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Thalidomide Comes Back

We will never accept a world with thalidomide in it,” wrote Randolph Warren on July 17, 1998, the day after the US Food and Drug Administration licensed a chemical that had, between 1956 and 1962, caused birth defects in as many as twelve thousand children. Warren heads the Thalidomide Victims’ Association of Canada. He was born with lower-body phocomelia after his mother was given thalidomide for nausea during pregnancy: the bones of his legs failed to develop, leaving his feet to articulate directly with his pelvis. His arms are shorter than usual, and each of his hands has only four fingers. Randolph Warren describes himself as a thalidomider.

The drug was rehabilitated in 1998 to treat a rare but serious condition called erythema nodosum leprosum (ENL), a complication of Hansen’s disease (also known as leprosy). No more than one hundred new cases are diagnosed each year in the US. But in making their intensely controversial decision, FDA regulators were in effect also saying that thalidomide could now be prescribed for unapproved use in many other diseases as a drug of last resort. Endorsement by a US government agency appeared like a betrayal to many thalidomiders. For while other countries had suffered epidemics of birth defects some forty years before, the US had uniquely protected itself from harm through the stubborn integrity of a legendary FDA official, Dr. Frances O. Kelsey, who in the Sixties prevented the FDA from approving the drug.

But it was the FDA itself which, in 1995, invited the manufacturers of thalidomide to look again at a drug that had, in their words, “the capacity to cure.”1 By 1996, an advisory committee set up by the FDA was reconsidering thalidomide’s capacity to cause birth defects. It concluded that if thalidomide was to be licensed, the FDA somehow had to “ensure that no pregnancy occurs while a patient is taking the drug.” In September 1997, the FDA, together with the National Institutes of Health and Centers for Disease Control and Prevention, convened a public workshop to discuss the evidence for and against thalidomide. Randy Warren was an invited speaker, along with Frances Kelsey.

The renewed use of thalidomide was based on the drug’s encouraging effects on patients with AIDS, various cancers, and diseases in which the body’s immune system attacks its own tissues. At the conference Kelsey set out the history of drug regulation in the US, and the way in which the thalidomide scandal helped to bring about more stringent rules for evaluating drugs. Warren spoke about the difficult balance between thalidomiders’ twin fears of unregulated access to the drug and the wider use that would inevitably follow its regulated availability. In his view, the first fear outweighed the second. He supported temporary approval of thalidomide but with several stipulations. The word “thalidomide” should always be used next to any other name for the drug. Patients must be fully informed about side effects. Doctors who prescribed thalidomide must be certified to do so. Research should seek to find safe alternatives. And “someone must be accountable for dealing with any new victims.”

In July 1998, Janet Woodcock, a director of the FDA’s Center for Drug Evaluation and Research, completed her supervisory review of New Drug Application 20-785 submitted by the Celgene Corporation. She described evidence, some of which was over twenty-five years old, from clinical trials examining thalidomide’s efficacy in treating ENL. Her findings were unambiguous: thalidomide consistently and rapidly improved symptoms for most patients with ENL. She also set out proposed “extraordinary restrictions” on the distribution of thalidomide.

These unprecedented measures included a System for Thalidomide Education and Prescribing Safety (STEPS); fully informed patient consent; creation of a mandatory registry of those taking thalidomide; monthly surveys to detect toxicity; a ban on sharing medications and on blood or sperm donation; agreement by women taking the drug to use two methods of birth control and by men to use barrier contraception; regular pregnancy testing; and limiting drug prescriptions to no more than twenty-eight-day supplies. The aim of these conditions was to “deter any prescribing that is not carefully considered.”

Still, Woodcock concluded that “the Celgene application meets the standard for demonstrating effectiveness of the drug for the intended use.” The first US new drug application for thalidomide was withdrawn on March 8, 1962. This same teratogenic poison was now given official government blessing for clinical use. “The goal,” according to Celgene, was “zero defects.”

1.

Medical journals in the late 1950s did much to create widespread clinical enthusiasm for thalidomide. On November 22, 1958, The Lancet ran an advertisement claiming that Distaval—the UK trade name for thalidomide—had “no known toxicity” and was “free from untoward side-effects.” This strong and unqualified statement came at a time when doctors were increasingly worried about the dangers of barbiturates as sedative agents. Thalidomide was, according to the advertiser’s copy, a sedative “particularly suitable for children.”

The hyperbole adopted by Distillers, the company that made Distaval, would eventually have a grotesque irony. In 1960 and 1961, The Lancet published advertisements depicting an inquisitive blond child playing with open medicine bottles. The headline asserted that “this child’s life may depend on the safety of ‘Distaval,’” and the company went on to claim that “there is no case on record in which even gross over-dosage with ‘Distaval’ had harmful results.” The drug was, Distillers said, “outstandingly safe.”

In their thoughtful account of the rise, fall, and subsequent rise again of thalidomide’s fortunes, Trent Stephens and Rock Brynner place the origins of this confidence firmly within prevailing 1950s naiveté about science. The introduction of thalidomide became the single most important event in ending the postwar mirage of an impending technological utopia. Its consequences were deep and long-lasting—yet they are in danger of being forgotten.

Thalidomide was inadvertently stumbled across in a series of experiments aimed at developing new antibiotics. The man who led this work was Wilhelm Kunz, chief of chemical research at the German pharmaceutical house Chemie Grünenthal. Company executives puzzled over what to do with this substance which did not kill bacteria and had the tantalizing quality of seeming unusually safe. They pushed hard to find a disease for thalidomide to treat since no matter how high the dose given, laboratory animals would not die from it. Thalidomide was tested without success as a treatment for, among other complaints, constipation, seizures, and influenza. Eventually, in 1957, after observing the drug’s calming effects, Chemie Grünenthal decided to market thalidomide as a sedative. Distillers signed up as UK dis-tributors the following year, avoiding any further human trials to check either safety or efficacy. Thalidomide would eventually be sold, usually without prescription, in forty-six countries.

Early experience with the drug proved promising. Doctors reported a surprising lack of toxicity despite accidental overdoses. Such anecdotal observations were confirmed by Distillers in the laboratory. Experiments on mice and rats showed that thalidomide caused far fewer adverse effects than a barbiturate.2 But by the end of 1960, questions were being asked about the drug’s safety. In the British Medical Journal, Dr. A. Leslie Florence described four patients who developed nerve and muscle disorders while taking thalidomide. The Distillers company played down this report by labeling the reaction “rare.” But further cases of neuropathy were described the following year. The typically wry British conclusion was merely that “the perfect hypnotic has not yet been discovered.”3

A gruesome twist came in December 1961, when Distillers first alerted doctors to thalidomide’s “harmful effects on the fetus in early pregnancy.” They withdrew the drug from the UK market immediately, a few days after it had been withdrawn in Germany.4 Two weeks later, on December 16, Dr. William McBride, an obstetrician working in New South Wales, Australia, reported in a letter to The Lancet severe congenital abnormalities in a fifth of women taking thalidomide during pregnancy.5 In his brief one-hundred-word letter, McBride described the beginning of a tragedy that continues today in the lives of approximately five thousand thalidomide survivors.6

Looking through the weekly scientific correspondence in medical journals during 1962 detailing thalidomide’s devastating toxicity, we can relive the panic of the time. Distillers made pleas for calm. Researchers undertook desperate efforts to find other causes for the reported birth defects. All those trying to secure more certain information about the evolving disaster were in a state of despair. The overriding impression left by these publications is one of the incomparable fragility of human embryonic development, a process that we usually take for granted. Otherwise spare scientific prose is punctuated with photographs of infants displaying thalidomide-induced deformities. Sometimes these newborn babies are screaming into the camera lens, their contracted limbs bent into seemingly impossible angles. Or else they are looking away, eyes fixed on a doctor perhaps, their gaze trusting. Occasionally, faces of children are blanked out, rightly to preserve privacy, but in a way that erases the human reality—and cost—of thalidomide’s legacy.

Stephens and Brynner justly credit an often forgotten German pediatrician, Dr. Widukind Lenz, as being the first to tie thalidomide publicly to human malformations at a conference in November 1961. Lenz mixed a passion for astute observation and inquiry with a desire to hold accountable those ultimately responsible for harming so many children. When Distillers urged that “the problem [of thalidomide] can be solved without emotion and alarm,” Lenz shot back, “I can hardly imagine that any person will be able to face the facts without emotion and alarm.”

When a criminal trial began in 1968 against executives of Chemie Grünenthal, Lenz was a key prosecution witness. But the German courts deemed his testimony unduly biased in favor of the thalidomide children, and his evidence was held to be inadmissible. Lenz’s response was quietly implacable: “I decided to take it as a compliment to my moral engagement, rather than an offense to my scientific honesty.”

After initial clinical reports by Lenz, McBride, and others, belated experiments investigating thalidomide’s toxicity showed that the drug could harm mouse, rabbit, chicken, and monkey (but not rat) embryos; any of these experiments, if performed earlier, might have alerted doctors to the risks of the drug in pregnant women. Indeed, it was the same G.F. Somers of Distillers, the person who had earlier praised thalidomide’s limitless safety, who later described multiple deformities in rabbits “remarkably similar to those seen in humans.”7

The debate quickly moved on from whether or not thalidomide was a teratogen—an agent that causes malformation of the fetus—to what should be done for the children and families affected. Terrible parental distress, stigma, and the child’s personal and medical needs all became pressing concerns. In a rush to make amends for this iatrogenic epidemic of disability, surgeons took knives to limbs with often damaging effect. Prostheses were forced on children when they had little use for them. And providing children with ridiculously complex (and wholly unworkable) power-assisted arms simply reinforced their feelings of physical inadequacy. Worst of all, many hospital staff members, themselves unable to confront such extreme deformities, provided little comfort. One mother wrote:

  1. 1

    The documents from which I have extracted quotations can be found on the FDA’s Web site, www.fda.gov.

  2. 2

    G.F. Somers, “Pharmacological Properties of Thalidomide, a New Sedative Hypnotic Drug,” British Journal of Pharmacology, Vol. 15 (1960), pp. 111–116.

  3. 3

    Editorial, “Thalidomide Neuropathy,” British Medical Journal, September 30, 1961, pp. 876–877.

  4. 4

    Thalidomide was not withdrawn so quickly elsewhere. In Canada, for example, thalidomide remained available until March 1962, and in Japan until May 1962.

  5. 5

    W.G. McBride, “Thalidomide and Congenital Abnormalities,” The Lancet, December 16, 1961, p. 1358. As the current editor of The Lancet, I should declare a potential conflict here. McBride has alleged, and Stephens and Brynner repeat his claim, that The Lancet rejected an earlier paper, submitted in June 1961, describing the link between thalidomide and birth defects. To my knowledge, there is no record of this submission, and McBride has never produced any evidence to back his claim. If what he says is true, however, Stephens and Brynner are right to caution that “had such a paper been published in July 1961, much suffering would have been prevented.” I would like to take this opportunity to invite McBride to submit a copy of the letter of rejection to The New York Review for independent verification. If such a letter exists, it is a vitally important historical document.

  6. 6

    In 1993, McBride was found guilty of scientific fraud in a case unrelated to his work on thalidomide. He was barred from medical practice, only returning to the Australian medical registry in 1998. Stephens and Brynner call McBride’s later career “a study in hubris.” He was continuing to publish papers on thalidomide up to 1999.

  7. 7

    G.F. Somers, “Thalidomide and Congenital Abnormalities,” The Lancet, April 28, 1962, pp. 912–913.

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