Medical Device Daily Washington Editor

SAN FRANCISCO — The next generation of anti-restenosis combination products are en route, although a number of observers at this year's Transcatheter Cardiovascular Therapeutics see even the most well-developed version of a bioresorbable stent (BRS) as needing several more years before they will get to market.

On the other hand, the drug-eluting balloon (DEB) might have a faster path to approval, but companies that make drug-eluting stents (DES) have nothing to worry about in terms of any direct competition from this class of device. According to several panelists appearing at a session addressing the latest anti-stenosis technologies, DEBs will almost surely be used primarily to deal with restenosis of already-stented vessels.

Moderator Mitchell Krucoff, MD, of the Duke Clinical Research Institute (Durham, North Carolina) asked the panel what sorts of things had snared their attention where anti-restenosis technologies are concerned, and Peter Fitzgerald, MD, of the Stanford University School of Medicine (Stanford, California), said he is a fan of "whatever gets the patient off Plavix."

All the same, Fitzgerald hinted at a substantial developmental timeline for the current crop of developmental BRS products, remarking, "to have a stent go away ... is very exciting, but we're not going to see that for quite a while."

The company with the most developmentally refined device in this space may be Abbott (Abbott Park, Illinois), whose BVS stent is said to have addressed the radial tension issue (Medical Device Daily, Sept. 24), although the device's second feasibility trial suggested that the degree of late lumen loss is proving nettlesome. Abbott promised to publish the results of its third feasibility trial later this year, which may suggest that another three years will pass before the company can enroll a pivotal trial and bring back data for a completed PMA filing. Another factor that will influence any timeline is the need for a hearing of the cardiovascular devices advisory committee on the application, and any substantive re-engineering of the stent at any point in this process would stretch the timeline even farther.

Fitzgerald recommended that device makers think outside the coronary artery disease box when it comes to BRSs. "There are opportunities to take bioresorbable technology" to market in a less worksome context, he said, suggesting that manufacturers spend some time "learning in the leg." He said he is unsure whether there is an unmet need in coronary artery disease, but sees plenty of room for treatments dealing with peripheral artery disease.

Ashley Boam, FDA's branch chief for interventional cardiology devices, said the agency sees "several challenges," including the trick of characterizing the degradation process, which she pointed out is sure to be "very product specific." Those issues include, "how does it degrade, what does it degrade into [and] where does it go."

Test methods are not particularly well developed for this class of devices, Boam reminded the audience, but she nonetheless acknowledged some fascination with the idea. "The exciting part is to end up with nothing" in the treated artery, she observed.

Boam also urged developers to get ahead of the curve, as it were, on some of these questions. "I would hope that we could find ways to" explore some of these questions prior to market, unlike the situation that emerged with DES products.

Andrew Farb, MD, a medical officer at CDRH, posed the question of what the comparator might be in a pivotal trial for a bioresorbable stent. Without committing to a DES as the control device, he acknowledged, "we can leverage a lot of what we do for DES" where preclinical and clinical testing are concerned, but a disappearing stent raises a new question. "As mass is lost, what happens to the artery?" he asked.

Farb was non-committal about which animal models are best suited for this kind of degradation scenario. "I don't know that we have the answer," he said, but he also remarked at one point that looming closer on his horizon are the bifurcation stents, "which are incredibly challenging" in terms of both engineering and clinical study designs.

Other device makers who seem to be absent from the BRS race are not necessarily unprepared to jump into the fray, but the general manager of coronary and peripheral artery devices for Medtronic (Minneapolis), Sean Salmon, hinted that his employer is content for the time being to let Abbott and others slog through the developmental swamp first.

"Is this a good time to be second or third?" Salmon asked rhetorically. He argued that for some patients, dual anti-platelet therapy is not all bad inasmuch as it offers some benefits outside of coronary artery considerations, such as reduction in the incidence of stroke.

On the other hand, Salmon took the position that anyone getting into the BRS space must ask, "what problem do you solve and how big is that problem?" He concluded, "it's not compelling to be first in this technology," even though "it is not smart not to have a [developmental] program ... in case you're wrong." Salmon concluded by echoing Fitzgerald's view that peripheral artery disease might be a better application of this class of devices, at least in the near term.

DES not a blueprint for balloons

As for the regulatory path for DEBs, Fitzgerald said that bootstrapping the DES experience will not likely work. "I do not believe that what we've learned about DES can be scaffolded" to DEBs, he observed.

"There is a lot of previous knowledge out there" which can be used to guide the development of a regulatory path for DEBs, Boam acknowledged, but she reiterated the principle that "one size doesn't fit all" in this technological category. Still, she said the DES ideas that will apply to balloons are elution characteristics and animal study results.

"The drug does seem to have some sort of impact, so we can't say the bar for DES just goes away," Boam cautioned, but she said the FDA will bear in mind "that there is not an implant there," so five years of follow-up might not be needed.

Farb said that at present, "we want to see proof of principal" for balloons and that the FDA will want to see how much time elapses before the endothelium is restored as well as what sort of damage is incurred along the way. "The goal is to see when the artery has reached a steady state," he said, reminding industry that the FDA also seeks "a comfort level" that long-term toxicity is not a problem.

One of the issues with DEBs as a first-line treatment for stenosis is the same as for the original angioplasty balloons, that of arterial recoil, a fact which suggests something about the place of the DEB in the firmament of devices for CAD.

Salmon said DEBs should not be a source of confusion for the practicing cardiologist. "I think it's complementary" technology and "is site-specific," he said. On one hand, "femoral arteries, for instance, are underserved," but in-stent restenosis is nonetheless a legitimate area of interest, and probably the best use of such a device in the coronary arteries.

Because of this, "we don't see [DEBs] as a threat" to stents, Salmon remarked.

Krucoff asked whether mere physical contact between a DEB and an artery would by itself suggest that mechanical action is the primary mode of therapy, hence driving the application for a DEB – which like a DES would be a combination device – to CDRH.

Krucoff addressed the possibility that the physical contact between a balloon and the arterial wall that serves primarily to introduce the drug of elution to the intimal surface might be an argument that the drug is the primary mode of therapy, which would make the Center for Drug Evaluation and Research the appropriate center for review of the application.

Boam more or less punted, noting that this question "would be the subject of a request for designation" to the Office of Combination Products. She reminded the audience that the primary mode of action usually guides the determination, but in the case of uncertainty on this point, "the [therapeutic mechanism] that has the more significant impact" on disease will guide the designation.

Mark McCarty, 703-966-3694;