FDA Previews New Drug-Eluting-Stent Guidance At CRT Meeting In D.C.

From the March 12, 2007, issue of "The Gray Sheet"

FDA's upcoming drug-eluting-stent guidance will emphasize long-term safety and shift the focus of trials from surrogate to clinical endpoints.

Interventional Cardiology Review branch chief Ashley Boam and CDRH reviewer Andrew Farb explained FDA's vision for the new guidance at the Cardiovascular Research Institute's Cardiovascular Revascularization Therapies meeting in Washington, D.C., March 7.

The guidance will recommend that future drug-eluting-stent trials include clinically relevant composite endpoints that incorporate both safety and effectiveness, Farb said.

Examples of clinically relevant safety endpoints include cardiac death, target lesion-related myocardial infarction and target lesion revascularization. The safety endpoints should be followed longer than 12 months, he said.

The agency wants manufacturers to shift the focus of drug-eluting-stent trials away from surrogate endpoints, such as late lumen loss, which are relatively easy to measure but do not provide much information on the long-term safety of the device. "Surrogate endpoints do still have a role to play, [but] it's more on the effectiveness side than the safety side," Boam explained.

Drug-eluting-stent researchers at the meeting agreed with the agency's direction, admitting that "perhaps the focus was misguided; we really focused on efficacy, how we were going to prevent restenosis, although we thought we were looking at safety endpoints," said Martin Leon, M.D., Columbia University Medical Center.

"That has clearly shifted from 2005 to the present," he explained. "Safety is clearly the prime consideration with respect to these new permanent implantable devices ... and efficacy seems to be almost least important."

David Kandzari, chief medical officer for Johnson & Johnson/Cordis Cardiology, and Donald Baim, chief medical and scientific officer for Boston Scientific, both said they "support" the FDA guidance.

The guidance, currently under review and due out this spring, is a collaborative effort among CDRH, CDER and the Office of Combination Products.

Once the guidance is published, the agency is planning a public workshop to solicit feedback from industry, professional societies and physicians, Boam said.

Guidance To Emphasize "Real World" Practice

Study populations should be representative of "real world" clinical practice, including patients with diabetes and with one- and two-vessel disease, and off-label use should be tracked in post-approval registries of consecutive patients, according to Farb.

Although angiography and intravascular ultrasound (IVUS) studies can provide useful information on the performance of drug-eluting stents, imaging has often confounded the interpretation of clinical endpoints, he said.

Previous studies have shown that interventionalists are more likely to stent a patient after seeing an image of the diseased coronary than they would without the image, so trials in which every patient undergoes imagery often show revascularization rates that are much higher than that of real world clinical practice where coronary imaging is not routine.

Therefore, trials should mandate protocol driven angiography and IVUS only after the clinical endpoint data has been collected, Farb said.

The Academic Research Consortium's controversial definitions for stent thrombosis are acceptable for drug-eluting-stent trials, the agency said. The ARC classification scheme is a hierarchical definition of stent thrombosis developed by researchers with input from FDA and stent manufacturers.

The agency previously addressed the stent thrombosis definition issue at a December meeting of its Circulatory System Devices Panel.

FDA acknowledges that sponsors of ongoing drug-eluting-stent trials developed their programs with the agency based on the best available information at the time, but FDA will review those programs in light of the new guidance. "There is no intent to put the breaks on, but we also don't have the blinders on either," Boam said.

One Year Rx Of Dual Antiplatelet Therapy From FDA

FDA also plans to change drug-eluting-stent labelling to include a 12-month regimen of dual antiplatelet therapy in those patients at a low risk of bleeding, in line with recommendations from both the December panel and professional societies.

Also, future trials using either approved drug-eluting stent - Taxus (Boston Scientific) or Cypher (Johnson & Johnson/Cordis) - as their control group should incorporate a year of dual antiplatelet therapy in their protocols, Farb said.

However, "it's reasonable to assume that this will not be the total answer," Farb said. Some data suggests that patients on dual antiplatelet therapy continue to have thrombotic events, but the relationship between long-term dual antiplatelet therapy and clinical events has not been thoroughly studied, he explained.

FDA would especially like to know the rate of significant bleeding complications associated with dual antiplatelet therapy, he said. Other unanswered questions with the drugs relate to patient compliance and prescription patterns beyond 12 months, frequency and duration of therapy interruption, bridging strategies during therapy interruption, and whether or not the drug therapy delays invasive surgical procedures.

Mitchell Krucoff, M.D., Duke Clinical Research Institute, agreed that many questions about dual antiplatelet therapy are unanswered, including the optimal duration of antiplatelet therapy following stenting.

"There's data that dual antiplatelet therapy or at least [antiplatelet] therapy might reduce stroke or myocardial infarction as part of the natural history of the disease," he added, explaining that it is important to tease out the drugs' treatment benefits, which likely extend beyond mitigating the risk of stent thrombosis.

Unfortunately, collecting data on antiplatelets in conjunction with drug-eluting stents is difficult because the drugs are not FDA approved for that indication, explained Carol Satler, M.D., Ph.D., who spoke on behalf of Sanofi-Aventis/Bristol-Myers Squibb. Satler's company manufacturers the common antiplatelet drug Plavix (clopidegrel).

"We do not have data in our database with drug-eluting stents and, based on our current indications, it's really not possible for us to communicate to patients or physicians how to utilize Plavix in the setting of drug-eluting stents."

Because corporate sales representatives cannot talk to doctors about antiplatelet therapy with drug-eluting stents, doctors may not be educating patients about the drugs, argued Robert Califf, M.D., Duke Clinical Research Institute.

Califf and William Maisel, M.D., Beth Israel Deaconess Medical Center, doubt antiplatelet manufacturers will seek a drug-eluting-stent indication for their drugs.

"I'm not sure there is any incentive to put it on the label where [the companies] then become liable for the use of the drug in this huge population when they're going to sell the medication anyway," Maisel explained.

Swedish Registry Is "Way Of The Future"

The panel also debated the value of a Swedish drug-eluting-stent registry, published in the March 8 New England Journal of Medicine. The study of almost 20,000 patients, many of whom would be considered off-label in the United States, shows an increased mortality risk associated with drug-eluting stents compared to bare-metal stents.

Leon downplayed the significance of the Swedish results. "There were so many differences between the two groups," including vessel size, lesion length and diabetes, so "to try to say that this trial should result in a dramatic change in therapy for an entire country is misguided."

Califf acknowledges the study's shortcomings but advocates the creation of a similar registry in North America.

"It is the way of the future because it's every case in Sweden," he said. "There is absolutely no reason that we can't have every cath lab in North America linked up the way Sweden is and to do randomized trials within the entire population. ... Then you've really got a national system that can create a fair playing field for people to do the right studies and let the best devices and drugs win."

CDRH Division of Cardiovascular Devices Director Bram Zuckerman agreed with Califf's suggestion that national structural changes are warranted, but took it one step further.

"This is a global problem," he said, "and one positive [thing] that the clinical community could help with is really trying to make this a global village for device development."

- Morgan Weiland

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