MEDICAL HISTORY


Saving Marilyn O


Allan Gaw recounts a cautionary tale of how commercial considerations in drug development can sometimes trump patient safety


N August 5, 1962, Marilyn Monroe was found dead in the bedroom of her home in Los Angeles. While


considerable controversy surrounds her death, what is not in question is that she died from barbiturate poisoning. Barbiturates had been widely used for over a century in sedatives and sleeping tablets, but their toxicity in overdose was always a serious problem. Efforts to develop safer, but still effective, sedatives had yet to yield tangible results though the major pharmaceutical companies recognised that any such product would offer a huge commercial advantage. A drug that seemed to fit this bill was


developed by the German company Chemie Grünenthal in the 1950s. Originally developed as an anticonvulsant, its sedative properties were quickly identified, and the apparent safety of the drug was striking. Company scientists found that there was practically no dose lethal to rats. Te drug in question was thalidomide, and


it was launched in West Germany as Contergan in October 1957 as an over-the- counter sedative. More than 40 other countries followed, including the UK where thalidomide was launched in April 1958 as Distaval. As the drug also reduced nausea it became a popular sleeping tablet amongst pregnant women suffering from morning sickness. Te first thalidomide victim is thought to


have been born in December 1956, before the drug was mass marketed. Te child’s father was a Grünenthal employee who received advance samples of the sedative, which he gave to his pregnant wife. However, it would be another five years before the link between the deformities and the drug would be made.


An easy one to start In September 1960, the new drug application for thalidomide landed on Frances Kelsey’s


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desk in Washington DC. Kelsey was a physician and pharmacologist, who had just been appointed as a medical officer and reviewer of new drug applications at the US Food and Drug Administration (FDA). She later recalled: “Tey gave it to me because they thought it would be an easy one to start on. As it turned out, it wasn’t all that easy”. Te American drug company Richardson-


Merrell had licensed the drug from Grünenthal and was poised to flood the American market once they had dealt with the formalities of the FDA. However, Kelsey, with her rigorous training in pharmacology and meticulous attention to detail, did not view her role as a formality and Merrell’s application, which was weak and shoddily put together, failed to impress. Kelsey responded to Merrell for the first


time on November 10, 1960, stating that their application was incomplete. At the time, the FDA had 60 days in order to process a new drug application, and a pharmaceutical company could go ahead with marketing their product if they heard nothing by this deadline. However, the deadline did not apply if the application was deemed by the FDA to be incomplete. On day 58 Kelsey threw out the application, presenting Merrell with their first rejection in a battle that would go on between them for 18 months. During this time Merrell visited, phoned


and wrote regularly trying to influence Kelsey. Teir superficial civility wore off fast and she was accused by company officials of stubbornness and simply avoiding making a decision, among other things. Kelsey later told a Life magazine reporter: “Many of the things they called me you couldn’t print”.


Big gun At one of these many meetings, Merrell brought a hired gun. On September 7, 1961, in her spartan office in the rather ramshackle


headquarters of the FDA, Kelsey met with three visitors—two company officials from Merrell and a third man, Dr Louis Lasagna from Johns Hopkins. Lasagna was a respected physician-scientist, an outspoken advocate of controlled clinical trials and evidence-based medicine, and he had recently given evidence against the pharmaceutical industry at hearings in Washington DC. In this context, Lasagna’s seat on the corporate side of the table at that meeting might appear puzzling. As it turns out, Lasagna had conducted


one of the few clinical trials investigating thalidomide, and Merrell had enlisted him as a paid expert to help argue their case in front of the ‘stubborn’ Kelsey. In 1960, he published a randomised placebo-controlled sleep study evaluating different doses of thalidomide. His study was part funded by Merrell, who also supplied the thalidomide he used. Whatever Lasagna said at the meeting, it


made no difference and Kelsey stood firm. Tree months later her concerns unfortunately proved to be justified as increased numbers of babies with a range of abnormalities were born in West Germany and in other countries where thalidomide had been sold. A striking feature of these abnormalities was phocomelia, which literally means seal extremities. Tese children had been born without the proper development of the long bones in their limbs, oſten giving their arms and/or legs a flipper-like appearance. Sylvia Plath in her poem Talidomide described this succinctly as ‘knuckles at shoulder-blades’. As publications appeared linking the


upsurge in these birth defects with thalidomide use in the first trimester of pregnancy, Grünenthal were forced to withdraw thalidomide from the European market on November 27, 1961. In the US, however, Merrell continued to badger Kelsey with claims that there was no proof of a link.


SUMMONS


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