Medical Device Daily Washington Editor

FDA and Metronic (Minneapolis) are said to be discussing at least some portion of the pivotal trial for the firm's CoreValve artificial aortic valve based on the question of whether it is any longer ethically legitimate to randomize the most profoundly ill patients to medical therapy. The development follows and is prompted by returns from the pivotal trial for the Sapien valve, made by Edwards Lifesciences (Irvine, California), which were announced during this year's edition of Transcatheter Cardiovascular Therapeutics (TCT) in Washington (Medical Device Daily, Sept. 24, 2010).

However, those data also seem to have fed an adjustment to the pivotal trial for the Sapien XT, a follow-on to the Sapien with a narrower diameter and presumably more facile delivery. Henceforth, PARTNER II will match the Sapien XT against its predecessor in at least the most diseased patients rather than force those patients onto medical therapy. One wild card in the discussion is the possibility that this development is forcing FDA to re-examine the question of how long it will accept medical management as the control treatment for this class of devices.

The data reported at TCT from the Placement of AoRTic TraNscathetER Valve Trial (PARTNER) trial indicated that mortality was down by 20 percentage points with the Sapien compared to medical therapy, which prompted an effusive response at TCT. Despite the resounding success of the trial, Bram Zuckerman, MD, chief of the cardiology devices branch at FDA's Center for Devices and Radiological Health, asserted that FDA's interest in randomized, controlled trials (RCTs) had not abated. He remarked that the mortality drop-off, derived from one-year data, offered only “very short-term results“ and noted that PARTNER was the first RCT in the U.S. for such a valve.

Zuckerman sought to dampen enthusiasm further by stating that “the DES (drug-eluting stent) trauma“ was still on the minds of managers and reviewers at FDA.

The discussions between Medtronic and FDA could migrate to yet another firm in the cardiovascular space, namely St. Jude Medical (St. Paul, Minnesota), whose Trifecta valve is the subject of several international studies. St. Jude earned a CE mark for the Trifecta earlier this year (MDD, March 3, 2010), and the firm announced the Canadian launch of the Trifecta in a statement posted to the company website yesterday. St. Jude declined to comment for this story other than to indicate in a statement e-mailed to MDD that the company “has not yet publicly disclosed details pertaining to the design“ of the U.S. trial for the Trifecta.

Medtronic reported earlier this year that it had won a CE mark for the use of a subclavian approach for implanting the CoreValve, which the firm picked up in its acquisition of CoreValve in 2009 (MDD, Feb. 24, 2009) for $700 million, a sum that will eventually be dwarfed by the market for such therapies, which some have estimated currently stands at $400 million outside the U.S. The addition of the U.S. market and the impending addition of a retirement generation in virtually the entire developed world – and in several very populous developing nations, such as India and China – almost guarantees that Medtronic will see healthy returns on its investment in CoreValve. FDA had only recently given Medtronic the go-ahead for the CoreValve pivotal trial (MDD, Oct. 18, 2010), and a company spokesperson told MDD at the time that the company expects to move into the market in 2014.

However, there have been indications that surgeons in the European market are migrating to valve replacement in the kinds of numbers suggestive of what was seen as the overly enthusiastic adoption of the DES. According to registry data compiled in Germany, more than half of the valves implanted in the central European nation were for patients who did not exhibit the severity of disease indicated for the valve (MDD, Dec. 6, 2010).

In an unattributed statement e-mailed to MDD, Medtronic states that the PARTNER results “are clearly very compelling and the findings demonstrate just how desperately these patients need effective therapy, as patients receiving OMM (optimal medical management) fared dismally. The change in protocol announced on Monday is a positive change for patients.“

Medtronic added that it is “having active discussions with the FDA to ensure that CoreValve can be studied fairly and effectively, and we subsequently will provide updates if conditions“ for the study change. “We are activating clinical sites and expect a first implant in the CoreValve trial soon,“ the statement notes.

David Teicher of the regulatory consultancy Duval & Associates (Minneapolis), told MDD that it is possible that Edwards anticipated the outcome of the PARTNER trial, even if the company did not have some sort of draft rewrite of the trial design to accommodate the change. “It is possible that the European data were looking very attractive and that some of these very sick patients would benefit“ sufficiently to prompt the company to make such a provision.

Still, the current situation gives FDA at least something to crow about, Teicher said. “I'm wondering if these therapies are very cost effective“ compared to medical management, he said. If the valves are both life-saving and cost effective, “we have a new technology and its a win for FDA and for the patient,“ he observed.

“Nowadays, you are absolutely dealing with cost effectiveness as well,“ Teicher said of healthcare in the 21st Century.

The development does seem to constitute a slight loosing of the attitude conveyed by Zuckerman at TCT. “Basically what FDA may be doing is allowing Medtronic to deviate from the Holy Grail of a randomized, controlled trial,“ Teicher remarked. “At this juncture, FDA is extremely risk averse and is in a terrible position with Congress“ for the past few years, he commented, but he also noted, “in general, risk aversion fits in with the current administration's approach“ to private business.

As for whether FDA is taking a closer look at whether medical management should be dropped as a control sooner rather than later, Teicher said, “it is possible. If this technology is so advantageous, FDA could start thinking like that.“

Mark McCarty, 703-268-5690