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.

Response to Clark Watts M.D., J.D. [Austin, Texas] commentary on the article published in Surgical Neurology International entitled: Pros, cons and costs of INFUSE in spinal surgery.

I am delighted that Dr. Watts has taken an extreme interest and aggressive stance against the inappropriate use of INFUSE. I can only agree with his opinions. However, I would like to add some points to his commentary on my article Pros, cons, and costs of INFUSE in spinal surgery.

In his first paragraph, Dr. Watts points out the tragedy which is unfolding particularly in the continued use of INFUSE in anterior cervical spine surgery. He was under the impression that I focused on cost more than INFUSE's complications in the cervical spine. However, I spent a considerable amount of space in the article under Results: Cons for INFUSE in Cervical Spine Surgery: A Literature Review, discussing the complications associated with INFUSE particularly in anterior cervical spine surgery. I begin the section noting that the complications are “well publicized.” I cited Mroz, Wang, Hashimoto et al. study that cited a 5.8% incidence of postoperative soft tissue swelling/dysphagia in instances where it was used in the anterior cervical spine.[ 2 ] In another study by Yaremchuk, Toma, Somers et al., clinical outcomes and fusion rates were compared for 260 patients having anterior surgery with INFUSE vs. 515 anterior control procedures performed without INFUSE.[ 5 ] Complications seen with INFUSE included a “significant increase in the length of stay, hospital charges, airway-related complications, (e.g. airway obstruction, reintubation, unplanned, tracheotomies, ICU admissions, hoarseness, dyspnea, respiratory failure), and the need for percutaneous gastrostomies”. Specifically acute airway obstruction attributed to INFUSE could occur on postoperative days 2-7 resulting in “unplanned intubations/tracheotomies.” The authors concluded, and I agree, that the use of INFUSE in anterior cervical surgery, therefore, posed an “unacceptable risk to respiratory function.”[ 5 ] I continued to discuss another retrospective anterior cervical series in which 35 [23.2%] of 151 patients having anterior diskectomy and fusion or anterior corpectomies with fusions developed complications associated with INFUSE.[ 4 ] Complications included 15 hematomas, 10 of which required surgical excision. Another 13 patients required longer hospital stays or readmissions due to swallowing/breathing problems or marked swelling. They concluded that INFUSE "contributed to high complication rates due to its generalized inflammatory impact." I would add that the statement that Dr. Watts refers to in his first paragraph, "the authors recommended that the indications for using INFUSE during anterior cervical surgery [should] be reassessed to determine whether it is safe in this location, at what dose, and with what morbidity", was not actually mine, but that of Shields, Raque, Glassman et al.[ 4 ]

I also cited an instance in which INFUSE utilized in the posterior cervical spine caused major complications. I refer to the article by Shahlaie and Kim in which they discuss a massive seroma resulting from a posterior occipital/cervical fusion utilizing INFUSE.[ 3 ] The authors subsequently questioned the safety of INFUSE in the posterior cervical spine.

I also commend Dr. Watt's for criticizing the study by Baskin, Ryan, Sonntag et al., in which patients undergoing anterior diskectomy/fusions were randomized to two treatment groups: 15 patients were assigned to the allograft/iliac crest bone group vs. 18 to the allograft/INFUSE group.[ 1 ] Baskin et al. observed that all patients in both groups fused without complications, but those utilizing iliac crest autograft exhibited longer lengths of stay due to iliac site pain. They went on to conclude, based on only 33 total patients [and only 18 patients utilizing INFUSE], that INFUSE was safe and effective. Shortcomings of this study include, therefore, the extremely small numbers in both groups, and an apparent total absence of notable complications. Where, for examle, are the complications cited with such high prevalence in the other anterior cervical studies utilizing INFUSE e.g. neck swelling, dysphonia, dysphagia, tracheostomy, gastrostomy, etc. Certainly, when industry sponsors research, they often hesitate to publish/disseminate negative information. Is that why it has taken several more years (e.g. 2003 vs. 2006, 2008, 2010) for many of these other complications to come to light?

In summary, as a spine surgeon, having reviewed these and other data, I agree with Dr. Watts that the use of INFUSE is contraindicated for use in the cervical spine. I thank him again for emphasizing this point.

Secondly, I appreciate Dr. Watt's views on the on-going legal battle regarding INFUSE. He noted that the “FDA is unable to act”... The main problem, he notes, is that “the company [Medtronic, Memphis, TN, USDA] made it quite clear in depositions given in the aforementioned lawsuit that is has no desire to act.” He further comments that it is, therefore, up to the profession to act. Specifically, if INFUSE were used “appropriately” and not liberally in an off-label capacity resulting in the complications cited [particularly for the cervical spine], there would be much less of a “legal” issue. Nevertheless, it frequently continues to be used off-label, and without constraint. Dr. Watt's observes that in the past, Dr. Schneider, as President of the AANS, took on chymopapain which resulted in its withdrawal from the market. Dr. Watts furthers question, where is the leadership today?

I agree. Where IS the leadership today?

References

1. Baskin DS, Ryan P, Sonntag V, Westmark R, Widmayer MA. A prospective randomized control cervical fuison study using recombinant human bone morphogenetic protein-2 with the Cornerstone-SR allograph ring and the Atlantis anterior cervical plate. Spine. 2003. 28: 1219-25

2. Epstein NE. Pros, cons, and costs of INFUSE in spinal surgery. Surg Neurol Int. 2011. 2: 10-

3. Laurie DeNeuri, Terry DeNeuri. U S District Court, Dist. SD, So. Div, Civ. 07-4172-KES. p.

4. Lu DC, Chou D, Rodts G, Mummaneni PV. Multilevel ACDF with and without BMP: A comparison of outcomes and dysphagia rates in 150 patients. J Neurosurg. 2010. 113: A406-

5. Merz B. The honeymoon is over: Spinal surgeons begin to divorce themselves from chemonucleolysis. JAMA. 1986. 256: 317-8

6. Shields LB, Raque GH, Glassman SD, Campbell M, Vitaz T, Harpring J. Adverse effects associated with high dose recombinant human bone morphogenetic protein-2 use in anterior cervical space fusion. Spine. 2006. 31: 542-7

7. Vaidya R, Carp J, Sethi A, Bartol S, Craig J, Les CM. Complications of anterior cervical discectomy and fusion using recombinant bone morphogenetic protein-2. Eur Spine J. 2007. 16: 1257-65

8. Baskin DS, Ryan P, Sonntag V, Westmark R, Widmayer MA. A prospective, randomized, controlled cervical fusion study using recombinant human bone morphogenetic protein-2 with the CORNERSTONE-SR allograft ring and the ATLANTIS anterior cervical plate. Spine. 2003. 28: 1219-25

9. Mroz TE, Wang JC, Hashimoto R, Norvell DC. Complications related to osteobiologics use in spine surgery: A systematic review. Spine. 2010. 35: S86-104

10. Shahlaie K, Kim KD. Occipitocervical fusion using recombinant human bone morphogenetic protein-2: Adverse effects due to tissue swelling and seroma. Spine. 2008. 33: 2361-6

11. Shields LB, Raque GH, Glassman SD, Campbell M, Vitaz T, Harpring J. Adverse effects associated with high-dose recombinant human bone morphogenetic protein-2 use in anterior cervical spine fusion. Spine (Phila Pa 1976). 2006. 31: 542-7

12. Yaremchuk KL, Toma MS, Somers ML, Peterson E. Acute airway obstruction in cervical spinal procedures with bone morphogenetic proteins. Laryngoscope. 2010. 120: 1954-7