Status of Women in Cardiovascular Clinical Trials

Changing the Face of Cardiovascular Trial Participation: Moving Beyond Middle-Aged White Guys

Female Recruitment Into Cardiovascular Disease Trials

Dispelling the Myths: Calling for Sex-Specific Reporting of Trial Results

Introduction Cardiovascular disease is the leading cause of death for women worldwide. Yet, women are often underrepresented in clinical trials of cardiovascular disease compared to population prevalence. Reasons for underrepresentation are multifactorial, and often attributed to trial criteria. Yet, women may also decide not to participate for more subconscious reasons, such as the perception of the trial acronym. Trial acronyms are used in patient communication and are often chosen to have a certain meaning, which can be perceived as gendered. We hypothesize that masculine trial names are associated with underrepresentation of women in clinical trials. Purpose To investigate if the perceived gender of the trial acronym, and other study characteristics affect the representation of women in cardiovascular clinical trials. Methods We performed a systematic search of ClinicalTrials.gov to collect information on randomized clinical trials testing drug interventions for cardiovascular disease. We extracted trial characteristics and acronyms from primary outcome publications. We conducted a survey among 148 cardiovascular patients (both women and men) recruited via an online patient forum and asked them whether they perceived trial acronyms names as more masculine, feminine or neutral. We defined female underrepresentation as those trials where the proportion of included women divided by the proportion of women in the disease population was below 0.8. We analyzed female underrepresentation and study setting, participant characteristics, and female first and last authorship. Results We identified 148 eligible clinical trials of which 29.9% of participants were women. Women were underrepresented in 61.5% of trials (Figure 1). Only 45.3% of publications reported sex-stratified results. The proportion of trials in which women were underrepresented increased between 1992 and 2022 from 48.3% to 70.5%. A total of 148 patients (67.6% women, mean age 61 y) evaluated the trial acronyms for their perceived gender. The majority (70.9%) of trial names was perceived as neutral, 17.6% as masculine and 11.5% as feminine. Female representation was not associated with the perceived gender of the trial name (OR 0.92, 95% CI 0.63 – 1.35) (Figure 2A). Trials had a higher odds of female underrepresentation if they recruited at an in-patient setting (OR 2.47, 95% CI 1.14 – 5.58), or if their participants were in the second-highest age group between 64.0 and 66.3 years (OR 3.93, 95% CI 1.25 – 14.18). Trials had lower odds of female underrepresentation if the last author was a woman (OR 0.10, 95% CI 0.01 – 0.49). Conclusion Female representation in cardiovascular clinical trials remains poor but is not depending on the perceived gender of the trial acronym. Female representation varies with recruitment type, participant age and last author gender, which are important starting points to improve participation rates of women.

Cardiovascular diseases represent the major cause of mortality in women and in men.1,2 However, gender differences in the clinical presentation of cardiovascular diseases have been demonstrated3 and some therapeutic options may not be equally effective and safe in men and women.4 Furthermore, gender differences in pharmacokinetics and pharmacodynamics may contribute to a different response to cardiovascular drugs in women when compared with men.5,6 Accordingly, preventive and therapeutical interventions should be tested in populations that fairly represent the gender distribution. In contrast, under-representation of women in cardiovascular trials has been clearly demonstrated in the past. The European Heart Health Strategy (EuroHeart) project of the European Society of Cardiology (ESC) and the European Heart Network (EHN), co-funded by the European Commission, addressed the issue of women representation in cardiovascular clinical research in Europe. The enrolment of women in cardiovascular clinical trials funded by the NHLBI was 38% between 1965 and 19987 and 27% between 1997 and 2006.8 Furthermore, only 13 of 19 studies reported gender-based outcomes. In the European cardiovascular clinical trials of the same period, the proportion of women enrolled varied between 16 and 25%, although the female prevalence of clinical conditions under study in the general population was similar to that of men. In 2005, the European Medicines Agency and the ESC Policy Conference on Cardiovascular Diseases in Women recommended a significant representation of women in clinical trials.3 The current representation of women in European cardiovascular research has been assessed in the EuroHeart project. Observational studies; randomized clinical trials, including meta-analyses; European registries; Guidelines and Statements of European Scientific Societies, published between 2006 and June 2009, have been analysed, focusing on the number and percentage of women enrolled, age of participants, time of follow-up, availability of the analysis of …

Historically, women have been underrepresented in clinical research, requiring physicians to extrapolate medical recommendations for women from clinical research done in cohorts consisting predominantly of male participants. While government-funded clinical research has achieved gender parity in phase-3 clinical trials across many biomedical disciplines, improvements are still needed in several facets of women's health research, such as the inclusion of women in early-phase clinical trials, the inclusion of pregnant women and women with physical and intellectual disabilities, the consideration of sex as a biological variable in preclinical research, and the analysis and reporting of sex and gender differences across the full biomedical research continuum. The National Institutes of Health (NIH) Office of Research on Women's Health and the Office of Women's Health of the U.S. Food and Drug Administration (FDA) cosponsored a preconference symposium at the 25th Annual Women's Health Congress, held in Arlington, VA in April, 2017, to highlight gains made and remaining needs regarding the representation of women in clinical research, to introduce innovative procedures and technologies, and to outline revised policy for future studies. Six speakers presented information on a range of subjects related to the representation of women in clinical research and federal initiatives to advance precision medicine. Topics included the following: the return on investment from the NIH-funded Women's Health Initiative; progress in including women in clinical trials for FDA-approved drugs and products; the importance of clinical trials in pregnant women; FDA initiatives to report drug safety during pregnancy; the NIH-funded All of Us Research Program; and efforts to enhance FDA transparency and communications, including the introduction of Drug Trials Snapshots. This article summarizes the major points of the presentations and the discussions that followed.

Prioritise research on vaccines for pregnant and breastfeeding women

This review describes and evaluates the representation of women in cardiovascular randomized controlled trials (RCT), it reports significant under-representation of women in clinical trials both as participants and researchers and discusses the ethical implications of under-representation. The under-representation of women as participants in cardiovascular RCTs is evident in trials investigating cardiovascular drugs, acute coronary syndrome, heart failure and interventional procedures and devices. Under-representation of women is also evident in the authorship of cardiovascular clinical trials and in trial leadership roles, and under-representation of women as trial investigators is independently associated with under- recruitment of women as trial participants. A notable lack of RCTs investigating conditions that disproportionately affect women is also evident, this triad of underrepresentation for women as participants, and investigators, and the lack of RCTs into conditions predominantly experienced by women, all contribute to the gender gap in cardiovascular outcomes. Better representation of women in clinical trials, in trial leadership and authorship is a key factor to address to equity, distributive justice and improve outcomes for women with cardiovascular disease.

Many studies have demonstrated that women are substantially underrepresented in cardiovascular trials, but few have considered that women develop cardiovascular disease at older ages than men. The extent to which observed gender enrollment inequalities persist after accounting for age-gender differences in disease prevalence is unknown. The purpose of the study was to compare observed rates of women participating in cardiovascular clinical trials with expected rates of female participation based on age- and gender-specific population disease prevalence. Publications between 1997 and 2009 in the three leading medical journals were included to calculate observed women's enrollment rates. Population-based data in Canada were used to determine the expected enrollment rates of women. Multicenter, randomized cardiovascular clinical trials that enrolled both men and women were analyzed. Two reviewers independently extracted data on women's enrollment and important clinical trial characteristics. The female enrollment rate was 30% in the included 325 trials, which ranged from 27% in trials of coronary artery disease, 27% in heart failure, 31% in arrhythmia, to 45% in primary prevention. Increased female enrollment correlated strongly with increasing age at recruitment in cardiovascular clinical trials (P < 0.001). After accounting for age- and gender-specific differences in disease prevalence, gaps in female enrollment were much lower than the expected enrollment rates estimated by 5% in coronary artery disease, 13% in heart failure, 9% in arrhythmia, and 3% in primary prevention. Only cardiovascular trials were evaluated in our study. Female underrepresentation in cardiovascular clinical trials is smaller than conventionally believed after accounting for age- and gender-specific population disease prevalence. Our findings suggest that greater representation of women in cardiovascular clinical trials can be achieved through the recruitment of older populations.

The U.S. Food and Drug Administration (FDA) has made efforts to encourage adequate assessment of women, racial/ethnic minorities, and geriatric participants in clinical trials through regulations and guidance documents. This study surveyed the demographics of clinical trial participants and the presence of efficacy and safety analyses by sex for new drugs approved between 2013 and 2015 by the FDA Center for Drug Evaluation and Research. New drug marketing applications submitted to FDA were surveyed for demographic data (sex, race, ethnicity, and age) and the presence of sex-based analyses for efficacy and safety. The Ratio of the Proportion of women in clinical trials for the indicated disease population relative to the estimated Proportion of women in the disease population (PPR) was calculated for new drug indications. Of the 102 new drugs in this cohort (defined as new molecular entity drugs and original therapeutic biologics), sex was reported for >99.9% of trial participants, and women accounted for 40.4% of these participants. An estimated 77.2% of participants were White, 6.4% were Black/African American, and 29.1% were aged ≥65 years. Sex-based analyses for both efficacy and safety were conducted for 93.1% of applications. PPR was calculated for 82 new drugs for a total of 60 indications, of which 50 indications (83.3%) had a PPR ≥0.80. Sex data are now collected for almost all study participants, and this study shows appropriate sex participation for most new drugs when estimated disease prevalence by sex (PPR) is considered. Therapeutic area and disease indication are important considerations when assessing the sex of participants because variation occurs depending on the disease under study. Some racial minorities, especially Blacks/African Americans, are still not well represented in most drug development programs and remain an area where improvement is needed.

The representation of women in clinical trials has been a controversial and frequently debated issue in recent years. In response to evidence suggesting that sexually-biased practices exist in drug research, several policy changes aimed at redressing existing inequities have been initiated. The United States Food and Drug Administration (FDA) is currently revising its guideline regarding the enrollment of women in early phases of drug testing. It appears that the revised policy will permit women of child-bearing potential to be enrolled in clinical trials prior to the completion of animal reproductive toxicology studies. The National Institutes of Health (NIH) has revised its “Guide for Grants and Contracts” to call for a greater involvement of women in clinical trials. The NIH has also instituted a comprehensive study termed the Women's Health Initiative to examine major causes of morbidity and mortality among women. These initiatives and policy changes will affect the clinical research practices of the ...

BACKGROUND Black adults in the United States (US) face significant cardiovascular health disparities, which are likely exacerbated by the underrepresentation of Black adults in cardiovascular clinical trials. The Black US population has experienced unique historical events, discriminatory practices, and practical obstacles that might contribute to this underrepresentation in clinical trials. Improved understanding of motivations that encourage or discourage participation in cardiovascular clinical trials can lead to more effective clinical trial recruitment and help mitigate these cardiovascular health disparities. OBJECTIVE Using an online survey, determine which motivational themes in clinical trial recruitment advertisements are most effective in encouraging Black adults to participate in a hypertension-focused trial. We also explored how trust in healthcare and various demographic factors influenced their decision to participate. METHODS We conducted an online survey with 829 self-identified Black adults in the US, using a between-subject design to test four literature-derived motivational themes in clinical trial recruitment advertisements: (1) contribution to science, (2) helping the community, (3) lowering blood pressure, and (4) access to perks ($500 worth of groceries or an equivalent cash amount). We assessed advertisement appeal, willingness to participate, and willingness to recommend clinical trial participation to others using Cumulative Link Mixed Models (CLMM). RESULTS Demographic factors played a more significant role than motivational themes in predicting advertisement effectiveness. Adults aged 40-59 and individuals diagnosed with high blood pressure were more likely to find the advertisements appealing and express willingness to participate. Urban residents engaged more with the advertisements compared to those in suburban or rural areas. Participants with liberal (OR: 1.37, 95% CI: 1.01-1.85, p = 0.044) and conservative (OR: 1.62, 95% CI: 1.09-2.40, p = 0.018) political views were more willing to participate in the clinical trial compared to those with moderate views. However, the “Lowering my blood pressure” theme was less effective among individuals who distrusted healthcare institutions (OR: 0.40, 95% CI: 0.16-0.97, p = 0.042) and also reduced willingness to recommend the trial (OR: 0.36, 95% CI: 0.15-0.85, p = 0.020). Additionally, higher trust levels were unexpectedly associated with lower willingness to participate when exposed to this theme (OR: 0.41, 95% CI: 0.17-0.98, p = 0.044). CONCLUSIONS This study contributes new empirical evidence on the science of inclusive trial recruitment and provides an evidence-based approach to using recruitment advertisements to improve clinical trial participant diversity.

In 2001, a sentinel publication from the Institute of Medicine, “Exploring the Biological Contributions to Human Health: Does Sex Matter?” concluded that ‘until the question of sex is routinely asked and the results—positive or negative—are routinely reported, many opportunities to obtain a better understanding of the pathogenesis of disease and to advance human health will surely be missed’ [1]. Given the acknowledged lack of enrolment of women in clinical trials, particularly cardiovascular trials, the National Institutes of Health (NIH) implemented guidelines in 1993, for the inclusion of women in all phases of clinical trials, and the requirement to design phase III clinical trials that specifically assess sex-based differences [2]. Nevertheless, an assessment of female enrolment in all NIH-funded clinical studies between 1993 and 1998 found one-fifth of the non-sex specific studies still failed to enroll female subjects. Furthermore, among the studies that did include women, 60 %–70 % did not analyze or report results based on sex [3]. Of note, European and other international trials, which lack legislation regarding inclusion of women in clinical studies, enroll a larger proportion of female subjects than do US-specific trials, although they still do not achieve levels representative of the diseased population [4]. The lack of information by sex and gender has very real implications for care. For example, between 2000 and 2007, the Food and Drug Administration (FDA) approved 78 highrisk cardiovascular devices, based on a patient population comprised mainly of men (67 %); 28 % of the studies did not even provide the sex-distribution of their populations; sexspecific analyses were reported in only 41 % (51/123) of studies [5]. The general lack of sex-specific analysis for new device approval is best illustrated by the implantable cardioverter-defibrillator experience where approval was granted despite very low enrolment of women in the key trials. The implications of this lack of data are now apparent; a metaanalysis has demonstrated a lack of efficacy of implantable cardioverter-defibrillators in primary prevention trials in women with heart failure [6]. A review of the key meta-analyses describing the efficacy of the key evidence-based medications for secondary prevention post-acute myocardial infarction reveals a general lack of data on women (women comprised between 18.8 % and 30 % of the populations analyzed) [7–9], and in the case of beta blockers, no evaluation of sex-specific outcomes were provided whatsoever [10]. These examples highlight the uneven approach to accommodating sex and gender issues in cardiovascular care and prevention, and they underscore the importance of conducting research that incorporates the study of sex differences in study design and reporting. Yet, important progress has been made recently. Legislation in the United States now requires sex-specific reporting. Recently enacted legislation, the Food and Drug Administration Safety and Innovation Act in 2012, requires the FDA to report annually and publicly on the extent to which applications for FDA approval of new drugs and medical devices are reported by sex, age, race, and ethnicity [11]. In Canada, the Canadian Institutes of Health Research (CIHR) established a Gender and Health Institute in 2000, which introduced guidelines requiring all applicants for CIHR funding to indicate whether they will consider sex/gender differences in their proposed research. And, there are indications that the Heart and Stroke Foundation of Canada will shortly follow suit. Nevertheless, these are only guidelines, and compliance with K. H. Humphries (*) Department of Medicine, University of British Columbia and Centre for Health Evaluation & Outcome Sciences, Vancouver, BC, Canada e-mail: Khumphries@providencehealth.bc.ca

IN 2000, THE NATIONAL INSTITUTES OF HEALTH (NIH) established ClinicalTrials.gov in response to congressional action 2 years earlier. Sponsors were required to register only those clinical trials assessing drugs for treatment of serious or life-threatening diseases. Compliance with even this limited scope of required registration was poor until 2 related events occurred in 2004: first, in June of that year, the New York State attorney general sued GlaxoSmithKline for failing to publish the negative results of a trial of paroxetine in pediatric patients. Second, in September, the International Committee of Medical Journal Editors announced that, effective July 2005, reports of clinical trials would be accepted for publication only if the trials had been properly registered. The number of trials registered on ClinicalTrials.gov increased substantially after these events. Before the US Food and Drug Administration (FDA) Amendments Act of 2007 (FDAAA), trial registration under US law did not require registering the results of clinical trials. Instead, registration was limited to disclosing the purpose of the trial, the eligibility criteria for patients in the trial, and the location of trial sites. In the FDAAA, Congress for the first time directed the NIH to require sponsors of clinical trials of drugs to post at least some results from those trials on ClinicalTrials.gov and also directed the NIH to adopt new regulations by September 2010 to require sponsors to post more complete results on ClinicalTrials.gov. The NIH is currently developing this regulation, which will be the important next step in the registration of clinical trials and an important opportunity for the NIH to improve the quality and reliability of clinical research of drugs. In addition, Congress directed the NIH to require sponsors to post the basic results data from clinical trials (other than phase 1 trials) of drugs that have been approved by the FDA. The basic results include the demographic and baseline characteristics of the patients, the number of patients lost to follow-up, the number excluded from the analysis, and the primary and secondary outcome measures. For the primary and secondary outcomes, results data must include a table of values along with the appropriate tests of the statistical significance of these values. A narrative summary of the clinical data, therefore, fails to satisfy this registration requirement. However, Congress permitted sponsors to delay posting even basic results until after the FDA approved the drug evaluated in the trial. If the FDA had previously approved the drug but the trial studied a new use of the drug “not included in the labeling of the approved drug,” the sponsor is permitted to delay posting the results from the trial until after the FDA approves (or rejects) the new use. For trials investigating an unapproved use of an approved drug, posting the results may be delayed up to 3 years after the trial is completed. This means that while a clinical trial may have been properly registered and the trial may have been long since completed and the data analyzed and reported to the FDA, the sponsor is not obligated to post even the basic results on ClinicalTrials.gov until the FDA acts on the drug or the new use under investigation in the trial. In the FDAAA, however, Congress directed the NIH, in adopting the new regulation expanding ClinicalTrials.gov, to consider whether to require sponsors to post results from trials of drugs not approved by the FDA. If the NIH decides that the new regulation should require posting results from trials of unapproved drugs, many of the delays that are now permissible would be eliminated. The NIH should decide in favor of this requirement. The other 2 most important issues facing the NIH in developing this regulation are, first, whether to require sponsors to include on ClinicalTrials.gov the full protocol for each trial, and, second, whether to require sponsors to do the same for all patient-level data for the primary and secondary outcomes. Even though sponsors are required to submit trial protocols to the FDA as part of the Investigational New Drug application process, the FDA traditionally has treated such applications, including protocols, as confidential proprietary information and does not make them public. Similarly, the FDA generally does not make public the patientlevel data submitted by sponsors. Instead, the FDA makes public, after approval, summaries of the data as part of its

Diversity and Inclusion in Pancreatic Cancer Clinical Trials