Yale to Provide Review of Medtronic's Infuse Data

Susan Jeffrey

August 05, 2011

August 5, 2011 — Yale University has received a grant from Medtronic Inc to provide independent review of the safety and efficacy of Infuse, the company's recombinant bone morphogenic protein-2 (rhBMP-2) product used in spinal fusion surgery that was recently linked to safety issues.

The grant "will fund reviews of the entire body of scientific evidence regarding the safety and effectiveness of Infuse," a statement from the company said. "The reviews will be conducted independently by 2 academic teams with full access to all Medtronic's clinical trial, post-marketing and safety data about rhBMP-2."

Yale views the move as the opportunity to develop a "landmark" new model for collaboration between industry and academia, says Harlan Krumholz, MD, professor of medicine at Yale, who will oversee the project. Dubbed the Yale Model for Independent Data Evaluation and Transparency, the aim of the project is on one hand to ensure that patients and physicians have all the information they need to make informed treatment decisions and, on the other, to provide industry with the confidence that the scrutiny will be scientifically rigorous, objective, and fair.

Dr. Harlan Krumholz

"I've been bothered for a long time that much of the evidence that patients and doctors need is out of public view because it's owned by companies and it's hard or impossible to evaluate," Dr. Krumholz told Medscape Medical News. "In fact there's no company that has ever fully shared their data, and when safety concerns are raised about a product, I think society has an over-riding interest in having access to the totality of the data rather than being told that it's proprietary...because every day, decisions are being made in clinical practice that are based on assumptions about risks and benefits that are informed by only a portion of the data."

Dr. Krumholz saw the situation with Medtronic as a potential case study to develop this model for disclosure of data when safety concerns are raised about an approved product, and approached them with the idea.

"And to Medtronic's credit, great credit, they agreed," he said. "No company in history has agreed to release data that they own like this. My hopes are not only that this gives us an opportunity to really survey what can be known about Infuse and to make some assessment of the quality of the literature, the adequacy of the literature and what you can infer about benefits and harms from the data, but also create a new standard whereby it will no longer be tenable for a company to say 'yes, safety concerns have been raised, yes we have data, and no, we're not giving anybody access to it,' because that's the situation that we have right now."

They plan to strike 2 independent research groups, both of which will review all of the data on rhBMP-2 separately and come to their own conclusions, to see if they agree on their assessments. In addition, a steering committee of 12 to 15 members will be formed, chaired by Ezekiel Emmanuel, MD, chair of the Department of Bioethics at the National Institutes of Health. The project will also make all Medtronic rhBMP-2 data available to researchers who wish to conduct their own analyses.

"We're just getting started but we're going to move quickly and try to get a lot of this done within 6 months," Dr. Krumholz said.

Adverse Events Unreported?

Questions about rhBMP-2 were raised in June by a series of review articles that appeared in The Spine Journal, reported at that time by Medscape Medical News. One, by Eugene Carragee, MD, editor in chief of the journal and chief of the Spine Surgery Division at Stanford University Medical School in California and colleagues, charged that several harmful effects of Medtronic's product went unreported in the published articles supporting its safety and efficacy.

Dr. Eugene Carragee

Clinical trial data submitted to the US Food and Drug Administration (FDA) made it clear that rhBMP-2 was associated with a significant number of adverse events, The Spine Journal review pointed out, yet none of the 13 published industry-sponsored studies reflected these results.

"The Medtronic-sponsored studies failed to report even 1 single adverse event of any type," Dr. Carragee told Medscape Medical News at that time. "And the FDA data are completely different. The FDA data show there was increased radiculitis, an increased number of leg pain events, increased infection rates, and an increased chance of sterility. It's astounding. But it was completely under the radar initially."

Dr. Carragee was especially concerned about the incidence of retrograde ejaculation, which causes sterility. A separate retrospective controlled trial done by Dr. Carragee and colleagues showed that the incidence of retrograde ejaculation was much higher in patients who received rhBMP-2 in fusion surgery than in those who didn't.

Similarly, he said, the full Medtronic study data submitted to the FDA show that 11 patients in the study group had retrograde ejaculation, compared with just 1 in the control group. In the randomized trial section, 5 in the BMP-2 group had a complication vs 1 in the control group. Extrapolating to all patients who have been treated with rhBMP-2, he said, "it's possible that hundreds of men may have been sterilized due to the use of this product."

The FDA-approved product, Infuse/LT-Cage, comprising rhBMP-2 combined with a threaded bone cage, is used to promote the growth of bone tissue in the healing process after surgery. The FDA approved Infuse in 2002 for use in anterior lumbar fusion surgery on skeletally mature patients, excluding pregnant women, but it has been widely applied off-label. In 2008, after receiving reports of serious complications, the FDA warned that the off-label use of Infuse in cervical fusion procedures was unsafe.

Nevertheless, it continued to be used in lumbar and cervical operations. Partly because bone tissue no longer had to be harvested from patients for this purpose, the number of complex fusion procedures in Medicare patients increased 15-fold from 2002 to 2007, according to a study released last year in the Journal of the American Medical Association. Today, Infuse generates about $900 million in annual revenues for Medtronic.

More recently, another product using rhBMP-2 but a different matrix device (Amplify) went before the FDA's Orthopedic and Rehabilitation Devices Panel in July 2010. The panel gave a reserved endorsement for approval for spinal fusion in degenerative disk disease, provided follow-up be performed to monitor particularly for cancer risk. In March this year, however, FDA declined approval, citing this latter risk.

In their review, based on the FDA data and more recent studies that also include data on the Amplify device, Dr. Carragee and his colleagues point out that no adverse events related to rhBMP-2 use were reported in any of the studies; the overall rate was 0%, with a 99% confidence interval of less than 0.5%.

Horse is Out of the Barn

Asked for comment on these new developments, Dr. Carragee was positive but still not certain that the Yale review will solve anything in this particular situation.

"Obviously we’re happy that [Medtronic is] going to release the data in some form and people will be able to review it," he told Medscape Medical News. "Dr. Krumholz certainly has a good concept and it could certainly be a good model for other industries to share the data in a prospective manner."

In this case, however, the retrospective review comes "way after the horse is out of the barn," he said. "The product has already been used for 10 years." And while they support the move, he added, "we do have some worries."

Primary among these is the fact that although there are a great deal of data on the use of this product in anterior lumbar procedures, all of which has been extensively reviewed already by the FDA, the bulk of its current use is off label in either the cervical spine or in procedures called posterior lumbar interbody fusions. So the usage where there is the greatest concern of hazard in the data produced by independent researchers, he noted, "Medtronic doesn't really have much data to produce."

A large trial of the use of rhBNP-2 in the Amplify product was in the posterior lumbar region, but that product is still not approved and so not yet in use.

I think the chances that that will be a comprehensive survey of the adverse events associated with BNP will be zero.

In addition, Medtronic's producing all voluntary adverse event reports since approval of the product occurs in the context of surgeons having had, for 10 years, the impression from published studies that no substantial adverse events are associated with rhBNP-2. In retrospect, Dr. Carragee has seen these adverse events regularly but over time he has never submitted one of these reports, he points out.

"So I think the chances that that will be a comprehensive survey of the adverse events associated with BNP will be zero, so I don't think we should get too excited about having a good audit of all the bad things that have happened," he said.

Still, he added, "I don't want to throw a wet blanket on this — I think it's a good idea."

Patient-Level Data; Retroactive Disclosure

In a statement released August 3, Medtronic announced the company had provided a grant to Yale to conduct "fully independent, third-party systematic reviews," of the safety and effectiveness data on rhBMP-2.

"Medtronic will provide Yale with all available patient-level data on rhBMP-2 from Medtronic-sponsored clinical trials, both published and unpublished, as well as all FDA-filed adverse event reports, for the purpose of executing an independent and comprehensive review of the entire body of evidence," the company statement notes. "Yale will assemble a panel of experts and will commission 2 academically recognized, publicly trusted clinical research organizations specializing in systematic reviews to conduct the analyses and ensure the findings are reproducible and of the highest integrity."

Further, the company pledges to voluntarily make all clinical trial results data publicly available on ClinicalTrials.gov, the clinical trials registry managed by the National Library of Medicine, and will retroactively register all data from premarket approval and postmarket clinical trials on the product that were done before the September 2007 requirement was established for registering such trials.

"Finally, Medtronic has agreed with Yale to develop a novel program to provide researchers access to all data on rhBMP-2 by means of a defined registration process and website," the company adds. "This planned program is unprecedented in the medical industry, and will differ from clinical trial publications or other data sources in that it will provide access to the full patient-level data sets possessed by Medtronic, including independent de-identified patient level data, not just the data summaries that are commonly used in meta-analysis and systematic reviews."

Rick Kuntz, MD, Medtronic's chief scientific officer, said, "Our pledge to support full access to the clinical data, in the form of independent patient-level data for the systematic reviews, retroactive registration of all trials with the National Library of Medicine, and the provision for broad investigator access of all patient-level data from Medtronic-sponsored studies, represents a novel and significant commitment to transparency and open-access scientific research."

Omar Ishrak, chairman and CEO of Medtronic said, "Integrity and patient safety are Medtronic's highest priorities, so it is important that a respected academic institution provide a publicly trusted source of information by way of these systematic reviews and the novel data access program for researchers." 

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