Menaflex’s FDA Horror Story

Imagine that you just went through one of the most extensive and grueling FDA reviews ever. The FDA, after massive internal infighting, finally clears your device through the agency’s 510(k) process and you are allowed to market your device.

But not so fast.

Out of nowhere, the FDA says wait a minute, we want a “do over” because we screwed up. And you find yourself accused on the pages of The Wall Street Journal and The New York Times of trying to unduly influence the FDA through political payoffs.

Welcome to the story of ReGen Biologics and its Menaflex surgical knee implant. Welcome to the FDA of the 21st Century.

A Car Crash

ReGen’s CEO, Gerald Bisbee, PhD, told Orthopedics This Week that he feels like he watched a slow motion car crash and his company got caught in the middle.

ReGen came puttering along as a broken FDA careened through an intersection at the same time Congress was pressuring the agency over a 510(k) program that some said put unsafe products into the marketplace. ReGen became collateral damage from a broken and dysfunctional FDA that crashed from internal infighting between factions of whistleblowing scientists and besieged managers at odds over the agency’s review and approval processes.

A Broken 510(k) Process

Who says the 510(k) process is broken? The FDA does.

In a report issued in October, the agency’s new leaders say the FDA failed to follow its own procedures, processes and practices as it considered ReGen’s request for clearance of its Menaflex device. In fact, the agency says its 510(k) process is so broken it’s paying the Institute of Medicine $1.3 million to review the whole program.

ReGen knew the clearance process was broken long before new FDA leaders came along after last fall’s election. When ReGen went to its congressional delegation and asked for assistance to ensure that the agency would treat the company fairly, the company was accused of trying to buy political influence. When you think a government agency is broken and believe you are being treated unfairly, your only recourse is to go to your elected officials.

This is a story that should make any medical device company which has had its device cleared in the last few years by the FDA go weak in the knees. Who will be next and how will the FDA decide who needs a “do-over”?

That question was partially answered a few weeks after the ReGen report when the FDA announced that 16 spine companies, with cleared spinal stabilization devices, will now have to submit new postmarket studies. 

Who is next?

This story is much bigger than ReGen Biologics and its Menaflex device. This story goes to the heart of the failure of the FDA’s 510(k) program to serve as a predictable, transparent and rational process that protects the public and works with industry to get innovative products to market.

In this two-part series, ReGen’s Chairman and CEO, Gerald Bisbee, PhD, and John Dichiara, the company’s regulatory, quality and clinical senior vice president, tell their side of the story and what their experience means for other device makers.

The Device

ReGen’s Menaflex has been in use in Europe for seven years and has been implanted in more than 2, 500 patients. The FDA cleared the device after a tumultuous FDA process and a meeting of the agency’s orthopedic panel.

The device is used in patients who have had an injury of the medial meniscus requiring the removal of part of the meniscus. It provides a resorbable scaffold that is replaced by the patient’s own tissue that then fills in the defect and reinforces the damaged meniscus.

A multicenter clinical trial started at the end of 1996 and was one of the largest controlled, randomized clinical studies done on an arthroscopic knee procedure. 

The company submitted the first module of a Modular PMA in 2004. However, after the FDA cleared other surgical meshes, the company filed a 510(k) submission for the device in December 2005, and the device was ultimately cleared on December 18, 2008.

FDA Report: “Predicate Creep”

Shortly after clearance of the device, the Obama administration installed new leaders at the agency who promised to address the long-standing feud over inconsistent and confusing standards for its 510(k) program. Years of “predicate creep” had created confusion about the definition of predicate devices.

In fulfilling its promise to review the 510(k) program and after conducting an internal investigation of the clearance of Menaflex, the FDA issued a report in September 2009 entitled:

Review of the ReGen Menaflex: Departures from processes, procedures, and practices leave the basis for a review decision in question.

The report found that over the 17-year review history of the Menaflex, multiple departures from processes, procedures, and practices occurred.

The report noted the agency’s “failure to respond appropriately to external pressure on decision-makers; the exclusion of individuals, if not viewpoints, from parts of the scientific debate; and the excessive reliance on advisory panel deliberations in reaching the final decision to clear the CS [Menaflex] device for marketing.”

The report concluded that a “focused scientific reevaluation of the decision to clear the device is warranted and that several aspects of the 510(k) review appear to have contributed to confusion and dissent during the review of the device.” Finally, it recommends an independent review of the 510(k) program at CDRH (Center for Devices and Radiological Health).

External Pressures

Those external pressures came from ReGen’s congressional delegation, and news stories quickly labeled ReGen as a company buying political influence.

Said ReGen’s John Dichiara,

“The press story sounds very good. You pay politicians…you got them to put pressure on FDA…you picked the panel…you did this and you did that, and it all sounds like a giant conspiracy. That is the complete opposite of the reality, but the reality doesn’t make as good a media story.”

Did ReGen exercise improper influence over the FDA? Did the company “buy” its Menaflex  FDA clearance through political contributions? Did a Republican-controlled FDA cave in to Democratic congressmen from ReGen’s home state, New Jersey?

According to Dichiara, “What really happened was that as with any 510(k) that would be given to the FDA, it is not unusual to hire advisers and regulatory lawyers. From the beginning we had advisers who worked with the company on regulatory matters.”

Dichiara told OTW that after 18 months of being under regulatory review, the company received a nonsubstantially equivalent decision (NSE) based on an illegal standard that was issued by the ODE (Office of Device Evaluation) Director. “We tried to resolve this matter internally within CDRH and considered other legal options but ultimately from a timing and cost basis it appeared to be in ReGen’s best interest to resolve this matter within FDA.” 

Gerald Bisbee said that since the company had exhausted all routes possible within CDRH to resolve the matter it needed to try to elevate this matter to the Commissioner’s Office to get a fair review based on the appropriate regulatory standard.

“As a small company, we of course did not have a Government Affairs person, so our advisors suggested that hiring a lobbyist would be useful in order to move forward with bringing this matter to the attention of some of our New Jersey legislators, ” said Bisbee.

The congressional delegation sent a letter to former Commissioner von Eschenbach that was vetted through the Senate Ethics Committee. Bisbee said this was all very transparent and the letter asked if the commissioner could take a look at the situation. “At no time did the letter or any other approach by any of these legislators, ever ask for the commissioner or the FDA to clear the product. What they were asking for was that this product receives the same sort of review applying the appropriate legal review standard as any other products, of a similar nature, had received.”

FDA Applies Wrong Review Standard

In the letter to the commissioner the lawmakers stated that the company had serious concerns about CDRH’s process and practices applied to the review of its 510(k) submission. 

Specifically, the letter noted:

“ReGen believes that the product should have been reviewed according to the standards applicable to other surgical meshes that the FDA found substantially equivalent to legally marketed devices and not what appears to be another standard. The company believes the differences in the review process resulted in unfair denial of its 510(k) submission. Based on their concerns, we would greatly appreciate your review of ReGen’s current submission. As you consider this case if there is an opportunity to meet and discuss this situation we would greatly appreciate it. A fair and equitable process is something we all agree is of utmost importance.” 

At the heart of ReGen’s complaint was that FDA reviewers were comparing the company’s device to a procedure and not a predicate device.

The FDA’s own report states that the “OCC (Office of Chief Counsel) advised that review of the 510(k) involves a comparison of a device to a predicate rather than to a standard of care and that there was no legal foundation for requiring a company to demonstrate clinical benefit in the 510(k).”

“This interpretation supported ReGen’s longstanding argument that the Center was holding the CS device to the wrong review standard, ” said Dichiara.

Bisbee added, “In essence they admitted that the information that we provided the legislators was correct information and I think that the important point is that the legislators pointed out a problem that ultimately the FDA remedied by providing clearance of the product after the [orthopedic] panel meeting.  Importantly, this report is the first time in almost 4 years of dealing with the FDA that they have actually admitted that they were applying the wrong standard.”

Bisbee said the report admits that the whole premise for turning this product down was wrong. “But then, [the FDA] tries to blame it on the company, because the company was too aggressive, or the legislators were too aggressive.”

So, basically it’s just a head scratcher that they can say we used the wrong standard but we’re going to, you know, re-review the product which basically is the outcome of this report,

Bisbee continued.

Yet in their own report they acknowledge the presence of widespread internal disagreement and confusion about the legal standards for 510(k) review, so they clearly are indicating that the process was not well understood in the first place, ” added Dichiara.

The FDA report admitted confusion by reviewers about the 510(k) standard and that the agency had applied a standard to the Menaflex that was not consistent with the FDA’s regulations.

Under The Spotlight

Bisbee and Dichiara are amazed at the implication that somehow the aggressiveness of the company caused all of these things to happen. 

“You have to remember that our review took place in an environment that was pervasive with the so-called whistleblowers and allegations against management of applying pressure on the staff to ignore scientific data.  Given what we found out about what was going on in the background, it’s clear that there was an incredible amount of scrutiny within the FDA during this decision-making process.

“There is no way that Dr. Schultz [former head of CDRH] could have made this decision in a vacuum and with no input from the Office of Chief Counsel. From the time of our meeting with the Commissioner, the person who was tasked to follow through and make sure that we did the right thing and that FDA reviewers applied the appropriate standard was the person in charge of the Office of Integrity and Accountability, ” said Dichiara

Who Is Next?

A final warning from Dichiara:

If FDA can re-review the CS product, how do they justify not questioning all of their other product reviews where they may or may not have applied the right regulatory standard?

“It seems that we were in the perfect storm. We were caught in the middle of a battle between review staff and management about applying scientific principles and it seems that the review staff applied scientific principles without regard to the appropriate regulatory standard. There was also pressure from the Hill on the 510(k) process and questions about whether FDA is doing a good job in regulating medical devices. 

“There was also pressure from consumer groups like Public Citizen. All of these things were in the background while ReGen’s 510(k) review was taking place. Originally, the whistleblowers didn’t include ReGen in their arguments and then once we became headline news with The Wall Street Journal, we became part of this debate.”

The ReGen experience in this time of FDA uncertainty gives cause for all device makers to wonder who could be next to have a device re-reviewed.

In part two of this series, OTW looks inside the FDA report on the Menaflex clearance to see how the agency plans to fix the deep-rooted problems identified in the 510(k) program. We’ll also see how this car crash has impacted ReGen Biologics as it tries to convince surgeons to implant the device into their patients and keep investors funding the company.