How well do clinical studies take sex and gender differences into account?

About Tara Haelle

Tara Haelle (@TaraHaelle) is AHCJ's medical studies core topic leader, guiding journalists through the jargon-filled shorthand of science and research and enabling them to translate the evidence into accurate information.

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The history of inequity in medical studies is long and harrowing, and it continues today. But at least today, there is more awareness of the history and the present-day problems that persist. For example, the Endocrine Society recently released a scientific statement demanding more research into sex differences for the sake of public health.

The fact that males and females — not to mention individuals who do not identify as either binary category — do not respond the same way to different diseases, drugs and other interventions has been a relatively new development in the history of clinical trials. As recently as 1977, women of childbearing age were explicitly excluded by the FDA from phase 1 and 2 drug trials. In practice, that often extended to phase 3 trials and other types of studies for various reasons.

The most apparent reason, influenced especially by the thalidomide disaster of the 1950s and 1960s (though it was never used in the U.S.), was concern that a woman could become pregnant during the trial and the drug would have adverse effects on the fetus. But the ban even included women who were using reliable contraception or married to husbands who had had vasectomies. Another reason for excluding women was concern that hormonal changes in women’s bodies, both monthly and over a lifetime, could interfere with learning about a drug. The irony is frustrating since this is the very reason such data is needed. But researchers have believed for too long that what happened in men’s bodies was adequate to foretell what would also happen in women’s bodies. If they could learn from men and apply it to both men and women, why bother with the challenges of those pesky changing hormones in women during a clinical trial?

It wasn’t until 1986 that the National Institutes of Health began officially encouraging researchers to include women in clinical trials. It took four more years for a federal report to be issued on the continued exclusion of women in trials. Then in 1993, two years after Bernadine Healy became the first director of the NIH, Congress passed a law requiring medical research to include women and minorities, among other conditions.

Still, the problem of inequitable inclusion of women — and particularly the problems surrounding testing drugs in pregnant women — continues today and was likely was among the for The Endocrine Society’s statement.

“Without exploring sex differences, some drug candidates that could be beneficial to women never have the chance to make it to market,” Aditi Bhargava, Ph.D., chair of the committee that wrote the statement, said in a press release. “The process of developing drugs using only males of a species in pre-clinical studies likely contributes to the higher rates of adverse drug reactions in women compared to men, failure to see efficacy in clinical trials and translation to therapeutics.”

But historical inequities with women certainly wasn’t the only reason for the statement. They point out that men are disproportionately affected by COVID-19, with more than double the fatality rate as women.

Notably, the society also distinguishes between sex and gender and notes the special medical needs of transgender and gender-diverse individuals, such as prostate cancer screening in transgender women and cervical cancer screening in transgender men.

What does all this mean for journalists? It’s mainly a call to pay attention. When writing about medical studies:

  • Look at whether gender disparities exist in recruitment, total population or attrition.
  • Also, look for subgroup analyses by sex.
  • Ask the researchers whether statistically or clinically significant differences exist among subpopulations, including different sexes and genders.
  • If there are differences, consider asking about outcomes and differences in outcomes for transgender, intersex or gender-diverse individuals, as well.

2 thoughts on “How well do clinical studies take sex and gender differences into account?

  1. Roxanne Nelson

    “As recently as 1977, women of childbearing age were explicitly excluded by the FDA from phase 1 and 2 drug trials.” That is perfectly understandable, and not something that should be considered “detrimental,” since phase 1 and 2 are very early trials testing experimental agents. The FDA did not want want to risk exposing a fetus to that–birth control was not a widely used as now and not as reliable, nor was pregnancy testing–to be able to detect pregnancy in its earliest stages.

    “But the ban even included women who were using reliable contraception or married to husbands who had had vasectomies.” Again, reliable contraception is only as reliable as the person using it, and quite obviously, drug companies and researchers did not want to be held liable. A husband with a vasectomy lowers the risk, but it doesn’t mean a woman can’t become pregnant with another man. These concerns were very valid, given the time period, and informed consent was not what it is today.

  2. Ruth Taber

    And what about age? For years nobody over 65 was included in clinical studies – then they threw in a few men – not sure how many older women made the cut.
    So 9th and 10th decade people get treated by non-geriatric physicians who often miss the boat in over diagnosis/over treat – medicate etc.
    How sad.

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