Medical device studies have shown persistent underrepresentation of women – a sex gap that could have a profound impact on the health of women who receive such devices.
In an attempt to correct this disparity, the Food and Drug Administration’s Center for Devices and Radiological Health (CDRH) issued draft guidance in December 2011 outlining the center’s expectations regarding sex-specific patient enrollment, data analysis, and reporting.
The goal of the guidance is to improve the quality and consistency of data on the performance of medical devices in both sexes, in particular addressing the underrepresentation of women in such studies. When the document is finalized after a 90-day comment period ending in March, it will represent the FDA’s current thinking on the topic.
In a recent evaluation of all cardiovascular Premarket Approval Applications submitted between 2000 and 2007, researchers reported that even among the pivotal studies that reported sex, an average of only 33.9% women were enrolled (Am. J. Therapeutics 2010;17:2-7).
This problem mirrors an earlier underrepresentation of women in clinical drug studies, which the FDA’s Office of Special Health Issues addressed in 2003.
Not a Matter of Political Correctness
As with drug trials, the lack of representation of women in clinical device trials is not just an abstract problem. There are very real differences in the responses and potential responses of women and men to medical devices, as described in the FDA guidance report.
For example, in recent studies of next-generation ventricular assist devices (VADs), females or covariates associated with sex (body surface area) exhibited a higher rate of stroke than males, at 18% and 6%, respectively, and women also showed a trend toward increased bleeding and infection. This led to an FDA Advisory Committee recommendation that a postapproval study be conducted with adequate collection of data on both sex and body surface area to determine whether differences existed in device performance.
The case of VADs is also instructive with regard to overall sex-related differences in initial device development and design. Original devices were generally too large for many women and the pediatric population. According to the National Heart, Lung, and Blood Institute, "until recently, VADs were too big to fit in many people’s chests, especially women. Only people who had large chests could get one. Now implantable VADs can fit in most adults and even some older children."
Devices for infants and smaller children are in various stages of development, with Berlin Heart’s Excor being the first to receive a Humanitarian Device Exemption from the FDA in December 2011.
Physiologic differences between the sexes also have the potential to affect device performance. In a recent study, post hoc sex-specific analysis demonstrated that cardiac resynchronization therapy defibrillators (CRT-Ds) – as compared to simple implantable cardioverter defibrillators – showed a significantly greater reduction in the composite end point of all-cause mortality or first heart failure in women vs. men (77% vs. 42%, respectively). This study also showed that left bundle branch block, which is a marker of an electrical conduction disorder in the heart associated with a greater benefit in patients receiving CRT, was significantly more common in women than in men (87% vs. 65%) (J. Am. Coll. Cardiol. 2011;57:813-20).
Addressing Enrollment Problems
Much of the current CDRH report addressing medical devices is based on the results of an FDA workshop held in 2008 to address the issue. Participants in that workshop admitted that there were significant barriers to the enrollment of women in clinical studies of medical devices, including:
• Fear of consequences to a fetus if the woman becomes pregnant (especially with regard to radiographic assessments or concomitant drug therapy).
• Lack of understanding of differences in disease etiology and pathophysiology that may lead to underdiagnosis and underreferral of women.
• Avoidance of female patients due to perceived difficulties in recruitment.
• Inclusion/exclusion criteria that may unintentionally exclude women (e.g., upper age limit).
• Family responsibilities that may limit participation of women.
Nevertheless, the FDA guidance makes specific recommendations for achieving representative enrollment of women in clinical trials. With regard to potential sex differences of relevance to a new device, the agency recommends providing background information on sex-specific prevalence of the condition; sex-specific diagnostic and treatment patterns; identification of proportions of women included in past studies for the target indication; and identification of any known, clinically significant sex differences in outcomes related to either safety or effectiveness.
This information should be included in study and submission documents, new or ongoing studies, completed studies in the marketing application stage, and postmarket studies – with specific details for each level of the studies.