WASHINGTON, DC — Almost five years later, the long-running Myxo ring controversy has taken another abrupt twist. This time, it's in the form of a hitherto-unreported study of the Myxo-ETlogix 5100 annuloplasty ring, undertaken by its inventor and approved by his institution, which also waived the need for patient consent.
As reported by heartwire , Sen Chuck Grassley (R-IA) sent a letter to the presidents of Northwestern University and its affiliated Memorial Hospital in late March when he first became aware of a second "echo" study. A lawyer representing the Northwestern entities replied March 21, but as Grassley's rebuttal makes clear, he's far from satisfied with the response.
Grassley's office has publicly released Northwestern's letter along with his own letters, although not the supporting documents Northwestern submitted. Many of those, however, are part of the public docket in the Cook County Circuit Court, along with other evidence filed by Dr Nalini Rajamannan, the whistle-blower who has repeatedly alerted Grassley to problems with the way the Myxo was used. The emerging details are troubling.
Second Study Comes to Light
The Myxo ring controversy dates back to a lawsuit in 2008 by a patient who consented to be in an atrial-fibrillation (AF) registry but says she was never told she'd be receiving an experimental mitral-valve annuloplasty ring, implanted by the man who invented it.
heartwire 's coverage led to Grassley's initial investigation, in which he asked Northwestern to provide copies of all internal communications and correspondence regarding the Myxo ring and the use of the device as part of an outcomes study between January 2006 and the date of the letter.
It now appears that Northwestern provided only materials related to a single institutional review board (IRB)–approved study (the AF registry, IRB 1532-003), known formally as the "Early and Late Outcomes Following Surgical Intervention for Atrial Fibrillation Database," and not a second study that actually looked more specifically at the Myxo ring (1532-004), "Mitral Valve Pathology: A Quantitative Assessment Pre- and Post-Repair." One of the primary objectives of this second study, according to the protocol that's now come to light, was to "evaluate results of myxomatous mitral-valve repair using the Myxo ETlogix Annuloplasty Ring."
Requirement for Patient Consent Waived
Critically, as the materials provided to Grassley show, McCarthy asked for and was granted a Health Insurance Portability and Accountability Act (HIPAA) waiver permitting him to use data from Myxo-treated patients who'd consented only to be in the AF registry (IRB 1532-003) to be included in this second study without informing them that their mitral-valve-surgery outcomes data would be tracked and used.
The results from the Myxo study were subsequently published in the Journal of Thoracic and Cardiovascular Surgery (JTCS) in 2008 as the "Initial clinical experience with Myxo-ETlogix mitral-valve repair ring." The paper notes only that patient information and follow-up data were obtained "from the prospectively maintained cardiac surgery outcomes registry" at Northwestern. Of note, both approval of the mitral-valve study and expedited approval of the HIPAA waiver from Northwestern's IRB are addressed to McCarthy only, not the coauthors later listed on the paper.
Rajamannan has previously noted that while she was a coauthor on the abstract for the study, which was first presented at a surgery meeting, she removed her name from the JTCS paper after learning that one of her patients had never consented to receive the Myxo ring or be included in a study of the ring. She also maintains she never knew of the existence of IRB 1532-004 until the plaintiff's lawyer in an ongoing lawsuit against McCarthy, Northwestern, and ring manufacturer Edwards Lifesciences showed her the documents sent to him by Northwestern as a part of discovery on November 19, 2013. Rajamannan was also the former valve director for the Bluhm Cardiovascular Institute at Northwestern; she left in 2011 when Northwestern denied her tenure and terminated her position.
Northwestern: Never Intended to Conceal
Grassley's April 30 rebuttal makes it clear he's incensed that documentation pertaining to the Myxo-specific study and HIPAA waiver were never supplied back in 2008, although Northwestern provided the materials with its March 21, 2014 letter. In it, Northwestern's legal counsel explains that it was never the intent to provide an "incomplete response"; rather, that they had decided to send only materials related to the single IRB-approved study (the AF registry study) after conversations with two finance committee staffers (their names are blacked out in the public document).
That response is not sitting well with Grassley, who demanded that Northwestern provide documentation of "any agreement to limit the scope of my December 3, 2008 request to IRB project number 1532-003" and, if none exists, to explicitly say so. Moreover, his letter notes, his staff have no recollection of agreeing to any plan to exclude materials related to this second study.
What's New?Grassley's latest letter also returns to a point he's hammered in the past, namely that all signs point to the fact that key parties—McCarthy, his hospital, and Edwards Lifesciences—all knew that the Myxo was a new and unique device, being tested for the first time, yet didn't go through appropriate FDA processes.
Back when heartwire first reported on the Myxo ring controversy, Edwards Lifesciences insisted that the Myxo was a commercially available device at the time it was first used, despite never undergoing FDA review in any form, because it contained only modest differences from a predicate device. Northwestern and McCarthy have long insisted that McCarthy was free to use the device as a commercial product based on their communications with Edwards.
But the newfound study protocol for IRB 1532-004 describes the Myxo as the "first ring" of its kind, substantially different from other rings, and intended for an unmet medical need. Grassley quotes a section of the protocol in his letter: "The Myxo . . . ring was specifically developed to help eliminate the need for the complex . . . sliding-plasty procedure. The Myxo ETlogix is the first ring . . . designed to reshape the annulus to accommodate the larger leaflets . . . by reshaping the [annulus] instead of cutting the [leaflets]."
Grassley also points out that the subsequent publication of the data from this study also describes the Myxo as "significantly larger" than existing commercial annuloplasty rings.
"Given Dr McCarthy's clear expertise in the field of heart-valve repair and his first-hand knowledge of the Myxo ring and other devices used in that field, there is a genuine question as to how he could have believed that the Myxo ring was only a 'minor modification' of existing devices when he himself designed and promoted the Myxo ring for a different purpose, with a different shape, and as 'significantly' different in size," Grassley writes.
Next: Grassley Seeks More Answers
Grassley, in his latest letter, has asked Northwestern whether it believes Dr McCarthy believed his Myxo ring to be "significantly larger" or just a "minor modification" and to clarify, in light of the study protocol, how Northwestern reconciled McCarthy's description of his new ring as "groundbreaking" with Edwards's assurances that the device was a minor modification.
Moreover, Grassley writes, the "belatedly disclosed" documents "bear directly on the question that precipitated my investigation in 2008 and remains unanswered: did Northwestern implant an unapproved device—which it knew, or should have known, required approval—in patients without obtaining their informed consent?"
Attached to Grassley's April 28 letter is a copy of the letter sent to his office by the FDA in 2008 confirming a piece of the puzzle that has never been stated publicly: namely, that the FDA determined five years ago that the Myxo ETLogix ring was not covered under any 510(k) clearance and that it was a "significant risk device" that would have required an investigational device exemption to be studied, something the Myxo never obtained.
Back in 2008, an Edwards spokesperson stated that the Myxo was "commercially available" as of March 2006. Tellingly, another interesting piece of information found in the Cook County Circuit Court documents is a "First in Human Use Approval Sheet" for the Myxo. It is dated March 2006. Yesterday, an Edwards spokesperson confirmed that the first human use was indeed the first "commercial use" as well.
As reported by heartwire , Edwards voluntarily pulled the Myxo from the market and filed a 510(k) in 2009, after it had been selling the device for two and a half years. It was subsequently approved under a new name (the dETlogix Annuloplasty Ring 5100), and according to an Edwards spokesperson, "continues to be a niche offering in Edwards’ extensive line of annuloplasty rings.” It is not, however, listed on the US product page. At least two patients have sued Northwestern, Edwards Lifesciences, and McCarthy, believing that their Myxo device was implanted without their consent and led to MIs and subsequent heart failure. The FDA's Manufacturer and User Facility Device Experience (MAUDE) database lists 27 adverse events associated with the "Myxo" ring and two for the renamed "dEtLogix" ring. Rajamannan points out that there are over 5000 events associated with the Edwards predicate devices—a family of nine annuloplasty rings approved via a common 510(k) process—including more than 650 deaths.
In all, 667 patients with mitral-valve disease received the Myxo device in the more than two years it was sold preapproval. According to Rajamannan, Northwestern has never taken the step of informing these patients that they received a device that was voluntarily pulled off the market, then deemed experimental after the fact.
Northwestern declined on behalf of its institution and McCarthy to comment on Grassley's latest concerns, citing legal reasons. An Edwards spokesperson reminded heartwire that the FDA has previously concluded that it believes the company had made "an honest attempt" to follow guidance as to when a new 510(k) applicantion was not warranted.
See also: The Myxo ring mix-up
Heartwire from Medscape © 2014
Cite this: Grassley Investigation Unearths Second, Secret, Myxo Ring Study - Medscape - May 02, 2014.
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