Cover image credit: Roberto Sorin, Unsplash.com
By Jan K. Kryca
The tragic launch of Thalidomide, a general purpose tranquilising drug which eventually became a standard recommendation for morning sickness relief by clinicians in nearly 50 countries, onto the consumer market, caused a wave of catastrophe, from ‘Thalidomide babies’, infants scarred for life by birth defects, to nearly 2,000 kids dying due to the drug in the late 1950s and 60s, marked the coming of a new age of a strictly regulated pharmaceutical and drug development market. Although the drug was mainly commercialised in West Germany and never made its way to being commercially distributed in the USA, it made its way into the US through clinical trials, unsanctioned by the Food and Drug Administration (FDA), or for that matter, any regulating body. These “clinical trials” involved 20,000 patients across the country up to 1962, and resulted in numerous birth defects and infant mortalities. The scarring effects of this embryotoxic drug pushed US policy makers to realising the importance of regulating the process through which pharmaceutical products found their way to consumers. Their response: the Kefauver-Harris Amendments of the 1938 Food, Drug, and Cosmetic Act, which laid down the foundations for the regulatory drug approval pipeline, and ruled that all testing of new drugs must be approved by the FDA.
Although closely regulating and standardising drug approval was an evident step in the right direction for the federal government, it now posed a new set of challenges for policymakers and the industry: how to ensure that the clinical trials themselves did not pose a threat to the study population? The Thalidomide tragedy was burned into the minds of pharmacologists and policy makers alike, and imagery of deformed newborns, damaged organs, missing limbs effectively framed the regulation of clinical trials in the US: any risk to pregnant women or newborns was not an option. By 1977, the FDA had implemented a near absolute ban running any phase 1 or 2 clinical trials of new drugs on pregnant and “women of child-bearing potential”, in its “General Considerations for the Clinical Evaluation of Drugs” guidelines. To rephrase the implications of this for young women, the drugs available to them in pharmacies and prescribed by clinicians will not have undergone phase 1 or 2 clinical trials on premenopausal women, because the regulators have deemed appropriate phase 3 clinical trial data sufficient enough to overcome limited phase 1 and early phase 2 data. This assumption is a broad generalization, with many exemptions in which phase 2 or even 1 data diverged from the conclusions based on the phase 3 data: I encourage you to refer to the report published by the US FDA in January, 2017 entitled “22 Case Studies Where Phase 2 And Phase 3 Trials Had Divergent Results”. Additionally, there is an assumption that if a drug has passed phase 2 of clinical trials, it is safe enough for a female study population. In reality, over 58% of drugs that have passed phase 2 and enter phase 3 do not successfully complete phase 3: in other words, completion of phase 2 clinical trials is not a strong indicator of a novel drug’s efficacy or safety in a more diverse population.
Taking on a moralistic perspective, we already see a concerning judgement, implicit in these 1977 guidelines; the potential harm of new drugs to unborn or even unconceived infants outweighs the harm these drugs may directly cause to healthy young women due to a lack of phase 1 and 2 clinical trial data. Furthermore, it puts the women who will participate in the phase 3 clinical trials at a significantly higher health risk, as there have been no young women in the study population of the phase 1 and 2 trials. This is a shocking contrast with the males participating in the phase 3 trials, who have had two previous male study populations have the new drug tested on them. This disparity in risk mitigation suggests the value of women’s health beyond the maternal context to lie at a level lower than men’s health and safety.
Clinical trial and drug development regulators who do not acknowledge the shortcomings of the underrepresentation of women in the drug testing and development process often resort to the argument that an individual's sex does not impact their response to a new intervention. For the purposes of understanding the inherent limitations caused by androcentricity in biomedical clinical trials, we can briefly look at a cases of how one’s sex impacts their response to a drug. For example, women exhibit slower zolpidem clearance than men, but the dosages of anti-insomnia and sleep enhancing drugs such as Ambien containing zolpidem were the same for both men and women in the US. As a result, women were continuously exposed to overdosing, and being placed at disproportionate risk by dangerous situations, such as driving while effectively mildly sedated, resulting in an increase in the number of traffic accidents. Consequently, the FDA has adjusted the recommended dosage for women by reducing it to 50% of the original dose- a striking difference in dosage.
Modern, 21st century policymakers continue to insufficiently address the issue of sex bias in drug development, despite the numerous historical and scientific cases which highlight the damaging impact of the current status quo. Furthermore, as pharmaceutical companies begin to experiment and deploy new data driven drug development techniques enabled by machine learning algorithms trained on existing clinical data, and testing of clinical trials using novel ‘organ-on-a-chip’ technologies we could see the exponential amplification of sex bias in both drug development and clinical trials, resulting in further deepening the gender gap in healthcare equity between men and women.
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 Liu, Katherine A, and Natalie A Dipietro Mager. “Women's involvement in clinical trials: historical perspective and future implications.” Pharmacy practice vol. 14,1 (2016): 708. doi:10.18549/PharmPract.2016.01.708
 Tantibanchachai, Chanapa, "US Regulatory Response to Thalidomide (1950-2000)". Embryo Project Encyclopedia (2014-04-01). ISSN: 1940-5030 http://embryo.asu.edu/handle/10776/7733.
 Irving Zucker, Brian J. Prendergast. Sex differences in pharmacokinetics predict adverse drug reactions in women. Biology of Sex Differences, 2020; 11 (1) DOI: 10.1186/s13293-020-00308-5