Wanted: Women in Clinical Trials

M ost biomedical and clinical research has been based on the assumption that the male can serve as representative of the species. This has been true in spite of increasing awareness of significant biological and physiological differences between the sexes, beyond the reproductive ones. Women and men differ in their susceptibility to and risk for many medical conditions, and they respond differently to drugs and other interventions. The close of the previous decade saw 8 out of 10 prescription drugs withdrawn from the U.S. market because they caused statistically greater health risks for women than men. Thus, what is true and good for the gander does not seem to be necessarily good for the goose. After a long history of underrepresentation of women and minorities in clinical trials, federal mandates now require their inclusion in federally funded clinical research in “sufficient numbers to provide for a valid analysis of any differences … in response to drugs, therapies and treatments.” The old paradigm of the “70-kg white male” has finally been replaced by a population sample that attempts to include women and minorities at rates proportional to disease incidence. This evolution of clinical trials has provided much new information about sex differences in healthy and diseased individuals. Sex is a basic biological variable and should be part of the clinical study design when relevant. Already, a few strategies to standardize methods for conducting such studies in animals and humans have been proposed. However, procedures to enhance the collection and analysis of sex-specific data need to be implemented. For instance, female-specific variables, including the stage of ovarian cycle and use of oral contraceptives or hormone replacement therapy, are factors that may influence intervention outcomes. Moreover, routine pharmacokinetic analysis during early phases of drug development (phases I and II) would be advantageous in determining potential sex differences in dosage recommendations and to prevent adverse responses. !Figure1 CREDIT: ALEX WONG/GETTY IMAGES (AVIAN FLU VACCINE CLINICAL TRIAL, UNIV. OF MD SCHOOL OF MEDICINE, 2005) Critics of sex-specific analysis claim that conducting scientifically rigorous trials with enough statistical power to detect sex differences is prohibitive in terms of time as well as cost. Nevertheless, when prescription drugs are withdrawn from the U.S. market because they cause greater health risks for women than men, the cost of not doing such analyses becomes a greater liability for drug companies. It is not necessary that every large, double-blind, randomized, placebo-controlled clinical trial be sufficiently powered to include sex as a covariant, if appropriate preliminary studies are conducted. Small pilot trials can provide information about drug or treatment efficacy for specific populations. These studies can be useful in establishing procedures, protecting against undesirable outcomes, and determining the statistically significant sample size for subgroup analysis. To this end, common protocols are still needed to determine whether subgroup analysis to detect sex differences must be conducted and whether larger clinical trials need to include sex as a covariant. What is still, unfortunately, lost to the biomedical community is unpublished information that could reveal sex differences. A failure to report such findings leads to the mistaken impression that they do not exist or that they are inconsequential (just last month, the Society for Women's Health Research reported that between 2000 and 2003, the U.S. National Institutes of Health awarded an average of 3% of its grants per year for research on sex differences, while the total percentage of grants awarded during the same period increased by 20%). Cumulatively, this may lead to public mistrust of the drug industry and physicians and ultimately hinder efforts to recruit male and female participants to clinical studies. The need for transparency of such information is being addressed by some resources such as ClinicalTrials.gov2, which provides regularly updated information about federally and privately supported clinical research using human volunteers. The creation of an international clinical trials registry could further streamline the application of meta-analytic techniques to help overcome the problem of limited statistical power in small studies. Researchers foresee a world in which they will be able to read a patient's DNA to gauge the likely course of the person's disease or response to drugs. Until that degree of individualization is possible, patients and doctors must continue to rely on the results of studies carefully designed and analyzed by patient type—including by sex—to obtain the clinical results that are useful and meaningful to the health of both women and men. 1: pending:yes 2: http://ClinicalTrials.gov