Case Study:  Francis Kelsey & Thalidomide in the US

This case study tells the story of Dr. Frances Kelsey of the Food and Drug Administration (FDA) and the drug thalidomide. The story illustrates the process by which drugs are approved and regulated in the U.S. It also shows the importance of actions of individual scientists.

Background Relating to Pharmaceutical Regulation:

The quality of food and drugs was virtually unregulated until the early 1900’s. The novel, The Jungle, by Upton Sinclair described the alarming practices in the food industry. People were so outraged by his descriptions that Congress passed a law to help regulate the production of food and drugs. In 1927, a separate law enforcement agency, known as the FDA, was formed to enforce food and drug laws. A complex process for safety-testing new drugs has evolved, along with a requirement that new drugs be safe and effective.

Thalidomide was first synthesized in 1953 and early tests in animals and humans indicated that the drug had little toxicity and that, in humans, it promoted sleep, although it did not have any sedative effect on animals. It was introduced in West Germany in 1957 and it soon became a popular sleeping pill, taken by both adults and children. It appeared to have little ill effects when ingested in large quantities and was thought to be so safe, that it did not require a prescription. Moreover, the drug prevented nausea due to pregnancy and was used for this purpose.

The German manufacturer of this drug began to license the distribution of thalidomide in other countries. In September, 1960, the FDA received an NDA from the American pharmaceutical firm, Merrell, who wanted to distribute thalidomide in this country. The NDA contained glowing claims for the drug and it was considered to be a routine approval. Its investigation was given to the newest medical officer, Dr. Frances Kelsey. Dr. Kelsey held a PhD. Degree in pharmacology and a medical degree. She worked as an editorial associate for the Journal of the American Medical Association. She reported, "I soon learned…that good scientists are almost invariably good writers and the poor writing is often a sign of poor science..when I came to FDA…, I found that many of the studies in support of safety of the new drugs were done by investigators whose work had not been accepted for publication in the Journal."

Several problems were noted in the NDA:

At the same time, the Merrell Company was anxious to get the drug approved and was pressuring the FDA to do so. Dr. Kelsey resisted. Five months into the process, Dr. Kelsey learned of the following problems:

In November 1961, more than a year after the application was submitted to FDA, thalidomide was withdrawn from the German market because of congenital abnormalities in children born to mothers who had used it. By 1962 the evidence was overwhelming that it caused crippling malformations of the arms and legs. Many of these victims were born with hands and feet protruding directly from their torsos and others had limbless trunks with toes extending from their hips; others were born with just a head and a torso; still others had cardiac problems. It is estimated that 8,000 to 80,000 thalidomide-deformed babies were born in Europe. Thanks to the skepticism of Dr. Kelsey and others at the FDA, this tragedy was largely averted in the US.

(There were 10 well-documented cases of women who had received thalidomide during pregnancy and delivered seriously deformed babies in the US. Apparently this was the result of Merrell’s distribution of thalidomide to more than 1000 physicians during the time that the NDA was reviewing the drug. At the time, this was not illegal.)

Dr. Helen Taussig, a physician, wrote articles and gave speeches on the effects of thalidomide in Europe and tried to bring this story to the attention of the American people. Senator Estes Kefauver of Tennessee had been involved in investigating the drug industry and, reading about Dr. Taussig’s crusade, decided to promote the story to help the passage of his bill to strengthen the regulation of drug testing in humans so that physicians could not casually distribute investigational drugs. The bill, known as the Kefauver-Harris Drug Amendments to the FDCA was passed in 1962.

The drug is now known to have complex, multiple effects on the body. It inhibits new blood vessel growth (angiogenesis). This growth provides a "road map" for the growth of limbs and organs during development. Interestingly, despite its devastating effects on the fetus, it may be useful in treating some diseases like cancer because it inhibits angiogenesis. Israeli physicians discovered that leprosy patients given the drug to help them sleep also experienced healing of the painful lesions that accompany leprosy. In 1998 the FDA approved thalidomide for the treatment of leprosy.

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