BB&T Executive Editor

After more than two years of questions raised by clinical data concerning the safety and efficacy of drug-eluting stents (DES), steep declines in the sales of DES devices because of these questions, and DES developers looking for R&D and regulatory guidance, FDA in late March issued a new set of guidelines, in draft form, concerning the development, testing and manufacture of DES devices — probably impacting the third generation and beyond of these devices.

In releasing the guidelines, the FDA acknowledged that it "and the clinical community" for some time have been tracking these devices, especially in monitoring "concerns over clot formation in some patients several years after implantation." No matter how often the companies making these devices have claimed that the occurrence of thrombosis post-DES implant is a rare event, these events do occur and with a high rate of death resulting.

The draft guidelines come more than 15 months after a two-day meeting in late 2006 — hosted by the agency to gather comments on DES issues — which was followed by the FDA's issuing a statement focused only on the need to emphasize better patient compliance with anti-platelet medications following DES implant.

The new draft guidelines now outline more specific pathways concerning its recommendations for pre-approval clinical evaluation of the devices and then post-approval studies, which, the agency said in a statement, "may provide data to better address [thrombosis] and other potential safety concerns."

Steeper path, higher hurdles

The guidelines provide a steeper path and higher hurdles for approval — no surprise to anyone familiar with the fairly rapid way in which the agency approved the first devices and the fallout from the issues that were then raised as the devices captured 80% of the stent market and received implantation in real-world settings.

Among a variety of specifications, the higher hurdles for approval include a "substantial portion" of enrolled patients followed for two year in pre-approval clinical studies, and a composite clinical endpoint including cardiac death and target vessel failure.

The composite endpoint requirement starkly contrasts with the initial evaluation of the first-generation devices — the Cypher DES from Cordis (Miami Lakes, Florida) and the Taxus from Boston Scientific (Natick, Massachusetts) — focusing almost exclusively on the rate of reclogging at the stent site (restenosis) and what was pitched as a steep reduction in the need to redo the stenting in comparison to the use of bare-metal stents.

In the area of post-approval monitoring, the agency is recommending 12-month clinical trial follow-up, compared to nine-month follow-up for the first-generation devices and five-year post-approval studies.

While these requirements mean greater expense and longer trials for new DES products, the guidelines should have the benefit of offering clarity, which has been largely absent, for manufacturers of the devices.

Besides providing more information related to the parameters for future clinical studies, the draft document focuses on the assessment of the drug used to coat, and then elute from, the stent, "both on its own and as part of the complete product."

Two tests for the drug used

Overall, there is a heavy emphasis in the guidance on the drug element of the device, its integrity in covering the stent and measurement of fatigue, all measured with a variety of tests.

Another large consideration in the guidance is a focus on particulates, one of the many concerns expressed about DES safety in the aftermath of product approvals.

It says, for instance, "FDA recommends measurement of particulate matter generated by breakdown of the coating or from the stent platform, stent delivery system, and product packaging, both at release and after aging."

The testing of particulate matter "provides an indirect evaluation of the coating integrity of the finished product" and "establishes the number of particles that can potentially be introduced systematically using the stent system" into the bloodstream.

The guidance follows up on the December 2006 FDA meetings which tended to focus on patient non-compliance with follow-on anti-platelet therapy (ATP). It repeats the guidlines for drug therapy that came out of that meeting and adds that companies should "address" various aspects of adjunctive antiplatelet therapy."

This should include: a profile of patient ATP complliance; a determination of how often dual ATP is disrupted; the reason for disruptions in compliance with APT: the capture of surgical procedures "that were deferred because of the need for continued APT"; and data concerning the "significant bleeding complications associated with APT."

Also included are draft recommendations for engineering tests, biocompatibility tests, and animal studies to assess the device's overall safety.

The guidance, the agency said, was developed through input from both the Center for Devices and Radiological Health and the Center for Drug Evaluation and Research (CDER), reflecting the device/drug combination of DES architecture and therapeutic action.

"This guidance demonstrates how FDA will need to work across traditional product boundaries to guide the development of innovative new products," said Janet Woodcock, MD, director of CDER.

Most recently, the FDA has given PMA approval to the first of the second-generation DES devices, the Endeavor from Medtronic (Minneapolis), and it has under review the Xience DES being developed by Abbott (Abbot Park, Illinois).

Needed: long-term safety data

Rick Wise, device analyst with Bear Sterns, issued a note referring to the FDA cardiovascular panel reviews of the Endeavor and the Xience, saying that those meetings "highlighted the lack of long-term safety data and the need for extended follow-up in more patients."

He judged that the proposed new guidelines are likely to impact future DES filings and that they are unlikely to impact the expected approval of the Xience, projecting that approval and product rollout by Abbott (and Boston Scientific, under a private-label agreement for a Xience DES branded as the Promus) in the third quarter of this year.

FDA said that it will, at some later time, set a workshop to received comments on the guidance, and it will accept comments for 120 days following guidance publication in the Federal Register, thus indicating that it will make official the final DES-development guidelines before the end of 2008.

In rolling out the draft guidelines the FDA put the number of patients treated with DES devices at 650,000 annually.