In a sign of the intense scrutiny CDRH is facing under the new administration, FDA is taking the rare step of performing an internal review of its decision process for a recently 510(k)-cleared device. The inquiry could potentially lead to a "reconsideration" of the clearance, the agency says.

The device is ReGen Biologics' Menaflex meniscus collagen scaffold for knee repair, cleared last December after two prior "not substantially equivalent" determinations (¹ 'The Gray Sheet' Jan. 5, 2009, p. 24).

The product, intended to facilitate new tissue growth following a knee injury, has come under significant controversy since the Wall Street Journal ran a page-one article in March reporting on a lobbying effort from the company and its congressional representatives to get the product cleared, and to influence the make-up of the advisory panel consulted by FDA.

ReGen said it was responding to reviewers who they believed were applying illegal standards to assess the firm's submissions.

Concurrently with the WSJ article, Iowa Republican Sen. Chuck Grassley sent a letter to FDA requesting information about the Menaflex review and panel meeting process.

In a ² letter dated May 8, FDA Acting Commissioner Joshua Sharfstein responded to Grassley with the update that a "preliminary internal review" of the Menaflex clearance process had been ordered.

"Your questions and the controversy surrounding this matter raise legitimate concerns about whether the agency's review process and decision to clear for marketing the ReGen collagen scaffold were compromised," Sharfstein writes.

According to the acting chief, the review will address five issues: whether established procedures were followed; whether the integrity of the advisory committee process was compromised; whether the integrity of the review process was compromised; whether changes should be made to any FDA policies, processes or procedures; and whether a "separate reconsideration of the decision to clear [Menaflex] for marketing should be undertaken."

510(k) Rescission Would Be A Steep Challenge

It would be "unprecedented" if the agency went ahead with such a reconsideration of the 510(k), says Mark DuVal, managing partner of FDA-focused law firm DuVal & Associates.

"Once you have gotten a cleared or an approved product, you arguably have a property right and the FDA can't just willy-nilly take it from you without due process," he said in an interview.

FDA does have explicit authority in the statute to withdraw a PMA or investigational device exemption approval based on evidence of fraud during the approval process or other issues (such as a finding that human subjects were not adequately protected in a clinical study supporting the application).

There is no such explicit withdrawal authority for 510(k)s, though FDA regulations do allow a commissioner to "reconsider a matter, on the commissioner's own initiative." The agency issued a ³ proposed rule in 2001 that employed the existing regulatory language to define an explicit authority to rescind 510(k) clearances, but that proposal was never finalized. In the draft regulation, FDA said that it had proposed six rescissions between 1997 and May 2000, though it does not say whether any of the actions were carried through.

In any case, the bar for proving sufficient misconduct by the company or FDA employees to support rescission is extremely high, DuVal said.

"I think Sharfstein is doing this to placate Congress," he said. "But his legal staff is going to be telling him, if you really want to take away this 510(k) clearance, it is an administrative and legal battle. It can't be done lightly or easily, and there is no suggestion that the agency will win."

Dan Schultz Singled Out By House Democrats

The Menaflex review was contentious, both between FDA and ReGen, and among CDRH reviewers and managers, according to agency memos and other correspondence that have since been made public (⁴ 'The Gray Sheet' March 16, 2009, p. 3).

Democratic leaders in the House Energy and Commerce Committee added to the public information in a May 11 ⁵ letter to Sharfstein, posted online, summarizing Menaflex review documents obtained as part of the committee's "ongoing investigation" of CDRH.

The documents are intended to "ensure that your review is complete," Committee Chairman Henry Waxman, D-Calif., Health Subcommittee Chair Frank Pallone, D-N.J., and Oversight and Investigation Subcommittee Chair Bart Stupak, D-Mich., wrote to Sharfstein.

The information released by the Energy and Commerce Committee paints CDRH Director Dan Schultz as almost a lone actor in getting the device cleared.

ReGen initially submitted a PMA for the device in 2004 based on a determination by FDA staff eight years earlier that the collagen scaffold was a Class III product. But the firm switched strategies and submitted a 510(k) in December 2005. Executives said they realized that, since the mid-1990's, FDA had 510(k)-cleared hundreds of resorbable surgical meshes that worked essentially the same way as Menaflex, but in different parts of the body.

CDRH reviewers rejected that rationale, finding that the scaffold had a different intended use and a lower benefit/risk ratio than predicates. Office of Device Evaluation Director Donna-Bea Tillman, though, was receptive at that point to ReGen submitting a new 510(k) with a revised indication, despite serious reservations from her reviewers.

Ultimately, however, the Energy and Commerce Committee documents disclose that it was Tillman who wrote the "not substantially equivalent" letter in response to the second 510(k) attempt in 2007 and then another NSE memo, never sent, in response to ReGen's third 510(k) submission from July 2008.

It was Schultz, the congressmen suggest, that reversed the tide. "Instead of accepting the recommendations of FDA scientists to reject ReGen's third application, Dr. Schultz sent a letter to ReGen on October 8, 2008, stating that he would seek input from an advisory panel of experts," they write.

Waxman, Pallone and Stupak say internal documents also put Schultz at the center of agency preparation efforts for the November 2008 panel, at which, they note, "FDA scientists who previously raised concerns about the safety and effectiveness of the device were not permitted to present their views."

The representatives also echoed concerns with the apparently active role ReGen played in ensuring the panel roster included arthroscopic sports-medicine surgeons.

It is not unprecedented for companies to take part in the panel selection process. It is also not necessarily inappropriate for the CDRH director to reverse recommendations from his subordinates. Under established CDRH policy, a supervisor can overturn a recommendation by documenting his or her rationale, as long as the original recommendation is filed appropriately without revision and a collaborative process for reaching consensus is attempted (⁶ 'The Gray Sheet' Feb. 2, 2009, p. 3).

It is rare, though, for a dispute to reach the director level. Regardless of the outcome for ReGen, Sharfstein's current inquiry steps up the pressure on Schultz, who is already under fire.

Anonymous CDRH whistleblowers have called for Schultz' resignation (as well as that of other center managers), alleging that reviewers are being "ordered, intimidated and coerced" into modifying scientific opinions (⁷ 'The Gray Sheet' Jan. 12, 2009, p. 7).

The internal review also could inform debate over whether regulatory or statutory changes are needed to improve FDA device oversight, which lawmakers including Waxman and Grassley are reportedly considering.

Grassley introduced legislation with Sen. Ted Kennedy, D-Mass., in April that would require the Institute of Medicine to assess FDA's device pre-market review program and come up with reform ideas (⁸ 'The Gray Sheet' April 27, 2009, p. 10).

FDA's internal ReGen review will be completed within 12 weeks, Sharfstein says. It is being led by Jesse Goodman, FDA's acting chief scientist, Michael Landa, the acting chief counsel and Jeffrey Shuren, the agency's associate commissioner for policy and planning.

- David Filmore (d.filmore@elsevier.com)