Full article reprinted from "The Gray Sheet" - July 6, 2009
Legislators looking for weak spots in FDA's device pre-market review program have honed in on a perceived loophole that allows firms to change existing 510(k) products without notifying FDA. Find out more...
Legislators looking for weak spots in FDA's device pre-market review program have honed in on a perceived loophole that allows firms to change existing 510(k) products without notifying FDA.
The mechanism is not new: the 510(k) regulations allow certain small changes to be made without notifying FDA if a company determines the change could not affect safety or effectiveness.
But the recent case of Edwards Lifesciences' dETlogix 5100 mitral valve repair device, which was marketed for more than two years without proper 510(k) clearance under this model, has drawn attention from Congress and others to this regulatory gray area.
"FDA presumably did not want to be inundated with minor changes and both waste industry's time and their own time rubberstamping changes that have no impact on safety, so they created this process by which companies could make changes and not report them to the FDA," explains William Maisel, a Harvard cardiologist and director of the Medical Device Safety Institute (see sidebar: " 1 PMA Parallels ").
"Conceptually, that's okay. The problem is that we end up with devices like the Edwards valve."
Edwards launched the device, then called the Myxo ETlogix annuloplasty ring, in 2006, as a "minor modification" to its 510(k)-cleared GeoForm ring. But when questions were raised about the product's regulatory status, Edwards opted to recall the device and submit a new 510(k) (2 'The Gray Sheet' Dec. 8, 2008).
The dETlogix and the IMR ETlogix annuloplasty ring were 510(k) cleared this April as substantially equivalent to GeoForm and two other Edwards annuloplasty rings.
Edwards says it relied on a 1997 FDA 3 guidance on when to submit a new 510(k) for changes to an existing device. But Maisel says, "I think most educated and uneducated people would certainly recognize that the device was a different device."
"I am uncomfortable giving industry that much authority to police themselves, to make a safety and effectiveness decision" about whether a new 510(k) is needed, he said. "I don't think it's realistic to think that they will make an unbiased decision."
Edwards says its decision was governed by its interpretation of the 1997 guidance, and that it followed appropriate internal procedures. But, "in a subsequent review, the FDA disagreed" with its conclusions, the firm said in a statement.
The firm says it has "learned a great deal" about FDA's interpretation of the 1997 guidance from the Myxo experience, and "has already incorporated this learning into its regulatory review process."
Edwards will not face any sanctions for marketing Myxo ETlogix without proper clearance, FDA says.
According to Maisel, that effectively sends a message to industry "that manufacturers can err on the side of not submitting these applications to the FDA, because it does not appear that the agency will sanction them."
FDA Finds 1997 Guidance 'Generally' Successful
The guidance in question was first drafted in April 1994, and after a torrent of comments, a second draft was issued in August 1995. Since the final guidance was released in January 1997, however, FDA says it has not received many more formal comments on the document.
"I think generally it's been very successful for the tens of thousands of 510(k)s we've had since this came out," said Heather Rosecrans, director of the 510(k) staff within FDA's Office of Device Evaluation.
The document provides a general guide to companies deciding whether or not to file a new 510(k) for changes to existing products--such as changes to labeling, technology, performance specifications or materials. But the guidance was not meant to be the final word on the subject.
"To be certain that a decision on when to submit a 510(k) is correct, one would probably need to enumerate all device types and all potential types of changes and then match each ... with a decision," the 1997 document states. "This would be an impossible task."
Companies are required as part of the Quality System Regulation to document all changes made to a device in the device master record, which FDA has access to during inspections.
The guidance explains, "For many types of changes to a device, it may be found that a 510(k) is not necessary, and the Agency may reasonably rely on good manufacturing practices to continue to assure the safety and effectiveness of the changed device."
But for any change that could potentially affect the safety or effectiveness of a device, companies need to submit a new 510(k), FDA stresses.
"It's not whether it does or doesn't" affect safety or effectiveness, Rosecrans emphasizes. "It's whether it could. That's sometimes where a firm might get hung up."
According to the regulation and guidance, it doesn't matter whether the change affects the device positively or negatively, adds Christy Foreman, deputy director for science and review policy within ODE. "It could affect it in either a positive or negative way." That is, even if a change enhances safety, it needs to go through the 510(k) process.
For the most complete understanding of which modifications require a new 510(k), firms should consult device-specific guidances, some of which specifically address device changes, FDA says. Device-specific guidances "supersede" the broader 1997 document, Rosecrans explained.
She urged companies to call FDA if products fall within a "gray zone" and available guidance still leaves them perplexed.
"You should always contact us," she said. "We knew when we wrote it, it's not going to cover every change of every single device type."
The 510(k) chief says she has been contacted by companies "hundreds and hundreds of times" with questions about how to interpret the guidance.
Companies should view the '97 guidance as just "the starting point," ODE's Foreman said.
"That's where companies should start, but certainly it's not the finishing point. There may be additional information that's needed, or other guidances to be read, or you might need to contact the agency."
Since 1997, FDA has been focusing more on creating device-specific guidances to help manufacturers make pre-market decisions, the staffers say. FDA does not have a specific timeframe for updating the '97 guidance, but will consider it during its next annual guidance review.
FDA: Firms Know Best How To Gauge Changes
FDA believes companies, not the agency, are best qualified to determine whether modifications affect a device's safety or effectiveness.
"Devices are so diverse, and there are thousands and thousands of changes that can be made to a device," Rosecrans said, and firms "generally understand their product best; they're the most familiar."
Some companies play it particularly safe and submit 510(k)s for changes that FDA considers too minor for a submission. "Others are not quite that extreme," she said. FDA's role is as "arbiter" of the company's decision.
Yet the concerns of Harvard's Maisel and others about allowing companies to police themselves have resonated with some members of Congress.
Sen. Chuck Grassley, R-Iowa, ranking member on the Finance Committee, launched an investigation into the Myxo matter last December, sending information requests to Edwards, FDA and Northwestern Memorial Hospital, home institution of Myxo inventor Patrick McCarthy.
Northwestern physician Nalini Rajamannan brought information about Myxo to Grassley's attention after one of her patients began questioning the regulatory status of the so-called McCarthy ring.
Grassley sent another letter this April asking then-acting and now deputy FDA Commissioner Joshua Sharfstein additional questions, including why firms are not required to submit documentation of minor modifications to FDA (4 'The Gray Sheet' May 4, 2009). FDA says it will respond to the request.
Maisel also raised the issue during a June 18 House Energy and Commerce Committee hearing convened by Rep. Frank Pallone, D-N.J., on whether FDA's device review process needs an overhaul (5 'The Gray Sheet' June 22, 2009).
In his testimony, Maisel hinted that the Edwards example is likely one among many.
"There have got to be numerous devices out there that have been modified in this way that the FDA is unaware of," he elaborated in an interview.
"The auditing process is not working," added Michael Burnett, attorney for the Northwestern Memorial patient who brought the Myxo concerns to light. Antonitsa Vlahoulis, along with another patient, are suing Edwards, Dr. McCarthy and Northwestern University for medical malpractice.
Burnett says there is no solid process to prevent companies from misinterpreting or abusing the leeway allowed within FDA's guidance.
"There should absolutely never be a system where industry can unilaterally decide to submit a 510(k) or not," he said during a recent conversation with "The Gray Sheet" in Washington, D.C.
Manufacturers should be required to notify FDA any time they make changes to a product, he says. In addition, there should be stronger enforcement mechanisms for noncompliance. FDA's response to Edwards' mismarketed device "wasn't even a slap on the wrist," he said.
ODE's Foreman said there probably are other firms that are misinterpreting the guidance. When it comes to light, often through an inspection or complaints from competitors, FDA reviews the facts of each case to determine whether enforcement action is necessary, she said.
"If you made an incorrect decision, we would have to look at the specific circumstances and facts behind that decision," she said. "But ultimately what you are doing is marketing an unapproved product."
'A Relatively Easy Loophole To Close' - Maisel
Harvard's Maisel also thinks FDA should see some form of a firm's internally documented changes.
"Quite frankly, this is a relatively easy loophole to close," he said. "Companies need to notify the FDA when they're marketing a modified device, whether or not they believe it affects safety and effectiveness, or whether or not they believe the intended use is different."
In that case, "at least the FDA is in the loop and has the opportunity to disagree with the company in a timely fashion, rather than two and a half years later."
This would add to FDA's already heavy workload, he notes--FDA estimates that hundreds of such minor changes are documented each year, per firm--but "if the right questions are asked, and the companies submit the proper information, I don't think it would take an inordinate amount of time for someone to review the application," Maisel said.
- Jessica Bylander
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