Medical Device Daily Washington Editor

WASHINGTON – FDA’s two-day hearing in December on drug-eluting stents (DES) probably raised as many questions as it answered (Medical Device Daily, Dec. 11, 2006/Dec. 12, 2006), but the agency is now using that hearing as a springboard toward development of a clinical trial draft guidance.

The agency held a workshop Wednesday in conjunction with the 2007 edition of Cardiovascular Revascularization Therapeutics, and FDA went over a few of its “post-December” recommendations as it works on a draft guidance on the technology likely to be issued this spring.

Mitchell Krucoff, MD, director of the ischemia monitoring lab at Duke University Medical Center (Durham, North Carolina), led the discussion by noting the obvious: that breakthrough technology can generate “unexpected performance and safety issues.”

Stent platforms and the eluted drug both contribute to both efficacy and safety problems, as do variations in surgical deployment, he said. As for clinical trial size, he said that registries provide longitudinal information, but that “with no concomitant comparator, there is a major unanswerable question mark.”

Meta-analyses of existing studies also have a tough time weeding out noise, according to Krucoff.

He opined that clinical trial design science now assumes that “the first generation [of a device] is the worst generation” but that the rapid pace of device iteration suggests that this rule doesn’t always hold.

And he announced that the agency intends to participate in DES discussions during a May 3-4 meeting in the nation’s capital that will include EU authorities.

William Maisel, MD, director of pacemaker and defibrillator services at Beth Israel Deaconess Hospital (Boston) and the chair of the circulatory systems advisory panel that reviews coronary stents, reviewed the results of the December meetings, stating that “the problem with the on-protocol definitions [of thrombosis] is that there is a bias against DES because patients who receive target lesion or target-vessel revascularization are excluded from analysis or censored from the final analysis, which biases the final result.”

The advisory panel deemed the definition provided by the Academic Research Consortium (ARC) adequate, but that effort was retrospective in nature, which several members of the panel found wanting. Also, industry sponsorship of that effort irked some.

Maisel noted that, overall, on-label use of DES is safe and effective, but most trials have been underpowered to detect small differences in thrombosis and mortality rates. And while the data on use of coated stents in diabetics is uneven, they nonetheless suggest greater risk.

Andrew Farb, a medical officer at the interventional cardiology branch of the Center for Devices and Radiological Health, reviewed current agency expectations for clinical trials, stating: “We continue to be very interested in a . . . composite endpoint that incorporates both safety and effectiveness” and looks more closely at “cardiac death, lesion-related MI [myocardial infarction] and target-lesion revascularization.”

Safety concerns are foremost on the agency’s agenda, and the next objective for FDA is to more accurately determine the rate of death from MI associated with DES, he said.

Antiplatelet therapy, which typically involves the use of both aspirin and clopidogrel (Plavix) is used “ideally up to 12 months for those at low risk of bleeding,” Farb said, adding that the areas of uncertainty regarding this therapy include the relationship of the “profile of patient compliance” to long-term events, as well as actual prescription patterns and the frequency of interruption of therapy. The rate of significant bleeding complications is another area of interest that calls for analysis, Farb said.

He indicated that the agency wants sponsors to enroll populations that are “closer to actual populations in practice,” including those with diabetes. The panel recommendations apply to all current and developmental DES, and FDA will release a guidance “later this season,” he promised, indicating a spring release of the draft.

Responding to the implication of flawed trials, David Kandzari, chief medical officer of Cordis (Miami Lakes, Florida), described the company’s Cypher DES product as “the most studied device in history,” with results from 45,000 patients published in more than 300 peer-review studies. Cordis, he said, supports “representation of real-world practice in clinical trials” and systematic and long-term safety/efficacy studies.

Saying that “off-label use [of DES] is not necessarily unstudied,” he said that Cordis opposes any effort by FDA to suppress DES use in off-label applications by physicians.

Donald Baim, MD, chief medical officer at Boston Scientific (Natick, Massachusetts), the only other company with an FDA-approved DES, said it is “incontrovertible that for on-label use, [the DES] is the most studied device in history.”

“What puzzles me,” Baim said, “is how we can have the best and most rigorous of trial designs” for a device that receives overblown media coverage and then expect a panel to come up with a good recommendation for future DES development.

Baim rebutted an earlier assertion that outside contract research organizations should handle all DES trials. “Hidden in that statement,” he said, “is the allegation that an industry-run and organized trial necessarily involves subterfuge.”

Jeffrey Popma, MD, director of interventional cardiology at Brigham and Women’s Hospital (Boston), said that the ARC definitions are not especially helpful for identifying very-late stent thrombosis and that existing data do not demonstrate “an absolute benefit of dual antiplatelet therapy after six months” for thrombosis prevention.

And he said that the agency should require trials to extend follow-up to 24 months.

He reiterated earlier comments to the effect that “all newer stent designs need to have more patients and longer follow-up,” but that stent makers need “a less rigorous pathways for iterative designs.” And he said that the agency will have to “accept [the fact] that complex disease will result in higher complication rates.”

Ashley Boam, a supervisory medical engineer at CDRH told Medical Device Daily that trials for stents coated with new drugs would be subject to a requirement of 2,000 enrollees and that the number of enrollees for trials that will study new materials used in stents is less certain.

“It depends” on a number of factors, she noted, adding that the standard trial size of 300 might not hold in such cases.