Two Reviews Question Quality Of Cardiac PMA Trials

Article preview reprinted from "The Gray Sheet" - January 4,  2010

Two recent studies question the consistency and quality of clinical trials intended to support FDA premarket approvals of cardiac devices. As one of the studies was conducted by agency scientists, new requirements for PMA studies may soon be in the offing. Read more...

Two Reviews Question Quality Of Cardiac PMA Trials

Article preview reprinted from "The Gray Sheet" - January 4,  2010

Two recent studies question the consistency and quality of clinical trials intended to support FDA premarket approvals of cardiac devices. As one of the studies was conducted by agency scientists, new requirements for PMA studies may soon be in the offing.

University of California, San Francisco, researchers performed a systematic review of 81 cardiac device PMAs and concluded that the studies are often inadequately designed and may be prone to bias.

The review, published in the Dec. 23/30 issue of Journal of the American Medical Association, sought to characterize the type and strength of data from 123 studies used to support the PMAs received by FDA between Jan. 1, 2000 and Dec. 31, 2007.

Meanwhile, FDA and Harvard scientists published their own review of 88 cardiac PMAs submitted over the same time period. The item was posted on the Web site of the American Journal of Therapeutics Dec. 24.

That review, co-authored by CDRH staffers Elias Mallis, Bram Zuckerman and Barbara Zimmerman and Beth Israel Deaconess physicians Daniel Kramer and William Maisel, found lapses in the specificity of safety and effectiveness endpoints and other issues, but was less critical than the UCSF review.

The FDA-sponsored review found that primary effectiveness endpoints, primary safety endpoints and subject accounting were deemed "high quality" in 81.8%, 60.2% and 77.3% of pivotal studies, meaning in those cases they were clearly defined and associated with a specific time point for analysis.

Overall, the results suggest there is insufficient precision in how study endpoints are defined, the authors conclude. The FDA review also identified other weaknesses. For instance, it noted that "key cardiovascular comorbidities" were infrequently reported and that studies rarely included patients younger than 18 years of age.

Researchers Argue For More Randomized Trials

The UCSF researchers argue that solid evidence supporting Class III devices is particularly important as companies are increasingly marketing their products directly to consumers and in light of the U.S. Supreme Court finding that PMA-approved devices are largely pre-empted from personal injury lawsuits ( The Gray Sheet' Feb. 25, 2008).

"It is essential that the study evidence on which device approval is based is of high quality," they write. "Ideally, this evidence should consist of randomized, double-blind studies with adequate controls, sufficient duration, and thorough follow-up on prespecified primary end points without bias."

However, their review "showed that the majority of studies are not blinded or randomized." Of the 123 studies, 33 (27%) were randomized and 17 (14%) were blinded. However, certain device categories had higher rates; for example, of the 24 cardiac stent studies, 13 (54%) were randomized and 11 (46%) were blinded.

The researchers say control groups were used in approximately half of the studies. They criticize the "common use of retrospectively selected controls [which] can introduce bias by allowing for the selection of control groups that favor the device."

The authors also raise concerns with use of surrogates for study endpoints, and the use of composite outcomes, which have been shown to compromise individual endpoints in cardiac trials, they say.

- Brooke McManus

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