Key Takeaways
- Historical Exclusion: Women were long excluded from clinical trials due to misconceptions that male physiology represented the entire population.
- The Thalidomide Catalyst: The 1950s-60s tragedy involving birth defects proved that drugs must be tested specifically for their impact on women and pregnancy.
- Regulatory Milestones: The 1993 NIH Revitalization Act was a turning point, mandating the inclusion of women and minorities in clinical research.
- Physiological Differences: Modern research confirms that drug metabolism, side effects, and treatment responses often differ significantly between sexes.
- Ongoing Progress: While representation has improved, efforts continue to overcome barriers like hormonal fluctuations and liability concerns to ensure medical equity.
Why women were excluded from early clinical trials
In the early days of clinical trials, women were often excluded due to societal norms and misconceptions about their physiological differences. Clinical research predominantly focused on men, assuming that their bodies were representative of the entire population. As a result, many medical interventions, drugs, and treatments were developed without considering potential sex-specific differences.
This exclusion was reinforced by the composition of the research community itself. During the 1970s, few women worked in either medicine or science, and women's health needs were widely regarded as a low priority in the scientific and medical fields. Without representation at the decision-making level, there was little institutional pressure to change how studies were designed or who they included.
The Thalidomide tragedy
The most consequential regulatory catalyst was the thalidomide crisis of the 1950s and 1960s, which exposed a fundamental failure in how drug safety was evaluated before widespread use. During this time, Thalidomide, a sedative and anti-nausea drug, gained widespread availability. It was marketed by 14 pharmaceutical companies across 46 countries, using at least 37 unique trade names. Notably, thalidomide was never approved for use in the United States, but was used widely throughout Europe and Canada. It was frequently prescribed to pregnant women as a treatment for morning sickness.
Unfortunately, the drug had not been tested on pregnant women and researchers were unaware that the drug could pass through the placental barrier and harm a fetus. Congenital defects included issues with limbs, internal organs including the brain, hearing, and eyesight – and because of the wide range of these defects, it took five years to determine that thalidomide was the cause.
The global impact of the Thalidomide tragedy included:
- 10,000+ infants impacted globally by congenital defects.
- 50% mortality rate among affected infants shortly after birth.
- 5 years required to identify the drug as the definitive cause of the defects.
This incident highlighted the urgent need for trials that consider unique female physiological aspects and pregnancy.
How policy changes shaped women's inclusion in clinical research
In response to the thalidomide tragedy, which exposed the potential consequences of insufficient research and exclusion of women from clinical trials, regulatory agencies and advocacy groups began a coordinated effort to reform the drug development framework and extend the authority of regulatory bodies over trial design standards.
In 1975, the US National Commission for the Protection of Human Subjects and Biomedical and Behavioral Research named pregnant women as vulnerable research subjects, and two years later women of childbearing age were banned from early phase clinical research in the US, with an exception for life-threatening conditions. The policy was remarkably broad: it recommended excluding even women who used contraception, who were single, or whose husbands had undergone vasectomy. The intent was caution. The effect was the systematic removal of nearly all women of reproductive age from the earliest and most formative stages of drug development.
Progress did not come quickly. In 1985, the Public Health Service Task Force on Women's Health Issues recommended expanded long-term research on how behavior, biology, and social factors affect women's health. The following year, NIH established a policy encouraging researchers to include women in studies. However, a 1990 investigation by the General Accounting Office (GAO) found that the policy had been poorly communicated and inconsistently applied, and that NIH had done little to encourage analysis of results by sex.
That investigation led to the founding of the NIH Office of Research on Women's Health (ORWH). In 1991, Dr. Bernadine Healy became the first female NIH Director and launched the Women's Health Initiative, a landmark set of clinical trials and observational studies enrolling postmenopausal women.
The decisive shift came in 1993, when the NIH Revitalization Act wrote inclusion into federal law, mandating adequate inclusion of women and minorities in NIH-sponsored clinical trials. Five years later, the FDA began requiring safety and efficacy data by sex. Similar changes were set in motion in the United Kingdom and across Europe, as regulatory bodies in these regions also recognized the imperative of including women in clinical trials.
At the same time, activists protested the exclusion of women from clinical trials, including trials for HIV drugs, arguing that individual women should be allowed to choose whether to accept the risks of participation. This advocacy played a direct role in shifting both public discourse and regulatory action.
Research also began to document meaningful differences between men and women in drug metabolism, side effects, and treatment responses. Women often require different dosages and experience different adverse effects compared to men. These findings confirmed that exclusion from trials had not been a neutral decision. It had produced an evidence base with significant blind spots.
Remaining challenges and progress in women's trial participation
While progress has been made, challenges persist in achieving full sex equality in clinical trials. Women continue to face barriers due to factors such as pregnancy, hormonal fluctuations, and the potential impact on fetal development. Understandably, concerns about liability and ethical considerations can also lead to hesitancy in including pregnant women in trials.
But the consequences of continued underrepresentation extend beyond equity. Biological sex can play a role in physiological, metabolic, hormonal, and even cellular differences that influence how diseases present and how effective treatments are. When drugs and devices are not adequately studied in women, the result is gaps in safety and efficacy data that affect clinical practice. Women have been shown to experience adverse drug reactions at higher rates than men, and medical devices designed primarily around male anatomy have demonstrated higher failure rates in female patients.
These are not edge cases. They reflect a structural gap in the evidence base that continues to shape how medicine is practiced.
Efforts are underway to address the remaining challenges and ensure greater representation across the board in clinical trials. The FDA continues to refine its guidelines to encourage sex, race, and ethnic diversity and improve the understanding of differences in drug response. Additionally, initiatives such as the Women in Clinical Trials campaign raise awareness about the importance of women's inclusion and advocate for their active participation.
There is also a growing recognition that framing women as a "special population" is itself part of the problem. As researchers and clinicians have argued, studying women is not an accommodation. It is a requirement for producing evidence that applies to the majority of the population.
This shift is particularly relevant as clinical research moves toward precision medicine and genetically stratified trial designs, where understanding biological variability, including sex-based differences, is essential to identifying the right treatments for the right patients.
Conclusion
The history of women in clinical trials is one of structural exclusion, regulatory correction, and ongoing gaps. Policies have changed, but the legacy of exclusion remains embedded in how trials are designed, how populations are recruited, and how evidence is generated.
Addressing this requires more than awareness. It requires designing recruitment strategies, testing workflows, and engagement models that account for the full diversity of the patient populations a treatment is intended to serve. By embracing broad diversity in clinical trials, with all sexes, races, and ethnicities appropriately represented, the industry can build an evidence base that reflects the populations it aims to treat.
To learn more about the work Sano is doing to drive diversity in clinical research, get in touch.