Data Reviews Question Use of rhBMP-2 in Spinal Fusion

Megan Brooks

June 17, 2013

Recombinant bone morphogenetic protein-2 (rhBMP-2, Medtronic Inc), used to promote bone growth in spinal fusion surgery, offers little or no benefit over bone graft and may be associated with more harms, possibly including cancer, according to 2 independent reviews of Medtronic-sponsored clinical trial data.

These 2 re-examinations of the data "should greatly temper enthusiasm for rhBMP-2," Christine Laine, MD, editor-in-chief of Annals of Internal Medicine, writes in an editorial in Annals published today. The editorial is 1 of 4 accompanying the reviews.

The independent reviews are the first initiative of the Yale University Open Data Access (YODA) project that seeks to tackle the problem of unpublished and selectively published clinical trial data.

"I've been involved for years in trying to push open science," YODA project leader Harlan Krumholz, MD, told Medscape Medical News. "We can't have evidence-based medicine if so much of the evidence is behind closed doors. Our motivation is to create a platform where more data gets into the public domain."

As reported by Medscape Medical News, Medtronic has faced controversy over its studies of rhBMP-2, and there are concerns over its safety.

Medtronic is the first company to contract with YODA to allow access to all of its clinical trial data for independent analysis. "They've taken a real leadership role in the field," Dr. Krumholz said. "They released all their data to YODA, paid for the analyses, and didn't have anything else to do with it. They didn't pick the reviewers, they didn't have publication rights over the results."

Dr. Harlan Krumholz

Using an open, competitive process, YODA selected 2 research teams — one at Oregon Health & Science University (OHSU) and other at University of York, United Kingdom — to perform the data analyses of rhBMP-2.

Evidence "Misrepresented" Early On

Rongwei Fu, PhD, and the OHSU team systematically reviewed individual-patient data from all Medtronic-sponsored studies, related internal documents, documents from the US Food and Drug Administration, and other published research on rhBMP-2 in spinal fusion as compared with iliac crest bone graft (ICBG) or other bone grafts.

They found that rhBMP-2 had no efficacy advantage over ICBG and was associated with an increased risk for cancer at 24 months (risk ratio, 3.45; 95% confidence internal [CI], 1.98 - 6.00), although event rates were low and cancer was heterogenous.

The OHSU team also found evidence that early journal reports "misrepresented the effectiveness and harms through selective reporting, duplicate publication, and underreporting." They say outcome assessment was not blinded and ascertainment of harms in trials was poor and no trials were truly independent of industry sponsorship.

The York team, from the Centre for Reviews and Dissemination, reviewed individual-patient data from 12 randomized controlled trials of rhBMP-2 and extracted adverse event data from 35 published observational studies. Mark C. Simmonds, PhD, and colleagues say their aim was to determine the effectiveness and safety of rhBMP-2 for pain and spinal fusion compared with ICBG.

At 24 months, Oswestry Disability Index scores were 3.5% lower (better) with rhBMP-2 than with ICBG (95% CI, 0.5% - 6.5%) and radiographic fusion was 12% higher (95% CI, 2% - 23%), the investigators report.

However, at or shortly after surgery, pain was more common with rhBMP-2 (odds ratio, 1.78 [95% CI, 1.06 - 2.95]) and rhBMP-2 offered no clinically significant reduction in pain at 24 months.

Cancer was also more common after rhBMP-2 (relative risk, 1.98 [CI, 0.86 - 4.54]), "but the small number of events precluded definite conclusions," the reviewers say.

The York team could not rule out a bias in pain assessment because participants were not blinded to the treatment received or their fusion status. They plan to publish results of their investigation of reporting bias separately.

"We believe that it is important that clinicians explain these findings to patients so that they can make informed choices about the type of surgery they would prefer," Dr. Simmonds and colleagues conclude in their paper.

Historic Moment

"The role of rhBMP-2 in spinal surgery is still being defined," 2 orthopedic surgeons say in another editorial in the journal.

Daniel Resnick, MD, from University of Wisconsin, Madison, and Kevin J. Bozic, MD, University of California, San Francisco, say the findings of the OHSU and York reviews are important for guiding clinical decision-making. They agree that patients "should be counseled on the relative benefits and harms of each option and should be allowed to actively participate in decision-making."

On the basis of the reviews, "using either autograft or rhBMP-2 to enhance fusion rates in patients having anterior lumbar interbody fusion or posterolateral fusions seems clinically reasonable," Dr. Resnick and Dr. Bozic write.

Richard E. Kuntz, MD, chief scientific, clinical & regulatory officer at Medtronic, writes in a separate editorial that while open analyses may not reinforce the company’s own evaluations and conclusions, "all stakeholders should benefit from a transparent process that produces reliable information about the benefits and harms of the products being studied."

"As shown by Medtronic's initiation, support, and endorsement of this open-access approach with YODA, we intend to continue to advance our principles and leadership in pioneering new models of clinical research, data sharing, and transparency," Dr. Kuntz writes.

In a statement, Charles A. Mick, MD, president of the North American Spine Society, said Medtronic's "critical self-analysis is praiseworthy."

"While we should celebrate this new transparency, we must never forget what this cautionary tale has shown us: the ongoing features of our current medical research and marketing system have demonstrated a need for greater vigilance. The impact of potential conflict of interest not only compromises scientific excellence but relegates the patient to potentially biased clinical decision-making," he said.

In his own editorial, Dr. Krumholz says the publication of these 2 independent reviews "heralds a historic moment in the emerging era of open science."

"Francis Collins (MD, National Institutes of Health director) once wrote that science is progressive and self-correcting and I think that's true if the data are available. There is no opportunity for self-correction if people have privileged access to the information so that you have to trust other people rather than replicate it," Dr. Krumholz said in an interview with Medscape Medical News.

What's next for the YODA project? "Right now, we are in advanced stages of talking with 2 pharmaceutical companies to do a similar analysis of their data," Dr. Krumholz said. "The companies have looked at our data use agreement, which call for unconditional release of data, and I'm optimistic they'll sign on. I've had strong interest, we'll have to see what happens going forward."

This new report based on open access to data comes hard on the heels of a paper published online June 13 in the BMJ, in which a group of experts proposed that thousands of pages of previously confidential clinical trial documents and study reports recently made public under new freedom-of-information policies should be used to report previously unpublished "abandoned" or "invisible" trials and to correct previously misreported trials.

Ann Intern Med. 2013:158:877-889, 890-902, 910-911, 912-913, 914-915, 916-918. York et al review, Fu et al review, Krumholz editorial, Resnick/Bozic editorial, Kuntz editorial, Annals' editors editorial

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