FDA vs. ReGen, Act II

Jeffrey Shuren, M.D., J.D.
Director of CDRHMake no mistake about it. The March 23rd FDA Orthopedic and Rehabilitation Devices Advisory Panel meeting to conduct an unprecedented “do-over” of ReGen Biologic’s Collagen Scaffold’s FDA clearance was about political theater, not science.

Not one shred of new scientific evidence was uncovered since the device was cleared by the FDA last year. Jeffrey Shuren, M.D., head of FDA’s medical device division, told OTW after the meeting that this hearing was held simply to review the FDA’s previous decision because the integrity of the FDA’s review process had been called into question.

But first, let’s get the science out of the way.

Favorable Safety Profile

For the second time, in spite of the agency’s assertion that the company didn’t provided adequate data to show that the knee device was safe; the Panel told the FDA otherwise.

John Kelly, IV, M.D./pennmedicine.orgThe panel’s opinion, summarized by its chairman and shoulder surgeon John Kelly IV, M.D., was that, “the ReGen device overall has a favorable safety profile. However the panel has some concerns that the company’s study does not fully fulfill the scientific method.”

But even panel member Brent Blumenstein, Ph.D., who has become the panel’s designated slayer of inadequately designed clinical trials, seemed as satisfied as he could be for a 510(k) device. After blowing apart the company’s study for not meeting level-one scientific evidence, he commended the company for its study and said, as case history, the study was valuable and the data was “probably better than the predicates.”

That was high praise from the panel member who sank Stryker’s OP-1 PMA application with his now famous, “Abuse of the Alpha” critique,

Filler and Scaffold

FDA staff desperately tried to get panel members to say the device “reinforced and repaired” a soft tissue injury. The panel members however, refused to pigeonhole what the device does into those terms. Panel member Stuart Goodman, M.D., Ph.D. and orthopedic surgeon, said the evidence clearly showed that the device “fills the space and creates a scaffold”, where, panel member Hollis Potter, M.D., and radiologist added, “no doubt growth of tissue will occur.”

The only rough spot for the company came during a “so what?” exchange.

Simply put, for what purpose are you subjecting a patient to the risk of surgery? What is the corresponding benefit? After a partial meniscectomy, a void remains. What’s the benefit of filling the void with the body’s own cells?

Ultimately, said company presenters, they believed filling the void will prevent the onset of arthritis. But proving that would take decades. 

The company was saved by a panel member who pointed out that the company didn’t need to prove that. It only needed to prove that the device worked at least as well as predicate devices.

In the end, Chairman Kelly told OTW that the panel agreed that the device was reasonably safe but the hard scientific evidence to declare it effective was missing. He declined to offer an opinion on whether or not the FDA should confirm their previous clearance.

FDA’s Summary

How did the FDA summarize the meeting?

Twenty-four hours after the meeting, the agency issued a statement that contained, in part, the following conclusions of the Panel’s findings:

• There was insufficient evidence that the device, at time zero, reinforces and repairs soft tissue injuries.
• The tissues that ultimately grow in place of the device, as it degrades, may serve to partially reinforce and repair in the long term, but not fully and that the definition of repair and replace should be further defined. 
• The device is a scaffold that fills a void that reconstructs the removed tissue.
• The anatomic design and comparisons to other products is generally considered safe, but the Panel had concerns about the overall effectiveness. 
• Due to the low number of device failures, the device can be viewed as reasonably safe, but the device’s effectiveness would need to be analyzed further. 

After the meeting Dr. Shuren said the agency will issue a decision within weeks.

He told OTW that the options available to the agency were to confirm its previous decision, confirm and order special controls, or move to reclassify the device to a level one device.

If the FDA, after being given the same answer from two advisory panels made up of many different members, does not confirm its previous clearance of the device, a safe product will be kept from doctors and patients and the medical device industry’s fears about an unpredictable and fair clearance process will be realized.

Political Theater

This brings us back to political theater, the real purpose of the meeting.

The panel meeting room at the Washington, DC Hilton looked like a wedding with guest of the bride and groom sitting on opposite sides.

The FDA side was filled to the brim with “a lot”, as one former FDA manager noted to OTW, of agency staffers. They were young, brightly clothed with full heads of hair. They sat dutifully behind their senior managers prepared to make the case against the device.

On the other side of the aisle sat six or seven gray and bald heads from the company. Behind them, empty seats. 

Industry Concerns

Before Chairman Kelly could call on the first presenter for the day, the industry representative on the panel, Robert E. Durgin, a senior vice president and attorney from Biomet offered a prepared statement.

Durgin stated, “The issue of greatest concern to industry as a whole, is the regulatory process—both the process leading to a 510(k) clearance and, in this instance, the regulatory process following that clearance. Now that ReGen Biologics has been granted a clearance, it is absolutely essential that it be afforded due process as the Agency re-evaluates the data submitted in support of that clearance.”

He asked the FDA to state what the Agency intended to do with any recommendations that the Panel may make today and what process will be used as the Agency considers those recommendations.

Chairman Kelly was clearly prepared for Mr. Durgin’s question and informed panel members that the purpose of this meeting was to consider scientific evidence and not regulatory procedures. 

Stifle Innovation

Four hours later during a public comment period, Susan Krasny, Ph.D., of Stryker Spine and President of OSMA (Orthopedic Surgical Manufacturers Association), echoed Mr. Durgin’s concern.

Dr. Krasny told the Panel:

“When a device undergoes the rigorous 510(k) process…and is cleared…manufacturers of those devices should be assured that those decisions are sound and that the device will not be re-evaluated unless there is evidence of problems associated with the use of the product. A re-evaluation…is not appropriate for procedural objections related to the review process.

“A lesser standard could subject any 510(k) decision to re-evaluation at any time, a result that would create uncertainty…and potentially stifle innovation by manufacturers.

“Finally, we are unaware of any legal or regulatory authority for reversing a 510(k) decision without any new evidence regarding the product. To overturn a carefully considered 510(k) decision without such new evidence would be detrimental to the 510(k) process and would surely lead both the public and companies to lose confidence in the 510(k) process.” 

Dr. Kelly admonished the speaker for introducing a “political” agenda into the proceedings and again noted that the Panel was here for scientific purposes only.

FDA Discomfort and Uncertainty

Apparently, industry was not the only one concerned with the FDA’s authority to review a previously cleared device. So were FDA lawyers.

Alicia Mundy of the Wall Street Journal reported the day before the panel meeting that she had reviewed a leaked FDA document which, “underscored concerns among some regulators over potential limits to the agency’s authority to revoke an approval, and over the kinds of safety and efficacy issues the FDA could present to the advisory committee.”

“If we cannot take the device off the market, does it help to have a panel decision one way or the other?” asked one FDA scientist during the January 8 meeting attended by the head of the device division, agency attorneys and scientists, reported Mundy.

Mundy wrote that some agency official said, “Uncertainty over the FDA’s ability to re-open approved cases could result in more intense agency scrutiny of medical-device applications, so as to avoid another controversy like the Menaflex approval.”

While the reason for the meeting was political, Chairman Kelly probably did the company a favor by squelching any talk of the regulatory process and continually herding panel members back into a discussion of the science. In fact, Dr. Kelly bent over backwards to assure that the FDA presented its strongest case against the device, once even inviting the FDA to “take liberties” to contribute to the discussion. No one will be able to question the integrity of the handling of the meeting. 

The Next Time

So where does this leave industry?

We asked Dr. Shuren if he will be responding to panel member Durgin’s question. He did not answer the question directly, but tried to assured us that this redo of the ReGen device was an isolated and unique situation.

While the FDA’s assurances sounded comforting, it is clear that no rules, procedures or predictable regulatory pathway exists that will guide how and when the FDA decides to do another “do over” of a cleared device.