CDU Washington Editor

While the dispute panel of the FDA's Center for Devices and Radiological Health can be a potential device graveyard, that panel last month offered regulatory limbo for Acorn Cardiovascular (St. Paul, Minnesota) and the company's primary product, the CorCap. Rather than killing off the CorCap — a type of mesh that is surgically implanted around a failing heart to reshape it for improved function — the panel sent Acorn back to the data drawing board.

Acorn has agreed to the panel's demand to boost enrollment to 300 from the originally proposed 170, to extend follow-up from six to a minimum of 12 months and to further modify the primary endpoint to one that conformed to the agency's definition of clinically meaningful changes.

The company had conducted a Phase III trial for the device, but had employed a combination of measures as primary endpoint, making assessment more difficult and doing nothing to smooth the way in front of the agency's panels. The composite endpoint consisted of mortality, major cardiac procedures and change in New York Heart Association (NYHA) functional class.

The company had plenty of backing — as expected when a company is pursuing approvals in a court of last resort. The company presented a statement of support signed by five physicians on the steering committee for the trial, among this group Michael Acker, MD, chief of cardiovascular surgery at the University of Pennsylvania (Philadelphia).

The letter noted the difficulties facing Acorn. It said that "designing such controlled clinical trials … is a challenge, given the lack of a predicate device and the ethical concerns that would arise" with the use of a sham procedure. Such a sham, the letter noted, would require a needless thoracic surgery.

The letter also cited support from another source. It said: "In fact, at the annual meeting of the Association of Thoracic Surgeons [April 2005] Dr. Craig Miller of Stanford University (Palo Alto, California) described this trial as the gold standard for surgical trials." Miller is a professor of cardiothoracic surgery at Stanford and is on the editorial board of the Journal of Thoracic and Cardiovascular Surgery.

And the letter noted "the many teleconferences and meetings" with the FDA's division of cardiovascular devices "to collaboratively design a meaningful clinical trial."

The split in the data collected for the study cohort was resolved by the use of a statistical tool known as the multiple imputation method. Clinical investigators collected the required baseline data for the first 174 enrollees, but the change to the protocol demanded by the agency added more baseline data as well as the additional primary endpoint data, thus introducing a need for a mathematical tool to untangle the differences in the two data sets.

Multiple imputation is one such control, and in a report on the subject by Donald Rubin, PhD, a professor of biostatistics at the University of Georgia (Athens), Rubin argued that "contrary to the reviewer's conjecture, several different analyses of the trial outcomes result in essentially the same conclusion, and that the results are not compromised by the use of multiple imputation to handle missing data."

The first issue that came up was that the agency wanted Acorn to blind the individuals who would rate the NYHA cardiac function scores after the trial had already commenced. The reason for that change, according to Rich Lunsford, president/CEO of Acorn, was that the FDA said that conducting the NYHA assessment at this site might bias the scores. "They wanted an independent instrument outside our site to verify the assessment," he said.

Lunsford told Cardiovascular Device Update that the NYHA score is "very subjective" and that the FDA was further concerned about "the motivation for doctors to get patients into the trial." He said he was under the impression that the FDA was "fine with the configuration at the start of the trial," though he acknowledged knowing that the FDA had "issues with bias." He said that company executives were under the impression that "we had addressed them."

Lunsford noted that the room was full of executives from other device firms, and that they were busy with pen and paper during the proceedings.

"I think that industry was surprised" about the requirement of a 300-patient trial, a larger cohort than has ever been recruited for this kind of device, he said. The original trial, he said, "had multiple committees and was modeled a lot like pharma trials … the fact that we could not get approval was surprising."

Lunsford offered the now-standard cautionary advice about doing business with the FDA: "Get as much on the table as possible when developing endpoints with the FDA so that you're able to define what the agency expects as far as clinically meaningful data ahead of time. It is really critical."