More Lessons from the BMP Trials Controversy

By: Terry Stanton

Terry Stanton

During a clinical research forum on ways to avoid wrong turns in the development of new products and therapies, members of the Orthopaedic Research Society included the issue of recombinant human bone morphogenetic protein–2 (rhBMP-2). Although various aspects of reporting the results of industry-sponsored trials have come under fire recently (See “Lessons Learned: What the BMP Trials Controversy Has Taught Us” in The Daily Edition—AAOS Now, Feb. 9, 2012), concerns about “off-label” use were also raised.

Thomas Mroz, MD, of the Cleveland Clinic, addressed some general issues associated with off-label—also called “physician-directed”—use.

BMP was discovered in 1965 by Marshall Urist, MD, but it was not until 2002 that one form, rhBMP-2, was approved by the U.S. Food and Drug Administration (FDA)—for use, and only in one-level anterior lumbar interbody fusion with an LT-Cage (Medtronic). Its use in any other procedure—cervical and thoracic fusions, posterolateral, posterior and transforaminal lumbar interbody fusions—is off-label. FDA regulations and other applicable laws recognize that physicians may prescribe or administer any legally marketed product for an off-label use, according to the physician’s well-informed medical judgment for the best interest of the patient.

Asking rhetorically, “If it works, what’s the problem?” Dr. Mroz cited the numerous problems previously detailed by Eugene J. Carragee, MD, of Stanford University, noting that many of them occurred in off-label usage and with high-dose usage. These complications included neuroinflammatory reactions of retrograde ejaculation and radiculitis, infection and wound problems, and cancer promotion or carcinogenicity.

Extrapolating from sales data, Dr. Mroz estimated that about 165,000 patients received rhBMP-2 in 2011, and 148,000 will do so this year. He estimated that two thirds of this usage is off-label. A recent survey of Spineline’s readership, for example, found that most of the responding surgeons use rhBMP-2 for various off-label fusion procedures.

The common way to obtain data about the safety and efficacy of the product is to review the literature, but Dr. Mroz noted that such a review will be based on a relatively small number of patients involved in studies, versus the large number who actually receive the product. Another consideration is the considerable heterogeneity in study design, reporting, and execution, as well as the conflict-of-interest problems outlined by Dr. Carragee.

Registries and insurance databases have great potential for following large numbers of patients, Dr. Mroz said. Theoretical merits include prospectively collected data and the ability to follow implementation of techniques and technologies in clinical practice. Such databases would also enable indications to be monitored across regions and over time and outcome comparisons to be made across regions and over time. However, he noted, such database management is complex and expensive. “The design is easy. Implementation is complex,” he said.

More transparency
Presenting an overview of the evaluation of industry-reviewed trials in the context of rhBMP-2, Kevin J. Bozic, MD, MBA, first noted that merits of industry’s involvement include its providing a source of capital, infrastructure, and risk for innovation.

“Physician-innovators, who tend to be risk-averse by nature, benefit from close collaboration with industry, which provides the capital, infrastructure, and willingness to take risk that are necessary for this type of innovation,” he said. Dr. Bozic also noted that the device industry provides much-needed support for clinical trials.

However, a number of concerns surround industry funding of clinical trials, including industry influence over selection of investigators, study design, and the dissemination of results.

Industry selection of investigators can lead to biased interpretation of results, Dr. Bozic said, noting that surgeons who receive consulting and royalty fees often have financial conflicts that may influence their objectivity in interpreting the results of a clinical trial. This issue can affect those who read manuscripts describing the results of industry-funded clinical trials, and the opinions of “thought leaders” often carry outsized influence with clinicians.

The public perception of bias is also an issue involved in industry funding, whether or not there is actually bias in the study. In terms of sharing results, Dr. Bozic noted that industry-funded research is proprietary, with no requirement for publication or dissemination. Many clinical trials that are conducted are never published; even among published trials, not all data are revealed.

Dr. Bozic chairs the Clinical Steering Committee of the Yale Open Data Access project (YODA), which is seeking to address some of the concerns with industry sponsorship of clinical research. Funded by Medtronic Inc., which manufactures the rhBMP-2 product used in the studies, the project’s stated goal is to “increase transparency and enhance the public trust in industry-funded clinical trials by facilitating the independent assessment and dissemination of data relevant to the benefits and harms of drugs and devices.”

Disclosure information: Dr. Carragee—Intrinsic Therapeutics, Simpirica; Dr. Mroz—Pearl Diver, AO Spine; Dr. Bozic: Agency for Healthcare Research and Quality, National Institutes of Health, Robert Wood Johnson Foundation, California HealthCare Foundation, Center for Health Quality and Innovation, BlueCross BlueShield Association, Integrated Healthcare Association, Pacific Business Group on Health, Ingenix, InVivo Link.