Thalidomide Tragedy Prompts Passage of the Kefauver-Harris Amendment

Date October 10, 1962

A response to the public outcry over the effects of the drug thalidomide, the Kefauver-Harris Amendment gave the Food and Drug Administration new powers to regulate the testing, marketing, and advertising of drugs and medications.

Also known as Drug Efficacy Amendment of 1962

Locale Washington, D.C.

Key Figures

• Frances Kelsey (b. 1914), American pharmacologist, physician, and FDA medical officer
• Estes Kefauver (1903-1963), U.S. senator from Tennessee, 1949-1963, and chair of the Senate Subcommittee on Antitrust and Monopoly
• Helen Brooke Taussig (1898-1986), pediatrician at Johns Hopkins Hospital

Summary of Event

The passage in 1962 of a major addition to the Food, Drug, and Cosmetic Act of 1938, the Kefauver-Harris Amendment, broadened the powers of the United States Food and Drug Administration (FDA) to license new drugs and to oversee their marketing and manufacture. The leading sponsor of the bill, Senator Estes Kefauver, had campaigned in Congress for several years for tighter regulations on American pharmaceutical producers. His efforts were given a high profile and a sense of urgency when, in 1962, controversy about the devastating effects on unborn children of the sedative thalidomide became public knowledge. Under great public pressure, Congress (which earlier had seemed ready to block drug reforms or to allow only mild new regulatory measures) passed and President John F. Kennedy signed the Kefauver bill, mandating stricter controls over new drugs by federal authorities.

The development and worldwide marketing of the drug thalidomide was directed by a German company, Chemie Grünenthal. Grünenthal was one of several firms in Western Europe that flourished as a result of an “antibiotics boom” after World War II. Grünenthal had been in the pharmaceutical industry for a relatively short time. Like several other antibiotics manufacturers at the time, it did not begin as a chemical producer, as had the older drug manufacturers, but instead had its roots in brewing and distilling.

Grünenthal tested thalidomide on humans in West Germany, offering it to physicians and collecting data from them about the drug’s effects. As a part of its communications with physicians participating in trials from 1955 through 1957, Grünenthal emphasized its belief that the drug was a nontoxic, barbiturate-free (thus nonaddictive) substance, suitable for widespread use as a sleep-inducing medication, even by children and pregnant women. The results Grünenthal gathered from human trials were mixed, yet the company pursued what it regarded as an extremely lucrative market, with assurances that the drug was completely safe—an almost unprecedented claim for a sedative. Grünenthal began offering thalidomide as an over-the-counter drug (but one that it encouraged physicians to recommend) under a variety of trade names, such as Distaval in Australia.

The parent company worked through several subsidiaries and licensees (such as Distillers Company Biochemicals Limited of Britain, or DCBL), but it controlled almost every aspect of the drug’s distribution and advertising in dozens of countries. At least one company (Smith, Kline, and French Pharmaceuticals) that Grünenthal approached in the mid-1950’s as a possible licensee for the United States market conducted its own tests of thalidomide. Because its testing found thalidomide to be ineffective in inducing sleep in animals, Smith, Kline and French declined to join with Grünenthal. It was not until the late 1950’s that another American drug producer, Richardson-Merrell, decided to link with Grünenthal. It embarked on the process of gaining FDA approval for thalidomide.

By 1959, thalidomide had become a great success in Europe for Grünenthal, with sales of tens of thousands of packets per month. By then, however, the company also was receiving a number of complaints from pharmacists and physicians about the drug’s side effects, which ranged from sleeplessness to dizziness and constipation. Such effects mirrored reports from the earlier clinical trials.

After 1959, as it sought FDA approval for thalidomide, Richardson-Merrell followed the practice of other Grünenthal licensees such as DCBL of relying on Grünenthal’s data from its human trials in West Germany when it informed U.S. physicians of the potential effects of thalidomide. Human testing in the United States, through clinical trials on consenting patients, was a necessary step in securing FDA approval for any drug newly marketed in America.

Richardson-Merrell considered thalidomide a potential goldmine, which it would market in the United States under the name Kevadon. The company sent samples of thalidomide to more than twelve hundred physicians for widespread experimental use in more than twenty thousand patients of all ages. Patients received the drug in containers that most often were unlabeled except for dosage instructions. No previous drug in the United States had ever been distributed to more than two hundred physicians nor had any experimental drug been administered to more than five thousand patients.

As it conducted human testing, Richardson-Merrell carried out its own animal tests of thalidomide. Although it did not test the drug on pregnant animals, the company implied to physicians participating in the trials that thalidomide could be prescribed safely to pregnant women and to children, in spite of the fact that Grünenthal had little evidence that the drug would not permeate the placenta. Comparatively few pregnant women in the United States took thalidomide as a part of the trials. Such was not the case, however, in other parts of the world. Physicians in the largest women’s hospital in Sydney, Australia, administered thalidomide as a sedative for pregnant women at about the same time as human trials in the United States began.

What at first seemed a routine application for FDA approval for Richardson-Merrell to market Kevadon in the United States proved upon closer scrutiny by one FDA official to be anything but routine. Frances Kelsey, a pharmacologist and new FDA medical officer, came across the Kevadon application. As she reviewed Richardson-Merrell’s request, Kelsey raised questions about the company’s animal-testing procedures, its unsophisticated descriptions of thalidomide’s chemical properties, the absence of follow-up in the human trials, an emphasis on sales rather than testing in the literature distributed to physicians, and the company’s failure to disclose to the FDA certain side effects that Kelsey had seen under discussion in European medical journals.

In the summer of 1961, physicians and public health authorities in both West Germany and Australia sounded an alarm in the medical community about thalidomide’s potentially grave effects on early fetal development. Physicians had noted a significant jump in the number of babies born with a previously rare set of physical deformities, particularly the absence of normal limbs and their replacement by flipperlike appendages, a condition known as phocomelia. Widukind Lenz, a pediatrician who headed Hamburg’s Children’s Clinic, pushed for an investigation by public authorities into the possible link between the babies’ birth abnormalities and their mothers’ taking of Contergan (the West German trade name for thalidomide) during pregnancy.

Confronted with the results of this inquiry, Grünenthal agreed to remove thalidomide from West German markets in November, 1961, and from any other markets shortly afterward. DCBL recalled thalidomide within weeks, and Richardson-Merrell withdrew its own FDA application in March, 1962. The distribution of thalidomide had been so widespread, however, and its application (even in clinical trials in the United States) so poorly monitored by drug companies that no one— physicians, companies, or patients—could be certain to whom thalidomide had been given. Concern about thalidomide led to the quick passage of the Kefauver-Harris Amendment.

Senator Kefauver, a respected congressional figure and leader within the Democratic Party since his vice-presidential bid in 1956, long had envisioned reform of the pharmaceutical industry in the United States. Kefauver had been instrumental in hearings on drug development and marketing as chair of the Senate Subcommittee on Antitrust and Monopoly. He had heard testimony since 1959 that convinced him of the need for curbs on advertising by drug companies, stricter federal regulations on drug pricing, and more authority for the FDA to test drugs prior to their approval.

Kefauver faced potent opposition from senatorial colleagues known to have close ties to pharmaceutical manufacturers when he sponsored legislation to achieve his goals, through an amendment to the 1938 Food and Drug Act, which had given the FDA many of its powers. Kefauver’s case was bolstered by the testimony of several convincing witnesses before his and other committees. These witnesses included Helen Taussig, a doctor at Johns Hopkins Hospital who had observed the devastating effects of thalidomide in Europe and noted that marketing of the drug was continuing in less developed countries. A Kefauver proposal for drug industry reform and regulation was before Congress when the scope of the worldwide thalidomide tragedy and the story of Kelsey’s timely intervention at the FDA were made public in national newspapers on July 15, 1962.

The public furor was immediate. Americans believed themselves to have had a narrow escape and called for action by Congress to prevent disasters on the scale of the thalidomide tragedy in other countries. In West Germany, more than five thousand children had been born with thalidomide-induced deformities; Great Britain, Australia, Canada, and Japan each had several hundred victims. In other nations, reporting procedures were so flawed that the number of babies affected could not be determined.

Thorny issues were raised in the United States by even the limited exposure of the public to thalidomide. When the few pregnant women in America who had taken the drug just prior to its effects being publicized tried to obtain abortions, they faced strict state regulations on abortions. In many other areas of the world where thalidomide had been distributed, abortions in cases of fetal deformity were easier to obtain.

Kefauver suddenly found himself with substantial support in Congress for his proposals, which were much more stringent than the Kennedy administration had recommended only months earlier. Editorial praise for the Kefauver-Harris bill was overwhelming and Kefauver himself was pleased with the measure. The passage of the law on October 10, 1962, was described as a great victory for consumers and a victory for the kind of administrative oversight of drug manufacturers that the FDA could provide.

Significance

The new law stated that FDA approval for drugs new to the United States was to be given only after pharmaceutical manufacturers had demonstrated the safety and effectiveness of the substances. Companies could not rely on the trials of drugs by foreign associates or parent companies; trials had to be performed in the United States. Federal authorities were granted greater scope to inspect plants where drugs were made. The FDA gained increased ability to withdraw from the market drugs that it deemed to be an immediate hazard. The bill mandated not only extensive animal testing, but also well-monitored human clinical trials. The FDA application process was lengthened, drug companies had to supply physicians with much more extensive information about side effects of medication, and generic names had to be clearly visible on drug product labels.

The Kefauver-Harris Amendment did not provide for tracking of the effects of drugs once FDA approval was gained. Plans for following drugs after initial approval were developed in Great Britain after the thalidomide tragedy there. Drug surveillance was recommended by the World Health Organization as well. The bid did not approach the comprehensive reforms in West Germany after its thalidomide experience. There, insurance laws provided for compensation from the state if state licensing or monitoring failed and patients were harmed by drugs.

The comprehensive nature of other nations’ responses to the thalidomide tragedy was related to the much higher number of birth abnormalities caused by the drug in those nations, where it was sold openly. In Great Britain, the episode changed the nation’s responses to drug testing and monitoring and altered long-standing British legal traditions. An investigative newspaper series on protracted litigation against DCBL was censored by British courts for interfering with the fair trial of the cases brought by thalidomide victims. In an important decision by the European Court of Human Rights, Great Britain’s contempt-of-court law (which seemed to forbid such “pretrial” publicity in spite of the fact that the litigation was at least ten years old) was ruled to be an unacceptable limitation on free speech.

Bibliography

European Court of Human Rights. The Sunday Times Case. Strasbourg, France: Greffe de la Cour, Conseil de l’Europe, 1979. Decision of the European Court of Human Rights declaring that British laws restricting printed discussion of the thalidomide controversy were an unwarranted intrusion on free speech.

Gorman, Joseph Bruce. Estes Kefauver: A Political Biography. New York: Oxford University Press, 1971. A sympathetic, readable discussion of Kefauver’s goals and methods as a somewhat maverick reformer, especially in the Senate. Emphasizes his relationship with liberals and the John F. Kennedy administration.

Knightley, Phillip, et al. Suffer the Children: The Story of Thalidomide. New York: Viking Press, 1979. Dramatic and well-written account of the development of thalidomide by Grünenthal, its medical testing, and the massive international repercussions of the thalidomide controversy. Includes appendix summarizing applicable scientific research.

Mintz, Morton. The Therapeutic Nightmare. Boston: Houghton-Mifflin, 1965. A discussion of the thalidomide controversy in the context of other drug scandals, written by a journalist who helped break the thalidomide story in the United States. Critical of FDA leadership and pharmaceutical makers, laudatory of Frances Kelsey.

Pray, W. Steven. A History of Nonprescription Product Regulation. Binghamton, N.Y.: Pharmaceutical Products Press, 2003. Study of over-the-counter drug regulation in the United States; includes a chapter on the Kefauver-Harris Amendment.

Roskies, Ethel. Abnormality and Normality: The Mothering of Thalidomide Children. Ithaca, N.Y.: Cornell University Press, 1972. A study of several dozen Canadian mothers of children with thalidomide-induced deformities, based on research between 1964 and 1969. Dry in tone, yet occasionally provides poignant commentaries from mothers about the emotional impact of the thalidomide tragedy.