The Case For Considering Sex And Gender In Clinical Studies

By Deborah Borfitz 

September 27, 2021 | Researchers in Europe have found that most COVID-19 clinical trials to date have paid scant attention to the impact of sex and gender on the efficacy of pharmacological interventions—even after it became clear that those variables could have a striking effect on the outcomes of infected individuals. The findings could help make the case for “more and clearer regulations” around sex- and gender-sensitive analysis of study results, according to Sabine Oertelt-Prigione, M.D., Ph.D., a physician specializing in internal medicine, gender medicine, and public health at Radboud University Medical Center (Netherlands). 

As recently reported in Nature Communications (DOI: 10.1038/s41467-021-24265-8), an analysis of nearly 4,500 COVID-19 studies registered with ClinicalTrials.gov reveals only 4% plan to address sex and gender in their analysis and about 21% consider sex and gender solely in the context of recruitment. A modestly higher proportion (roughly 18%) of published studies, through Dec. 15, 2020, report sex-disaggregated results or subgroup analyses. 

Given the spread between intentions and actions, it may be that some of these researchers had a “moment of reckoning” tied to growing societal discourse about the impact of sex and gender on disease outcomes, says Oertelt-Prigione. But mass media attention to a topic does not automatically translate into changes in research policies and practices.

That, she says, will take targeted implementations. Her group, in the department of primary and community care at Radboud University, is building “shorter connections and tighter networks” locally and across Europe with stakeholders that could include policymakers. 

Changes Afoot 

In a press release, the chair of the European Parliament’s Committee on Women’s Rights and Gender Equality referenced the Nature Communications study in advocating for gender to be considered in studies for COVID-19 treatments, she notes. Coincidental to the study’s publication, a debate was also underway in Parliament about extending a mandate by the European Medicines Agency (EMA) to broaden public availability of sex and gender data generated by clinical trials. 

If approved as planned, says Oertelt-Prigione, the regulatory update might make a lot more aggregated sex/gender data accessible to researchers. Exactly how much sex-specific data has even been produced and shared with the EMA remains a mystery because the agency only vaguely requires study sponsors to include “a reasonable proportion” of women in trials to better assess if sex differences exist or not.

The EMA last year announced changed to its organizational structure to keep up with advances in science and technology following its relocation to Amsterdam. Data analytics and methods to deliver robust evidence for benefit-risk decision-making was named as one of the high-priority areas. 

The U.S. Food and Drug Administration, like the EMA, currently has no clear-cut requirement regarding women’s inclusion in clinical trials, and in a 2014 action plan stated its intention to make demographic subgroup data more available and transparent. No such data sharing is currently mandated. 

Data Availability 

It has been well reported that women tend to be underrepresented in studies, notably cardiovascular clinical trials. In the COVID-19 studies Oertelt-Prigione and her colleagues examined, the representation of women overall was “pretty good,” she says. 

Women were under-represented on the hospital-based trials, since men on average have a more severe course of the disease, she says. But they accounted for about half of all participants in mRNA vaccines trials, thanks especially to their enrollment in the U.S. In trials for the AstraZeneca vaccine, 60% of enrollees were female since recruitment initially focused on healthcare workers who are disproportionately women. 

It’s not that additional data needs to be generated, says Oertelt-Prigione, but that the existing data should be used for subgroup analysis. If the number of women in a study isn’t large enough to adequately power such analysis, “make the data available as supplementary or open access data so someone else can do a meta-analysis.” 

With larger studies, researchers might more often consider including sub-analysis in their statistical analysis plan, she adds. “Sometimes it is really a matter of awareness.”

The pandemic has certainly served to highlight the relevance of sex and gender for disease, notes Oertelt-Prigione. Men tend to do more poorly and have a higher mortality, for example, while many women have had to work longer hours or juggle extra caregiving responsibilities that can in turn increase their risk of exposure to the virus. 

Separately, Oertelt-Prigione’s research team is trying to figure out the most feasible way to measure multigender variables, she adds. As covered in her 2012 book with co-author Vera Regitz-Zagrosek, “Sex and Gender Aspects in Clinical Medicine,” gender can influence the therapies offered to patients as well as their response to those treatments. The term has come to reference a range of identities that do not correspond to established ideas of male and female. 

Standard Practice 

The infrequent consideration of sex and gender in COVID-19 clinical studies came as a surprise to Oertelt-Prigione. “I did not expect 100% uptake, but I also did not expect the numbers to be [so] low.” 

The time pressure might be partly to blame. “People were rushing from all corners of the world trying to find pharmacological solutions and an incredible number of trials were being registered initially, some of them of questionable quality [not all seeing the light of day ultimately] and most done in hopes of producing some kind of treatment for this [novel] disease.”

Less justifiable was skipping sex-sensitive analysis a few months into the pandemic when data began surfacing worldwide that men and women are differently impacted by the disease, she says. The “urgency” argument may hold up to a certain point but would not in any case preclude making the data available to other researchers. 

It is also not standard practice to do either sex- or gender-sensitive analysis, so it follows that researchers would not change their habits in a time of crisis, Oertelt-Prigione adds. Only people outside the research enterprise are ever surprised by the omission. 

The field of sex- and gender-sensitive medicine did not even exist when Oertelt-Prigione was in medical school in the 1990s, she shares. The first investigations into sex differences in cardiovascular disease were underway but there was not yet either a discernible movement or discipline. 

She “serendipitously” stumbled into the arena 15 years ago while working on a ward for patients with an autoimmune disease, such as multiple sclerosis, who were most often women. During her postdoc years at UC Davis, she started looking at the origins of autoimmune disorders that naturally brought up the connection to sex differences.

By the time she returned to Europe, Oertelt-Prigione had come to appreciate the complexity of biological (sex) as well as gender (behavioral and social) differences on health. She earned her master’s degree in public health from the University of London to better understand the implications, including the impact of “systemic [gender] discrimination.” 

Science Skepticism

Advocacy efforts have moved beyond a grassroots movement, particularly over the past five years, she says. Funding agencies in the U.S., Canada, and Europe are now requiring sex- and gender-sensitive analysis as a criterion for awarding grants. Institutions also more often ask researchers to look at sex and gender when doing their experiments—or justify why they don’t. 

Studies revealing the potential of sex and gender differences to affect drug safety and effectiveness have moved those considerations from an “emancipatory political topic to a good scientific practice topic,” says Oertelt-Prigione. Consequently, many more people have poured into the field to “energize” discussions.

Whether any of this helps curb science skepticism depends on the audience, she says. For those with genuine concerns about how research gets done and interpreted, efforts to expand the relevancy of data to more than half the population should help. People highly polarized in their opinions may, for now at least, be “kind of lost in a fringe movement.”

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