History of Women in Clinical Trials

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Mar 08, 2025

Women in Clinical Trials – Overcoming a History of Bias and Exclusion

Healthcare should be tailored to everyone, yet for decades medical research has largely overlooked nearly half of the global population. As of February 2025, women make up 49.6% of the world’s population¹, and according to the United Nations, this sex ratio is expected to become even more balanced by 2050². On average women tend to live longer than men, though the life expectancy varies by country.

Women also access healthcare services more frequently and account for significantly higher share of health expenditures in comparison to men. Yet up until the early 1990s - a period during which many drugs still in use today were approved - women faced significant underrepresentation in clinical trials. This lack of inclusion has resulted in critical gaps in our understanding of how particular treatments impact women, increasing the risk of adverse effects and limiting the effectiveness of medical interventions tailored to their needs.

Despite making up almost half of the world’s population, women have historically been misrepresented in clinical studies. For decades, medical research conducted primarily on men has been used to draw insights into diseases, drug efficacy and medical devices - often applying these findings to women without sufficient evidence. However, a woman’s anatomy, genetics, hormonal balances, and organ systems differ significantly from those of men. Given these differences, it is neither accurate nor appropriate to assume that treatments studied predominantly in men will have the same effects on women.

This underrepresentation is seen through a history of inequitable trials. In 2021, over 80% of preclinical studies assessing drug safety and efficacy were conducted solely in male mice and as few as 22% of phase I trial patients are female³. Despite the significant progress that has been made in promoting gender equality over recent years and the rapid pace of change we are witnessing in the medical field, there is still an imbalance when it comes to providing equal opportunities independent of sex.

In 2022, a large-scale study further highlighted this issue. An analysis of 1,433 trials with over 300,000 participants found that, on average, only 41.2% of participants were female⁴. This imbalance can and has had serious consequences, particularly in fields such as cardiology, where for years, women have been systematically excluded from clinical research.

Historically, cardiovascular clinical trials predominantly focused on men due to the widespread misconception that heart disease was primarily a male condition. This skewed focus on men’s health resulted in treatments and guidelines being developed without fully accounting for the distinct ways heart disease affects women. The issue was further exacerbated in 1977 when the FDA issued guidelines discouraging the inclusion of women of childbearing age in clinical trials due to concerns about potential fetal harm⁵. As a result, sex-specific differences in cardiovascular disease went largely unstudied.

To fully understand the impact of this issue, it is essential to consider the historical context of women in clinical trials and sex-based drug research (sex being the biological variable traditionally reported in clinical trials, whereas gender is typically recognized as a social construct relating to personal identity and perceptions of oneself).

A Brief History of Women’s Involvement in Clinical Trials

The exclusion of women from clinical trials can be traced back to the early 1970s when men were still viewed as the ‘dominant’ gender and few women were working in the field of medicine. The prevailing belief at the time was that Caucasian males constituted a ‘normal’ study population, alongside concerns about females’ fluctuating hormone levels making them a more complex group to study, leading to their exclusion from biomedical research.

Many clinicians also voiced concerns about pregnant women being a ‘vulnerable’ group and these fears were only magnified by incidents such as the thalidomide tragedy, in which expectant mothers who were given the drug gave birth to babies with severe limb defects⁶. This led to the Food and Drug Administration (FDA) issuing guidelines in 1977 which banned expecting mothers from participating in phase I/II clinical trials. However, this ruling also applied to single women, those using contraception, or those whose husbands were vasectomized. Unfortunately, this cautious approach has had a deleterious impact, with a lack of research about a new drug or treatments’ effect on the female body leading to various safety concerns.

In the late 1980s, the National Institutes of Health (NIH) began to put policies in place recommending the inclusion of women in scientific studies and in 1991 appointed their first female director who launched the Women’s Health Initiative, to study a range of conditions predominantly affecting postmenopausal women⁷. However, it wasn’t until 1993, when the FDA’s 1977 guidelines were reversed and the inclusion of women in clinical trials became part of Federal law, that the numbers of female patients steadily began to increase.

While the inclusion of women in clinical trials has improved since the 1990s, disparities in biomedical research remain. Women, along with other underrepresented populations, continue to be enrolled at lower rates in many studies, leading to gaps in understanding sex- and gender-specific responses to treatments. To address this, the Food and Drug Omnibus Reform Act (FDORA) of 2022 introduced Diversity Action Plans (DAPs), requiring clinical trial sponsors to implement strategies for improving enrollment diversity⁸. In 2024, the FDA issued draft guidance reinforcing these efforts, emphasizing the need for equitable representation in drug research to enhance the safety and efficacy of medical treatments across populations.

The Critical Importance of Analyzing Drug Response by Sex

Despite the historical perspective that the male experience represents the ‘norm’, we now know that disease presentation, pathophysiology, and therapeutic response are all influenced by a person’s sex. For example, it has been indisputably shown that the pharmacokinetics of a drug are distinct depending on whether it is given to a male or female patient. This means that drugs may be distributed, metabolized, or excreted differently in women compared to men. Measuring a treatment’s safety, efficacy, and/or side effects in patients of one gender, therefore, does not provide a representative picture of the effect it will have on the other.

Take the body’s response to consuming alcohol, for instance. Males are, on average, composed of a higher percentage of water than females, who typically have a higher proportion of body fat. This means that a single unit of alcohol will be more diluted in their bloodstream and they, therefore, exhibit a lower blood alcohol concentration. Additionally, women often possess less of the enzyme alcohol dehydrogenase, which catalyzes the breakdown of ethanol in the stomach, meaning that it takes longer for their system to metabolize and clear the drug⁹.

Another example is the case of an insomnia drug initially approved for use in 1992 before the regulations were introduced mandating the participation of women in clinical trials¹⁰. After it was noted that women were becoming involved in significantly more driving-related incidents the night after taking the medication than men, studies began to investigate the cause of the drug’s differential effects. They found that women had twice the concentration of active drug in their bloodstream than men who had taken an equivalent amount, leading to dosing guidelines for women immediately being cut in half. Whilst this was one of the first cases in which researchers identified a need for sex-based drug dosing, it is by no means the only.

When we apply this theory to pharmacologically more broadly, it quickly becomes apparent that decisions regarding drug administration should be based not only on a patient’s size, but also account for the hormonal and metabolic differences which exist between males and females. As we are in the era of personalized medicine, studying these idiosyncrasies and gathering data on this important biological variable will be vital in ensuring that future treatments are safe and effective for all.

Women have been underrepresented in clinical trials for many decades across most therapeutic areas, and also racially, socially and demographically. This can lead to gaps in knowledge about how medications impact a female's health. This misrepresentation can be due to a number of factors, fundamentally historically a general lack of diversity in clinical trials, which can be multifaceted including:

The trial design and not adhering to a diversity quotient.
The awareness of the trial to the potential patient groups.
Logistical barriers and how to manage, for example transportation and childcare support.
Emotional considerations associated with being part of a clinical trial, for example cultural backgrounds, biases, communication and engagement approaches.
Clinical trial materials; for example consent can influence women's comfort with participating in a clinical trial.

How Is This Being Addressed by Regulators? Not Just for Women but All Under-represented Groups.

Regulations and guidance from health authorities play a role in ensuring that clinical research is both ethical and representative, helping to bridge the gaps in medical knowledge, and better health outcomes for all populations. To combat these disparities, regulators across the globe have implemented various new policies to promote diversity in research, as further discussed below.

As mentioned previously, the U.S. Food and Drug Administration (FDA) has issued guidance to enhance diversity in clinical trials by requiring sponsors to implement diversity action plans. These plans aim to reduce barriers to enrollment and retention amongst underrepresented populations. Sponsors must outline strategies to increase participation not just on sex but also across other demographic factors, including race, ethnicity, and age, assuring that clinical research more accurately reflects the populations it seeks to serve. Under the new Trump Administration, key FDA documentation relating to diversity and inclusion were removed from official governmental websites without forewarning¹¹. As of February 11th, 2025, FDA Guidance on Diversity Action Plans has been restored by court order.
In addition, the Medicines & Healthcare Products
Regulatory Agency (MHRA) and Health Research Authority (HRA) have also issued guidance on incorporating diversity plans into clinical research¹².

These recommendations further emphasize the importance of designing studies that include these underrepresented populations to ensure research findings are applicable to a broader population.

References

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