The Schizophrenic Career of a “Monster Drug”

The strange twists and turns in the history of thalidomide, the so-called “monster drug,” have almost been forgotten. Now, a haunting account1 of the tragic events that took place half a century ago has been written by Trent Stephens (an anatomist and embryologist, who has been studying the mechanism of action of thalidomide since 1972) and his collaborator, Rock Brynner (a historian who, as a patient, received the drug for pyoderma gangrenosum—an extremely rare autoimmune disorder). Their tale ends in the here-and-now with an amazing phoenix-like dénouement.The story begins in the West German village of Stolberg in 1954, when Chemie Grünenthal, a small and relatively inexperienced pharmaceutical company, launched a search for a low-cost method to manufacture antibiotics from peptides. The company’s chief of chemical research heated a commercially available chemical named phthaloyisoglutamine and produced α -phthalimidoglutarimide, which the company labeled “thalidomide.” The new molecule was patented, and they began to “cast about for a disease that thalidomide could cure.”The Grünenthal investigators were unable to demonstrate antibiotic activity, or any other promising medicinal effects in mice and rats, but they were encouraged when they found that the new chemical seemed to be harmless. Extremely high doses did not kill rats, mice, guinea pigs, rabbits, cats, and dogs; moreover, no other side effects were detected. This led the team to describe thalidomide as “nontoxic;” the apparent safety of the new drug made its commercial prospects very attractive. Thalidomide exhibited no sedative effects in experimental animals; even so, Grünenthal management reasoned, “a nonlethal sedative would have enormous market potential.” The company decided to explore the possibility that the new agent might act as a sedative in humans.Early in 1955, with no scientific rationale and with no formal plan to monitor immediate results or to conduct a systematic follow-up, Grünenthal distributed free samples of the new drug to doctors in West Germany and Switzerland. (It was later noted2 that “Thalidomide was introduced by the method of Russian Roulette. Practically nothing was known about the drug at the time of its marketing.”)The new drug was first prescribed for the prevention of epileptic seizures; although no anticonvulsant effect was found, patients said they experienced “deep all-night ‘natural’ sleep.” These early anecdotal reports suggested that the drug was a “hypnotic which directly induces sleep.” The haphazard “testing” continued and patients reported “soothing, calming and sleep-inducing effects.” A few patients reported side effects, but these were not thought to be serious.In the town of Stolberg, on Christmas day in 1956, 10 months before thalidomide was placed on the market in Germany, a child was born without ears. The father, an employee of Chemie Grünenthal, had brought home samples of the new drug for his pregnant wife; years later, he learned that his daughter was the first living victim of the subsequent epidemic of thalidomide-induced infant deaths and malformations.Many physicians were favorably impressed by the drug’s hypnotic action. However, thalidomide could not be sold in Germany until the company provided some confirmation of the purported effect in animals. (An odd turnabout, because drug effects are usually demonstrated in animals before they are tried in humans). Because sedative effects had not been observed in animals, the Grünenthal researchers were hard pressed to devise a test that would satisfy the requirement. Finally, they created a “jiggle cage” to measure very slight movements of mice. Using this unusual test, the company was able to convince the licensing authorities that although the thalidomide-treated animals remained awake, their “jiggling” movements were reduced more effectively than the suppression measured in mice treated with other sedatives. And, most importantly, Grünenthal pointed out, their “powerful hypnotic drug was completely safe.”On October 1, 1957, thalidomide was released as a sedative (under the name “Contergan”). Because of the explicit claim of safety, the drug was sold over-the-counter, first in Germany and later in other European countries. In a massive publicity campaign, the company claimed that “Even a determined suicide could not take enough Contergan to cause death,” and “accidental overdoses by children would be unheard of with this drug.” Sales grew steadily, and, “by 1961, thalidomide was the best selling sedative in Germany… 5 times [more than] its leading competitor.” Soon, and with no additional independent testing, the drug was sold in 46 countries throughout Europe, Scandinavia, Asia, Africa, and in South America, where it was marketed under “at least 37 names.” A British pharmaceutical firm, Distillers Company, used the trade name “ Distival” and advertised the drug as “a completely safe solution to the mounting toll of barbiturate deaths.” In August 1958, Grünenthal wrote a letter to all German physicians declaring that “thalidomide was the best drug for pregnant and nursing mothers;” Distillers quickly added this claim to the drug’s label in Britain. Before long, thalidomide was marketed as “the drug of choice” for pregnant women with morning sickness and nausea. But studies of the effect of the drug on the fetus were never conducted by Distillers or by Grünenthal. (Dally recently argued3 that the medical profession and the company were misled by the prevailing belief in the 1950s that “the placenta is a perfect barrier.” Both ignored evidence, then extant, that teratogenic substances could cross the placenta.)In 1959, 1 year after thalidomide was released, a German neurologist wrote to Grünenthal to ask whether anyone had reported symptoms of peripheral neuritis. He was told, “We have no idea how these cases … could have been caused by Contergan.” This reply, Stephens and Brynner charge, “was a deliberate and bold faced lie.” By the time the first report of peripheral neuritis associated with thalidomide was published in the British Medical Journal, in December 1960, the company had already received ∼100 letters reporting severe neuropathy, and some 1500 reports of other side effects. Meanwhile, the new drug “was breaking sales records, in some countries selling second only to aspirin.” The company’s sales force was instructed “to deny any connection between Contergan and peripheral neuritis;” and Grünenthal resisted mounting pressure to restrict sale of the drug only by a doctor’s prescription.In America, Richardson-Merrell Company submitted an application to the US Food and Drug Administration (FDA) on September 8, 1960, asking for approval to market “Kevadon,” its trade name for thalidomide. At that time, American law did not require evidence of effectiveness of new drugs; the only prerequisite was proof of safety. Richardson-Merrell was confident there would be no problem in approving the application; and they began to plan for the introduction of “the first ‘completely safe’ over-the-counter sedative.” Because preapproval of clinical trials was not required by the FDA, the company had already distributed thalidomide in the United States “a year and a half before the application … [Three months later] these ‘trials’ were expanded to include pregnant women.” The “investigation” was organized and implemented by the American company’s sales and marketing division! Stephens and Brynner report that Richardson-Merrell “distributed more than 2 and a half million tablets [in the United States] to ∼20 000 patients handed out by 1267 physicians.” American doctors were told,“We have firmly established the safety, dosage, and usefulness of Kevadon by both foreign and US laboratory and clinical studies. This program is designed to obtain widespread confirmation of its usefulness in a variety of hospitalized patients. Doctors need not report results if they don’t want to …”The company’s pseudo-experiment was larger than any previous drug trial conducted in the United States, but Frances O. Kelsey, a newly appointed doctor assigned by the FDA to review the company’s application, was not impressed. She found many shortcomings in the application; not the least of these was the disturbing fact that the company knew about the risk of nerve damage, but failed to disclose this important information to the FDA. Richardson-Merrell resubmitted the application on 6 occasions, but no new relevant evidence was presented. Despite mounting pressures, Kelsey refused to budge from her decision to withhold approval of the application.In November 1961, reports from Australia4 and Germany5 linked thalidomide to a sharp increase in the numbers of infants born with a variety of birth defects, including the rarely seen and grotesque malformation known as phocomelia (literally seals’ flippers—markedly stunted growth of limbs). Widukind Lenz, a German pediatrician, described 161 infants with malformations in association with thalidomide given to pregnant women, and he found astonishingly narrow limits of danger. “Women who took even 1 tablet of thalidomide between the 20th and 36th day after conception were at risk of delivering malformed infants… beyond that time thalidomide caused no deformities at all.”In December 1961, the alarming story was printed in a German newspaper, and the implications for pregnant women who had taken Contergan, were widely publicized for the first time. After this disclosure, Chemie Grünenthal withdrew the drug from the German market, and they notified Richardson-Merrell (before thalidomide was ever released for over-the-counter sale in the United States). Grünenthal explained that their action was taken reluctantly: “merely a response to the sensationalism.” Within days, Stephens and Brynner write, “newspapers, radio and television were alerting women [throughout] Germany not to take the drug.” But pills were “still available in some stores 6 months or more” after the news reports. The confusion of brand names delayed the embargo in some countries; for example, authorities in Brazil “seized two-and-a-half million pills 6 months after the withdrawal in Germany, along with another 100 tons” of the drug in bulk form. “In Italy and in Japan thalidomide remained on the market for … 9 months” after the withdrawal in Germany.It has been estimated that ∼40 000 people developed drug-induced peripheral neuritis; ∼8000 to 12 000 infants were malformed, and, of these, ∼5000 survived beyond childhood. But the exact numbers will never be known because the records kept by the companies and by physicians were woefully incomplete.Stephens and Brynner’s book documents the endless legal wrangling that dominated the rest of the thalidomide-as-monster story in the aftermath of the epidemic. Similarly, the bizarre convolutions of the story in Britain were set down in detail, >20 years ago, by the Insight Team of the Sunday Times London.6 (The team probed the huge number of relevant documents for years, but they were not allowed to publish their findings. A court-ordered gag rule [in connection with first lawsuit] forbade all mention of the disaster in British newspapers for 10 years—from 1962–1972.) The dismal experience gave no hint of the amazing positive development to follow: Thalidomide-as-dramatic remedy!The completely unexpected turn of events began in a French hospital with an observation in 1964 by Jacob Sheskin, a physician caring for a critically ill patient with erythema nodosum leprosum (ENL), an extremely painful complication of leprosy. Sheskin rummaged around the small hospital, looking for something that might help his pain-wracked patient who was unable to sleep. The doctor found “1 bottle of 20 thalidomide tablets.” Sheskin knew the drug had been banned, but he remembered that it had been effective in helping mentally ill patients sleep. Feeling there was nothing to lose, since his patient was dying, he gave the suffering man 2 tablets of the forbidden drug. The patient “slept soundly for 20 hours, and, on waking, [he] felt well enough to get out of bed without assistance.” Stephens and Brynner7 report that this dramatic result was soon followed by additional favorable experiences which were then tested in a controlled clinical trial. The amazingly successful treatment of ENL revolutionized the care of leprosy. “Because of Doctor Sheskin’s discovery,” Stephens and Brynner write, “90% of the leprosy hospitals around the world were shut down” in the past 35 years.The remarkable success of the resurrected drug in ENL patients led to the use of thalidomide in a wide assortment of disorders, eg, immune system disorders, including the inflammatory symptoms in auto immune deficiency syndrome and tuberculosis; multiple myeloma and many other malignancies; and “ refractory autoimmune conditions from multiple sclerosis to pyoderma gangrenosum.” (In 1998, the drug was approved for use in the United States under a strict monitoring program called “System for Thalidomide Education and Prescribing Safety.”) Renewed clinical interest also sparked research to uncover the mechanism of action of the drug at a molecular level that might explain the paradoxical effects. For example, it has been demonstrated that thalidomide reduces the elevated levels of tumor necrosis factor-α found in ENL patients, and in other autoimmune disorders. The decrease in this cytokine has been associated with clinical improvement. It has also been shown that the drug inhibits the growth of budding blood vessels.8 And Stephens has proposed that this antiangiogenic effect (mediated by insulin-like growth factor-1 and fibroblast growth factor-2 acting, for example, on the vasculature of the developing-limb bud in the embryo) is the disordered mechanism responsible for the thalidomide-induced malformations.Stephens is optimistic about the possibility of developing a safe analog of thalidomide (“which produces no birth defects and has an exponentially greater power to inhibit tumor necrosis factor-α”). Needless to say, human testing of the “safe” new drug will attract worldwide attention, particularly by “thalidomiders” (as the victims of the 1957–1961 disaster call themselves): One of their spokespersons has said: “We’re going to be watching.”Note: Sheskin’s paper7 is not cited in Medline, but, as Sir Iain Chalmers pointed out to me, the report does appear in the Cochrane Controlled Trials Register.