Are women underrepresented in cerebrovascular disease clinical trials? A systematic review using the FDA database

BACKGROUND AND PURPOSE Clinical trials provide essential evidence in the US Food and Drug Administration (FDA) drug approval process. Women were underrepresented in the enrollment of clinical trials for many medical conditions other than cerebrovascular disease (CVD). We investigated women’s participation in FDA-registered CVD-related interventional clinical trials and assessed whether women CVD patients in the United States were underrepresented. We also evaluated the association between the underrepresentation and the features of design and operation among these trials. METHODS We systematically reviewed the phase 2 and 3 CVD-related interventional trials started in 2002–2017 in the FDA database. The proportions of women enrolled in these trials and the proportion-to-prevalence ratios (PPRs), defined as the ratios of the proportions of women enrolled in these trials to the proportion of women prevalent among US CVD patients during the same period, were calculated and summarized by a meta-analysis approach. We used boosted regression tree, a machine learning model, to identify the determinants of women’s underrepresentation in CVD-related trials. RESULTS According to our selection criteria, we analyzed the data of 145 CVD-related trials, among which 40.9% (95% CI: 38.3–43.5%) of the patients enrolled were women. Their PPR was estimated to be 0.843 (95% CI: 0.796–0.890). We found that four factors substantially influenced women’s underrepresentation in these trials: the number of enrollment sites, the starting year, randomization, and academic institution sponsorship. CONCLUSIONS Generally, women with CVD in the United States were underrepresented in FDA registered trials started in 2002–2017. In addition, trials with greater numbers of enrollment sites, randomization, and non-academically sponsored trials had a higher risk of underrepresenting women with CVD in the United States. Investigators should take these factors into consideration in clinical trial design in the future, by either increasing women’s participation or stratifying the enrollment by gender. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by The Tisch Cancer Center Support Grant (1P30CA196521). The only role of the funder was in administrative support. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This is meta-analysis study and the analysis was not based on individual-level human subject data. No IRB approval is needed. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The study data were obtained from FDA database.