Sex Bias in Pharmacological Studies

This article was originally published in our Spring 2021 print issue.

Women have mainly been excluded from studies in pharmacology. This manifests in the exclusion of subject sex in the data parameters/summary and lack of separate analyses between male and female data. Possible dangers of sex exclusion within pharmacological studies include disporportionate burden of adverse side effects and a lack of drug educational materials, all of which call for increased discussion, accountability and regulation within research.

Researchers mention the female reproductive cycle and hormone differences as potential reasons for the lack of female experimentation in pharmacological studies. During the stages of menopause, women experience changes in reproductive hormones (mainly estrogen) and physical state, which is perceived by researchers as a change in baseline conditions and increased difficulty for accurate study. Additionally, at least 26.1% of women aged 15-49 in the United States from 2015 to 2017 were using some form of hormonal birth control, which disrupts natural hormone levels in those women. The most popular form of birth control, the oral contraceptive pill, contains and releases estrogen and/or progestin to prevent pregnancies. Thus, women using hormonal contraception may also be classified as suboptimal for study, similar to menopausal women.

Pregnant women are especially difficult to study because the clinical trials only account for a small window of time in the individuals’ lives, from a couple of months to a few years. The subsequent effect on their offspring and their development cannot be studied within the confines of the study. Professor Emeritus Irving Zucker—a researcher in integrative biology and the author of multiple articles on pharmacological inequality—explains that the “duration of the studies is not such that you are able to pick up things that happen 4 or 5 years later. Most of the adverse effects in humans come from post-marketing reports, and sometimes it can take as long as 15 years. So, for example, a woman who is taking antidepressants during pregnancy–her offspring may be at much greater risk for depression when they’re 20 years old.”

Because of these reasons, women are underrepresented in Phase 1 clinical trials, which is the first part of drug-testing on a smaller group of human subjects, mostly to evaluate for drug safety, longevity in the blood, and possible side effects. Sex differences in the pharmocological effects of one-third of all drugs are unknown.

Failing to conduct separate clinical trial data analyses for either sex and, more specifically, extrapolating one sex’s data for the other’s usage causes various problems. For one, there are innate biological differences between the two sexes, or sexual dimorphism, in components as basic as cells or tissues. Males and females express their metabolic enzyme systems differently, which leads to a different timeline of drug-clearance. For example, women have a lower glomerular filtration rate, so drugs that exit the body through the kidney exit slower in women than in men. Assigning the same dosage to all adults, after conducting most clinical trials on males, increases the risk of toxic effects and overmedication in females

The history of drug trial regulations begins with the blatant removal of female trials. In 1977, the FDA passed the General Considerations for the Clinical Evaluation of Drugs which barred women of child-bearing potential from participating in early clinical trials. This sparked as a result of the then-recent birth defects linked to thalidomide drug usage during the mother’s pregnancy. Consequently, clinical drug researchers erred on the side of caution, and ended up excluding or misrepresenting women in general. 

Many women’s advocacy groups publicly disapproved of the legislation, arguing that it deprived women of their autonomy in the realm of informed consent. This conversation was accelerated by the AIDS epidemic in the 1980s. When researchers began studying AIDS, they focused on male subjects because the disease was thought to mostly affect men, even though AIDS was a rapidly increasing cause of death among women in the U.S. Moreover, a study published by the General Accountability Office in 1990 revealed that federally funded studies routinely excluded women

Motions to balance the representation in drug studies include the 1993 Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs guidance, which underscored the analysis of drug safety and efficacy by sex. In 2000, the Amendment to Clinical Hold Regulations permitted the FDA to halt drug trials that excluded either sex on the basis of their reproductive potential. 

While some legislation exists, oversight by the FDA concerning the fair representation for drug trials is limited. To illustrate, data submitted by the drug companies to the FDA are not publicly shared and do not undergo any peer review processes. In addition, the implementation of these guidelines have not completely eliminated the sex bias in Phase 1 trials, although women’s participation has increased from the 22-25% range to 31% from 2002 to 2007.

At this point in time, the ethical and scientific basis of including women, regardless of their pregnancy status, in clinical trials continues to present problems. This is effectively illustrated by the recent COVID-19 vaccine trials and administration, as well as their effect on women of both child-bearing and non-child-bearing status. 

Because of COVID’s negative effects on the health of mothers and newborns during delivery (e.g. increased hospitalization and Cesarean delivery rates), pregnant individuals have been approved for COVID vaccine administration; however, there is less evidence for its safety and efficacy compared to what is available for non-pregnant individuals. For vaccination advice, pregnant women are encouraged to consult their primary care physicians, many of whom “don’t have the training or knowledge to answer those kinds of questions,” Professor Zucker says. Even as pregnant women are integrated into vaccine trial designs, it will still be a complex process, because ultimately, the professor emphasizes, “it is an individual decision.” 

Moving forward, to increase the accountability of drug companies by the greater science community, data from every step of the drug trial process should be made publicly available for peer review. Stakeholders from similar disciplines and within healthcare systems can continue to monitor the post-market effects of drugs and collaboratively contribute to FDA databases. The personal initiatives of these stakeholders, along with more recent legislation like the FDA Amendments Act, will create a more comprehensive understanding of drug effects on all users.

Additionally, as suggested by the Task Force on Research Specific to Pregnant Women and Lactating Women, government agencies should instate a proactive protocol that outlines the early and intentional integration of pregnant women in clinical trials. Professor Zucker also suggests that behavioral studies of lactating rodents should be conducted in parallel to drug development and continue during human Phase 1 clinical trials. “The beauty of doing animal work is that it doesn’t take as long, because they have a short life span,” he reasons. With the use of animal models, drug companies would have more data to prove the safety of–or caution against–future drugs for women of child-bearing potential and their children.

Although the exclusion of women from clinical drug studies began as a safety precaution, the lack of accurate drug information could lead to even more long-term adverse effects. Using data collected from male drug trials could be toxic due to innate molecular differences between the biological sexes. Generally, regulations should require more nuanced studies, such as those that include pregnant women or utilize rodent models, to study treatment effects on women regardless of their reproductive state. With the implementation of a few of these suggestions, it is hopeful that future pharmacological treatments will be safe and supported with evidence for all parties, including all women, before hitting the market.