Flowchart of study enrollment.
Ding EL, Powe NR, Manson JE, Sherber NS, Braunstein JB. Sex Differences in Perceived Risks, Distrust, and Willingness to Participate in Clinical TrialsA Randomized Study of Cardiovascular Prevention Trials. Arch Intern Med. 2007;167(9):905-912. doi:10.1001/archinte.167.9.905
Multiple sex differences exist in cardiovascular disease burden and treatment efficacies; adequate participation of both sexes is crucial to clinical research.
A multicenter, double-blind, randomized study evaluated sex and trial scenarios on willingness to participate (WTP) in cardiovascular prevention trials and examined sex differences in perceived risks and distrust. Hypothetical trial scenarios randomized multifactorial vignettes of adverse effects, trial durations, sponsors, financial incentives, and conflicts of interest.
With 783 participants across 13 clinical centers, women showed lower distrust of medical researchers, perceived greater risk of myocardial infarction, and perceived greater risk of harm from trial participation than men. Men had 15% greater WTP than women (33.1% vs 28.7%; relative risk [RR], 1.15; 95% confidence interval [CI], 1.02-1.31); adjusting for explanatory mediators, we found that sex differences in perceived risks and benefits explained the sex gap in WTP. Although greater perceived probability of harm (RR, 0.41; 95% CI, 0.23-0.72), health benefit (RR, 2.99; 95% CI, 1.63-5.46), and quality of care (RR, 1.71; 95% CI, 1.12-2.61) strongly predicted WTP (for perceived probabilities ≥80% vs <20%) similarly in both sexes, and perceptions of distrust and myocardial infarction risk predicted WTP differently between sexes (P≤.01 for interactions), age, history of coronary artery disease, hypertension, and diabetes mellitus increased WTP in men but not in women (P≤.05 for sex interactions). Compared with no financial conflict, disclosure of investigator patent ownership increased WTP in women, while it decreased WTP in men (P = .02 for sex interaction). Monetary incentives were overall more effective on WTP in women (P = .03 for sex interaction).
In this multicenter study, women perceived greater risk of harm and myocardial infarction and showed lower WTP in cardiovascular prevention trials. Evidence underscores the importance of sex in influencing clinical trial enrollment.
Although cardiovascular disease (CVD) is a major health care burden and the leading cause of mortality in the United States among both men and women,1 sex differences in disease cause, progression, clinical treatment, efficacy of interventions, and cardiovascular outcomes have been recognized.2- 8 In 1993, the National Institutes of Health established requirements for equal inclusion of women in clinical studies.9 Subsequently, considerable attention and controversy has surrounded the issue of balanced sex representation in large clinical trials,10- 16 particularly for CVD prevention. However, previous assessments have been retrospective and have not fully evaluated the inherent difficulty of enrolling both women and men in trials for CVD prevention.
Although large clinical trials conducted in women, such as the Women's Health Initiative17- 19 and Women's Health Study,20- 22 have helped allay some concerns regarding the representation of both sexes, the underrepresentation of women in cardiovascular clinical trials continues to be an issue of considerable contention,10- 16 even years after the launch of these major trials in women. A recent study of National Heart, Lung, and Blood Institute (NHLBI) grant investigators indicated that most scientists believe that inclusion of women remains a clinical research priority.23 However, official NHLBI guidelines for inclusion of women in the “same proportions as in the U.S. population having the disease entity being studied”23 would indicate inadequate inclusion of women in clinical trials of CVD, various cancers, and human immunodeficiency virus.13,15,16,24- 26
In addition to women potentially perceiving lower risk of myocardial infarction (MI), lower representation of women in trials may plausibly be a result of women perceiving fewer benefits and more or greater risks from trial participation, potentially related to the general aversion of women for risk-taking behavior.27 Furthermore, given evidence that trust is an important determinant of willingness to participate (WTP),28- 33 sex differences in distrust may also explain imbalances in representations in clinical trials. Thus, the influence of clinical trial characteristics, such as trial duration, adverse effects, study sponsors, and monetary incentives on trial participation, may substantially differ between sexes.
To our knowledge, no study has comprehensively examined how sex, distrust, perceptions of risks and benefits of trial participation, and various trial protocols together influence WTP. Therefore, we herein report the findings of a multicenter randomized study to examine such sex influences on participation in clinical drug trials for CVD prevention.
We conducted a multiple clinical center, randomized trial and cross-sectional study among participants 18 years or older. The study centers were 13 Maryland-based internal medicine and cardiology clinics chosen on the basis of their geographic location (urban or suburban) and affiliation (academic or community) to afford a socially diverse study population. Depending on the system and volume of each clinic, individuals were approached by trained recruiters either before or after their health care provider visit in either consecutive fashion or a random sample of patients in high-volume clinics. Owing to practical limitations of recruiting staff, the sampling fraction varied daily, depending on clinical patient volume. Eligibility criteria required individuals to (1) be visiting the clinic for a scheduled appointment with a health care provider, (2) possess English fluency or ability to translate the survey, and (3) have sufficient cognitive capacity to comprehend the study. Between April and October 2002, we selected 783 subjects for the study from 1440 individuals approached and 925 found to be eligible and consenting (Figure).
Participants were informed that the general purpose of the study was to (1) understand individuals' attitudes about medical research and the physicians who performed such research and (2) learn why people chose to participate or not participate in clinical trials. Using study vignettes, we randomly assigned each participant a standardized 1-page description of a hypothetical randomized, double-blind, placebo-controlled cardiovascular drug prevention trial and asked them about their interest in enrolling. Multifactorial trial vignettes randomized in each hypothetical trial scenario included adverse effect severity (mild: “mild nausea, bloating, and diarrhea”; or moderate: “stomach aches, liver irritation, muscle pain, and moderate bloating and diarrhea”); adverse effect probability (“1 in 100” or “1 in 10”); trial duration (6 months or 3 years); study sponsor (US government, nonprofit organization, or pharmaceutical company); presence of potential researcher financial conflict of interest (no profit, paid $2000 for every person who joins the study, or ownership of the drug patent with the potential to profit if drug is effective); and monetary compensation provided for participation ($25, $250, $500, $750, or $1250). Trial elements uniformly disclosed included the voluntary nature of the study, alternative treatment options, right to withdrawal, and free trial-related health care during the study. At the time of study enrollment, recruiters were blinded to the trial scenario assignment of each participant. Furthermore, though aware of the hypothetical nature of the scenario, participants were blinded to knowledge of trial vignettes and the existence of alternative scenarios.
After reading the administered trial scenario, participants rated their WTP in the hypothetical trial using a 5-point Likert scale, dichotomized into the following primary WTP outcomes: “very likely/likely” (positive response) and “unsure/unlikely/very unlikely” (negative response). To internally validate self-reported WTP in the hypothetical trial with behavior, we validated WTP by asking, “If previously ever approached to join a clinical trial, did you agree to join?” Among those who reported joining a prior study, we asked, “Would you ever join another study if approached again?” Responses to these questions were correlated with WTP, with nonparametric z scores of 4.4 (P<.001) and 5.4 (P<.001), respectively. Self-reported WTP has also been documented to be predictive of actual participation in another validation study.34
After using the trial scenario description to primarily assess WTP, we undertook the second phase of the study, a cross-sectional survey used to assess patients' attitudes toward specific elements of the described trial, medical researchers, and the health care system. Mediating factors for explaining differential WTP were also considered, including distrust, perceived 10-year risk of MI, and perceived harm and benefits of joining the trial. The degree of distrust of physicians and medical researchers was measured on the 7-point Corbie-Smith distrust index,35 which incorporates several elements of distrust: distrust in full and truthful physician-patient communication, distrust in physicians and researchers to protect patients from harm, and potential of nonconsensual medical experimentation. Perceptions of the risks and benefits were measured using a 100-point visual analog scale.36 Specifically, participants rated (1) “the chance that [they] would experience personal harm or injury, such as a side effect from the study drug, by joining the study”; (2) “the chance that [their] health would benefit from joining the study”; and (3) “the chance that the quality of [their] health care would improve by joining the study.” The 90-item self-administered survey, completed in the clinic or at home, also collected information on self-reported medical conditions, health status, prior health care experience, and sociodemographic characteristics.
The clinical trial description read at a Flesch-Kincaid37,38 grade level of 7.2 (statistical analysis performed in Word 2000; Microsoft Corp, Redmond, Wash), akin to a typical consent form used in CVD trials. In addition to pilot testing at a recruitment site, we had an expert panel of survey methodologists face- and content-validate all questions and measures in the instrument, and an expert panel of cardiovascular clinical trialists face- and content-validate the trial design and hypothetical trial scenarios. Because of the fictional nature of the trial vignettes (no actual medical intervention was provided to patients), this study was exempt from clinical trial registration.39 The study protocol was approved by the institutional research review boards of Johns Hopkins Medical Institutions and local hospitals affiliated with each clinical site.
Relative risks (RRs) were calculated to assess the association between sex and positive WTP as well as the associations of perceived MI risk, distrust, perceived harm and benefits, and each trial vignette with WTP. Relative risks were estimated using Poisson regression with robust variance40,41 and clustering on clinical site owing to the multicenter design. To determine effects of individual trial vignettes on WTP, we undertook sex-stratified analyses mutually adjusted for other trial vignettes and age (<40, 40-49, 50-59, 60-69, ≥70 years). Analyses for association of sex and demographic characteristics were adjusted for age, race (white, black, and other [which included Asian, Native American, and self-reported “other”]), education (<12th grade, grade 12/high school graduate, some college, college graduate/some postgraduate, or graduate degree), household income ($0-$29 999, $30 000-$49 999, $50 000-$74 999, or ≥$75 000), marital status (single, married, widowed, or divorced/separated), insurance type (Medicaid or none, Medicare, managed care/health maintenance organization, private, Champus/Tri-Care), employment status (part-time/full-time, retired, disabled, or unemployed/student/other), overweight (yes or no), smoking status (current, former, or never), self-reported clinical conditions (cancer, coronary artery disease, congestive heart failure, peripheral vascular disease, hypercholesterolemia, hypertension, and/or diabetes mellitus), and hospitalization within the past year.
Furthermore, we examined whether sex differences in distrust of medical researchers, perceived risks, health benefits, and health care quality benefits (5 categories) explained any sex differences in WTP by further adjusting for these mediators. The missing indicator method was used to adjust for variables with missing values, and exclusion did not affect the results. Multivariable regressions also assessed sex differences in perceived probability of risk and health benefits, 10-year risk of MI, and high distrust (≥5 points). Analyses were conducted using STATA software, version 8.2 (StataCorp LP, College Station, Tex). All tests were 2-sided.
The descriptive characteristics of the study subjects are summarized in Table 1. Descriptive characteristics were also balanced between the multifactorial randomized vignettes.
In age-adjusted and multivariable models controlling for demographic differences, men overall had higher WTP than women in cardiovascular prevention trials (Table 2). Even with further adjustment for clinical characteristics including coronary artery disease and diabetes mellitus, which are known to biologically differ in prevalence between sexes, men still had 15% higher WTP than women (multivariable RR, 1.15; 95% CI, 1.02-1.31). In searching for explanatory sex perception differences that might mediate such differences, we found that the results remained robust even after adjustment for sex differences in distrust of medical researchers (P = .03) and perceived 10-year risk of MI (P = .04) (consistent RR, 1.15 after controlling for both). However, in additional explanatory models, differences in perceived probability of experiencing harm and benefits fully attenuated the sex difference in WTP (RR, 1.01; 95% CI, 0.88-1.15), with perceptions of benefits and harm contributing equally to explaining the overall sex disparity.
In addition, stratified results indicate that sex was important in consistently modifying the influence of many demographic and clinical characteristics on WTP (Table 2). Notably, older men and men with a history of coronary artery disease, hypertension, and diabetes mellitus were more willing to participate than men without such conditions; such patterns were not observed among women (P = .05, P = .03, P = .01, and P = .04 for sex interaction in age, coronary artery disease, hypertension, and diabetes mellitus, respectively). Results also indicate that sex strongly influenced the effect of various employment status and household income levels on WTP (P = .002 and P<.001, respectively, for sex interaction). Notably, higher income was generally associated with increased WTP among women but not among men.
In analyses of sex differences in perceived risks, benefits, and distrust, results indicate that men perceived lower risk of harm from trial participation (P = .003) and lower 10-year risk of MI (P = .04) but had greater distrust (P<.001) (Table 3). Further stratifying the actual risk of harm described in the randomized trial vignettes of “10 in 100” and “1 in 100,” we found that men and women both felt that the risk of harm was greater than the actual risk described in the trial scenario (P<.001 for both sexes). Moreover, men and women without prior MI both overestimated their 10-year risk of MI compared with any age-specific Framingham42 coronary heart disease risk, with a greater proportion of women than men overestimating 10-year MI risk (96.1% vs 90.7%; P = .01 for sex difference).
Perceptions of risks and benefits and distrust were also strongly associated with WTP (Table 4). Notably, compared with individuals with perceived probability ranging from 0% to 19%, those with perceived probability ranging from 80% to 100% had an almost 60% lower WTP for perceived harm (RR, 0.41; 95% CI, 0.23-0.72) (P<.001 for trend), a 3-fold higher WTP for perceived health benefit (RR, 2.99; 95% CI, 1.63-5.46) (P<.001 for trend), and a more than 70% higher WTP for perceived quality of health care improvement (RR, 1.71; 95% CI, 1.12-2.61) (P = .002 for trend). However, results indicated a significant sex difference for perceived 10-year risk of MI (P = .01 for interaction), with greater perceived MI risk being associated with lower WTP only among women (P = .01 for trend). Greater distrust (≥5 vs 0 points) was also associated with significantly lower WTP (RR, 0.53; 95% CI, 0.36-0.79) (P<.001 for trend), although distrust had a relatively stronger relation among men (P = .002 for interaction).
For the effects of randomized vignettes on WTP in clinical trial scenarios, sex appeared important in determining the effect of monetary incentives and researcher financial conflict of interest on WTP (Table 5). Compared with no conflict of interest, participant knowledge that the researcher owned the patent with potential to profit if the drug were to be successful decreased WTP in men (RR, 0.62; 95% CI, 0.37-1.00), while such knowledge of researcher patent ownership increased WTP in women (RR, 1.37; 95% CI, 1.04-1.80) (P = .02 for sex interaction). Although no clear dose-response trend in WTP was observed with increasing monetary incentive, monetary incentive expressed as a proportion of annual income did clarify the effects of monetary incentive, which showed a more clear sex difference such that monetary incentives were overall more effective in increasing WTP in women (P = .03 for sex interaction). Other randomized vignettes of trial characteristics did not show significant sex differences in effects on WTP.
Our multicenter, multifactorial randomized study of clinical trial participation and risk perceptions demonstrated that women perceived greater risk of MI, had less distrust, perceived greater risk of harm, and possessed significantly lower WTP in cardiovascular prevention trials. Additionally, sex was important in modifying the association of effect of monetary incentives, conflict of interests, income, employment, age, and presence of CVD risk factors on WTP in cardiovascular prevention trials. Given the clear strong sex differences in the cause, disease prognosis, and treatment efficacy of cardiovascular conditions,2- 8,43 a focus on sex-specific clinical research and understanding of sex differences in risk perceptions and trial participation are important. To that end, to our knowledge, this study is one of the first to elucidate sex differences in perceived risks, distrust, and WTP.
Similar to findings that women were less willing to participate in percutaneous transluminal coronary angioplasty and coronary artery bypass graft trials,44 as well as in oncologic13,45,46 and genetic and biomarker46- 49 research studies, the body of evidence from past studies and the present study indicates that the overall lower WTP of women and greater difficulty in enrolling women may be systemic in medical research. However, consistent with studies suggesting that greater belief in benefits and lower negative opinions of clinical trials were important aspects of WTP,32,50- 53 our results indicate that efforts to clarify perceptions of risks and benefits in men and women may help improve the sex disparity in WTP.
Although this study helps clarify sex differences in risk perceptions and WTP, certain results also raise more questions and concerns regarding the lower WTP in women. In particular, despite perceiving greater risk of future MI and having lower distrust than men, female sex surprisingly remained associated with consistently lower WTP. Furthermore, compared with men, women were less susceptible to influence by the presence of various cardiovascular risk factors such as age, history of coronary artery disease, hypertension, or diabetes mellitus. Exact reasons for these sex differences are not known. The findings may suggest a general aversion to participation among women but a more sensitive propensity for trial participation among men with CVD risk factors. The overall paradox of greater perceived MI risk but lower WTP in women may potentially stem from a general male predilection and female aversion for risk-taking behavior,27 such as participating in a scientific experiment. We found that sex differences in perceived harm may partially explain the sex disparity in WTP, and this might extend to the notion that female aversion to risk is likely important in determining sex behavior in trial participation.
Although it is possible that potential differences in comprehension of trial descriptions may explain the sex disparity, studies specifically examining research consent forms did not indicate sex was related to comprehension.54 However, the finding that both men and women estimated the risk of harm to be substantially higher than that actually described in the trials' informed consent descriptions supports the notions of inadequate comprehension on the part of patients.54 Alternatively, it may also suggest that participants do not fully trust risk estimates provided in trial descriptions, which is a potential area warranting further study.
This study has certain limitations. First, false-positive results may arise from multiple comparisons. However, the number of significant sex differences observed (13 of 24 tests showed significance beyond P = .05) exceeded the number expected by chance by over 10-fold. Second, because WTP was self-reported, subsequent trial participation is not guaranteed. However, we included a priori internal validation questions to assess the validity of participation response, and these indicated that self-reported WTP was highly associated with behavior. Furthermore, because of the inherent voluntary nature of all trials, participant self-response of positive WTP is indeed the primary step for trial recruitment. Third, although the study was conducted in 13 clinical sites over a wide range of sociodemographic settings, the generalizability of the results are less certain. Nevertheless, the wide variety of urban and suburban, academic and community, and internal medicine and cardiology clinical sites reflect the typical population base of participants visiting clinical trial centers in the United States. Finally, sensitivity analyses for the primary analyses of sex, risk perceptions, and WTP externally standardized to the age-race distribution of the 2000 US population yielded similar results.
In conclusion, risk and benefit perceptions and distrust were important determinants of WTP, and women perceived greater risk of MI, had lower distrust of medical researchers, perceived greater risk of harm from potential trial participation, and were less willing to participate in cardiovascular prevention trials than men. Evidence underscores the importance of sex in determining clinical trial participation. However, overcoming sex differences in risk perceptions and WTP remains the duty and obligation of public health and medical professionals to equally include men and women in clinical trials to develop clinical treatments for prevention of all human diseases.
Correspondence: Eric L. Ding, BA, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115 (email@example.com).
Accepted for Publication: January 18, 2007.
Author Contributions: Mr Ding and Dr Braunstein had full access to all study data and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Braunstein, Powe, and Ding. Acquisition of data: Ding, Sherber, and Braunstein. Analysis and interpretation of data: Ding, Manson, Sherber, and Braunstein. Drafting of manuscript: Ding, Manson, Sherber, and Braunstein. Critical revision for important intellectual content: Ding, Manson, Powe, and Braunstein. Statistical analysis: Ding and Braunstein. Obtained funding: Powe and Braunstein. Administrative, technical, or material support: Powe, Manson, and Braunstein. Study supervision: Manson and Braunstein.
Financial Disclosure: Dr Braunstein is currently President of LifeTech Research Inc, Edgewater, Md, and Centegen Inc, Baltimore, Md.
Funding/Support: This study was supported by a grant from the Robert Wood Johnson Foundation (Dr Braunstein).
Acknowledgment: We thank Vera M. Zlidar, MHS, Oyelola O. Faparusi, MBBS, PhD, Steven P. Schulman, MD, and Susan Shultz for their invaluable assistance.