In 1956, the West German pharmaceutical company Chemie Grünenthal brought a brand-new sedative to market. The new drug was thalidomide, which Chemie Grünenthal sold under the tradename Contergan.} Thalidomide was somewhat of a wonder drug. Testing on laboratory animals failed to produce any apparent side effects whatsoever: no changes in blood pressure, in respirations, in metabolic functions or cellular structure were observed in animals. What’s more, human patients raved about thalidomide, reporting that it induced “a deep, natural, all-night sleep without a hangover.”} An early thalidomide advertising campaign from Chemie Grünenthal proclaimed, “In pregnancy and during the lactation period, the female organism is under great strain. Sleeplessness, unrest and tension are constant complaints. The administration of a sedative and hypnotic that will hurt neither mother nor child is often necessary.”

But thalidomide was not free of side effects as its laboratory testing had initially suggested. For the women who turned to thalidomide for relief, it had devastating consequences.

Thalidomide’s Tragedy Unfolds

The first inkling that thalidomide was not completely harmless came from patients who reported experiencing peripheral neuritis—nerve damage in their limbs—after taking thalidomide; for many, the damage was irreversible, even after they stopped taking the drug. But since the number of cases reported was relatively small, alarm bells did not ring. Chemie Grünenthal, which had known that peripheral neuritis was a potential side effect of thalidomide, had never informed its British licensee, Distillers, of the possibility when they licensed them thalidomide. Compounding this siloing of information, Distillers did not inform Chemie Grünenthal when British patients began reporting cases of peripheral neuritis. Distillers’ solution was to add a warning to thalidomide’s label about the potential for peripheral neuritis.

Frances Oldham Kelsey and the FDA

While thalidomide was popular throughout much of the world, its use was much less widespread in the United States. In 1960, the United States Food and Drug Administration (FDA) hired Dr. Frances Oldham Kelsey to review drug approval applications. One of her first assignments was to review Richardson-Merrell’s application to bring Kevadon, its brand name for thalidomide, to market in the United States as a tranquilizer and to treat morning sickness.

Thalidomide was already in circulation in the United States on an investigatory basis; more than 2.5 million thalidomide tablets had been distributed to 1,000 physicians throughout the country. Thalidomide had subsequently been dispensed to nearly 20,000 patients. It was later estimated that more than 3,700 of those patients were women of childbearing age.

With the thalidomide application on her desk, Dr. Kelsey, a pharmacologist by training, requested further data from Richardson-Merrell about how the human body absorbed thalidomide, concerned about a lack of evidence on its effects in humans. During World War II, Dr. Kelsey had worked on the federal government’s anti-malaria project, where she studied quinine, a teratogen—a substance that disrupts fetal development. Aware that one of the intended uses for thalidomide was to alleviate morning sickness, she also requested further data that showed thalidomide was safe to use during pregnancy.

While Dr. Kelsey waited for more data from Richardson-Merrell, she happened by chance to come across a reference in the British Journal of Medicine about reports of thalidomide-induced peripheral neuritis. In turn, she asked Richardson-Merrell for more data about the cases of peripheral neuritis and learned that warnings about this side effect had been part of the labeling of the British version of thalidomide since August of 1960. This warning was not supplied by Richardson-Merrell as part of its application to market thalidomide in the United States. Dr. Kelsey, concerned that no one could apparently determine what was causing the peripheral neuritis or whether it was reversable, refused to approve thalidomide and continued to press Richardson-Merrell for more data. Correspondence between Richardson-Merrell and Dr. Kelsey revealed that throughout 1960 and 1961, Richardson-Merrell continued to press her to approve its application to bring thalidomide to market, which she continually denied.

The Thalidomide Generation

While Dr. Frances Kelsey pressed for more scientific data on thalidomide’s side effects, across the Atlantic, West German doctors started noticing an alarming increase in children born with phocomelia. Phocomelia is usually a very rare congenital defect that results in children born with extremely short arms and legs with flipper-like} hands and feet. But doctors were now seeing more and more cases of this normally rare disorder. Two such cases were presented at the annual meeting of West German pediatricians in October 1960. Both children almost completely lacked upper arm bones, causing their hands to extend almost directly from their shoulders, and had a large vascular tumor (called a hemangioma) extending from their forehead down to their upper lip. Neither child had a family history of these conditions. The presenting physicians, who worked at the Institute of Human Genetics in Münster, noted that they had never seen such a combination of birth defects in their careers.

In November 1961, Dr. Widukind Lenz, a West German pediatrician, first publicized a tentative link between thalidomide taken during the early stages of pregnancy and these birth defects. In another hemisphere, Australian doctor William McBride also linked an increase in phocomelia to thalidomide when taken in early pregnancy. As more doctors around the world shared similar reports, the circumstantial evidence seemed to link thalidomide to the birth defects. On November 26, 1961 Chemie Grünenthal pulled thalidomide from the West German market in response to the reports. Thalidomide was withdrawn from the British market on December 2, with other countries withdrawing the drug shortly thereafter.

In January 1962, renowned pediatric cardiologist Dr. Helen Taussig, who helped develop the revolutionary Blalock-Thomas-Taussig shunt at Johns Hopkins to treat the congenital heart defect Tetralogy of Fallot, traveled to West Germany to examine the thalidomide babies and interview their doctors. Dr. Taussig shared her findings with Dr. Frances Kelsey and published her findings in the June 1962 issue of the Journal of the American Medical Association.

With thalidomide’s risks now apparent, Richardson-Merrell withdrew its application for thalidomide from the FDA on March 8, 1962.

Thalidomide’s Aftermath

Later studies would prove that when taken in the early stages of pregnancy, thalidomide caused severe birth defects, including phocomelia, congenital heart disease, and organ deformity. Data suggested that the risk of such birth defects were “probably higher than fifty percent.” More than 10,000 babies around the world were born with thalidomide-induced birth defects.

In the August 11, 1962 issue of the medical journal The Lancet, an editorial concluded with the following lamentation:

How had such a serious side effect been missed when animal testing of thalidomide seemed to indicate it was safe? Further studies would reveal that in order to produce the same birth defects in animals, staggeringly high doses of thalidomide needed to be administered to replicate the same results that occurred in human subjects. For example, one study on rats only produced one malformed offspring after the mother rat had been given 1,200 times the usual dose. Studies done on rabbits required dosages 90 to 120 times higher than the comparable human dose to produce malformed offspring. That the drug would behave differently in humans than it did in animals had not been appropriately considered.

In the years after the thalidomide disaster, many affected countries passed legislation to compensate victims. In 1968, German prosecutors brought manslaughter and injury charges to nine executives at Chemie Grünenthal. In 1970, Chemie Grünenthal agreed to establish a compensation fund for victims, into which they paid 100 million DM, with the government also contributing to the fund. In 1976, Germany passed legislation that strengthened liability and compensation laws for drug-induced injury.

In the United Kingdom, protracted litigation stalled compensation for British thalidomide victims. Suits against Distillers were first brought in 1962, and by 1968 all but five of these original suits were settled out of court. Still, hundreds of victims were excluded from compensation. On September 24, 1972, the Sunday Times ran an article titled “Our Thalidomide Children: A Cause for National Shame,” decrying the paltry settlements that Distillers’ had paid out and the legal system that was stymieing further victims from receiving justice. Distillers argued that the article constituted contempt of court, and an injunction was granted against the Sunday Times to stop publishing articles on the thalidomide victims. After protracted appeals, in 1974 the Sunday Times took the case to the European Commission of Human Rights, arguing their freedom of expression had been violated. The Commission agreed in its 1977 ruling. Public outcry spurred by the Times’ articles eventually led to the establishment of a multi-million pound compensation fund for the victims.

In the United States, the full effects of the thalidomide tragedy were largely avoided. The thalidomide tragedy, and Congressional testimony from Drs. Frances Kelsey and Helen Taussig on the crisis, were instrumental in passage of amendments to the Federal Food, Drug, and Cosmetic Act. The 1962 amendments, more commonly known as the Kefauver-Harris Amendment, expanded FDA oversight over drug manufacturers and required manufacturers to prove their drugs were safe and effective before approval.

For resisting pressure to grant FDA approval to thalidomide, in 1962 President John F. Kennedy granted Dr. Frances Kelsey the President’s Award for Distinguished Federal Civilian Service, the highest federal award for civilian employees.

Thalidomide has found a second life as an effective cure for leprosy and a modified version of thalidomide is currently on the market in the United States as a treatment for multiple myeloma. It continues to be studied as a potential treatment for an array of diseases.

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