Evaluating sex differences in medical device clinical trials: time for action.

THE SAFETY AND EFFECTIVENESS OF MEDICAL TREATments can differ in men and women for many reasons related to different epidemiologic characteristics, physiology, and body size. In general, women have higher bleeding rates and procedural morbidity and mortality than men, which means that their risk/benefit ratios for many implanted medical devices can differ from men. Therefore, sex-specific safety and effectiveness data are necessary for informed patient decision making. In 2008, the US Food and Drug Administration (FDA) convened 2 workshops on this topic that included multiple stakeholders— patient groups, medical device industry representatives, academia, and government officials. In December 2011, the FDA released a draft guidance informed by these workshops, entitled “Evaluation of Sex Differences in Medical Device Clinical Studies. ” This document discusses the underrepresentation of women in medical device clinical trials and provides recommendations for increasing enrollment of women and performing sex-specific analyses. A 90-day public comment period began on December 19, 2011. The FDA draft guidance document provides a number of helpful guidelines to support adequate enrollment of women in clinical trials. For studies that have not yet been completed, the draft guidance recommends keeping enrollment open until a prespecified number of women are enrolled. Following this recommendation so that women are enrolled in proportion to disease prevalence would do the most to ensure sufficient data about the effect of a medical device on women. The draft guidance document also recommends that outcomes data be analyzed by sex. By not limiting its guidance to new studies, the FDA is indicating that it hopes changes will occur more immediately. This approach is laudable; the difference between men and women in terms of effectiveness and safety of medical devices has long been understudied. The recommendations in this draft guidance may help ensure safe and effective use of medical devices in both sexes. However, the notation on this guidance stating that it “Contains Nonbinding Recommendations” raises the fundamental question of whether these important guidelines will be followed. This is not a new question. In 1994, FDA issued a “Gender Bias” directive stating that FDA Summaries of Safety and Effectiveness Data, which are released on premarket approval for all high-risk medical devices, should examine clinical trial data for differences in safety and efficacy by sex. However, an examination of compliance with this directive found that it is routinely ignored. Among 78 high-risk cardiovascular devices approved during the years 2000 through 2007, the overall patient population in these studies was 67% men with no increase in the enrollment of women over time, although women make up 46% of all patients with cardiovascular disease. The analyses by sex specified in the 1994 FDA directive occurred in only 41% of studies (51/123). When these analyses were completed, 26% (12/47) identified some difference in device safety or effectiveness by sex. In 28% of device studies (34/123), no sex distribution of the patient population was stated. As a result, clinically important sex-specific differences related to use of many medical devices are unknown. For example, the implantable cardioverter-defibrillator (ICD), a device shown to be lifesaving in selected populations, is commonly implanted in men and women. At the time of device approval, there were gaps in the data because of very low enrollment of women in the pivotal studies. In 2003 the Medicare Coverage and Advisory Committee was convened pursuant to a manufacturer’s request for expanded Medicare coverage of ICDs for primary prevention (which was granted). During the meeting, when asked why there were so few women in the pivotal Multicenter Automatic Defibrillator Implantation Trial II, the trial’s principal investigator stated, “we are contemplating a trial in the