Many Cardiovascular Devices Approved by FDA Without Sex-Specific Data

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Most applications for high-risk cardiovascular devices such as heart valves and stents that are eventually approved by the US Food and Drug Administration (FDA) lack information on how the devices perform in women, according to a study published in the March 1, 201l, issue of Circulation: Cardiovascular Quality and Outcomes. This omission occurs despite the agency’s policy to include gender-specific safety and efficacy data.

Researchers led by Rita F. Redberg, MD, MSc, of the University of California, San Francisco (San Francisco, CA), reviewed statements of gender bias, reporting of demographics with regard to sex, and analyses of results for all approved premarket approval (PMA) applications for high-risk cardiovascular devices submitted to the FDA from 2000 through 2007.

Of 123 studies submitted in support of 78 PMA applications, 28% did not report the gender of study participants and only 41% contained the gender-bias statement currently required by the FDA for device approvals. Such statements explain whether the proportion of men and women in the study reflects that of the population being treated.

Of studies that included this information, 94% discussed examining results by sex, but only 10% did so with reference to a primary endpoint. In all, 26% reported differences in safety or efficacy between men and women.

No Gain for Women Over 8-Year Period

Populations of studies that reported enrollment by sex were 67% male on average, with the majority of studies (88%) enrolling more men than women. The sex breakdown was similar regardless of whether studies did or did not include comments on gender bias (P = 0.487). Overall, there was no change in the presence of gender bias comments or analyses during the 8-year study period (P = 0.490) nor was there any increase in the percentage of women enrolled over the same time frame (P = 0.957).

When the study authors looked at comments justifying the low percentage of women in clinical trials, they found that some reports linked the inadequate numbers to a low disease rate in women. In one example, a defibrillator study that included only 22% women stated that the gender distribution was typical for defibrillator studies in the United States. But Dr. Redberg and colleagues counter that a national sample of Medicare beneficiaries indicated that women account for 49% of patients with impaired left ventricular systolic function.

Calling for Change

According to Dr. Redberg and colleagues, “the continued underrepresentation of women in cardiovascular device trials and the resultant lack of sex-specific data may perpetuate the status quo.”

They suggest that more precise and rigorous standards for the reporting of sex-specific data for FDA-approved devices are needed. “For example, if PMA applications missing sex-specific data were not accepted until the required information was added, it would ensure that the necessary data were included for men and women,” the authors write.

But Alexandra J. Lansky, MD, of Yale University School of Medicine (New Haven, CT), said while the study raises some important red flags, the authors may be unrealistic in their expectations.

“I absolutely agree that gender subgroup analyses should be formally evaluated and universally reported in all PMA applications without exception,” Dr. Lansky said. “However, whether sample size should be expanded for female patients is debatable. Approval trials are powered for the overall patient population and by definition the female subgroup will be underpowered. Formal interaction testing will provide evidence of whether the safety and performance of the device are similar or dissimilar by gender.”

In short, she said, “powering a device trial for the female population seems unrealistic, overly burdensome and unprecedented.”

Dr. Lansky also said that despite the authors’ assertion that the percentage of women in clinical trials does not reflect the gender distribution in the US population, overall the representation of women in interventional trials “does tend to track” in terms of the number of PCIs performed in women in the United States.

For example, Dr. Redberg and colleagues refer to a coronary stent study in which 68.1% of the patient population was male that, justifying its enrollment, concludes that this percentage “reflect[s] the percentage of males in the US cardiac population as a whole.”

Can’t Bog Down the System

As for the criticisms that the FDA is not being thorough enough with regard to the studies included in PMAs, Dr. Lansky pointed out that in some cases this can lead to excessive delays that can erode patient care. As an example, she pointed to the many patients now traveling abroad for transcatheter aortic valve implantation because the device widely available in Europe is not yet approved in the United States.

“At the end of the day, it’s really about finding the right balance for device evaluation and establishing reasonable assurance of safety and effectiveness for our patients,” she said. “We must be cautious not to impose excessively burdensome requirements that can paralyze the regulatory system and ultimately stifle innovation, as we have witnessed in the United States in the case of percutaneous aortic valve therapy. You never want to compromise safety and effectiveness, [but] we can’t be so overly cautious that we are holding back devices that are known to be beneficial to our patients.”

Dr. Lansky noted that while the points made by Dr. Redberg and colleagues are well taken, the FDA has made efforts in the last few years to improve reporting of sex-specific data and even convened a conference in 2008 to discuss the matter. A white paper based on the recommendations from that meeting is pending, Dr. Lansky reported, adding that other measures mandated by FDA such as post marketing studies are specifically designed to better understand outcomes in subgroup populations.

Comparing Apples and Oranges

Dr. Redberg and colleagues also contend that few gender bias comments or analyses provide raw data or statistical analyses in the FDA’s Summaries of Safety and Effectiveness Data (SSED), a document mandated by the Federal Food, Drug, and Cosmetic Act to be publicly available upon issuance of an approval order of a premarket approval application.

For instance, they highlight a study published in 2005 that looked at gender differences in the TAXUS IV trial (Lansky AJ. J Am Coll Cardiol. 2005;45:1180-1185). Not only did women have more TLR than men, they also exhibited a higher rate of TVR (10.8% vs. 5.7%; P = 0.03), a difference driven by increased need for repeat PCI (9.2% vs. 4.1%; P = 0.02). The study therefore suggests that “the Taxus stent is more effective in men than in women, which is not consistent with the SSED’s statement about effectiveness,” they write.

But Dr. Lansky countered that Dr. Redberg and colleagues missed the point about her research.

“When you are looking at device safety and effectiveness for women you need to assess device performance within the female subgroup. Use women as their own standard and see if the device improves outcomes in women,” she said. “Comparing men and women is like comparing apples and oranges.”

 

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Source:
Dhruva SS, Bero LA, Redberg RF. Gender bias in studies for Food and Drug Administration premarket approval of cardiovascular devices. Circ Cardiovasc Qual Outcomes. 2011;4:165-171.

 

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