EBM Tools for Practice: Gender Differences in Clinical Trials

The disparity in treatment effects between men and women has long been established. In some cases, these differences are quite large. While researchers once relied on the assumption that treatment effects in women would be similar to those in men, the historical lack of inclusion of women in clinical trials has highlighted treatment differences as clinical trial information is applied across gender. Today, the proportion of treatments to which men and women respond differently remains unknown.

Controversy over inclusion of women in clinical trials has been motivated, in part, by theoretical concerns about the effect of gender differences on treatment and, in part, by fears of exposing fetuses to investigational drugs. Other reasons have been put forward as to why these disparities traditionally have existed.¹ The exclusion of women from clinical trials means that women’s healthcare is compromised by a lack of sex-specific information about drug dosing and unique indications.

Cardiovascular clinical trials and research notoriously have perpetuated these differences. Three-fourths of cardiovascular clinical trials do not report sex-specific results, making it difficult for researchers and clinicians to draw conclusions about their effects on women.^2,3 (Figure 1)

The historic rationale for studying only men in cardiovascular trials also stems from an apparent misimpression that there is a lower incidence of cardiovascular disease among middle-aged women compared to middle-aged men and a desire to minimize the heterogeneity of the trial population. The differential incidence pattern of disease between men and women should be accounted for when including women in clinical trials. Among the first major trials to exclusively study women was the Women’s Health Initiative, which identified the dangers of combined hormone replacement in postmenopausal women in terms of cardiovascular and cerebrovascular disease.⁴

Beginning with the National Institutes of Health (NIH) Revitalization Act of 1993, there has been a sustained effort to recognize underrepresentation of women and ethnic diversity in clinical trials. This effort stems from the inability to adequately answer two questions: 1) Do results of clinical trials apply consistently across all clinically meaningful subclasses of patients enrolled in the studies? 2) Can the results of studies be extrapolated to patients who did not participate in the original research? NIH-funded trials now must have sample sizes adequate to support a “valid analysis” of gender and racial subgroup effects. Prior to 1993, most primary-prevention cardiovascular trials only studied men.

Gender-based differences in cardiovascular disease exist in terms of incidence, prevalence, presentation, diagnosis, and treatment. Women in the early stages of coronary artery disease (CAD) often present with symptoms such as fatigue; abdominal discomfort; and back, jaw, or neck pain.⁵ These symptoms are all considered “atypical” because diagnostic standards mostly were established via research on men. Diagnostic tests, such as exercise electrocardiography and radionuclide myocardial perfusion imaging, do not detect CAD with the same sensitivity in women as in men.⁶

The testing and treatment of pregnant women is another challenging problem, because of a reluctance to expose developing fetuses to investigational drugs. The implication is that pregnant women are unable to weigh the potential benefits against the risks of treatment. Pregnant women traditionally have not participated in early stage clinical trials, creating significant safety concerns for treatment.⁷ Although the 1993 guidelines have increased the number of women in clinical trials, criticism is ongoing because of continued under-representation of women in some study groups. More women than men are now enrolled in NIH-sponsored Phase III trials.⁸ (Figure 2) However, this is mainly attributable to large, single-sex studies for breast and cervical cancer, the Women’s Health Study and The Women’s Health Initiative. This causes a skewed perception of female participation in clinical trials.

Identifying and remedying differences in clinical trials is only part of recognizing previous sex-difference underrepresentation. Researchers also have identified differential responses to treatments based on test animal gender and even sex chromosome status in individual cell cultures.⁹ The NIH is now developing guidelines and complex data-mining techniques to study these differences even in preclinical research.¹⁰ There also are hormonal differences and differences in the way genes inherited from the father and mother are phenotypically expressed. Biomarkers, which indicate the presence or severity of disease, may have to be used selectively, depending on the gender of the patient. Disease states may highlight these variations.

How can further improvements be implemented? First, scientific journals should require authors to clearly label single-sex studies and to address sex-based differences in their research designs and analyses. Second, regulator y bodies and funding agencies should insist on the appropriate representation of both sexes in human and animal trials. Third, it is vital that knowledge of sex differences makes the leap from lab to clinic and becomes an essential consideration in physicians’ interactions with patients. Finally, health organizations should encourage more women to join clinical research trials.

Disclosure statement: Dr. Kroll received speaker honorarium from LipoScience.

References are listed on page 39.