Medical Device Daily Washington Editor

GAITHERSBURG, Maryland — Thursday's meeting of the circulatory systems advisory committee made clear again how much detail FDA seeks in its regulation of high-risk medical devices. FDA convened the panel for ideas about what should be required for a clinical trial for a cardiac anti-adhesion device in adult populations, but the feedback was not as extensive as the agency may have hoped.

Perhaps the only take-away message FDA heard, however, is that the panel was flatly unable to tell FDA whether there was any legitimate difference between pediatric and adult populations where adhesions and a device's efficacy are concerned.

At present, the only anti-adhesion device available in the U.S., the Repel CV, is indicated only for pediatric use. The product's sponsor, SyntheMed (Iselin, New Jersey), won a vote of approvability from the panel in 2007 (Medical Device Daily, Sept. 21, 2007), only to have to wait for another year and a half before the agency finally gave the product the nod (MDD, March 12, 2009).

SyntheMed obtained a CE mark for the Repel CV's use in all patients in 2006 and regulatory approval in Australia for all patients earlier this year. The company got the nod from Health Canada in July 2008 for pediatric patients only.

SyntheMed's original application was for patients of all ages undergoing open heart surgery, but the data presented at the 2007 advisory committee hearing was for pediatric patients and the panel was averse to extrapolating to adult patients, hence the agency's approval for only the study population. In FDA's documents for Thursday's hearing, the agency acknowledges, however, that "the formation and pathophysiology of adhesions is generally the same in pediatric and adult populations."

One of the peculiarities that arose in the pivotal trial for the original PMA submission was that while controls did indeed experience more adhesions (42.7% vs. 21.3% of subjects on the study article) upon re-operation at an average of 150 days, overall rates of adverse events were similar.

Among the adverse events that were more common in the study group was mediastinitis, an inflammation of any one or more of several organs and blood vessels of the thorax. The study group also experienced a higher rate of deaths, although the difference was not deemed statistically significant. Also problematic for the pivotal trial was that blinding of the physician was not possible inasmuch as the surgeon who performed the second procedure on the subjects was usually the same surgeon who implanted the device in the first operation on the patient.

The first question FDA posed to the panel was essentially a request that the panel discuss the similarities between adults and infants regarding the physiology of adhesion formation and whether the duration of the efficacy of the device was age-dependent. After some discussion, panel chairman Jeffrey Borer, MD, of Weill Cornell Medical College (New York), summarized, "the panel's overall opinion is that we don't have any evidence that there is any fundamental difference . . . because there aren't many data relevant to this point." Borer observed that the paucity of data means that physicians "don't know how to pick out which patients will develop" adhesions. As for whether data from the from the pivotal trial's neonatal population can be extrapolated to adults, Borer summarized, "the general consensus is that the pediatric population" is a reasonable surrogate.

One panelist said it would be reasonable to assume the device would work in patients other than those who received ventricular assist devices (VADs) if the device showed efficacy in VAD patients. On the other hand, Borer observed that a device's failure to cut down on adhesions in a VAD population would not rule out its efficacy in other populations.

Because neonatal patients typically are re-operated on relatively quickly because of the severity of their heart defects, FDA sought opinions as to whether the longer stretch between surgeries in the typical adult candidate was meaningful. Once again, however, the panel more or less shrugged. "The shorter interval [for pediatric patients] may indeed be meaningful," Borer summarized, "but we can't know in any rigorous way."

As to a method for evaluating device efficacy over time, Borer opened the discussion saying, "the best candidate procedure for this is MRI," but added, "it hasn't been validated for this use yet, thought it could be." Tagged echocardiography is another candidate, he said.

Panelist Michael Domanski, MD, of the National Heart, Lung and Blood Institute made the case that "some real effort should be bent around developing the non-invasive imaging" to evaluate adhesions, which he said is "not necessarily an extraordinarily difficult" task and which he characterized as "relatively inexpensive."

As for what the benefit of the Repel CV might be in patients with ventricular assist devices (VADs), the panel concluded that the current generation of VADs do present a risk of adhesion, but one panelist noted that the next generation of VADs will present a smaller surface area and hence will soon render such considerations obsolete. "Within two years, you're not going to see pulsatile devices" serving to augment the function of the ventricle, said Brett Sheridan, MD, of the University of North Carolina (Chapel Hill, North Carolina). After further discussion, Borer said the gist of conversation was that "there are situations in which a study of the device . . . could be very useful in a VAD population" but that "there are concerns about the extrapolability" of such a study.

Regarding FDA's questions about a trial's safety endpoints, the committee drew few definite conclusions, but among those discussed were mediastinitis, cardiac tamponade (fluid buildup within the pericardial membrane) and mortality.

Panelist Eugene Blackstone, MD, of the Cleveland Clinic (Cleveland), remarked, "I find it difficult to believe that mortality as an endpoint would be more than noise" to no dissent. Domanski opined, "I think myocardial infarction as an endpoint" may be useful because of contact between the barrier and the coronary arteries in some instances. He recommended a year or so to follow up.

Taking up efficacy endpoints, Domanski restated an earlier position: "I want to put in a pitch again for imaging" to validate the device. "I think a reasonable endpoint is in fact having someone who is blinded to the treatment [to] grade the severity" of adhesions.

In the context of non-inferiority safety margins, Borer summarized the panel's view with the observation that it is "very difficult to infer efficacy in a rigorous way" because of lack of quantitative links. "Given that we can't measure the benefit" directly, he said, "it's hard to conceive of allowing" the device into the market with a risk "that is substantially greater than none at all."