Women Are Still Underrepresented in Clinical Trials for Cardiovascular Disease Drugs

While cardiovascular disease (CVD) is the leading cause of death among women as well as men, and while both sex and gender differences in CVD and its treatments have been well documented, women continue to be less represented than men in clinical trials of drugs to treat CVD. Among proposed reasons for this phenomenon are the recruitment of younger patients, inclusion criteria that tend to select men, and exclusion criteria that are more common in women.

In light of these concerns, the FDA has published a new article¹ on women in clinical trials supporting the approval of cardiovascular drugs. The paper’s authors say that, in trials supporting 36 cardiovascular approvals, of 224,417 participants, just 34% were women. The participation of women varied by trial, from 22% to 81%, with a mean 46% of women per trial. Overall, the percentage of women participating in screening visits was similar to the percentage of women eventually enrolled in a trial, and while a higher percentage of women were screened out of all trials, most differences were too modest to account for the observed differences in participation.

The authors suggest that factors before screening, such as identification of potential trial participants, and the ability of a candidate to participate, may be more important than screening practices in creating lower enrollment of women. Another possibility is that women are less likely than men to consider participating in trials.

Despite the lower participation of women, the authors say that they found few clinically meaningful gender-related differences in terms of safety and efficacy of the drugs assessed. In an analysis of efficacy results, in 14 drugs approved on the basis of clinical trials with a binary efficacy end point, similar effects were observed for men and women, and for 22 drugs approved on the basis of trials with continuous endpoints, only 1 drug had a gender difference: ranolazine did not reduce angia frequency or nitroglycerine use as much in women as in men. Only 3 drugs had clinically meaningful differences in safety by gender: Women and the elderly had increased rates of diarrhea with aliskiren and with aliskiren/hydrochlorothiazide, and the frequency of edema was higher in women than men with amlodipine/olmesartan.

For these drugs, the FDA says that the participation of women was sufficient to assess the possible differences in safety and efficacy by gender, but the agency does encourage companies to enroll patients who are likely to reflect the makeup of the population who will use the product being tested. The paper’s authors note that various groups have suggested a target enrollment that represents a participation to prevalence ratio of 1, there are currently no regulations mandating target enrollment in trials. Further research will be needed to identify and address gender-related factors that lead to underparticipation, especially those factors that occur even before candidates are screened.

In a linked editorial,² Louise Pilote, MD, MPH, PhD, and Valeria Raparelli, MD, PhD, say that, while women’s participation in clinical trials has increased in recent years, cardiovascular trials still have the lowest inclusion of women, especially in trials of ischemic heart disease and heart failure, which are common conditions affecting women. Pilote and Raparelli question the original paper’s conclusion that screening failure was not a contributor to underrepresentation, and warn that continued inadequate participation “…could result in several significant issues, including male-patterned inclusion criteria, sex-biased outcomes measurements, inadequate data analysis, and the missed opportunity to transfer results in clinical practice.” Furthermore, they note that, while the FDA reported a lack of gender differences in drug efficacy and safety, “…the likelihood that these results are less likely to be generalizable to women should be of immediate concern.”

In continued dialogue on this topic, the FDA’s Office of Women’s Health, which conducts research initiatives that facilitate regulatory decision making, will hold a debate titled “What is Enough…Women in Clinical Trials?” that will evaluate CVD clinical trials, challenges, and complexities associated with enrolling women participants. The debate, between Ellis F. Unger, MD, and Rita F. Redberg, MD, will be streamed live on May 16, 2018.

References

1. Scott PE, Unger EF, Jenkins MR, et al. Participation of women in clinical trials supporting FDA approval of cardiovascular drugs. J Am Coll Cardiol. 2018;71(18):1960-1969. doi: 10.1016/j.jacc.2018.02.070.

2. Pilote L, Raparelli V. Participation of women in clinical trials: not yet time to rest on our laurels. J Am Coll Cardiol. 2018;71(18):1970-1972. doi: 10.1016/j.jacc.2018.02.069.