examining the effects of gender or sex on a given outcome. Thus, the issue is not simply including women in trials but including sufficient numbers to test effects on both women and men. To be fully informative, findings need to be reported separately by sex or gender. If a subpopulation, such as women in this case, is excluded or underrepresented in the sample, it is difficult to know whether the results will apply to the subpopulation or whether it would have responded differently. For example, that lack of data can delay translation of research findings on effective treatments to the excluded or underrepresented subpopulation or can lead to adverse outcomes because of inappropriate application to one population of treatments developed on another.
It might seem obvious that poor clinical outcomes can occur if it is presumed that there are no sex or gender differences when they do exist, but false inferences and bad outcomes can also result from a presumption of sex or gender differences when such differences do not exist (Baumeister, 1988). For example, the first randomized clinical trial of estrogen therapy, the Coronary Drug Project, was done in men. That study was discontinued prematurely because of a lack of evidence of a positive effect and a trend toward increased cardiovascular mortality in the treated group (The Coronary Drug Project Research Group, 1973). The doses in the trial were much higher than those given to women, so the results were thought not to be relevant to women, and estrogen therapy continued to be prescribed to women to reduce cardiovascular risks. More than 20 years after the study, postmenopausal hormones were still among the top-selling drugs in the United States—an estimated 15 million women were taking them (Hersh et al., 2004). Conversely, statins (that is, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) were first shown to be effective in lowering cholesterol in a Scottish trial in men (Shepherd et al., 1995). Of 5 randomized controlled trials published in 1994–1998, the Scottish trial was in men only, and the other 4 included 14–19% women. That small number of women in statin trials limited conclusions for women and led to questions about the extrapolation of the data to women. LaRosa and colleagues (1999) conducted a meta-analysis of data from those trials and concluded that the risk reduction from statins is similar in men and women.2 Meta-analyses, however, are not optimal, especially when evaluating the leading cause of mortality in women, and more recently the efficacy and safety of statins, especially for primary prevention, has been questioned and is still being evaluated (Abramson and Wright, 2007; Mascitelli and Pezzetta, 2007; McPherson and Kavaslar, 2007; Ridker, 2010).
Before 1987, women were underrepresented in key randomized controlled trials because of policies that limited or prevented their participation mainly owing to concern about potential exposures of fetuses. Changes in National In-