Myxo Ring Dispute: Tale of Two Studies Plunges Northwestern's IRB Into Controversy

Shelley Wood

May 14, 2014

CHICAGO, IL — The institutional review board (IRB) at the heart of a long-running controversy over the Myxo annuloplasty ring and its use prior to formal FDA clearance had rules in place that would typically have triggered FDA notification and patient consent before allowing a study of the device to proceed, heartwire has learned. At the very least, say experts, language and objectives outlined in a recently discovered study protocol should have raised some red flags among reviewers charged with protecting human research subjects.

The undisclosed "Mitral Valve Pathology" protocol and patient-consent waiver have only recently come to light, unearthed by Sen Chuck Grassley (R-IA) in his six-year-long investigation into the Myxo-ETlogix 5100 annuloplasty ring (Edwards Lifesciences). It's now clear that this previously undisclosed protocol led to the published study[1], which in turn formed the basis for the after-the-fact regulatory clearance of the controversial Myxo ring, as reported by heartwire .

That's despite the fact that this pivotal paper cites a "prospectively maintained cardiac surgery outcomes registry" as the source of the patient information and follow-up data, and not the newly unveiled Myxo-specific study quietly approved in 2006.

Moreover, Northwestern officials have repeatedly stated—most notably in response to patients seeking answers as to how they came to receive the Myxo ring—that it was the consent granted for the prospective A-Fib Surgery Registry that permitted patient information to be published. Neither Northwestern nor Myxo ring inventor Dr Patrick McCarthy appear to have ever publicly mentioned the second MV Pathology protocol until Grassley learned of it. The paper, "Initial clinical experience with Myxo-ETLogix mitral valve repair," was published in 2008 in the Journal of Thoracic and Cardiovascular Surgery.

A Tale of Two Studies

In August 2005, Northwestern's IRB approved the A-Fib Surgery Registry study protocol, with McCarthy, the hospital's newest star surgeon, as the principal investigator. It was a two-part application: Part A, a retrospective chart review, and Part B, a prospective study evaluating and comparing success rates with surgical AF treatments. Part B required patient written consent. There is no mention in the AF Registry protocol of mitral-valve repair and in the section querying use of approved or investigational devices, the answer provided is "no".

Then, in June 2006, McCarthy approached the IRB again with his more focused MV Pathology protocol, looking specifically at patients treated with the Myxo or another annuloplasty ring, the CMR-IMR. For this study, he sought and was granted a waiver permitting him retrospective access to the records of all patients who had undergone MV repair between April 2004 and June 2006, without needing their consent.

heartwire asked three experts to review both the A-Fib Registry protocol and the retrospective MV Pathology protocol. Two of the three reviewers agreed that both protocols appear to comply with standard IRB processes, and all noted that it is not uncommon for patient informed consent to be waived for a retrospective study looking at a procedure that has already occurred, as described in the protocol for the MV Pathology study.

Alarm Bells?

Two of the reviewers, however, agreed that the fact that the protocol for the previously undisclosed MV Pathology study describes the Myxo as the "first" ring of its kind, "specifically developed" for the treatment of myxomatous mitral-valve disease—language typically associated with experimental research—should have raised some red flags within the IRB.

And, conspicuously, the aims of the A-Fib Registry were "to evaluate the success rate and the morbidity in patients receiving surgical treatments for AF" and "ultimately . . . develop practice guidelines." By contrast, one of the objectives of the MV Pathology protocol is "to disseminate research findings through scientific conferences, peer-reviewed journalists, and other publications."

The language used in the MV Pathology protocol, as well as its explicit intent of publishing and disseminating new research findings, experts agreed, would usually tip off the IRB that something more than a retrospective analysis was being proposed.

One of the experts who reviewed the protocols for heartwire was bioethicist Dr Arthur Caplan, director of the division of medical ethics at NYU Langone. He said it's clear that the Myxo ring "was a novel innovative device about which data were published verifying that this was so."

He believes the first protocol should have noted that devices might be used and studied and should have contained language that clarified that the study would in part be used for researching an innovative device, rather than merely tracking a therapy.

"The consent obtained in the first protocol was not adequate for a novel device and usage," Caplan told heartwire . The second protocol, he continued, "is plainly trying to piggyback on the first."

"The fact that a paper was published about the risk/benefit and utility/efficacy of the device ends any discussion about whether or not this was a research study—you are now in the research ethics category, so consent has to be consistent with that. It raises the question of whether the journal should have even published these data," he said.

IRB's Own Guidance Flagged Annuloplasty Rings

In March 2009, after the device had been in use for almost three years, the FDA told Grassley that the agency had determined the Myxo annuloplasty ring to be a "significant-risk" device, warranting study under an investigational device exemption (IDE), necessitating FDA oversight and patient informed consent.

Northwestern University's IRB, like many academic institutions, publishes its guidance online to help researchers navigate the FDA requirements for conducting research on human subjects. Of note, the published IRB policies in use at the time the IRB granted McCarthy the MV Pathology waiver includes annuloplasty rings in a list of "significant-risk" devices. Put another way, Northwestern IRB's own guidance at the time specified that studying an annuloplasty ring would require not only patient consent, but also an IDE, formally reviewed and approved by the FDA. Yet, the FDA, according to documents previously made public, first learned about the existence of the Myxo in 2008. The agency didn't officially clear the ring until 2009, after Edwards voluntarily withdrew the device and formally filed the 510(k) paperwork to have it FDA approved.

Of note, the version of Northwestern IRB's "Human Subjects Protection Policy Manual" member handbook available online today does not include the five-page-long list of "significant-risk" devices—annuloplasty rings among them—that earlier iterations of the Northwestern IRB policies have included. What's more, the copy of the IRB policy manual sent by Northwestern to Grassley over the course of his protracted hunt for answers—still accessible on the Senate Finance Committee website—also omits the pages listing the examples of significant-risk devices. Requests from heartwire this week to Northwestern University's IRB and Northwestern Medicine's Media Affairs office for the list of examples of significant-risk devices no longer found in the online guidance went unanswered.

Grassley Presses On

McCarthy, Edwards Lifesciences, and Northwestern have long maintained that the Myxo was only a "minor modification" to existing, already-approved devices. That's been the rationale provided by Edwards as to why it decided to commercialize the ring without notifying the FDA, based on its interpretation of the FDA's own "justification-to-file" document—a decision the FDA later disagreed with but didn't find fault with Edwards. Northwestern and McCarthy have repeatedly stated that this is the reason they did not consider the device to be experimental.

According to Caplan, that explanation is simply "not persuasive."

"There are many things out on the market, both drugs and devices, that can be used in very experimental ways. There will always be innovative uses of already-approved devices . . . and surgeons are given that discretion, but they do still have to get permission and inform their patients that that's what's going on. And if you say, I'm going to [treat] the next 20 people in a novel manner and publish the findings, then you are firmly in the research belt, and you need to get consent from patients."

Grassley seems to be thinking along the same lines. He's been investigating the Myxo ring's tortuous path from development to regulatory clearance since late 2008, after heartwire first reported on a patient who sued Northwestern, McCarthy, and Edwards, claiming she'd never consented to receive an experimental device. Back then, Grassley asked Northwestern for all internal communication related to the Myxo ring.

It is now clear, to Grassley's evident chagrin, that Northwestern lawyers over the years provided him with documents related only to the A-Fib Registry, and not for the Myxo ring– and IMR-specific study. As reported by heartwire , Grassley learned of this second study only when the MV Pathology waiver turned up in documents sent from Northwestern to a lawyer representing a former patient of McCarthy's as part of a discovery in an ongoing lawsuit.

Now Grassley, in his most recent letter to Northwestern, is demanding answers as to why a study protocol purporting to be examining a novel device design, intended for a novel indication, didn't prompt more questions from Northwestern authorities.

"How," he asked, "did Northwestern reconcile Dr McCarthy's description of the Myxo ring as a ground-breaking design with Edwards's assurances that the device was merely a 'minor modification' "?

What the Whistle-blower Wants

That's a question that's long been asked by the original whistle-blower, Dr Nalini Rajamannan, who was a former coinvestigator on the Myxo ring study until she learned that one of her patients had never consented to receive the device. Since 2008, she's been seeking full transparency on the use of the Myxo at Northwestern.

It was Rajamannan who alerted Grassley to the existence of the MV Pathology waiver, when, she says, she first learned of its existence in November 2013. Of note, while Rajamannan and three other physicians are listed as coinvestigators with McCarthy on the MV Pathology protocol, Rajamannan says she was never aware of this separate protocol, and McCarthy is the only name on the application for the waiver of patient consent.

Rajamannan points out that there have been multiple occasions over the past six years when information about the MV Pathology protocol and waiver would have proved helpful. The failure to release these documents, she believes, "point toward Northwestern's repeated attempts to conceal the waiver to lessen their liability not only for the clinical testing of the experimental devices but for the $500 million of research funding that is protected under the common rule."

She's hopeful that Grassley's renewed investigation will lead to a reversal of Northwestern's decision not to inform the hundreds of Myxo- and IMR-treated patients that they received the devices "during the investigational time period." By law, she insists, "they have the legal right to know what happened."

She also hopes the FDA "will review the over 5000 adverse events and 700 deaths related to the Edwards Lifesciences annuloplasty rings and the mechanisms of why these events are high and why the numbers tripled in 2008."

Contacted by heartwire , FDA press officer Susan Laine said in an email: "The FDA continues to review adverse-event reports from Edwards. The FDA takes reports of problems with these devices very seriously, reviews them carefully, and undertakes appropriate follow-up, as necessary. As part of our ongoing postmarket surveillance activities, we continue to monitor all safety information (including adverse event reports) for marketed devices to determine whether additional regulatory or public-health action may be needed."

Laine also noted that while the medical-device reporting, cited by Rajamannan, provides "a valuable source of information, this passive surveillance system has limitations" and as such is just one of several postmarket surveillance data sources relied upon by the FDA.

McCarthy himself is not returning calls, and a Northwestern Medicine spokesperson cited legal concerns around discussing issues related to Grassley's investigation. At the time of publication, Northwestern had not responded to questions related to IRB decision making and in particular why a study protocol focused on a novel, significant-risk device failed to prompt internal reviewers to request a prospective study (with an IDE and informed patient consent).

Meanwhile, a second patient-initiated lawsuit is also wending its way through the courts, this one by a patient who received the Myxo without explicit consent but whose data were not included in the published study. She had a heart attack periprocedurally and was later told by Northwestern that her mitral-valve-repair data did not make it into the paper (and thus, the FDA's subsequent compliance review) because of her underlying rheumatic heart disease (RHD), a prespecified study exclusion criterion. Rajamannan notes that there were, in fact, no signs of RHD on her pre- or postprocedure echos, as reviewed by numerous outside experts.

Read all of our coverage at The Myxo Ring Mix-up

McCarthy has previously disclosed receiving royalties for the Myxo ring but claimed he donates them to the Greater Chicago Food Depository. Caplan is a paid blogger for Medscape's Business of Medicine and sits on Medscape’s editorial advisory board. Rajamannan has no disclosures and noted she has not received payment for witness testimony.

 

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