Washington, DC - Sen Charles Grassley's (R-IA) announcement last week that he was investigating the Edwards Lifesciences Myxo ETlogix annuloplasty ring 5100 is putting a spotlight on an issue many people both within and outside the FDA acknowledge to be a delicate topic: how to balance the need to make sure medical devices are safe while expediting the commercialization of products that represent an improvement on their commercially available predecessors.
One of the controversies at the root of the senator's inquiry is whether the Myxo ring was indeed appropriately cleared for market—as Edwards insists—or was investigational, at the time Dr Patrick McCarthy (Northwestern University, Chicago, IL), coinventor of the device, used it in Antonitsa Vlahoulis in April 2006. That question is also at the heart of a lawsuit Vlahoulis has brought against McCarthy and Edwards and is at least one focus of the FDA's own ongoing investigation. One of the cardiologists whose patients were among some of the first treated with the Myxo has said she believed the device to be investigational/experimental.
Northwestern and McCarthy relied on communications with Edwards to reassure them that the device was commercially available. Edwards, for its part, has said from the outset that the device was legally on the market at the time it was used because it incorporated only minor changes to a previously 510(k)-cleared device, the GeoForm Ring 4200, cleared August 26, 2003. In a statement provided to heart wire back in October, an Edwards spokesperson clarified that the Myxo ring "represents a modification to an existing Edwards annuloplasty ring that was cleared through the FDA's 510(k) process as a class II device. The modification was analyzed, relying on the FDA's guidance document 'Deciding when to submit a 510(k) for a change to an existing device' (January 10, 1997), and the conclusion was made that a separate 510(k) premarket notification was not required for the device."
That document provides companies with a set of criteria, definitions, and a flowchart to help them decide whether a product that has been altered or improved warrants submission of a new 510(k). The sorts of modifications discussed include changes to labeling, composition, technology, or performance. In the statement it released last week, Edwards emphasized that it had addressed the guidance set out in this document, compiling a 300-plus page "justification to file" that documents why a new 510(k) was not required. This document had been kept in-house, as per FDA guidance, until it was provided to the FDA in recent weeks as part of the current investigation.No-win situation
Vlahoulis, who was 38 at the time she received the ring, is suing because she believes the device is responsible for a series of adverse events experienced following her initial surgery—an exaggerated inflammatory response followed by a chain of secondary effects leading to a second mitral-valve surgery, a redo Maze procedure, and a permanent pacemaker. Her case may hinge on whether the FDA agrees that the Myxo is not substantially equivalent to previously approved rings. Vlahoulis, who is not a doctor, points to the fact that the Myxo ring is triangular—a visibly different shape from other rings, which are roughly oval or saddle-shaped; it was also designed specifically for myxomatous mitral-valve disease.
Cardiologists familiar with the regulatory process point out that the American public demands access to ever newer and better devices as fast as possible but has zero tolerance for imperfect devices. "They can't have it both ways," Dr Peter Berger (Geisinger Health, Danville, PA) told heart wire . "And the FDA is in a no-win situation—heavily underfunded and dependent on Congress for guidance. It's a recipe for a disaster."
One FDA insider told heart wire that the agency is currently contemplating changes to its "'Deciding when to submit a 510(k)" process, but an official FDA spokesperson said only that no announcement has been issued regarding updates to this guidance. Separately, the US Government Accountability Office has been reviewing the 510(k) process, focusing specifically on class II devices.
Commenting on the process for heart wire , Dr Bram Zuckerman, head of the division of cardiovascular devices in the FDA's Center for Devices and Radiological Health, acknowledged that it's a delicate balance.
"Assessing risk and benefit—ie, a reasonable assurance of safety and effectiveness—requires careful analysis of scientific data and application of clinical judgment. It's a difficult balance—we cannot compromise safety for the sake of effectiveness. But when sponsors, investigators, and the FDA do their jobs well, the public is served by getting safe and effective products to patients more quickly, and healthcare providers can make educated recommendations among available treatments. This guidance is one of many documents that help manufacturers and the agency with making safety and effectiveness decisions on the wide variety of medical devices already on the market."An after-the-fact 510(k)
In a curious twist, Edwards recently revealed that, within weeks of heart wire 's first story on the Myxo ring controversy, the company had gone ahead and filed a 510(k) for the Myxo, more than two and a half years after it first started selling the product. In the meantime, Edwards has voluntarily elected to "collect" Myxo rings currently stocked by its customers, suspend new shipments of the product in the US, and remove any product information from its website.
Commenting on the latest developments, Dr William Maisel (Beth Israel Deaconess Medical Center, Boston, MA) told heart wire , "It is unusual for a 510(k) to be submitted more than two years after a product is marketed. More commonly, there are iterative changes to devices, and it can be challenging to determine when a new 510(k) should be submitted and when one doesn't need to be submitted. . . . I think the fact that they're submitting a 510(k) now would tell you what the FDA thinks."
Edwards's actions "are to all intents and purposes a recall," Maisel added. But he also cautioned that a recall does not necessarily mean there is any kind of medical problem or malfunction with a product. "A product recall can also be due to misbranding or mislabeling or it may be what the FDA might term a violative product, meaning that it is marketed illegally."
A separate issue is whether Edwards appropriately registered its intention to market the Myxo ring with the FDA prior to offering it to customers. h eart wire previously reported that the Myxo ring did not come up in a search of the FDA's Medical Device Listing, a mandatory list of devices commercialized by companies. But in fact, the Myxo is, in fact, registered, but in a listing titled "Ring, Annuloplasty 4100/4200/5100," encompassing the GeoForm 4200, the Carpentier-McCarthy-Adams IMR ETlogix Mitral Annuloplasty Ring 4100, and the Myxo ETlogix 5100. According to an FDA spokesperson, that listing was first created in December 2007, and it "does not appear the company has modified the information since that time," although companies, not the FDA, are responsible for inputting their own information and the listing in itself does not confer FDA approval or clearance, she clarified.
Of note, information about the 4100 model, which was also deemed by Edwards to be substantially equivalent to the GeoForm and therefore was not the subject of 510(k) submission, has also disappeared from the Edwards website. Both the Myxo ring and the IMR ETlogix 4100 are available in Europe.
Heartwire from Medscape © 2008
Cite this: Myxo ring controversy spotlights regulatory gray area: When does a tweaked device constitute a new product? - Medscape - Dec 11, 2008.