The gender gap in clinical trials: Why women are still underrepresented

International Women’s Day was Saturday, a fitting moment to assess how women are represented in the biotech industry – more specifically, in clinical trials. Indeed, while there’s more awareness about fair representation across industries, women’s underrepresentation in clinical trials has been a persistent issue.

Historically, women were often excluded from clinical studies due to concerns about hormonal fluctuations and potential risks during pregnancy. Indeed, in 1977, the U.S. Food and Drug Administration (FDA) issued guidelines that effectively barred women of childbearing potential from participating in early-phase clinical trials. This exclusion was partly a reaction to tragedies like the thalidomide incident in the late 1950s and early 1960s, where the drug caused severe birth defects in over 10,000 children across 46 countries.

​Despite policy reversals in the early 1990s, the underrepresentation of women in clinical research remains a concern. For instance, a 2020 analysis of data from ClinicalTrials.gov found that women represented less than 40% of participants in heart disease and stroke clinical research. This underrepresentation spans multiple disease areas: Women represent 42% of trial participants in psychiatric disorders while they represent 60% of patients, and 41% of participants in cancer trials while they represent 51% of patients. 

However, according to Katherine Seay, executive vice president of Clinical Trial Media, while we are still in a situation where women aren’t adequately represented, we are going in the right direction. “Until recently, trials had been more focused on men, but it is getting better. We are not there yet as data in the last five years still indicate that women are underrepresented even in diseases that primarily affect them. Still, we are witnessing a shift and an uptick in women’s participation in trials.”

While Seay is optimistic about the future, the situation still raises another question: If trials have excluded women and still struggle to integrate them, is biotech doing enough to address conditions that primarily affect them?

Why are women still underrepresented in clinical trials? 

While women were historically and effectively excluded from clinical trials in the past, since the early 1990s, regulations have evolved to include them and ultimately reach a more realistic population sample in trials. Fast forward 30 years later: women are more represented but still not to the level we should be aiming for – why?

Seay thinks time is the most important factor and the shift will be progressive to ultimately reach the objective of having a more representative trial population. “In addition to the historical reasons for this exclusion, I think there was a misperception that men’s responses to drugs could simply apply to women. We’ve since seen a lot of research that showed that women metabolize medication differently. We have reached a point where there is greater recognition of the problem but it takes time to address it.”

While regulations have evolved, historical biases continue to influence current research practices. This exclusion has resulted in a scarcity of data on the safety and efficacy of medical interventions for these populations. Consequently, healthcare providers often lack evidence-based guidelines for treating pregnant women, leading to reliance on outdated or less effective medications. By trying to protect pregnant women from the risks of research, biotech is exposing them to the risks of outdated treatments.

In an article published by Clinical Trial Arena, Jill Fisher, professor of social medicine at the University of North Carolina, reported a case of a trial facility that conducted a trial with an adequate population of women and results showed more adverse effects than expected. The facility conducted the trial a second time, excluding women, and obtained a safer profile. In the article, Fisher indicated that not only does excluding women from trials save the companies from potential liabilities, but it makes their drugs appear safer. 

Beyond concerns over liability and side effects, deep-rooted cultural misconceptions further harm women’s healthcare. In September 2024, The Guardian published an article titled “Women dying ‘unnecessarily’ of heart disease, say experts.” Indeed, cardiovascular diseases are the perfect lens through which to look at this disparity.

The paper reported that while cardiovascular diseases were the number one killer of women, it was perceived as a “man’s disease”. Indeed, movies and TV series often depict the barbecue-loving father at risk of heart attack; the mother, however, less frequently so. 

According to The Guardian, women’s symptoms weren’t taken seriously enough, leading many to pass away unnecessarily because they were underdiagnosed, undertreated and globally underrepresented in clinical trials. 

In addition to the cultural misconceptions, societal roles are another obstacle to recruiting and retaining women in clinical trials. “One of the primary barriers for women is that many work and are the primary caregivers for children and potentially for older family members too. This makes them a lot less flexible to be, and stay involved in a trial even if they want to,” noted Seay.

Underrepresentation means inadequate treatment

The consequences of not including enough women in clinical trials are quite evident. Clinical trials are meant to assess the efficacy and safety of treatment across the most representative population sample possible. “If a particular demographic is most likely to be affected by a disease – for instance, lupus that is more prevalent in black women – it is imperative to include that demographic in the trial to have an accurate representation of how the drug will perform in the population it will mostly be used on,” explained Seay.

“Women can potentially face different and sometimes more severe side effects to drugs that would not accurately reflect on the label of the drug if it was not adequately tested on women,” said Seay.

Drugs tested predominantly on male subjects may not account for gender-specific responses, potentially leading to unforeseen adverse effects in women after approval. The exclusion traditionally concerns phase 1 trials and if the initial data is established in only one sex, the chances are the bias will move forward in the development of the drug.

If women are underrepresented in clinical trials in broad conditions, what is the situation like for women-specific indications? Last year, Australia faced a shortage of pregnancy drugs because of these disparities. Indeed, as time passed, the drugs registered as safe for pregnancy became less profitable for pharma companies, which discontinued their distribution. Since we don’t test on women as much, fewer new specific drugs are developed.

The Guardian reported that labetalol, a frequently used drug for high blood pressure, had become difficult to obtain since late 2023. According to Stefan Kane, director of maternity services at Melbourne’s Royal Women’s Hospital, these shortages can be traced to the systematic exclusion of pregnant women from trials. He told The Guardian that because of the 1950 thalidomide incident, we have gone too far the other way by excluding women from clinical trials.

Endometriosis is another example. It is believed to affect 10% of women, yet takes on average eight to nine years to be diagnosed. In a way, because of this exclusion bias, women have been denied the pharmaceutical advances others have benefited from in the last few decades. However, Seay notes that research and the industry are giving more and more attention to women-specific conditions.

“Women-specific condition research has been lagging but I also think this is improving and we are seeing an increasing number of clinical trials in conditions such as endometriosis or menopause and also breast and ovarian cancer, to name a few. I am hoping these conditions will follow the trajectory of breast cancer research – a breast cancer prognosis is less scary today than it was in the 1980s,” said Seay. 

How to keep this transition toward inclusion going

According to Seay, to successfully operate the transition, it is important to address each obstacle that prevents women from being adequately represented in clinical trials.

“Sponsors need to work with clinical trial sites to have more flexible schedules – it could be evening or weekend hours or even remote visits via telehealth solutions when it’s possible and this is beginning to happen.”

Seay thinks that since women are often less flexible, the clinical trial sites should accommodate them. ”Since women are often the primary caregivers, there may be times when they have no choice but to bring their children on site, and the site should be prepared for this and become a child-friendly environment, it doesn’t have to be a huge investment – a coloring book can be enough for a child but also the mother to feel welcome.”

Seay noted that the FDA’s recent discussions about women’s inclusion in clinical trial designs are going to further accelerate things. Indeed, in January, the FDA issued an industry guidance containing three key points. 

The first and most important is to “lift a restriction on participation by most women with childbearing potential from entering phase 1 and early phase 2 trials, and encourage their participation.” Rather than excluding women from trials to avoid the risk of in-trial pregnancy, the FDA asks sponsors to monitor pregnancy to conduct the trial safely.

The second guideline is to collect sex-related data and analyze these data in addition to other variables such as age or race. This means that sponsors should “include a fair representation of both sexes as participants in clinical trials so that clinically significant sex-related differences in response can be detected.”

​​The industry guidance also requests sponsors to assess three specific pharmacokinetics during the trial: The effects on the menstrual cycle, the effects of exogenous hormonal therapy including oral contraceptives, and the effect of the drug on oral contraceptives. 

These guidelines can seem long overdue, but better late than never.