With covid-19 vaccine rollouts well underway the world over, the subject of clinical trials has been a focal point of discussion lately. Of course clinical trials are applicable to every drug, not just vaccines, and the class of molecules on which my own work focuses includes perhaps one of the most famous case studies of why clinical trials are necessary: thalidomide.
The teratogenic effects in unborn infants of this seemingly innocuous small molecule are well documented and infamous. But at the time of its initial use a treatment for morning sickness in the mid twentieth century, little was known about its mechanism of action. Only within the last 20 years has the molecular glue-type nature of thalidomide and its analogues (collectively known as immunomodulatory imide drugs, or IMIDs) become apparent. Armed with this knowledge, we know not only understand how thalidomide works in useful situations (such as curing cancer), but also how it exhibits its less desirable effects (recruiting SALL4 to the E3 ligase cereblon, leading to SALL4’s degradation and subsequent embryogenesis havoc).
Do we always understand exactly how a drug works before letting it be used therapeutically? Of course not – salicylic acid has been used for pain relief since before Jesus, yet we only started to properly understand how atoms worked around the turn of the 19th century. But even now, with a myriad of structural and computational techniques under our belts, just because we might be able to elucidate how a drug carries out its desired effect at a molecular level, that doesn’t mean we can rule out it doing other things too. And this is why clinical trials are necessary – to show as concretely as possible that a drug is not only effective, but also safe, before it enters into common use.
Enter Frances Oldham Kelsey. In the 1960s, when thalidomide was already being used in several countries to treat morning sickness in pregnant women, she had just started in the FDA. She rejected an application by the pharmaceutical company Merrell to market thalidomide in the USA, to which Merrell responded by calling her fussy and nit-picking. They wanted to get thalidomide approved in time to have its sales boom over the Christmas period. Did Oldham Kelsey know that it would cause birth defects? No – no one did at the time. But she rejected Merrell’s application because her years of experience as a pharmacological scientist led her to believe that their safety data was lacking.
As Merrell sent in several more applications – and Oldham Kelsey rejected them one by one – news of thalidomide’s adverse side effects became apparent, and it was immediately pulled from the market in countries where it has been used. Amazingly Merrell still tried to get it approved in the USA for some months afterwards, before eventually resigning. Presumably the pull of the potential profits to be gained from the American market was too great for them to do the responsible thing straight away.
People realised how many lives had been saved by Oldham Kelsey’s ‘nit-picking’, and in 1962 she was awarded the President’s Award for Distinguished Federal Civilian Service by John F. Kennedy.
Years prior, when she was accepted for a graduate position at the University of Chicago, her acceptance letter was addressed to ‘Mr Oldham’, and she joked that had her name been ‘Elizabeth’ or Mary-Jane’, her career may have ended there. Had sexist undercurrents prevented her from progressing in her scientific career, perhaps those lives may have not been saved after all. Sexism kills, people.
(Go watch this TED Talk, from which I got much of this info: https://www.youtube.com/watch?v=4wIBCoxuOJ0)
