Frances Oldham Kelsey

FDA Consumer, March, 2001 by Linda Bren

FDA Medical Reviewer Leaves Her Mark On History

It was early 1942 and war was raging in the jungles of the Pacific. In addition to fighting the Japanese, Allied troops found themselves under attack by malaria-carrying mosquitoes. And since enemy soldiers had already captured several plantations of cinchona trees, the source of the anti-malarial quinine, the search was on for an effective quinine substitute to combat the disease.

A possible treatment--in the form of a dark, inky substance--arrived for testing in the pharmacology department at the University of Chicago. Pharmacologist Frances Oldham Kelsey, like many other university researchers throughout the country, had enlisted in the search for synthetic cures for malaria.

As it turned out, the inky substance had been sent by a veterinarian in Texas. "He said that he had just tried it on his secretary without ill effects," says Kelsey, "and he planned next to try it on cattle. It showed the relative value placed on women and cattle in Texas at that time," Kelsey says with amusement. The good humor and equanimity Kelsey displays at this slight are symptomatic of the way she approached most of life's adversities.

The war ended without finding a good substitute for quinine. But Kelsey did learn something valuable from the experience. She learned that rabbits metabolized quinine rapidly, but pregnant rabbits had less ability to break down the drug, and embryonic rabbits could not break it down at all. She also learned that drugs could pass through the placental barrier between mother and unborn child. These insights would serve Kelsey well some 15 years later when in early 1960, as a new Food and Drug Administration employee, she was asked to evaluate a drug most thought was harmless. That drug was thalidomide.

Although pressured by the manufacturer to quickly approve a drug already in widespread use throughout the rest of the world, Kelsey held her ground. When she repeatedly asked for more data and effectively forestalled the approval of thalidomide, Kelsey did more than keep a dangerous drug off the market. She set into motion a series of events that would forever change the way drugs are tested, evaluated, and introduced in America.

In recognition of Kelsey's vigilance, President John F. Kennedy, on Aug. 17, 1962, presented her with the highest honor that can be bestowed upon a U.S. civilian: the medal for Distinguished Federal Civilian Service. And nearly 40 years later, Kelsey was once again honored. On Oct. 7, 2000, she was inducted into the National Women's Hall of Fame in Seneca Falls, N.Y. Kelsey joins such other women of distinction in the Hall as American Red Cross founder Clara Barton, first American woman physician Elizabeth Blackwell, and human rights activist and first lady Eleanor Roosevelt.

The Thalidomide Tragedy

All they wanted was a good night's sleep, and a drug called thalidomide gave it to them. It brought a quick, natural sleep for millions of people who had trouble drifting off, and it also gave pregnant women relief from morning sickness. The drug's German manufacturer claimed it was non-addictive, caused no hangover, and was safe for pregnant women. And, unlike barbiturates, its lack of toxicity made it a poor choice for a suicide attempt.

By 1957, thalidomide was sold over-the-counter in Germany. By 1960, it was sold throughout Europe and South America, in Canada, and in many other parts of the world. To introduce it into the United States, the Richardson-Merrell pharmaceutical company of Cincinnati submitted an application to FDA in September 1960 to sell thalidomide under the brand name Kevadon.

The application was assigned to medical officer Kelsey, who had joined FDA just one month earlier. It was her first drug review assignment.

Under the law at that time, FDA had 60 days to review a drug application. If an FDA medical officer notified the company that the application was incomplete, it was considered withdrawn and the company would have to resubmit it with additional data. With each resubmission, the 60-day clock would start again.

Kelsey had concerns about the drug from the beginning. So did the pharmacologist and chemist who assisted Kelsey in the drug review. The chronic toxicity studies were not long enough, the absorption and excretion data were inadequate, and the manufacturing controls had shortcomings. "We were concerned about the non-absorption," says Kelsey. "That you could give enormous amounts, both to animals and humans, without toxicity. We felt that there might be conditions, illnesses, or other drugs that might change the absorption, and toxic effects might appear." After Kelsey detailed these deficiencies in a letter to Richardson-Merrell, the company sent in additional information--but not enough to satisfy Kelsey.

"The clinical reports were more on the nature of testimonials," says Kelsey, "rather than the results of well-designed, well-executed studies."

Kelsey continued to request more data to show the drug's safety, and with each request, the 60-day clock restarted. Dr. Joseph Murray, Richardson-Merrell's representative, grew increasingly frustrated. He made repeated phone calls and personal visits to Kelsey, and complained to her superiors that she was unreasonable and nit-picking, and that she was delaying the drug's approval unnecessarily.