Including Women in Clinical Trials Isn’t Enough

Despite making up almost half of the world’s population, women have historically been underrepresented in clinical studies. It was only in 1993 that the NIH Revitalization Act established that women and minorities had to be included in all NIH-funded clinical research. That same year, the FDA issued guidance encouraging the inclusion of women in clinical trials, including early-phase studies. This legacy of exclusion has left critical gaps in our understanding of how diseases and treatments affect women, with potential consequences for drug safety and efficacy.

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.

The inclusion of women in clinical trials has significantly increased since the 1990s, but representation is still uneven. In 2022, a large-scale analysis of 1,433 clinical trials involving more than 300,000 participants found that females accounted for just 41.2 percent of participants on average — despite representing 51 percent of the US population. The analysis examined trials across cardiovascular disease, psychiatric disease, and cancer, comparing female participation with the proportion of women affected by each disease. Across all three therapeutic areas, women were underrepresented relative to their expected share of the disease population.

But inclusion is only part of the problem. “While the number of women enrolled in studies has grown, the ability to make meaningful conclusions regarding biological sex differences based upon those enrollments remains limited due to underpowered study designs and an absence of consideration of hormonal status or life stages,” Brian Honeyman, a board-certified physician at Marietta Springs, told DDN.

In other words, enrolling women does not automatically make a trial capable of answering questions about sex differences. So what does meaningful inclusion actually look like — and what might drug development still be missing when it comes to understanding how medicines affect women?

Inclusion isn’t enough

For decades, researchers often treated the male body as the default when studying disease and developing treatments. However, there is substantial evidence that sex can influence disease presentation, pharmacokinetics, treatment response, and adverse effects. That means enrolling women without subsequently examining their outcomes separately can still leave important biological differences hidden.

“Simply including women in a study does not guarantee that the results will provide useful information regarding sex differences. A study must be designed to look at sex differences and the results must be analyzed and reported by sex to create scientifically valid results,” Ayesha Bryant, Clinical Advisor of Alpas Wellness, told DDN.

Despite this, sex-specific analysis is still uncommon. In a 2022 analysis of Australian clinical literature, only seven of 71 mixed-sex studies analyzed the data by sex. Another study from 2024 examined sex outcome comparisons across oncology clinical trials and found that only 472 of 89,221 trials (0.5 percent) reported any sex comparison data. Yet among the trials that did report these comparisons, the researchers found differences in both treatment outcomes and toxicity. Women generally had better post-treatment outcomes in several cancer types, while men experienced fewer side effects. The researchers also identified sex-specific differences associated with particular treatments, including EGFR inhibitors in non-small cell lung cancer and rituximab in non-Hodgkin lymphoma.

Simply including women in a study does not guarantee that the results will provide useful information regarding sex differences. A study must be designed to look at sex differences and the results must be analyzed and reported by sex to create scientifically valid results.—Ayesha Bryant, Alpas Wellness

This is not isolated to oncology. Sex differences have been found to influence transplant outcomes, antidepressant response, trauma response, Parkinson’s disease, metabolic disorders, and so much more. If clinical outcomes are averaged across an entire study population, a treatment effect that occurs primarily in one sex can become extremely difficult to see.

As evidence accumulates across therapeutic areas, researchers are increasingly recognizing that sex differences are not isolated exceptions but fundamental components of physiology. Rather than introducing unnecessary complexity, incorporating sex into study design offers an opportunity to better understand disease mechanisms, identify more precise therapeutic targets, and improve the likelihood that promising drug candidates will translate successfully into the clinic.

When averaging hides a difference

Not interrogating sex differences can have insidious consequences. One example of this is digoxin therapy, which once was one of the most commonly prescribed medications for heart failure. However, a post hoc analysis published in 2002 found that women taking digoxin had a significantly higher mortality rate than women taking placebo, an effect that was not observed in men. Subsequent analyses suggested that the higher mortality among women may have been linked to higher digoxin concentrations in the blood, even one month after dosing.

The findings highlight the complexity behind how sex can influence a drug’s effect . The post hoc analysis suggested that differences in heart failure pathophysiology, hormonal influences, and even hormone replacement therapy could all contribute to how patients respond to the same treatment.

These differences are not unique to digoxin. Drug absorption, distribution, metabolism, and excretion often vary between men and women, affecting how quickly a medicine is cleared from the body and how much of it patients are exposed to.

In 2024, a pharmacokinetic analysis of 99 approved anticancer drugs found significant sex-related differences in clearance for 15 medicines, with some differences exceeding 20 percent. This included chemotherapy agents, targeted therapies, and atezolizumab, an immune checkpoint inhibitor. In general, women were found to clear these drugs more slowly, increasing their drug exposure and potentially contributing to differences in toxicity or treatment response.

Differences in how men and women process medicines are often attributed to something as simple as body weight. However, the researchers found sex differences even after accounting for weight, suggesting that other biological factors may affect how drugs behave in the body. These could include differences in body composition, blood flow to organs, and drug metabolism.

“Researchers need to evaluate whether differences in factors such as metabolism, hormones, immune response, pharmacokinetics and disease progression may affect how a treatment works or how side effects are experienced. Trials should be designed with these questions in mind and, where appropriate, powered to analyze outcomes by sex rather than relying solely on overall results,” Katrina Rice, Chief Delivery Officer at eClinical Solutions, told DDN.