Analyzing Sex Bias in Medical Research
In order to improve medical studies and the efficacy of treatments available for all patients, it's important to understand how sex bias in clinical trials affects the results. Recent studies analyzing these trends highlight some of the gaps in medical research.
An increase in female-only research
Power, a platform based in San Francisco that connects patients with clinical trials, analyzed the past decade of U.S. clinical trials based on data from the National Library of Medicine to find trends and areas of improvement. One of the areas was sex bias in medical research.
"The vast majority of clinical trials include both men and women, however, disparities between studies on men's and women's health still exist. It's important to fix this issue, as men and women can respond differently to the same disease, intervention or medication," the Power study authors wrote.
The study found 88 percent of trials target both men and women. Female-only research is twice as common as male-only, at 8.6 percent and 3.6 percent, respectively. Even though female-only studies currently dominate the research field, that's a relatively new phenomenon. The share of studies focusing only on women increased by about 3.5 percent in 2021.
"In 2021, the increase in the share of women's health studies—and the accompanying decrease in men's health studies—was the largest single-year change in the last decade," the authors noted.
A brief history of sex bias in medical studies
Some historical context is important here. Though misogyny in healthcare and medicine far preceded the development of the scientific method, the modern persistent underrepresentation of women in clinical trials was strongly influenced by more recent events: the numerous negative effects of diethylstilbestrol (DES) on pregnancy-exposed female children, followed by the tragedy of thalidomide, a drug that was found to cause serious birth defects.
This led to a 1977 ban by the U.S. Food and Drug Administration (FDA) on participation in early-stage clinical trials for most women of child-bearing potential. This ban effectively barred reproductive-age women from participation in stage 1 trials where basic safety is determined and early stage 2 trials that look at efficacy.
Although there was immediate recognition that this huge gap in data was going to be problematic, the ban was not formally rescinded until 1993.
Disparities exist for both men and women
Today, there are medical research fields in which both women and men are underrepresented, according to a Northwestern Medicine study published in 2021 that cross-analyzed 20,020 U.S. clinical trials with 5 million participants between 2000 and 2020.
Areas of research that disadvantage men are psychiatry, preventive medicine and musculoskeletal disease and trauma. Women, on the other hand, are marginalized in other medical fields.
"We found that oncology, neurology, immunology and nephrology had the lowest female representation, compared to the corresponding number of DALYs [disability-adjusted life-years]. It's a measure that's commonly used to represent burden of disease," said Jecca Steinberg, M.D., lead author of the Northwestern study and a medical resident in the department of obstetrics and gynecology at Northwestern University Feinberg School of Medicine in Evanston, Illinois.
After adjusting for other trial factors such as phase, year and other confounding variables, Steinberg discovered that cardiology and pediatrics had the greatest negative association with female enrollment.
Steinberg highlighted, however, that this study covered only diseases that affect both men and women. Therefore, the study excluded women-specific research on subjects such as gynecological conditions and male-specific research on topics such as urological conditions. Other studies she has been involved in showed a scarcity of obstetric trials (representing less than 2 percent of all clinical trials) and gynecology trials (less than 4 percent) in the clinical trial database.
Less funding for women's health
It's also important to note that disparities exist in the funding of male-only versus female-only research, according to a 2021 study published in the Journal of Women's Health regarding the National Institutes of Health (NIH) allocation of funding.
"Of the 34 diseases that afflict proportionately more of one gender, 25 are male-favored in that they are either female-dominant and underfunded, or male-dominant and overfunded; the other 9 are female-favored. Furthermore, the disparity between actual funding and burden-commensurate funding is nearly twice as large for the male-favored diseases compared with the female-favored diseases," stated the author of the study, Arthur A. Mirin, Ph.D., an independent researcher in California.
The impact of this disparity
"The paucity of data on female-specific conditions is quite alarming," Steinberg said, adding that most women endure a gynecological condition during their lifetime.
As a result of the NIH Revitalization Act of 1993 encouraging diversification in clinical trials, in the early 2000s, female representation accounted for over 50 percent of the NIH-funded trials.
"We do know through other studies and literature that this under-enrollment has grave effects and has resulted in a data and knowledge gap that disproportionately negatively affects women's health," Steinberg said.
FDA drug recalls often happen due to adverse effects in women that "were previously under-detected because the trials were underpowered to capture female effects," Steinberg noted. Another example Steinberg gave was cardiology and how a heart attack has different symptoms in women and can go unrecognized.
"The stereotypical symptoms that were documented and searched and were the gold standard for how to clinically suspect an MI, or myocardial infarction, were based on male-specific symptoms, and this led to the underdiagnosis and under-detection of this life-threatening condition in women," Steinberg explained.
A focus on breast cancer
Historically, male-specific diseases get more research funding, although breast cancer research has had a huge triumph in recent years.
Breast cancer was the most commonly studied condition in the United States over the past decade, with more than 2,000 clinical trials, according to the Power study. It was also the top condition studied in 25 of the 50 U.S. states during this time.
However, between 2020 and 2021, breast cancer trials fell to second place as COVID-19 research surpassed it with more than three times the number of studies.
Though COVID took center stage, breast cancer research still saw an increase in clinical trials in 2020 and 2021 compared to previous years. The Power report suggests that the possible reason behind this rise is the link between how underlying health conditions might result in a more serious outcome for people who have contracted COVID.
Steinberg noted that the focus on breast cancer research could extend to other types of female research with the help of awareness, fundraising and national media campaigns.
"A greater awareness is really key, [along with] not excluding females from clinical trials on the basis of antiquated concepts of maternal-fetal liability or other concerns of harm to female reproduction when unnecessary, and increased funding for female-specific illnesses," Steinberg said.
Low patient participation compounds the issue
Power co-founder Bask Gill added that among other concerns, lack of patient participation has always been a major issue, even before the pandemic.
"Even in a world where things 'return to normal,' we'd still have 86 percent of trials materially delayed, with the median drug requiring over a billion dollars and seven years to be brought to market," Gill said.
He believes barriers of awareness, ability and understanding are behind low patient participation. Since most trials take place in high-end, academic medical centers, the average patient is not aware of trials for which they might be eligible. Another barrier is the language of the resources. When people try to do their own research into trials, it proves challenging because the information available is written for physicians, Gill explained. Lastly, it's difficult to understand what costs, reimbursements and stipends are available to patients.
Power is trying to improve this process for patients.
"We're working to build a tool that lowers all of these barriers," Gill said. "We've built a patient-friendly search engine, translated medical jargon into everyday English, and summarized key statistics around side effects, costs and reimbursement, all with the goal of empowering patients to access trials that previously would've been out of reach."