High-Tech Allograft Valve Approvals Deserve Full PMA Treatment: FDA Advisors

October 10, 2014

GAITHERSBURG, MD — A lopsided majority in an FDA advisory panel sided with the agency position that allograft heart valves that have been substantially altered by manufacturing processes be subject to full premarket approval (PMA) review. That would tighten past approval standards for such devices, of which there is only one representative on the US market, which got there via the 510(k) process that required only "substantial equivalence" to other available allograft valves.

"Because of the stakes here," he would contend that "a level of oversight consistent with class III PMA is necessary," said Dr Richard L Page (University of Wisconsin School of Medicine & Public Health, Madison), chair of the Circulatory System Devices Panel.

Federal law defines class II devices as "moderate-to-high risk" and appropriate for the 510(k) process and class III as applying to "high-risk" devices in need of PMA review. The critical FDA question to the panel was whether it agreed with the agency's take that what it calls "more-than-minimally manipulated" (MMM) allograft valves should be in class III.

The manufacture of MMM allograft valves includes a substantial degree of manufacturing, by the FDA's definition. For example, the CryoValve (CryoLife) pulmonary valve, the only approved MMM allograft valve, is made with a process that strips the graft of "cells and cellular debris for the purpose of reducing antigenicity," according to FDA documents.

Of note, the panel's 12-to-4 unofficial vote for a more stringent approval process included a large contingent of "temporary nonvoting members" in the panel. But the tally among "voting members" reflected the larger count at 4 to 2.

Among those temporary members, Dr Kristen K Patton (University of Washington, Seattle) said she agreed with the FDA position that the devices be in class III. "I think that if implanted heart valves aren't class III devices overall, what would be?"

That there haven't been many MMM-valve approval precedents befuddled much of the day's deliberations. Moreover, panelists were seemingly in agreement the CryoValve evidence base pointing to safety and efficacy is substantial and solid.

Indeed, the CryoLife valve already on the market seems to have "met all the requirements that we usually look for in recommending approval for a PMA device," observed Patton, echoing others on the panel.

"It seems to me that the 510(k) process has worked," Dr John C Somberg (Rush University Medical Center, Lake Bluff, IL) said during the deliberations. "So I'm unsure why, with all the problems in the world, and even reducing that to the regulatory world, we are focused in this area where I don't see a major problem, [instead of the] many areas I have seen major problems. So I'm very loath to change what is working." He voted against the FDA's class III stance.

But many on the panel pointed to a time when other MMM allograft valves would vie for approval; they wondered aloud whether their supporting data would be as strong and therefore whether the 510(k) process would be stringent enough.

According to panelist Dr E Magnus Ohman (Duke University Medical Center, Durham, NC), "this discussion would have been dead easy if CryoLife hadn't done such a good job of actually providing data" and reiterated the view that the 510(k) process seemed to work this time. "But going forward we really cannot predict what's going to happen, and therefore I think it has to stay class III."

Page pointed out a common view on the panel that CryoLife and the FDA should work together to find "the least burdensome path possible for the PMA process to be undertaken and for this device to be available to patients who need it."


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