Throughout history, doctors have considered women’s bodies atypical and men’s bodies the “norm,” despite women accounting for nearly half the global population and outnumbering men in the United States since 1946. Though policy and social changes in the 1990s have helped turn the tide, women remain underrepresented in research, sometimes grossly so. Many medical researchers even avoid conducting studies on female mice due to greater costs associated with purchasing and housing both sexes and concerns that the fluctuating hormones and reproductive systems of female mice might confound the study results.
Historical bias, policies designed to shield unborn children from exposure to drugs and treatments, and ongoing challenges to recruiting and retaining women in clinical trials and medical research limit the understanding of how women, and particularly women of color, experience disease and how best to treat them for many conditions.
This may contribute to health care disparities, as biological sex can play a role in physiological, metabolic, hormonal, and even cellular differences that can influence how diseases present and the effectiveness of pharmaceuticals and medical devices. Failure to study medications and other interventions in a broad sampling of women has contributed to women experiencing adverse effects from medications at twice the rate of men. One 2013 study found that women with metal hip replacements were 29% more likely than men to experience implant failure, possibly due to anatomical differences and inadequate testing in women. And, despite heart disease being the leading cause of death in the United States for both men and women, the medical field only recognized that women experience different symptoms of the disease than men when the American Heart Association published a Guide to Preventive Cardiology for Women in 1999. Separate from biological sex differences, women also are less likely to receive appropriate prevention and management of heart disease due to gender bias.
“There’s still science that we don’t know,” says Barbara Bierer, MD, a hematologist/oncologist and professor of medicine at Harvard Medical School in Boston, as well as the faculty director of the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard Medical School (MRCT Center), a research and policy group focused on improving clinical trials. “These are issues that are very important that do affect a product’s safety and effectiveness.”
“Women shouldn’t be [put] in a ‘special populations’ category,” adds Martha Gulati, MD, a cardiologist at the Smidt Heart Institute at Cedars-Sinai in Los Angeles, and director of prevention and associate director of the Barbra Streisand Women’s Heart Center and president of the American Society for Preventive Cardiology. “It’s important to study women to find out how to care for [51%] of the population. We are the majority of the population. So, although women are special, we are not a ‘special population.’”
A timeline of women in clinical trials
Women were already poorly represented in medical research before the 1970s, but progress in researching drugs and medical devices in women was further set back in 1977, when the Food and Drug Administration (FDA) created a policy to exclude women of reproductive potential from Phase 1 and 2 clinical trials unless they had a life-threatening condition, according to the National Institutes of Health (NIH) Office of Research on Women’s Health. This was in reaction to a tragedy in the previous decade when a drug called thalidomide, which thousands of pregnant European and Australian women took for morning sickness, was found to cause severe birth defects — and sometimes death — for their babies. The drug had been tested and approved in Europe and Australia for its sedative effects, though it was never approved in the United States. Nevertheless, the FDA’s policy to exclude women of reproductive potential from most clinical trials was interpreted broadly, excluding nearly all premenopausal women, including those who were on birth control, had sterile partners, or abstained from sex.
It was not until nearly a decade later, in 1986, that the policy to exclude women from clinical research was revisited. And in 1993, the U.S. Congress passed a law requiring the inclusion of women in clinical research.
As recently as 2019, women accounted for roughly 40% of participants in clinical trials for three of the diseases that most affect women — cancer, cardiovascular disease, and psychiatric disorders — despite representing 51% of the U.S. population, according to a 2022 study by researchers at Harvard Medical School. Concerns also persist about the lack of information about medications and other interventions during pregnancy, since pregnant people are even more commonly excluded from trials.
The picture is even more bleak for women of color. The MRCT Center published an article in 2022 pointing out that often clinical trial data do not report the intersection of biological sex and race, and that some systematic reviews of clinical trials that report such information show significant underrepresentation of women of color.
“Given the number of people who are seen and [the amount of] products that are prescribed annually, we should be able to develop a better way of accessing real world data,” Bierer, one of the study authors, says. “For many reasons, people are now much more alert to the need to include different populations that have been historically underrepresented in clinical trials … both for social justice reasons and for the scientific insights we can glean, which we hope in time will reduce health disparities.”
That will require a rethinking of how researchers recruit and retain participants, says Danielle Mitchell, CEO and founder of Black Women in Clinical Research, an organization focused on furthering the inclusion of Black women working in the field.
Mitchell’s mission is to bridge the gap between Black communities and the clinical research field. She talks about clinical research at churches and hair salons. She hopes that the people leading clinical research will do their part by broadening their scope when it comes to hiring people at their research sites, from the receptionists to the coordinators to the principal investigators.
“When people go into [a] clinic, often times they don’t see anyone who looks like them,” Mitchell says, explaining that this creates missed opportunities to build trust and educate about clinical trials. “From my perspective, we need to have those tough conversations with people about what happened in the past for people to consider clinical trials as a health care option."
Making progress
Despite the late start in studying many aspects of women’s health, there has been progress in increasing the inclusion of women in medical research, says Maria Brooks, PhD, a professor of epidemiology and biostatistics and co-director of the Epidemiology Data Center at the University of Pittsburgh School of Public Health. Brooks leads several national, large-scale studies, including one focused on menopause.
“I’ve been working in the field for a long time, and I’ve seen clear progress over these last 30 years,” she says. “There’s an emphasis on including women, and a focus on health conditions that everybody has but [that] might manifest differently in women than in men.”
However, when it comes to understanding and properly treating disease, there is still ground to cover in order to achieve equity between men and women, and particularly women of color. Experts say these strategies could help move the needle:
Attract and retain a diverse group of women in leadership roles for medical and clinical research.
Celina Yong, MD, the director of Interventional Cardiology at the Palo Alto VA Medical Center and an associate professor at Stanford University, conducted a study analyzing the sex of principal investigators for cardiovascular clinical trials and found that just 18% of the trials were led by women, but those led by women enrolled more female participants.
“For a long time, the field of cardiology has been male-dominated,” Yong says. “But more and more, we’re seeing women pursue the field, which is changing the pipeline for future leadership.”
Incorporate how biological sex differences affect medical care into medical education.
Gulati, who gives lectures at medical schools about sex differences in the heart and in cardiology care, says many students tell her that they are learning about these differences for the first time from her lectures. Often, she says, male biology is still taught as the “default,” and learning about how female biology is different — from organ systems to hormones to cellular differences — is considered “special interest.”
“I think that’s where we can try to solve things,” she says. “In medical education, [students] need to be educated on sex differences, not just about heart disease, [but for] every organ system, there should be a component about what is the same, what differs, and what is unknown. Students need to leave medical school understanding these differences.”
More robust and inclusive research and data collection.
Just eight years ago, in 2016, the NIH instituted a policy that requires researchers with NIH funding to collect data on biological sex differences in preclinical research and animal testing, analyze the data, and report on differences in the findings. According to the policy, “Appropriate analysis and transparent reporting of data by sex may therefore enhance the rigor and applicability of preclinical biomedical research.”
Still, Gulati says there is a lack of accountability when researchers don’t follow through on their commitment to enroll a certain percentage of women in their clinical trials. Though the NIH’s policies have helped move the needle, she thinks there should be measures in place to further progress, such as requiring a pause in the research until the pre-specified number of women are enrolled.
Researchers can make further progress in recruiting women from other underrepresented in research groups (such as those with low socioeconomic status, older women, or those living in rural areas), by designing trials in a way that makes them more flexible and accessible for people with caretaking responsibilities or transportation issues, Brooks says.
It’s a challenge she hopes the field will embrace. “I feel hopeful and confident that, in general, the research community has become aware and is quite dedicated to ensuring that we enroll and retain a broader group of research participants.”
