Full article reprinted from "The Gray Sheet" - December 8, 2008
Find out how Edwards Lifesciences removed a mitral valve repair device from the market in October and submitted a 510(k) for the product in the midst of an FDA inquiry into whether the device was being marketed without proper clearance.
Sen. Chuck Grassley, R-Iowa, ranking member on the Finance Committee, launched an investigation into the matter involving the Myxo ETlogix 5100 annuloplasty ring Dec. 3, sending off separate information requests to Edwards, FDA and Northwestern Memorial Hospital in Chicago - where the inventor of the product practices medicine.
Grassley gave the parties until Jan. 5 to respond to a series of questions about the use of the product, Edwards' interactions with FDA about marketing of the device, and the firm's relationship with Northwestern cardiothoracic surgeon and Myxo inventor Patrick McCarthy, among other matters.
According to Nalini Rajamannan, the valve director of the Bluhm Cardiovascular Institute at Northwestern University who brought information about Myxo to Grassley's attention, the investigation is part of the senator's broader interest in assessing the 510(k) process.
Myxo Launch Based On Minor Modification Claim
The Myxo ring was designed specifically to treat patients with myxomatous disease, a degenerative mitral valve condition typically impacting younger patients that present with particularly complex surgical repair cases.
It is designed to facilitate a more straightforward repair process in these patients and to replace the need for outright replacement with a mechanical valve, which requires lifelong reliance on anticoagulant therapy.
The device was first implanted in the U.S. in 2006 and launched nationwide by Edwards in January 2007 during the Society of Thoracic Surgeons annual meeting. But the firm acknowledges that it never sought or obtained FDA clearance or approval.
Edwards launched the product on the basis of it being only a "minor modification" to the previously 1510(k)-cleared GeoForm annuloplasty ring, according to the company.
The firm cites a 1997 FDA 2guidance document detailing the recommended process for determining whether a change to a 510(k)-cleared device or its labeling necessitates a new 510(k).
Those guidelines are intended to describe how a device sponsor should classify a product to be "significantly changed or modified in design, components, method of manufacture, or intended use," which is the threshold for a new pre-market notification.
The guidance includes multiple decision flowcharts for each potential type of change (labeling, material, and technology, engineering and performance).
Based on the guidance, Edwards decided a 510(k) was not necessary and instead put together a "300+ page Justification to File" document detailing its decision process, an Edwards spokeswoman said in an email.
Similarities between the Myxo and GeoForm rings include "the intended use, materials and operating principle; the modification was in the dimensions of a device previously cleared through the 510(k) process," the Edwards rep explained.
Rajamannan, who was involved in a post-launch clinical study of the device, says that in her view the differences between the products are not trivial.
"This ring is triangular shaped; it is not the saddle shape of all of the other rings, so it is quite a big modification," she said in an interview, adding that Myxo has more silicone in it than other rings and that the very specific indication for myxomatous disease is a departure from rings like GeoForm.
Patient Initiated A Complaint With FDA
Questions involving the Myxo ring were first described on the Web site theheart.org in October.
The matter arose after Rajamannan referred one of her patients with atrial fibrillation and mitral regurgitation to get Myxo in April 2006 as part of a study looking at early experience with the device.
The procedure was performed by McCarthy, who has invented several annuloplasty devices and is a consultant for Edwards.
Results from the 129-patient observational study were ultimately published in July 2008, demonstrating, the authors concluded, "a safe operation with low morbidity, a high rate of repair (96%), and excellent early results with little residual or recurrent" mitral regurgitation.
The Journal of Thoracic and Cardiovascular Surgery article notes McCarthy's role as the device inventor and primary surgeon and describes efforts to reduce the bias. It recommends follow-up randomized studies at other institutions to confirm the results.
Rajamannan was initially an author on the study but instructed the journal editors to remove her name after she became concerned that patients were not provided appropriate informed consent about the device.
Some time after her procedure, Rajamannan's patient, Antonitsa Vlahoulis, developed an inflammatory reaction involving her mitral leaflets and required follow-up treatment, including an eventual valve repair surgery, according to Rajamannan.
Vlahoulis is now suffering from New York Heart Association Class 2 heart failure, and "has been through a lot of trauma," the cardiologist said.
Vlahoulis was prompted to check into the status of the Myxo device with FDA earlier this year after she received a warranty card identifying it as the "McCarthy," rather than "Myxo," according to Rajamannan.
This made the patient wonder whether the device she was implanted with was some sort of prototype version and also alerted her to the fact that the product was invented by her surgeon, a fact she said had not been disclosed.
In a July 30 email exchange obtained by "The Gray Sheet," Vlahoulis questioned FDA to find out when the device "became approved."
Barbara Stellar, a public affairs specialist within CDRH, responded that "we have not approved the McCarthy myxoetlogix annuloplasty ring 5100 model. Due to our confidentiality concerns, we are unable to provide any information about a product until after it is approved."
Edward's 510(k) Follows Months-Long Dialogue
Edwards says that it has been "working closely and in collaboration" with FDA since early August on the patient inquiry into Myxo. In this context, the firm "has elected to take a number of voluntary actions."
On Oct. 27, the company submitted a 510(k) to FDA. It also suspended shipments of the device in the U.S. and will be collecting any units that remain in customer inventory. Further, it removed Myxo marketing information from its Web site.
"These decisions were not prompted by safety, effectiveness or product performance issues, but instead reflect the company's commitment to working with the FDA and conducting its business in an appropriate matter," Edwards said.
FDA confirms that the 510(k) is under review. The agency also "will respond directly to Sen. Grassley on the questions and issues raised in his correspondence, all of which we take very seriously and will give full consideration," FDA spokesperson Peper Long said.
Meanwhile, Rajamannan had approached Northwestern Memorial administrators to ask about their understanding of the device's status and whether the facility's institutional review board had approved the 2006-initiated research.
"I think everyone at Northwestern thought the ring ... had some sort of approval, whether it was IDE or 510(k)," she said.
A follow-up assessment by the hospital's Office of Research Integrity, which cited Edwards' analysis that Myxo was only a minor modification to GeoForm, found the device not to be investigational. Therefore, IRB approval or specific consent from the patient was not needed for use of the device, the office said.
"They said, 'we have FDA approval,' [but we said,] 'here is the email from FDA saying they did not have approval,'" Rajamannan recounted.
She says she is concerned that if "a company decides internally to make an approval, then how do you know what you are getting?"
Grassley Inquiry: 510(k)s, Physician Payments
After several months of waiting on a more detailed response from FDA, Vlahoulis and Rajamannan decided to take their concerns to members of Congress, including now-President-elect Barack Obama, Illinois Democratic Senator Dick Durbin and Grassley.
Rajamannan believes Grassley decided to open a formal investigation because the matter aligned with his broader interest in evaluating the 510(k) pre-market notification program, which has generally fallen under enhanced scrutiny during the past year (3"The Gray Sheet" Nov. 17, 2008, p. 7).
His Dec. 3 letter to FDA Commissioner Andrew von Eschenbach includes a series of questions seeking information on communication between FDA and Edwards on the Myxo ring and queries about how the 510(k) product modification assessment process works.
Another important issue to Grassley, a co-sponsor of the Physician Payments Sunshine Act, is the disclosure of financial relationships between doctors and manufacturers.
Grassley's letters to the hospital and Edwards ask for detailed data on payments received by McCarthy from Edwards and other manufacturers going back almost six years.
Edwards identifies McCarthy as an "educational consultant," and says Myxo royalties were paid not to the doctor but to the Cleveland Clinic, the institution where McCarthy was employed when he developed the device.
A spokeswoman identified Myxo as a "niche product" for Edwards, generating less than $1 million in 2007 sales. Edwards paid the Cleveland Clinic less than $25,000 in royalties for Myxo in 2007.
- David Filmore
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