Details trickling into the public sphere about CDRH's device review process reveal heightened tension between reviewers and management over the proper response to a 510(k) submission.

Earnest scientists within the device center are reportedly digging deeper into premarket notification submissions and asking more and more in-depth questions about the clinical effectiveness of new products. But supervisors take pains to stay within the bounds of the "substantial equivalence" 510(k) requirements and, more generally, to honor CDRH's congressional mandate to take the "least burdensome" approach to regulation.

The friction is feeding an intensifying debate in Washington, D.C., about device regulation and, in particular, 510(k)s, the process by which a substantial majority of devices reach the U.S. market each year.

Anonymous letters from eight CDRH reviewers to federal policymakers charging center management with staff intimidation and illegal application of device regulations are perhaps the most public display of the internal strife (¹ Also see "Former ODE Staffers Dispute Claims Of Office Corruption And Coercion" - Medtech Insight, 2 February, 2009., p. 3). But there have also been other signs, including public acknowledgements by Office of Device Evaluation leadership that at least a segment of the current cadre of reviewers may not be trained as well as they should be on the federal device statutes (² Also see "ODE Chief Tillman Defends 510(k) Program At Minnesota Industry Meeting" - Medtech Insight, 15 December, 2008., p. 9).

As a result, some in industry suggest that misunderstandings over the 510(k) regulation within FDA are increasingly forcing sponsors to comply with reams of inappropriate, and sometimes ambiguous, requests, as part of what device industry attorney Mark DuVal calls the "510(k) dance."

"At times it can be an interminable dance," DuVal said.

ReGen's Menaflex: Three-Year Road To Clearance

A telling illustration of this "dance" is the case of ReGen Biologics' Menaflex meniscus collagen scaffold device.

The product, a bio-resorbable structure intended to help facilitate tissue growth in knee injury patients whose damaged meniscus tissue is surgically removed, gained a 510(k) clearance in December after two prior "not substantially equivalent" determinations in 2006 and 2007 (³ Also see "Third Time Is The Charm For ReGen’s Knee Repair Collagen Scaffold" - Medtech Insight, 5 January, 2009., p. 24).

A recent Wall Street Journal article suggested that intense lobbying by the company and members of Congress pressured FDA to ultimately clear the product. ReGen asserts that FDA reviewers were using illegal standards to evaluate their product, and the firm had no choice but to fight for its rights.

In any case, it appears that the debate running through the entire three-year FDA process was as much about the fundamental regulatory requirements for Menaflex as about the strength of evidence supporting the device.

"Clearly, there is a tension, almost like constant battling, between the reviewers and the supervisors. We recognized that and saw evidence of that throughout the process," ReGen CEO Gary Bisbee said in an interview.

Internal Dispute Displayed At Reviewer Meeting

Bisbee relates his experience at one 2006 meeting with the agency as an example.

Menaflex received its first NSE letter in July 2006. ReGen appealed the decision, but it was upheld by ODE Director Donna-Bea Tillman in November of that year.

In rejecting ReGen's appeal, Tillman also agreed with the company that a revised 510(k) submission could be submitted with a more clearly defined intended use to "reinforce and repair" the meniscus, rather than "replace" it, according to ReGen and an internal FDA review ⁴ memo (originally leaked to the Wall Street Journal). Surgical mesh products, which have been cleared for different anatomical indications including general surgery, shoulder procedures and hernia repair (though not use in the knee), could act as predicates, she said.

"Given the large number of 'reinforce and repair' indications that we have cleared for surgical mesh, it would be appropriate to review 'reinforce and repair' indications for the meniscus as a 510(k)," Tillman wrote in November 2006.

According to Bisbee, Tillman instructed the company to meet with ODE reviewers to get guidance on what clinical data was needed to support the proposed 510(k).

The meeting took place the following month, but Bisbee said the company hit a brick wall.

"The first 45 minutes of the meeting was [the review staff] beating up on Dr. Tillman for coming down on the side of 'this could be viewed as a surgical mesh,' and they were telling us they didn't agree with her."

At some point in the conversation, according to Bisbee, a supervisor instructed his staff to refocus on the question of what data would be needed to support the 510(k), noting that the matter of using surgical meshes as predicates had already been settled by Tillman. "And for the next 15-30 minutes, they basically said nothing," Bisbee said.

PMA Evolves Into A 510(k), Or Does It?

ReGen first approached FDA about its meniscus scaffold in the mid-1990s. Agency reviewers recommended the company pursue a PMA for the product as a meniscus replacement. In response, the firm embarked on what would be a 300-plus-patient trial, comparing use of Menaflex to non-use of Menaflex in patients undergoing partial meniscectomy.

A partial meniscectomy is the removal of meniscus tissue that has been damaged, often as a result of an athletic knee injury. It is performed on many of the 80%-85% of individuals with meniscus tears that are not repairable with sutures and is often effective in allowing patients to return to normal activity in the short term. But over the long haul, the tissue loss can contribute to degeneration and osteoarthritis development.

Menaflex, inserted in the knee following a partial meniscectomy, is intended to facilitate the growth of new tissue to help slow long-term degeneration.

ReGen started submitting a modular PMA in 2004, but by the following year it switched gears and decided to pursue a 510(k) instead.

ReGen says it made the switch because it had come to realize that since the company's initial interaction with FDA, the agency had 510(k)-cleared hundreds of resorbable surgical meshes that worked essentially the same way as Menaflex, but in different parts of the body.

In the initial, July 2006 NSE letter, Bisbee said the agency referred back to its prior guidance instructing ReGen to seek a PMA. From there, he charges, reviewers in the orthopedic joint devices review branch continued to view Menaflex as a meniscus replacement product requiring PMA-like proof of safety and effectiveness, rather than as a surgical mesh requiring only proof of substantial equivalence to predicates, despite instructions by superiors to do otherwise.

ReGen submitted its second 510(k), for the "reinforce and repair" claim, in December 2006. FDA delivered another NSE letter the following August (⁵ Also see "ReGen Says Lack Of FDA Sports Med Specialists Blocks Its Knee Product" - Medtech Insight, 1 October, 2007., p. 17).

Bisbee said the letter was "clearly illegal," because it relied primarily on a comparison with partial meniscectomy - a surgical procedure - and not with the intended use, technological characteristics and safety and effectiveness of predicate meshes.

At that point, Hackensack-based ReGen decided to contact its congressional representatives in New Jersey with the intention, the company now says, to help arrange a meeting with the FDA commissioner's office. Senators and representatives from the state contacted the agency on ReGen's behalf; a meeting was arranged in January 2008 between the company and Commissioner Andrew von Eschenbach, along with CDRH Director Dan Schultz and other agency officials.

Subsequently, the commissioner assigned William McConagha, director of FDA's Office of Integrity and Accountability, to be ReGen's primary FDA contact, and Schultz was instructed to take a more active role ensuring the ReGen review was handled fairly.

Before the year was out, Menaflex would go before an FDA advisory panel and gain clearance. But there is no sign that consensus was ever reached within the review office about the standard by which the product should be judged.

ODE Review: Menaflex Risk/Benefit Profile Lacking

A third NSE ⁶ memo, never sent, was drafted Aug. 14, 2008, by reviewer John Goode.

The memo said the product was not substantially equivalent because it had a "new intended use" compared to the predicates. Specifically, he writes that although ReGen claimed "reinforcement and repair," the patients enrolled in the clinical study - published in the July 2008 issue of the Journal of Bone and Joint Surgery - had, by requirement of the study protocol, "irreparable injury." Thus, the data presented is for replacing, not repairing, the meniscus tissue, Goode asserted.

ReGen's clinical data failed to show that Menaflex has superior outcomes to partial meniscectomy alone, he wrote. Goode said an activity score index, employed by the company to claim enhanced function levels in Menaflex-treated chronic injury patients, was uncontrolled and "post-hoc."

The reviewer, who also complained that management had given him too short a time period to perform a comprehensive review, added that there were more serious adverse events in the Menaflex group, concluding that the risk/benefit profile for Menaflex "is not comparable to the standard of care 'partial meniscectomy' for the type of meniscal injury described in the IDE study."

ReGen disputes the conclusions, touting the clinical benefits as bona fide and asserting that there was in fact no statistically significant difference in serious adverse events between Menaflex and control patients by their calculations. More fundamentally, the firm charges that the points raised by the reviewer are largely moot when considering substantial equivalence to surgical meshes.

"A comparison for a 510(k) requiring superiority to a standard of care has no meaning," said John Dichiara, ReGen's senior VP for clinical and regulatory affairs. "You can't say it is substantially equivalent if you say it has to be superior."

FDA did not follow the reviewer recommendation. The agency's Orthopedic Devices Panel was asked explicitly during its Nov. 14, 2008, meeting to compare Menaflex safety and performance with surgical mesh predicates; that is the standard by which the product was ⁷ cleared Dec. 18 for "reinforcement and repair of soft tissue injuries of the medial meniscus."

Predicates Questioned To The End

Whether Menaflex should have gone through the 510(k) path in the first place remains debatable for some.

FDA panel members did not take an official vote on whether the product should be cleared, but voiced a general consensus that Menaflex is as safe and effective as and fosters tissue growth in a manner similar to the predicate meshes. They also concluded that the device did not add any measurable risk to a partial meniscectomy.

But skepticism was evident among the advisors about the utility of the predicates themselves, with several panelists noting the difference between the mechanical forces at play in the knee and elsewhere in the body (⁸ Also see "ReGen’s Collagen Scaffold Efficacy Data Questioned By Panel" - Medtech Insight, 1 December, 2008., p. 9). John Kelly, IV, a sports medicine orthopedic surgeon at the University of Pennsylvania, for instance, answered "yes" to the question of whether Menaflex is as safe and effective as the predicate, but noted, "I'd like to qualify it by saying I'm not crazy about the predicates."

Within CDRH, a similar sentiment was held not only by some ODE reviewers, but also by scientists in the Office of Science and Engineering Laboratories. At the behest of ReGen, Schultz requested OSEL perform an independent evaluation of the Menaflex data in 2008.

In his report, then-OSEL Director Larry Kessler wrote to Schultz of the office's concern that the "weight-bearing forces" that the device will need to undergo in the knee "are not comparable to those experienced" by the predicates. "There is no statistical basis demonstrating effectiveness for this product," he writes.

"The 510(k) process is generally a very good one, but in making thousands and thousands of decisions, some of them may not be optimal," Kessler, now chair of the health services department at the University of Washington, said in a brief interview with "The Gray Sheet."

"Endemic" 510(k) Overreaching?

Still, decisions like this one, particularly when detailed on the front page of the Wall Street Journal, will inform efforts by policymakers interested in reforming 510(k) laws or making personnel changes within CDRH.

Sen. Chuck Grassley, R-Iowa, for one, sent letters to FDA and ReGen March 6 seeking more information about the Menaflex review process, pointing to it as another example of what he sees as an overly "cozy" relationship between FDA and industry.

ReGen's Bisbee said he never felt much coziness, and often felt like he was getting the run-around in dealings with the agency, all the way through to the 510(k) clearance letter, signed by Dan Schultz, which cleared Menaflex for repairing medial meniscus injury, but not, to the company's surprise, lateral meniscus injury.

"The tissue is the same. The biologics are exactly the same.... The issue had never come up in discussions between the company and FDA," Bisbee said. He claims the first they heard about the limitation to medial was in the clearance letter.

Bisbee also thinks it is ironic that Menaflex would be considered a rallying cry for tightening 510(k) requirements. "This product had more clinical data - 162 cases - than any other surgical mesh, and maybe all of them combined," he said.

Mark DuVal, who handles 510(k) submissions for device firms on a daily basis as managing partner of DuVal & Associates, but was not involved in the ReGen matter, contends that the Menaflex experience does not show the need for stricter 510(k) requirements, but the opposite. The incident is symptomatic of a larger trend of FDA overreaching in 510(k) reviews, he said in an interview.

Reviewers are increasingly asking questions that are interesting, but go way beyond what is necessary to compare a product to predicate, DuVal observed. As CDRH has hired more young reviewers with impressive scientific and medical backgrounds, but insufficient experience with FDA device statutes, the issue has become "endemic," he said.

"I am on my umpteenth [510(k)] appeal this year," DuVal lamented. "I can't tell you how many times as of late I have gone into an FDA meeting on appeal and my opening statement is something like, 'when I was handed this file by my client, I found that the additional information letter was largely irrelevant to a substantially equivalent determination.'

"If this keeps up, most things are going to go on appeal to Donna-Bea Tillman and Dan Schultz. That will be a bottle neck. They are two human beings, and they can't possibly process all of these."

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

Device Center Discord: 510(k) Review Process Is Flash Point At CDRH

More from Archive

More from Medtech Insight