Off-label use of rhBMP-2.

Dear Sir, Dr. Nancy Epstein has summarized the experience with the Food and Drug Administration (FDA)-approved bone morphogenetic proteins, rhBMP-2 (BMP-2), marketed by Medtronic.[2] She concludes after addressing, primarily, the costs and complications that the off-label use of BMP-2 in cervical spine surgery should be re-examined with regard to indications, safety, and efficacy. While I am in agreement with these ascertained information, I am concerned that Dr Epstein is missing the tragedy, which may be developing because of the current practice of the off-labeled use of BMP-2. This unfortunate story, at its core, concerns the failure of the leadership of spinal surgery, from neurosurgery and orthopedic surgery, during the no-holds barred off-label use of BMP-2 in anterior cervical fusions. Shortly after the FDA approved the use of Medtronic's commercial version, Baskin et al. reported the results of their clinical trial of the use of BMP-2 in anterior cervical fusions with an FDA-approved investigational protocol. A total of 33 patients were randomly assigned to either the control group fused with an allograph containing autographic iliac crest bone (15 patients), or the study group fused with allograph containing BMP-2 (18 patients). Adequate fusions occurred in all patients, and there were no notable complications. The only difference between the two groups of patients was prolonged complaints of discomfort at the site of the bone harvest from the iliac crest. The investigators have concluded in their pilot study that the use of BMP-2 is sufficiently safe for it to be studied in a larger clinical study.[1] The larger study has not been performed yet. However, in the eight years since the Baskin report, there have been increasing numbers of reports of retrospective analyses of series of cases in which BMP-2 was used.[2] These reports have created a number of concerns. Increasing numbers of complications related to dysphagia and airway complaints have been reported.[4] There are recurring observations of the lack of an agreement on standards regarding dose, technique, or indications for the use of BMP-2 in the cervical spine.[7] To these concerns, those raised by Epstein regarding costs can be added. A fourth concern flows from the foregoing and that has to do with the content of any discussion carried out for the purpose of obtaining patient consent for the procedures. Regrettably, Baskin has stepped into the void created by the lack of definitive studies with a report in a recent medical liability lawsuit stating that his study, which he initially characterized as a pilot study, has established the safety, efficacy, cost effectiveness, and indications, with no new data.[3] It is recognized in the heavy regulated practice of medicine that it is often easier to sit back and let the government answer the important questions. With BMP-2, however, the FDA is unable to act, and the company has made it quite clear in the deposition given in the aforementioned lawsuit that it has no desire to act.[3] This leaves it up to the profession to act, especially if it believes that it offers some value to the patient. There is reason to believe that if BMP--2 were used appropriately, the issues of risk and cost would be settled. For example, currently, the equation of increasing risk and cost in the face of marginal, if any, improvement in the generally attainable high fusion rates in the cervical spine makes the use of BMP-2 problematic. If, however, this same equation is applied to the use of BMP-2 in salvage cases, such as those at high risk of pseudoarthroses or those with established complex pseudoarthoses, the conclusions might be more favorable.[6] Organized neurosurgery in the late 70s and early 80s, beginning with the leadership of Dr Richard Schneider, President of AANS, who raised concerns about the conflicting results from questionable studies of the use of chymopapain in chemonucleolysis, began a series of inquires with suitable panels, committees, and study groups. Those with the capability of doing so were encouraged to perform appropriate clinical studies. Eventually, support of the orthopedic surgery community was obtained and joint educational efforts were undertaken to bring the resulting data and conclusions to the members of the two specialties. Included in the list of participants were the FDA and the company. As a result, a creditable knowledge base was created, which persuaded the company that the agent was neither safe nor efficacious, and thus the FDA application was withdrawn.[5] These actions on the part of leadership were taken out of a sense of responsibility to the public, a critical element in the legitimacy of a profession. Sadly, we have not seen this from our current leaders. It should be noted that a co-author of the Baskin paper was a President of AANS. The leadership seems content to open its journals and meetings to reports of increasing risks in the face of increasing costs.[4] Unfortunately, this posture may result in decreasing availability of the agent for those studies that might demonstrate that this agent has limited, but important, places in anterior cervical fusions, or perhaps, other conditions. While some surgeons are voluntarily declining to use BMP-2 for cervical spine fusions,[7] it is reasonable to believe that in the face of high costs and risks, but marginal improvement in outcomes, a perfect storm for liability lawsuits, hospitals may elect not to permit the use of BMP-2 for fusions in the cervical spine. It could be argued that undertaking such studies would be unethical in the face of what is known of BMP-2 in the lumbar spine. This position can certainly be challenged on the basis of the difference between the local wound environment in the cervical spine and that of the lumbar spine, obvious in the different sets of complications reported.[2] Clearly, the dose, the technical use of the agent, indications for use, and its cost effectiveness need be established. This cannot be achieved with the present profile of use. Instead of supporting the current position of spine surgeons that off-label use is acceptable merely because the FDA does not have jurisdiction, the leadership of spine surgery should provide leadership.