Women’s Exclusion from Cancer Clinical Trials

by Ananya Pinnamaneni

October 31, 2023

Throughout history, the medical field has failed to adequately include women in clinical trials, especially those for cancer treatments. In fact, despite women making up 51% of cancer patients in the US, only 41% of patients in cancer trials are female. 

That statistic already makes it clear that there is a widespread disparity, but this issue was even more prevalent a few decades ago. It all started in the 1970’s with a few cases of drugs that were being clinically tested, such as thalidomide and diethylstilbestrol, resulting in birth defects for pregnant women. This led to the Food & Drug Administration (FDA) passing a guideline in 1977 called the General Considerations for Clinical Evaluation of Drugs that advised the exclusion of women of childbearing potential from early dose-ranging studies. Although the document specified that women should be included after sufficient safety data was established, the guidance was misinterpreted as exclusion of women from all clinical trials in general. This contributed to the initial gender disparity in clinical trials, including those involving cancer. 

Advocacy groups who supported the study of women’s health realized the complications brought about by this and urged the National Institutes of Health (NIH) to establish a policy in 1986 that encouraged the inclusion of women in studies. Unfortunately, this didn’t do much to fix the problem as an investigation by the General Accounting Office in 1990 revealed that women were still routinely excluded from medical research studies supported by federal funds.

While detrimental to all types of clinical trials, it is especially harmful when it comes to cancer. Sex-based differences have a huge effect on tumor biology, immune responses, and the microbiome, but they are often disregarded. With far more men being studied in clinical trials than women, there simply isn’t enough data about women to take these differences into account when creating treatments. In fact, the effect of sex on treatment response was not included in the data that led to drug approval in 46% of hematologic malignancy studies and 28% of solid tumor studies. As a result, a meta-analysis of 20 randomized controlled trials of immune checkpoint inhibitors for the treatment of a variety of solid tumors demonstrated that the pooled reduction of risk of death was double the size for male patients than it was for female patients.

To combat this issue, it’s important to first recognize the barriers that hold women back from participating in clinical trials. Some of these barriers are common across all patients, such as limited awareness of trial opportunities, limited trial availability for the patient’s cancer type and stage, and overly stringent eligibility criteria. However, there are also several patient-specific factors affecting women, including study burden and inconvenience, distrust of researchers and research institutions, lack of understanding about the importance or role of clinical research, and fear of risk and randomisation. Negative attitudes towards women as study participants from sponsors and medical professionals may also contribute; these include misperceptions that women are more difficult to recruit, that women are vulnerable to unwilling participation, and that women bring complexity to scientific design. A study of accrual barriers onto breast cancer prevention clinical trials across Massachusetts revealed that a woman is 10.5 times less likely to enroll if she feels that the clinical trial would be too inconvenient. Examples of inconvenience caused by study participation included increased office visits, greater travel requirements, need to maintain daily logs or specific treatment regimens, and disruptions in daily lives and family responsibilities. This same study also showed the patient-clinician relationship plays a central role in accrual onto clinical trials, namely that the clinician has sufficient expertise and knowledge and is able to convey the value of the trial to the patient.

With all of that being said, it’s now time to focus on the most important topic in this article – how to fix the issue. In 2011, the FDA Office of Women’s Health, the Society for Women’s Health Research, and the FDA Office of Minority Health convened the meeting ‘Dialogues on Diversifying Clinical Trials’ to discuss ways to improve recruitment and retention of women and minorities in clinical trials, among other topics. Recommendations for improving recruitment included diversifying the study team by recruiting female and minority physicians, building trust with patients through communication, education of patients on trial opportunities, education of physicians regarding gender disparities, partnership with women’s groups, redesigning clinical trials to improve diversity, and incorporation of new technologies for recruitment. More recently, the FDA developed a guidance document on enhancing diversity of clinical trial populations through broadening eligibility criteria and ‘improving trial recruitment so that the participants enrolled in trials better reflect the population most likely to use the drug’. Approaches recommended by the FDA include decreasing the burden of trial participation (eg, electronic communications to replace site visits, provide reimbursements for travel and lodging) and adopting enrollment and retention practices that enhance inclusiveness (eg, working directly with patients on clinical trial design, incorporating public outreach and education). These are all great solutions to the issue at hand, but many of these changes have yet to be implemented. 

As advocates for a greater emphasis on women’s health and sex differences in the realm of cancer, it is our responsibility to bring this issue to the forefront and push for these changes to move past just being recommendations to real implementation.

Sources:

Women are still underrepresented in clinical trials, Erin Blakemore, Washington Post

Gender and sex disparity in cancer trials, Eudocia Lee & Patrick Wen, available through Esmo Open

Underrepresentation of Women in Clinical Trials Persists, Andrea S. Blevins Primeau, Cancer Therapy Advisor