Apparent study bias in 13 original industry-sponsored clinical trials evaluating the safety and efficacy of recombinant bone morphogenetic protein-2 (rhBMP-2) raise questions about the limitations of current methods used to assess new medications and medical devices.

Editors from The Spine Journal dedicated the entire June issue to explore discrepancies between the original 13 studies, which involved 780 patients receiving rhBMP-2 and reported no rhBMP-2-associated adverse events, and subsequently published independent clinical reports and FDA documents.

In a critical review article, Eugene J. Carragee, MD, of Stanford University School of Medicine in Redwood City, Calif., and colleagues found that estimated adverse events associated with rhBMP-2 spinal fusion were 10% to 50% higher than originally reported.

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“The presentation of rhBMP-2 morbidity in the original industry-sponsored publications did not fully reflect the data available from those trials as reviewed in FDA documents and subsequent clinical reports,” the researchers wrote.

After anterior interbody lumbar fusion, patients taking rhBMP-2 had higher rates of implant displacement, subsidence, infection, urogenital events and retrograde ejaculation (which can result in infertility) than controls, according to the researchers.

Complications associated with posterior lumbar interbody fusion include radiculitis, ectopic bone formation, osteolysis and poorer overall outcomes. For posterolateral fusions, 15% to 20% of patients reported early back and leg pain, and the risk for adverse effects was equivalent to or greater than that of iliac crest bone graft harvesting.

“It is important to consider that identification of problems during the early industry sponsored lumbar trials may have averted (or at least raised concerns about) complications before significant morbidity and mortality were eventually seen with widespread use,” the researchers wrote.

In addition to failing to report rhBMP-2 complications, critics allege the original study authors failed to transparently report financial disclosures; and are guilty of publication and research misconduct; editorial board improprieties in regard to bone growth factor research; and improper representation of U.S. Senate testimony regarding rhBMP-2.

Additionally, study authors involved in early clinical trials had financial ties to rhBMP-2 manufacturer, Medtronic, with some authors receiving as much as $26 million per study, according to information provided in an editorial published in The Spine Journal.

“The history of rhBMP-2 research is a cautionary tale for all medical professionals, researchers and patients,” acting editor-in-chief, Christopher M. Bono, MD, of Brigham & Women’s Hospital in Boston, wrote. “We find ourselves at a precarious intersection of professionalism, morality and public safety.”

Bono called the publication process for new research, a “broken system.” He announced that The Spine Journal will unveil several “editorial-, procedural- and disclosure-related changes,” in upcoming issues in hopes of “achieving a better balance in critical manuscript review, conflict of interest disclosure and publication presentation.”

Earlier this week, MedPage Today reported that the U.S. Senate committee has launched an investigation to determine if doctors with financial ties to Medtronic were aware of potentially serious complications with rhBMP-2, but failed to reveal these problems in published journal articles.

EJ Carragee et al. The Spine Journal. 2011; Vol. 11, No. 6:463-468.

EJ Carragee et al. The Spine Journal. 2011; Vol. 11, No. 5: 471-491.