despite ongoing pressure from the drug’s sponsor).”
In 1962, soon after Merrell withdrew their application and the dangers of the drug became internationally known, Congress passed the Kefauver-Harris Amendment. This key amendment required more oversight for clinical studies, including informed consent by patients in the studies and scientific evidence of the drug’s effectiveness, not just its safety. In the wake of its passage, President Kennedy awarded Kelsey the President’s Award for Distinguished Federal Civilian Service, making her the second woman to receive such a high civilian honor.
In her memoir, Kelsey says that the honor did not belong just to her. “I thought that I was accepting the medal on behalf of a lot of different federal workers,” she writes. “This was really a team effort.” She was quickly promoted to chief of the investigational drug branch in 1963, and four years later, she became director of the Office of Scientific investigation—a position she held for 40 years until she retired at the age of 90. She lived until the age of 101, and passed away in 2015.
Kelsey spent the majority of her life in public service, and her story continues to stand out as a testament to the essential role of the FDA in maintaining drug safety.
Editor's Note, March 14 2018: This article has been updated to reflect accurate and appropriate language according to the National Center on Disability's style guide.