Evolving Safety Profile of rhBMP-2 Revealed in Study

Evolving Safety Profile of rhBMP-2 Revealed in Study: "Evolving Safety Profile of rhBMP-2 Revealed in Study

Investigation Shows Actual Patient Risk 10-50 Times More Than Reported in Original Industry-Sponsored Studies

June 28, 2011 at 5:00 p.m. EST

(Burr Ridge, IL)—A critical review of 13 industry-sponsored studies on a spine surgery product found that the actual risk of adverse events was 10 to 50 times the estimates originally reported. The product in question is recombinant bone morphogenetic protein-2 (rhBMP-2), a controversial synthetic bone growth factor often used as a bone graft substitute in spine fusion surgeries. This eye-opening study, “A critical review of rhBMP-2 trials in spinal surgery: emerging safety concerns and lessons learned” is included in a special BMP-focused issue of The Spine Journal.

“Years ago, spine surgeons read the amazing reports on rhBMP-2 in trusted medical journals and eagerly began to use the product on thousands of patients for both FDA-approved and off-label uses,” said Eugene J. Carragee, MD of the Stanford University School of Medicine, Redwood City, CA and the editor in chief of The Spine Journal. “When adverse effects and even catastrophic complications began to be reported by independent researchers, whispers and then, ultimately, shouts of research and publishing improprieties started swirling. On behalf of patients, their families and spine surgeons, The Spine Journal’s editorial team felt compelled to take an independent look at this controversy.”

Dr. Carragee and The Spine Journal’s editors for Evidence & Methods, Eric L. Hurwitz, DC, PhD of the University of Hawaii in Honolulu, HI and Bradley K. Weiner, MD of The Methodist Hospital, Houston, TX, reviewed the literature published on controlled trials of rhBMP-2 use in spinal surgery from 1995 to 2010. Relevant articles as well as primary evidence from government and administrative databases (e.g., FDA, CDC) from 2000 to early 2010 were systematically reviewed and from these, additional references were added for review. Ultimately, 13 seminal industry-sponsored study publications were identified.

Serious potential problems, such as the association of rhBMP-2 with infection, sterility and cancer risks, were prominently discussed in FDA documents and hearings on these trials at the time. However, the review of the published versions of these same trials, incredibly, found a glaring absence of clinical adverse events related to rhBMP-2 use in nearly 800 study patients. In contrast, The Spine Journal’s systematic review found that rhBMP-2-related complications and adverse events, as documented in original FDA reports and subsequent publications, are conservatively 10-50 times the original estimates calculated from the industry-sponsored studies. Among those adverse events are: back and leg pain, cyst formation, disc space collapse, infection, retrograde ejaculation, implant displacement and malignancy.

The comprehensive review found four main areas of concern among the 13 original industry-sponsored studies:



* Conflicts of interest were either not reported or were unclear in each study.
* Study design appeared biased against common alternatives for spinal fusion, which could inflate the apparent benefit of the products.
* The studies included invalid claims about the risks and complications associated with using the patients’ own bone to assist fusion.
* In the larger trials, common and serious potential complications associated with the industry products were not reported.



Disclosure documents and a corporate physician registry reveal that many of the authors of these original 13 studies had significant financial associations with the product maker. Even with very limited disclosure data, the median financial association with the industry sponsor ranged from $12 to 16 million per study.

In an accompanying commentary, “Resetting standards for sponsored research: do conflicts influence results?” Dan M. Spengler, MD of Vanderbilt Medical Center and the co-founder and former editor-in-chief of the Journal of Spinal Disorders, said “Carragee et al have carefully supported their systematic review. The result is a thoroughly documented treatise that reviewed the initial experiences with rhBMP-2.” Dr. Spengler concluded the review “offers insight into the sometimes flawed processes that can occur in the development of a clinically applicable biological product.”

In a commentary, 'Folly of FDA‐approval studies for bone morphogentic protein,” Sohail Mirza, MD of the Dartmouth Medical School wrote that Carragee and his colleagues’ “conclusion is well supported by rigorously referenced evidence.” Dr. Mirza concluded that “biased research placed patients at risk for harm without clear compensatory benefit,” and asked “how do we not get fooled again?”

“Medical professionals must be able to rely on the integrity of peer-reviewed literature to keep them informed of the safety and efficacy of treatments and medicine for the benefit of their patients,” said Dr. Carragee. “Medical journals have an obligation to be watchdogs, not rubber stamps. We must have greater author and editor transparency and ask the hard questions every step of the way.”

In the spirit of that obligation, Dr. Carragee notes that one of the more controversial of the original rhBMP-2 industry studies was published in The Spine Journal in 2004. The study, “Posterior lumbar interbody fusion using recombinant human bone morphogenetic protein type 2 with cylindrical interbody cage,” was published with a disclosure that the authors were consultants for the rhBMP-2 manufacturer and that one of the authors was one of its stockholders. The article was also accompanied by a critical commentary by Neil Kahanovitz, MD that provided balance and questioned the study’s too-promising conclusions and the authors’ objectivity.

“Among medical journals, The Spine Journal has one of the most rigorous disclosure policies,” said Dr. Carragee. “All authors must provide detailed financial information about their relationships with industry and we publish that data clearly in our journal. If the ties are perceived to be too strong and the presentation unbalanced, we reserve the right to refuse to publish the research. We also often offer our readers an alternative perspective through an accompanying commentary by a qualified and independent expert on the topic in question so our readers can draw their own conclusions.”

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The Spine Journal is the scientific, peer-reviewed journal of the North American Spine Society (NASS). NASS is a multidisciplinary medical organization dedicated to fostering the highest quality, evidence-based and ethical spine care by promoting education, research and advocacy. NASS is comprised of more than 6,200 members from several disciplines including orthopedic surgery, neurosurgery, physiatry, neurology, radiology, anesthesiology, research, physical therapy and other spine care professionals. http://www.spine.org/. Find NASS on: NASS Facebook and NASS Twitter.



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