1. Sledge, George W. Jr. MD

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Recently I learned of the death of Frances Kelsey. I was somewhat surprised, not that she had died, but in the "I didn't know she had lived that long" sort of way one has sometimes in reading the obits. Kelsey had become a national figure when I was in my early teens, at a time when John Kennedy was president, and I had not given her a second's thought in decades.

GEORGE W. SLEDGE, JR... - Click to enlarge in new windowGEORGE W. SLEDGE, JR., MD. GEORGE W. SLEDGE, JR., MD, is Professor of Medicine and Chief of the Division of Oncology at Stanford University and Chairman of

Kelsey's story is inextricably linked to that of thalidomide. It is an old story, and its outlines are familiar to most, but let me share it with you in case you missed it or misplaced the memory. In the 1950s thalidomide was developed as a sleeping pill and was used as such in Europe. It was particularly valued for its benefits in pregnant women. Rights to thalidomide had been sold in the United States to the William S. Merrell Company.


Glass Ceiling

Kelsey was, at the time, a brand-new staffer at the Food and Drug Administration. Prior to this she had performed research at the University of Chicago, where she had earned both a PhD and an MD degree. When she applied to the PhD program at the University of Chicago, the acceptance letter was addressed to "Mr. Oldham" (she had been born Frances 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 told an interviewer. Fortunately, her McGill University thesis professor said, "Don't be stupid. Accept the job, sign your name and put "Miss" in brackets afterward." She did.


The First Task

Arriving in Chicago in 1936, she was set to work identifying the toxic agent in a batch of sulfanilamide. Initially entering the market in tablet form, the antimicrobial had been converted to liquid form for intravenous use. This new compound had promptly killed 107 patients, many of them children. The modern FDA is a stickler regarding drug formulation, and this dates to the antifreeze-like industrial chemical that had been included in the intravenous sulfa. In 1938 Congress passed the Food, Drug and Cosmetic Act in response to the tragedy.


As a new FDA staffer, Kelsey was tasked with evaluating thalidomide. She would later say that she had been assigned the evaluation not because it was considered a difficult case, but because it was a simple one-a drug already on the market, with thousands of patient-years of experience...a slam-dunk approval, a no-brainer.


Except that Kelsey was meticulous, and had a brain. In pouring through the documentation provided by the company, she was impressed by the lack of information provided by Merrell. The clinical data supplied involved little more than doctor testimonials, which Kelsey later characterized as "too glowing for the support in the way of clinical back-up."


While the evaluation was ongoing, she noticed a publication in the British Medical Journal suggesting that thalidomide was associated with peripheral neuropathy. Merrell's packet to the FDA had failed to mention peripheral neuropathy, immediately alerting Kelsey that something might be wrong. In those days, astonishingly, drugs were automatically approved by a certain date unless the FDA specifically disapproved them. Such approval by default seems amazing today, but those were different times. Then, as now, no one at the FDA wanted to disapprove a drug without sufficient cause.


Standing Firm

The out was that the FDA could put an approval on hold if it requested additional information. Kelsey invoked this rule. The Merrell representative, after much grumbling, admitted that yes, there had been some reports of peripheral neuropathy, but the company felt the drug was not to blame, that it was probably related to poor nutrition, and it wasn't all that big a deal in any event.


Kelsey still demurred and demanded real data. She and her colleagues at the FDA were particularly interested about the effects of the drug on the fetus, given that a pregnant woman might take the drug for months. Merrell reported that it did not know of any problems with the drug in pregnancy, but had not conducted a study. They were anxious to get the drug on the market, and hounded her for a quick approval. They also pressured her superiors and threatened to go to the Commissioner of the FDA. Kelsey stood firm.


But peripheral neuropathy was the least of thalidomide's problems. While Kelsey awaited more data, reports began to emerge from Europe tying the agent to birth defects in pregnant women. The famous Hopkins cardiologist Dr. Helen Taussig (the heroes in this story are women) heard of the issue and traveled to Europe to investigate. Babies there were being born, in the thousands, with flipper-like arms and legs, a condition known as phocomelia. The drug also significantly increased the rate of miscarriage. When Taussig came home she met with Kelsey, and later testified about thalidomide in front of a House committee considering strengthening drug approval laws.


In 1962 then-president John F. Kennedy awarded Kelsey the President's Award for Distinguished Federal Civilian Service. At the award ceremony he testified, "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."


Kelsey, ever modest, consistently maintained that she received the award on behalf of a team. She did not think she had done anything exceptional.


More to the Story

Kelsey's story did not end there, though that is most anyone has ever heard of her. The outcry over thalidomide, once the story broke, led to passage of the Kefauver-Harris Amendment in 1962 to strengthen drug regulations. The bill had languished in Congress for six years prior to the thalidomide revelations.


To get some sense of how different a time 1962 was from today bear in mind that at the Senate hearing for the amendment, Senator Jacob Javits could ask the question, "Do people know they are getting investigational drugs?" The answer was "no." Many of the U.S. participants in thalidomide trials were unaware they were receiving a drug that had not been approved by the FDA. Thalidomide changed that. The requirement for informed consent dates to Frances Kelsey. She became the first chief of the Investigational Drug Branch and created the modern process for new drug testing.


Fifteen years ago I sat on the FDA's Oncology Drugs Advisory Committee (ODAC). There I developed a deep and abiding respect for FDA staffers as dedicated public servants with an essentially thankless job. If the FDA approves a drug and later has to pull it from the market for reasons of some unexpected and rare but serious toxicity (think: COX-2 inhibitors), they are pilloried for not having done due diligence during the regulatory process and are accused of being stooges for the pharmaceutical industry. If, on the other hand, they delay drug approval, or reject a drug, the Wall Street Journal publishes an editorial titled-and this actually happened-"FDA to Patients: Drop Dead!" Basically, they cannot win.


I have had my own gripes with them over the years: lack of consistency and (on occasion) a seemingly poor understanding of biology. But that does nothing to diminish my respect for the FDA medical officers I have met, serious professionals who could be earning multiples of their government salary by crossing the street into industry. They are proud of Kelsey's legacy, as they should be.


I suspect-though I do not know this to be the case-that they may sometimes invoke Kelsey's memory to justify obstructionist behavior, just as some newspaper reporters consider themselves to be Woodward and Bernstein's progeny whenever they publish some minor expose. But I would far rather live in a world where public servants protect the public good, just as I want a world full of investigative journalists to counter the influence of the rich and powerful.


Frances Kelsey, a tireless public servant, worked until she was 90 and died at the age of 101. She had two children; accurate enough a count if one omits the thousands of babies born with two arms and two legs because of her courage.