How a courageous physician-scientist saved the U.S. from a birth-defects catastrophe

The auditorium at the Food and Drug Administration’s headquarters was buzzing. For the massed ranks of FDA officials, it was an opportunity to mark a defining moment in the agency’s history. Half a century almost to the day, the central figure in a case that changed the face of drug regulation was returning to the FDA.

Frances Oldham Kelsey, MD, PhD, then 96 and frail, was chaperoned by her two daughters for the occasion. She beamed as FDA leaders honored her in speeches before presenting her with the Dr. Frances O. Kelsey Award for Excellence and Courage in Protecting the Public Health. 

"It was pretty moving," recalled FDA historian John Swann. 

From September 1960 through November 1961, Kelsey and a handful of FDA colleagues were all that stood between the nation and the drug thalidomide, which caused massive birth defects and fetal deaths throughout the world. At the time, the drug was available in more than 20 nations, including Britain and Germany, where it was given to pregnant women to ease morning sickness.

Kelsey, who died in 2015 at the age of 101, was the key figure in what Swann called the FDA's "most impactful near-miss."  It was a drama in which the University of Chicago loomed large. Kelsey had trained at the University and later became a faculty member alongside her future husband, F. Ellis Kelsey, PhD, another key player in the thalidomide case. The University also was home to renowned scientist Eugene Geiling, MD, PhD, who mentored Kelsey and brought her to the agency. Geiling was part of a clutch of University of Chicago alumni and faculty who shaped the course of drug regulation.

It was at the University that Kelsey got her first exposure to the perils of lax drug oversight. As a graduate student in 1937, she played a part in the other landmark drug regulation case of the 20th century — one that triggered an earlier round of regulatory reform and bequeathed to the FDA the very powers that Kelsey would wield to such effect more than two decades later.

"A quaint little course"

Growing up on Vancouver Island, Kelsey’s chance meeting with a vacationing teacher ignited an interest in biology. She studied biochemistry and “a quaint little course called pharmacology” at McGill University in Montreal. She stayed on to pursue a master’s degree, and when Eugene Geiling, fresh from Johns Hopkins, established a pharmacology department at the University of Chicago, she was accepted as his first PhD student in 1937.

Kelsey got to Chicago in the midst of a national emergency. The FDA was scrambling to impound supplies of the S. E. Massengill Co.’s elixir sulfanilamide, a medicine widely prescribed for colds and other infections that was linked to a mounting nationwide death toll. Kelsey was assigned to a team assembled by Geiling to identify the toxic agent. The group identified the culprit as diethylene glycol, used as a solvent in the preparation. It is better known today as the active ingredient in antifreeze.

The scandal exposed the inadequacy of existing regulation. Massengill had failed to conduct any toxicology testing on a drug that claimed 107 lives, yet the only negligence it had committed under the law was an infraction in billing the product as an elixir — a description reserved for alcohol-based solutions. The case spurred legislation in 1938 requiring companies to file an application with the FDA to market a new drug. If the agency was not satisfied the drug was safe, it had a 60-day window in which to reject the application.

Chicago connections

After earning her PhD, Kelsey remained at the University during World War II to conduct research into antimalarials — work that sensitized her to the distinct effect of drugs on fetuses. Having married colleague F. Ellis Kelsey in 1943, the couple faced restrictions on spouses serving on the same faculty, so Frances Kelsey — who was more interested in medicine and had already completed most of the basic science courses required — enrolled in the University's medical school in 1946.

After earning her MD in 1950, she worked for a time as an editor for the Journal of the American Medical Association. In 1960, Geiling recruited Kelsey to work at the FDA in the new pharmacology center he headed.

Just one month in, Kelsey was assigned to review an application to sell a sleeping aid already widely prescribed in other nations for morning sickness, among other conditions.

“This couldn’t be the perfect drug”

Kelsey’s memory of her first reaction to the application from the William S. Merrell Co. to market thalidomide, under license from German manufacturer Chemie-Grünenthal, in the United States is sharp. “It was just too positive; this couldn’t be the perfect drug with no risk,” she recalled.

The transcript of the subsequent communications between Kelsey and Merrell offers a glimpse into a distant era of regulation in which there were no formal requirements governing data submitted in support of new drug applications, and pharmaceutical companies regarded “open-door access” to FDA officials as a prerogative.

But even by the standards of the day, Merrell waged an aggressive campaign for approval. West Germans were consuming 1 million doses a day of thalidomide in 1960. If such success could be replicated in America, the world’s largest and most lucrative drug market, the firm could expect blockbuster profits.

“Lobbying at the FDA could be done,” Swann said, “but this took it up a notch.”

Merrell executive F. Joseph Murray, PhD, peppered Kelsey with phone calls, letters and visits. Based on thalidomide’s distribution elsewhere, Merrell regarded approval to sell it in America — under the brand name Kevadon — as a formality. But Kelsey insisted on hard evidence to back Merrell’s claims for the drug’s safety and refused to be browbeaten.

In Merrell’s initial application, Kelsey noted the reliance on anecdotal testimony in place of clinical data. She ran it by her husband, who then worked as a pharmacologist at the National Institutes of Health. One section of the submission he branded “an interesting collection of meaningless pseudoscientific jargon apparently intended to impress chemically unsophisticated readers.” Elsewhere, he noted “the very unusual claim that thalidomide has no [lethal dose].”

“No other substance can make that claim,” he wrote. Kelsey’s concerns escalated when in February 1961 she saw a letter from a physician in the British Medical Journal reporting cases of peripheral neuritis — nerve damage in the hands and feet — among patients he’d treated with thalidomide.

“The burden of proof that the drug is safe ... lies with the applicant,” Kelsey wrote Murray on May 5, 1961. “In this connection, we are much concerned that apparently evidence [of] peripheral neuritis in England was known to you but not forthrightly disclosed.”

An indignant Murray telephoned Kelsey’s boss, Ralph Smith, MD. “He said . . . he considered [the letter] somewhat libelous,” Smith reported. “He inquired whether the firm was dealing personally with Dr. Kelsey in this connection and if so whether the letter was subject to reconsideration.” Smith affirmed that Kelsey had the agency’s backing.

The peripheral neuritis report was significant in another respect. It prompted Kelsey to request, with grim prescience, proof the drug was not harmful to the fetus.

Merrell insisted that this and the other concerns could be dealt with through a warning label and in September initiated a fresh push for FDA approval. Around the same time, reports had begun to trickle in of a spike in birth defects in Europe and Australia. Authorities scrambled to connect the dots and identified thalidomide as the common denominator. Four times Kelsey had invoked the regulatory lever available to her under the 1938 legislation to reject Merrell’s application on the grounds of insufficient data. Now on the company’s fifth attempt to secure approval, Merrell notified Kelsey it was rescinding its application.

A global tragedy

Worldwide, the births of roughly 8,000 infants with missing or malformed limbs (a further 5,000 to 7,000 may have perished in utero) were linked to thalidomide’s widespread usage among pregnant women.

Americans did not escape the tragedy completely. The FDA subsequently identified 17 cases — 10 linked to Kevadon that Merrell had distributed to 1,267 doctors under the auspices of its “investigational” trial. But the country was spared the broad-based catastrophe visited upon Europe.

Still, the U.S. public might have remained oblivious to the close call but for contemporary political machinations. Democratic Senator Estes Kefauver of Tennessee had been investigating pharmaceutical companies — chiefly their pricing practices — since 1959, but he had failed to rally support behind reform. In the aftermath of the revelations from Europe about thalidomide, the senator’s staff dug into the FDA’s deliberations on the drug and unearthed Kelsey’s dealings with Merrell. Spotting the story’s political capital, they leaked it to The Washington Post, which reported it to an unsuspecting nation on July 15, 1962.

Kelsey, the self-effacing scientist, found herself thrust into the public eye. On August 7, 1962, President John F. Kennedy presented her with the President’s Award for Distinguished Federal Civilian Service at a ceremony in the White House.

The case’s visceral impact prompted regulatory reform. Legislation signed by Kennedy in October 1962 required the agency’s assent before a drug could be sold.

Kelsey was appointed to head the Investigational Drug Branch, the new FDA division charged with implementing the regulations on the ground, presiding over a new oversight regime that transformed drug regulation and, by extension, drug development.

The regulations stipulated that evidence of drugs’ safety and efficacy be “based on adequate and well-controlled studies.” The agency used the edict to introduce sweeping new protocols governing clinical trials, specifying distinct phases and control studies. It also adopted a provision of the 1962 drug amendments that required human subjects give informed consent.

Later, Kelsey helped spearhead the new Division of Scientific Investigations, tasked with inspecting clinical sites to vet the integrity of data. The group earned the moniker “Kelsey’s cops.” She retired at 90 in 2005.

The agency’s preoccupations today are different from those of Kelsey in her prime. But her personal example still resonates. “I felt an instant connection,” said Leslie Ball, Kelsey’s successor as director of the Division of Scientific Investigations. “She’s the embodiment of someone who took her responsibilities seriously and [impacted] not just Americans, but people worldwide through the regulatory structure that emerged from her.”

This story appeared in Medicine on the Midway in 2011.