A legacy of drug safety

There are many careers that allow a scientist to make an impact on society. For pharmacologist and physician Frances Oldham Kelsey, who died last Friday at the age of 101, a position at the U.S. Food and Drug Administration (FDA) reviewing applications for new drug licenses made her one of the most influential scientists of the 20th century. In the early 1960s, Kelsey’s scrupulous scientific standards, staunchness, and courage kept the drug thalidomide off the American market, saving countless American children and their families from the tragedy of severe birth defects. Unknowingly at the time, such birth defects had already begun to befall children in Europe, ultimately affecting an estimated 10,000 worldwide, according to the Chemical Heritage Foundation. Kelsey’s subsequent 45-year government career helped shape the legislation and policies that have since aimed to protect the nation from unsafe drugs for more than half a century.

Kelsey’s single-mindedness and determination in insisting on a significant delay permitted time for evidence about thalidomide’s disastrous effect on the developing fetus to emerge.

“Her exceptional judgment in evaluating a new drug for safety for human use has prevented a major tragedy of birth deformities in the United States,” said President John F. Kennedy in 1962, as quoted in an obituary in , when he presented her the President’s Award for Distinguished Federal Civilian Service—the nation’s highest civilian honor—at a White House ceremony. Only one other woman had ever before received it.

By the time Kelsey arrived at FDA in 1960, she had earned both a Ph.D. in pharmacology and an M.D. and worked as a laboratory researcher, a medical editor, a university professor, and a family physician. Her arrival coincided with the application for permission to sell thalidomide, which had gained wide use in Europe as a sleeping aid and a remedy for morning sickness in pregnant women. The William S. Merrell Company in Cincinnati, Ohio, had rights to distribute the drug in this country and expected an equally large and lucrative market. They hoped for the relatively speedy FDA approval that was common in those days.

As she described in her FDA oral history, Kelsey received thalidomide just over a month on the job, as one of her first FDA assignments. “I was the newest person there and pretty green, so my supervisors decided, ‘Well, this is a very easy one. There will be no problems with sleeping pills.’” As highlighted in an article published by on Friday, almost immediately, however, Kelsey became suspicious of the safety information that Merrell had provided, which struck her as inadequate and misleading. Unbeknownst to the scientific world at the time, the drug was already causing increasing numbers of European children to be born with severely deformed and flipper-like arms and legs, a birth defect that normally happened once in 4 million births.

As Kelsey recalls in her FDA history, early in 1961 a letter from a physician published in the British Medical Journal confirmed Kelsey’s intuition by alerting the medical community to a possible adverse effect—peripheral neuritis—of thalidomide, which caused her to worry about the possible effects of thalidomide on a fetus. Although evidence to the contrary had begun causing concern at FDA, medical dogma at the time still generally held that substances such as drugs and alcohol did not cross the placenta from the mother to the fetus.

“I had the feeling that [company executives] were at no time being wholly frank with me, and that this attitude has obtained in all our conferences, etc., regarding this drug,” she once wrote, as quoted by the Times. “For a critical 19-month period,” according to the Post article, “she fastidiously blocked its approval while drug company officials maligned her as a bureaucratic nitpicker.”

Kelsey’s single-mindedness and determination in insisting on a significant delay permitted time for evidence about thalidomide’s disastrous effect on the developing fetus to emerge and gain scientific acceptance, which led to its ban in the United States. With the horror of the mounting number of thalidomide children in Europe fresh in the public’s mind, reporting by The Washington Post on Kelsey’s struggle with Merrell brought the cause of strengthening drug safety regulation to national attention. This ultimately provided impetus for the passage of legislation sharply tightening the previously lackadaisical drug review process. The case also permanently destroyed beliefs about the supposed protective powers of the placenta and made pregnancy testing standard for drug approvals.

“She had a huge effect on the regulations adopted in the 1960s to help create the modern clinical trial system,” according to FDA history expert Daniel Carpenter, a professor of government at Harvard University, as quoted in the Post article. “She may have had a bigger effect after thalidomide than before.”

This was because, as FDA created new structures to strengthen drug approvals, Kelsey played a leading role. First, she headed the investigational drug branch and when, in 1963, the FDA created its Office of Scientific Investigations, she became director and remained in that post until 1995. Then, until she retired at the age of 90, she worked at the agency’s Center for Drug Evaluation and Research.

Standing up to opposition was not new to Kelsey, however. As a woman who aspired to be a scientist in an age when very few succeeded, she almost missed the chance to pursue her scientific work beyond the master’s degree she earned at McGill University in her native Canada, as highlighted in the Post article. Applying for a job as research assistant at the University of Chicago, where she would ultimately earn her Ph.D. and then her M.D. and serve as an assistant professor, she received an acceptance letter addressed to “Mr. Oldham.” “When a woman took a job in those days, she was made to feel as if she was depriving a man of the ability to support his wife and child,” she later recalled, as quoted by the Post. “But my professor said: ‘Don’t be stupid. Accept the job, sign your name and put “Miss” in brackets afterward.’”

Arriving in the laboratory of pharmacologist Eugene Geiling in 1936, she helped with the FDA’s request to identify the toxic agent responsible for the death of 107 patients who had all taken the drug sulfanilamide. The antibiotic sulfanilamide had proven strikingly effective against bacterial infections and safe in tablet and powder form. The new liquid form, however, which was given to many children, contained a toxic industrial chemical similar to antifreeze. The ensuing catastrophe resulted in the passage of the 1938 Federal Food, Drug, and Cosmetic Act, which first brought drug safety under the federal government’s purview.

While in Chicago, the then Frances Oldham met and married a fellow pharmacologist, Fremont Ellis Kelsey, who died in 1966. The Kelseys, who became parents of two children, moved to Washington, D.C., when Fremont accepted a position at the National Institutes of Health.

To this day, Frances Oldham Kelsey’s influence endures in the nation’s drug safety regime. She joined FDA at a time of great national optimism about the powers of science, as symbolized by the glamour of the space program that President Kennedy espoused. “In a way, they tied her to the moonshot in showing what government scientists were capable of,” the Post quotes journalist Stephen Fried, author of a book about the pharmaceutical industry. “It was an act of incredible daring and bravery to say we need to wait longer before we expose the American people to this drug.” In Fried’s opinion, Kelsey was “the most famous government regulator in American history.”

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