Caveat – any reference to female/ woman and male/ man, is based on the biological and physiological characteristics of females and males and in no way covers gender or gender identifiers


Current policy doesn’t allow women to be sufficiently included in early-stage clinical trials.  Where does this exclusion come from, and does policy need to change to drive greater inclusion?

By focusing on protecting the woman and the fetus, the FDA has restricted females’ participation in clinical trials. The exclusion of females in the early stages of drug trials has resulted in a significant gap in understanding how various medications impact females and males differently. An example is the increased chemotherapy toxicity experienced by females compared to males. Paradoxically, policies such as those implemented by the FDA to safeguard against potential harm to the fetus during clinical trials are now hindering scientific progress. But why haven’t these policies been updated when risk evaluation and mitigation strategy (REMS) programs are proven to mitigate the risk of fetal exposure without excluding the female from the clinical trial?

For decades, the responsibility for preventing pregnancies has fallen on women. Some make the choice to resort to termination when prevention fails. This contraceptive responsibility continues today, in part due to the lack of male contraceptives and education. Additionally, the recent Dobbs decision in the US has eliminated the option of termination, increasing the responsibility and burden for female contraceptive measures.

There is a substantial willingness among men [ranging from 34% to 82.3%] to use contraceptives. However, despite this interest, no male birth control product has progressed to Phase 3. Could the availability of more male contraceptives, with the aim of distributing contraceptive responsibility more evenly, lead to increased female participation in clinical trials? Is there a need for a new policy to address this and promote sex-inclusive research practices?

The male physiology has been the default setting in clinical research. In 1977, the FDA guideline “General considerations for the clinical evaluation of drugs” disallowed women of child-bearing potential from participating in early-phase clinical research, except for life-threatening conditions. This policy further recommended excluding women who used contraception, were single, and even whose husbands were vasectomized. This “cautious” approach was the result of the thalidomide tragedy, which had the right intentions to alleviate debilitating symptoms of nausea during pregnancy but with devastating consequences of severe birth defects in thousands of children. It also highlights how women’s health conditions are regularly minimized with only symptomatic treatment, instead of investigating the actual cause. It has taken over 60 years since the use of thalidomide for the cause of pregnancy sickness to be discovered. In December 2023, a Cambridge-led study by Professor Sir Stephen O’Rahilly identified the GDF15 protein, a hormone produced by the fetus, to be the cause. The severity of the pregnancy sickness depends on a combination of how much the hormone is produced by the fetus and how much exposure the mother had to the hormone before becoming pregnant. This discovery has now yielded new preventions, such as exposing mothers to GDF15 ahead of pregnancy to build up resilience and further showcases the importance of treating the cause and not the symptom.

What if there was a way to reduce the risk of fetal exposure, which would subsequently drive improved inclusion, informative data, and a greater financial return on sales for the pharmaceutical company? Recruiting female subjects appears to add additional layers of cost and burden to sponsors as they are more likely to have adverse reactions and age-related biological differences create further subpopulations – another unintended consequence of current policies? What would it take for pharmaceuticals to start bridging this gap, especially if there are potential cost burdens? Is it that policy needs to mandate a threshold, or ratio, of females to males that aligns with the disease epidemiology? BMS’ (previously Celgene) Phase 3 trial investigating Revlimid in patients with untreated multiple myeloma is an example of a clinical trial that didn’t exclude women due to their reproductive potential and put contraceptive responsibility on both the male and female. REMS programs are in place for lenalidomide (Revlimid) and thalidomide, which enhance patient understanding resulting in high levels of compliance with the birth control precautions essential to prevent fetal exposure. For patients enrolled in the REMS programs, compliance with birth control requirements was greater than 90% when starting therapy and at follow-up. If more trials put the contraceptive responsibility on both females and males – not only could this increase the inclusion of females but also increase the demand for novel male contraceptives. To additionally support male participation in using contraceptives, trials could utilize previously identified behavioral models, which have previously been shown to significantly increased condom use.

Male contraceptives represent a new market where companies are developing a drug to prevent a condition in another person. It currently appears to be an undiscovered market potentially worth between $40 billion to $200 billion, assuming a market size of 10 million men in the US and 50 million men worldwide. Additionally, there is a growing demand for “novel male contraceptives” with initiatives being set up such as the Male Contraceptive Initiative advocating for reproductive autonomy for all and improved family planning by providing more male birth control options. Many promising male contraceptives have been investigated, but none have made it to market. Trials have been cancelled because of side effects that are similar to those women put up with, including mood changes, acne and reduced libido. According to Gregory Pincus in the 1960’s “Many [males] feared a contraceptive pill would interfere with their sex drive. [That] can’t be considered acceptable” (insert eye roll here…), yet the side effects females have borne for the last 60 plus years have been perfectly acceptable? This may have been driven by the fact that reproductive control and freedom for women outweighed the side effects. However, what was considered acceptable then, is not acceptable now. In Britain, trials are currently underway for the first male non-hormonal contraceptive pill. YourChoice Therapeutics is investigating YCT-529, a retinoic acid receptor-alpha inhibitor, which works by blocking access to vitamin A, preventing sperm production.

It seems likely that the interplay between policy and societal dynamics seems to be perpetuating the underrepresentation of females in early-stage clinical trials and the lack of available male contraceptives. The historical legacy of the FDA guideline limits females’ roles to reproductive potential and also limits the comprehensive understanding of sex-based differences in treatment effects. The proposal to shift contraceptive responsibility to both genders not only has the potential to enhance female inclusion but also fosters demand for novel male contraceptives. The untapped male contraceptive market, estimated at billions, highlights a compelling financial opportunity for pharmaceutical companies. Initiatives like the Male Contraceptive Initiative and the latest clinical advancements in ongoing trials signal a changing landscape, emphasizing the need for policies mandating sex-inclusive thresholds in clinical research. As we seek equitable healthcare, bridging this gap in clinical trials and promoting male contraceptives present not only scientific but also ethical requirements for a progressive and inclusive future for women’s health.


Contact us

Reach out to us if you’d like to partner with us, want to join our team or would like a conversation about how we shape the smartest choices in healthcare.