Medical Device Daily Washington Editor
WASHINGTON — The lead-up to the drug-eluting stent (DES) guidance published by FDA earlier this year (Medical Device Daily; March 28, 2008) probably triggered at least a fair amount of anxiety among firms working on new DES products, a fact that was not lost on the organizers of the 2008 edition of Transcatheter Cardiovascular Therapeutics (TCT 2008). One of the sessions held Wednesday, deemed a hot topic, was titled, "New DES Guidance: Does Preserving Safety Blunt Innovation?"
Leading off the discussion was Ashley Boam, chief of the interventional cardiology devices branch at FDA's Center for Devices and Radiological Health (CDRH). Boam quickly recapped the essentials of any clinical study of a new stent, reminding industry that stent thrombosis "will continue to be an important secondary safety endpoint." She also reiterated the agency's standing invitation to industry to "come early, come often" to discuss the particulars of an application. "We're open to a global approach," she said in reference to the possibility of using data from outside the U.S. (OUS) to support a PMA.
Elizabeth Hillebrenner, a scientific reviewer at CDRH, said the agency "received many excellent comments" after the publication of the guidance, "and now we're at the editing phase," adding that there are more changes to come.
"The area you'll see the most change is the engineering section," Hillebrenner said. On the topic of coating integrity, she said a baseline test would consist of expanding the stent to its nominal diameter in air. To simulate deployment, sponsors should use a mock blood vessel in an aqueous solution and dilate a single stent to its maximum-labeled diameter after maneuvering the stent through "a tortuous path."
Particulate matter testing is a concern and "we want to make sure there is no embolic risk from downstream particles," Hillebrenner said. For baseline testing, FDA will require expansion of a single stent to the maximum-labeled diameter in an aqueous solution and in an unconstrained environment to test for such precipitates.
The requirements for simulated deployment are a bit more rigorous. Hillebrenner stated that "for simulated deployment for particulate matter tests," sponsors will have to track multiple stents through a tortuous path and expand the stents to the maximum diameter "in an overlapped configuration in a mock vessel bent to a clinically relevant radius of curvature," again in an aqueous solution.
Hillebrenner said there was something for industry in this first round of edits. "I think everyone will be happy to see that the revision eliminates the need for long-stent studies in animals," but this is the point at which she dropped the news that half of patients enrolled in the pivotal study have to have made it to 18 months at the time of submission of a PMA. "Please keep in mind that our recommendations for this or any other study" may change given the dual antiplatelet study that industry and FDA will collaborate on in the coming months (see sidebar).
The agency does not have a fully fleshed out set of amendments to the guidance, but Hillebrenner said "we hope to have the modified document posted in four to six months." She also said "we will issue a Federal Register notice to announce its availability."
Also on the dais was Campbell Rogers, the chief technology officer at stent maker Cordis (Miami Lakes, Florida), whose reaction to the news of an 18-month requirement was not at all negative. He said "the pace of approvals for stents in the pre-DES and DES era" shows a significant slowdown, but this slow-down parallels the rise of technologically challenging stents.
Rogers said the discussions on the guidance between the agency and industry "have been extremely productive and timely," and said he is of the opinion that some of the requirements "get to be extremely enabling because it becomes a very clear and specific roadmap," the value of which "cannot be overstated."
In the modern medical device world, resource allocation "is overwhelmingly tipped toward development, not creation," Rogers stated, which means "eliminating options early" and investing in the more promising early contenders. The chief question posed by the guidance, Rogers said, is whether "the clinical benefits of possible incremental safety ... outweigh the opportunity costs" of improved therapeutics.
Donald Cutlip, MD, chief of interventional cardiology at Beth Israel Deaconess Medical Center (Boston), posed the question: "Will it become more difficult to bring a new DES to market?"
Cutlip said the answer is a flat "yes" because of the longer duration of trials and the larger number of patients. Safety is still the crux of the matter, he said, adding, "even a similar risk is important if it occurs without a significant benefit" that exceeds the current state of the art. He said even though stent thrombosis "is a low-frequency event," it is as the factor that prompted the discussions over DES safety.
Mitchell Krucoff, MD, professor of medicine at Duke University Medical Center (Durham, North Carolina), said the post-approval study is based on "the notion that we would not be pursuing pre-market issues in a post-market study," but he said this is difficult to take verbatim if only because adverse events that occur at low rates will not show up in a PMA study.
"What we all agree is [a] reasonable [assurance of safety and efficacy] becomes the tipping point" between PMA studies and post-approval studies, Krucoff said. He asked: "What is the difference between 12 months and 18 months?"
"This is millions of human beings and billions of dollars, and delaying it for six months is a huge reallocation of resources" for industry, Krucoff said, "but these stents will go into a lot of patients."
Boam responded that "the initial recommendation was to have a substantial number of patients out to 24 months" because a lot of patients drop their anti-platelet therapy at 12 months. "We wanted to see some sort of reassurance" that "people didn't fall of the cliff after 12 months." She said industry was okay with 18 months, but also said FDA is aware of the burden on industry. "I agree with Dr. Cutlip's comments that we don't see 18 months as an undue burden given the levels of enrollment."