CDRH Explores Recommendations For Gender-Specific Cardiovascular Studies

Full article reprinted from "The Gray Sheet" - June 9, 2008

FDA's device center is developing recommendations for industry on the inclusion of gender-specific device performance information in pre-market applications and device labeling.

CDRH convened a workshop June 2 with participants from government agencies, academia, professional societies and device companies to discuss development of policies on the investigation and analysis of sex differences in clinical studies for cardiovascular products.

The meeting addressed under-representation of women in cardiovascular trials, barriers to enrolling women and improperly designed trials that fail to account for the unique characteristics of women.

There currently is little scientific basis for a specific quota of women to be enrolled in all clinical trials, the meeting participants concluded, but further research should seek to define the appropriate number of women needed for trials of each product.

The group offered suggestions for enrolling more women in trials, such as targeting clinical centers known to recruit the target populations, pre-determining the number of women needed and maintaining open enrollment until that threshold is met, and involving the community in outreach.

Pre-market results should lead to post-market studies powered to assess the impact of sex, they decided. Gender-specific subgroup analyses from all clinical trials should be reported in the labeling, including the analyses' implications and limitations.

Workshop Will Hopefully Lead To FDA Guidance

"There are challenges right now for enrolling appropriate numbers of women in our pre- and post-market trials," Bram Zuckerman, head of the cardiovascular devices division within CDRH's Office of Device Evaluation, told "The Gray Sheet."

Zuckerman said the agency is very interested in addressing the problem and expects FDA will develop future guidance based on input from this meeting and other information gathering efforts.

FDA is planning to host a follow-up meeting targeted at industry in the next year.

"The knowledge gap will never be closed if the pre-market investigation paradigm is not changed," said Kathryn O'Callaghan of the cardiovascular devices office, who organized the workshop with help from FDA's Office of Women's Health.

CVD Is Not Just A "Man's Disease"

Cardiovascular disease is the leading killer of both women and men in the United States, but many women still consider the condition a "man's disease," several participants observed.

In every year since 1984, more women than men have died of coronary heart disease, which encompasses myocardial infarction, angina pectoris, stroke, congestive heart failure and cardiac arrest, according to data from the Agency for Healthcare Research and Quality (AHRQ).

Women typically present with coronary heart disease up to 10 years later than men, and more often exhibit atypical symptoms of MI such as nausea, vomiting, fatigue, shortness of breath and mid-back pain, increasing the likelihood that women will be misdiagnosed or inappropriately treated. Women also tend to have more bleeding complications than men, studies have shown.

Sex differences have "a huge impact" on the efficacy of treatments, side effects and on aspects of trial design, according to panelist Lori Mosca, Columbia University Medical Center, representing the American Heart Association.

Historically, most trials have been powered for fatal and non-fatal coronary heart disease, but women are more likely to present with unstable angina and stroke. "We need to include the full spectrum of cardiovascular disease in all our clinical trials," she said.

According to an AHA literature review, only 70% of trials over the past 100 years included women at all. In those that did include women, very few reported sex-specific analyses, making it difficult to create guidelines for use in women, Mosca said.

"For about two-thirds of all diseases affecting both women and men, studies have been conducted primarily in men, making extrapolation of our research findings to women inappropriate," explained Rosaly Correa-de-Araujo, M.D., HHS Office of Global Health Affairs.

Fewer Hospitalizations, Referrals For Women

AHRQ and the National Institutes of Health Office of Women's Health found that women were less likely than men to be referred for cardiovascular tests and procedures, even when they showed the signs and symptoms of cardiovascular disease or myocardial infarction.

Women are also less likely to receive aspirin, clopidogrel, beta blockers and statins, research shows.

"There's an enormous amount of money spent on cardiovascular disease," commented panelist Patrice Desvigne-Nickens, of NIH's National Heart Lung and Blood Institute. "The lion's share of that money has historically and perhaps still continues to be used on men.

"This is a problem that we have to figure out. It's not 50% women, or 50% men. It's making sure the resources are used appropriately so we're getting the best care for men and for women."

Fixed Enrollment Bar Unlikely, Says FDA Staffer

Unfortunately, when choosing between enrolling more women and completing trials on time, researchers are often forced to choose the latter, several workshop attendees noted.

They agreed that more women should be included in trials, but debated whether there could or should be equal representation.

"We are half the population; we should be half the representation in clinical trials. I know it costs a lot of money, and I know there's going to be a lot of push back, but it is the right thing to do," Columbia's Mosca said.

She later ceded that women and men respond similarly to many interventions, so it may not be necessary to seek equal participation in every trial. But "not including women to the degree to give us a correct and valid answer is going to cost us a lot more in the long run to treat women unnecessarily and potentially untoward adverse effects that also have cost," she concluded.

Panelist Eileen Hsich of the Cleveland Clinic suggested the onus could fall on FDA to demand that new devices and therapies analyze an "adequate number" of women prior to approval. ODE biomedical engineer Owen Faris questioned whether FDA would ever set a specific fixed bar.

"Rather than trying to say for all cardiovascular devices, there has to be 'X' amount of women in the studies, or that you'll do additional studies post-market, for certain of those devices we may be able to determine whether there's a signal for a difference," workshop attendee Ashley Boam, acting deputy director of Engineering and Science Review in the Office of Device Evaluation, explained in an interview. "Some areas we already know, in some areas there isn't enough data, and there are others that fall in between."

"Considering the range of different devices and clinical trial data submitted to FDA, an allowance for ODE judgment on a case-by-case basis is appropriate," Medtronic representative Teresa Skarr told "The Gray Sheet."

All available gender data should be published in some form so physicians can make more informed decisions, Skarr and others suggested. Though trials for the Endeavor drug-eluting stent were not powered to look for gender differences, Medtronic was allowed to pool the number of women across trials and make a statement, though not a formal labeling claim, that the device performed no differently in women, she said.

Practicing physicians should be involved in early discussions with FDA and sponsors to help define whether trials should include specific analyses for women or other subgroups, Skarr suggests.

Differences do not necessarily amount to a "disparity," University of California, San Francisco's Rita Redberg emphasized. Implantable cardioverter defibrillators are another example of a cardiovascular therapy applied more often to men, but there is little data on whether this leads to poorer outcomes for women.

"I would never withhold something from a woman that could prevent sudden death, as long as there's no harm," Cleveland Clinic's Hsich added. "The question is: is there really no harm?"

- Jessica Bylander

Click here to start your 30-day free trial of "The Gray Sheet"