Bone Morphogenetic Protein: The State of the Evidence for On-Label and Off-Label Use

Disposition of Comments

Comments received from draft review on Bone Morphogenetic Protein: The State of the Evidence for On-Label and Off-Label Use.

Project ID: BMPE0109

Table 2: Public Review Comments

Reviewer Name¹	Reviewer Affiliation²	Section³	Reviewer Comments	Author Response⁴
Anonymous Reviewer 1	NA	General	This is a comprehensive review of the state of the evidence of on and off-label use of bone morphogenetic protein. This report is well written, to the point and well documented scientifically. I have been working in this field for over twenty five years and there are no grievous omissions in their background section or references. The report is well organized and broken into easily discernible sections and the Result section focuses on 10 Key Questions which have been identified by the group and pertinent to this body of knowledge. I concur with the assessment and the Key Questions. These have been carefully formulated and documented. The summaries and conclusions seem to be well supported and I believe the report to be objective. I did not see any sections that indicated investigator bias on the part of the team members. Therefore, in general I would rate the overall report as outstanding, objective and technically accurate.	We appreciate the comments. No further response.
		Executive Summary	The executive summary is precise, clearly written and outlines the medical aspects of the search and the methods in which the Key Questions were formulated and answered which is clearly illustrated in a summary table which evaluates the Key Questions and Conclusions. This is very easily readable and the conclusions are based on sound scientific evidence.
		Introduction/Background	The Introduction/Background is to the point covering specific areas in which the “products” can applied as a substitute for bone graft. It is well referenced. Additionally, the indications for the FDA approvals are clearly outlined and referenced. I do not see any glaring omissions in this introduction and background section.
		Methods	The Methods Section was clearly delineated, understandable and thoroughly covered all the areas of interest. Additionally, the group outlined specific questions, and gave appropriate references, and provided data analysis mechanisms of rating the body of evidence. I found this approach to be clearly stated and provided objectivity.
		Results	Search results were clearly documented in the body of the text, as well as in numerous tables which were easy to read and well referenced. The statistical analysis and powers, emphasizes are clearly stated in the evidence that is presented according to the various key questions that were posed by the group. I found these questions, tables, and information to be accurate and clearly written. I thought this was an outstanding section and the approach allowed for logical conclusions and well documented judgments.
		Discussion/Conclusion	Summary and Discussion/Conclusion section is precise to the point and easy to interpret and verify. I found this easy to follow and based on my own knowledge of it by the work and their methods believe that they came to logical rational conclusions based on scientific evidence.
		Tables	Tables were detailed, many in number, however they were easy to read and referred back to specific points in the text. I believe these were supportive, although tedious to read.
		Figures	N/A
		Appendices	Complete, extensive and pertinent to the text of the body. The references were complete and no obvious omissions were made in the reference list.
Anonymous Reviewer 2	NA	General	I and each of the five other spine surgeons in my hospital routinely use BMP for interbody and posterior lateral onlay fusions. It works. The goal of the surgery is fusion.	No response
Baker, Ray MD	NASS	Results	Our main critique focuses on the need for clarification about the surgical approach implied by on-label and off-label use, as detailed in the executive summary. For example, in the response to question number 6, the authors cite studies that have demonstrated "cervical swelling" with use of BMP in the cervical spine. This, according to the studies cited, is quite specific to the anterior cervical approach. This should be made clearer in the executive summary. The same critique applies to the statements about off-label use in the lumbar spine. Presumably, this is BMP for posterolateral fusion or posterior lumbar interbody fusion. This distinction should be made clearer. Reasonable interpretation and extrapolation of the data supporting BMP-2 use inside an LT cage would support that use of BMP-2 in other cages or interbody implants has similar efficacy and results and should therefore not be categorized as a similar off-label indication as posterior lumbar fusion.	So noted, with text and tables revised as suggested. So noted, text and tables were revised to reflect these in the RCTs. Summary conclusions and GRADE tables were revised to reflect the changes. We acknowledge Dr. Baker may be correct in his assertion, but the assessment was based on strict adherence to the FDA-approved marketing label for each BMP product.
Callaghan, John MD, et al.	AAOS	Conclusions	The key questions were adequately developed and the summaries were consistent with study data, however, the conclusions presented are vague and are inadequate to support clinical decision-making. The lack of specificity may be attributable to the need for more research describing outcomes and opportunities for BMP usage.	The conclusions were based on analysis of the body of evidence for each use according to the AHRQ-modified GRADE convention. They reflect the quality and extent of published literature at the time the assessment was prepared.
		Results	We would like to note that packaging problems occurred during initial shipments of OP-1 and this quality control issue may have affected the efficacy of the product. Further, there are current concerns over the percentage content of BMP in comparable commercially prepared dosages. The technology assessment does not discuss variations in BMP dosages, which may generate bias in the literature.	Agreed. However, we are not aware of any controlled studies that were designed to investigate the effect of dose on clinical outcomes. We recorded doses used as available, but synthesis of this information is complicated by variability in study design and quality, patient characteristics, and actual use of BMP (i.e., with bone graft extenders).
		Cost-Effectiveness Analysis	We acknowledge the difficulty to assess cost since all applications may not be specifically coded as BMP. However, cost-effectiveness studies used in this TA may not have taken into consideration the costs of rehabilitation, amputation, repeated surgery and prosthetic fittings. Evaluations of alternative therapies demand such factors should be considered to provide a balanced assessment of the options.	We were limited by the available data sources on the occurrence of secondary interventions. No data sources addressed the occurrence of rehabilitation, amputation and prosthetic fittings. We chose to model outcomes for which we had evidence.
Kemner, Jason	Medtronic, Inc.	Introduction, Background, Methods	No comment	No response
		Results	Clarifications on BMP formulations, dose, and FDA status were provided. Similarly, we would like to note a discrepancy regarding the notation used for Stryker’s OP-1 formulations. It is noted in several locations that this product is rhBMP7/ACS (for example, page App1-127). This product uses a different carrier from that used in INFUSE Bone Graft. It is a granular collagen carrier that is derived from bovine bone as compared to the ACS, which is derived from bovine tendon and is a contiguous sheet. Also, in Table 36, the first column is mislabeled for Jones et al. (Ref # 90) and Boraiah et al. (Ref # 108). These should be labeled as BMP2 Studies. On page 29, and in other areas of the report ?Reference 73? (Dawson 2009) is categorized as an on-label application of rhBMP-2. This is an important piece of evidence and should be included in the assessment. However, this particular study evaluated rhBMP-2 in an application that has not been approved by the FDA and should be included in the off-label category. The review of clinical literature in the report does not include the long-term follow up data of those included in the ALIF IDE trial. The following citation provides important data regarding the long-term results of those treated with INFUSE Bone Graft. (Burkus JK, Gornet MF, Schuler TC, Kleeman TJ, Zdeblick TA, Six-Year Outcomes of Anterior Lumbar Interbody Arthrodesis with Use of Interbody Fusion Cages and Recombinant Human Bone Morphogenetic Protein-2. J Bone Joint Surg Am., 91:1181-1189, 2009.) On pages 16 and 17, the report identifies an INFUSE Bone Graft MasterGraft 2008 HDE device approval for symptomatic, posterolateral lumbar spine pseudoarthrosis among patients for whom autologous bone and/or bone marrow harvest are not feasible or are not expected to promote fusion, such as diabetics and smokers. This HDE approval was voluntarily withdrawn by Medtronic in early 2010. This action was not the result of any quality or safety concerns identified by Medtronic or the Agency. Please update the assessment regarding the voluntary HDE approval withdrawal.	Clarifications were noted and text was revised to reflect this input. Text was revised to reflect this comment. Table was revised to address this comment. Text, tables, and conclusions were revised to reflect this discrepancy. This did not alter conclusions. We became aware of this paper after the draft was prepared. Upon examination, we determined its results do not change the assessment conclusions but do footnote it in the Results chapter. This comment was addressed in revised text and tables.
		Cost-Effectiveness Analysis	The base case cost-effectiveness analyses, which are conducted from the perspective of Medicare, are the primary analyses. As reported in Tables 50 and 53, the base case cost-effectiveness analyses of spinal fusion and open tibial repair find BMP to be the dominant strategy compared to the standard of care, thus yielding lower costs and higher quality-adjusted life years. The results of the base case analyses are not included in the executive summary table page 9. While a discussion of the sensitivity analyses may not be inappropriate in the executive summary, the primary focus should be the results of the base case analyses. The base case is consistent with the necessary assumptions of a Medicare perspective cost-effectiveness analysis which is that spine fusion cases performed with or without BMP are assigned to the same DRGs and thus generally receive the identical payment amount. The same is true for tibial repair cases performed with or without BMP. In the general context of the Medicare payment system, the dominant findings from the base-case cost-effectiveness analyses should be noted in the executive summary. Additionally, in Table 44 and thus within the CEA, invasive secondary interventions of bone graft, exchange nail or plate fixation may more likely be inpatient encounters with costs reflective of a DRG payment. This may better reflect clinical practice and associated costs and could influence results of the base case as well as sensitivity analyses.	The opening paragraph of the executive summary section on the cost-effectiveness analyses has been revised as follows: When base case analyses assume identical initial hospitalization costs within the Medicare diagnosis-related group payment system, use of rhBMP-2 dominates the alternative strategy for both open tibial fracture ans spinal fusion. In sensitivity analyses, the incremental cost-effectiveness ratios (ICERs) for both open tibial fracture and spinal fusion are highly influenced by the assumed added cost of rhBMP2 Evidence was lacking on whether secondary interventions were performed in outpatient or inpatient settings. We decided to assume secondary interventions were performed as outpatient procedures as a conservative approach.
		Discussion/Conclusion, Tables, Figures, Appendices, References	No comment	No response
Rutka, James, MD, PhD	AANS	Results	The assessment qualified the FDA HDE approval for rhBMP7 as follows: “the use of OP-1 Putty will not expose patients to an unreasonable or significant risk of illness or injury and the probable benefit to health from using the device outweighs the risk of illness or injury”. Major issues dealing with the use of BMP as an adjunct to spinal fusion, however, remain unaddressed by this assessment and the current literature. Identified risk factors for failed fusion surgery include: Cigarette smoking, diabetes, osteoporosis, dialysis dependent renal disease, etc. Individuals with these characteristics are typically excluded from the majority of clinical trials because of their propensity to develop a non-union. Nonetheless, these patients, often because of these risk factors, require spinal fusion surgery due to disabling symptoms. The potential for BMP to enhance fusion rates, as demonstrated in many studies and reported in this assessment, may prove to be a significant clinical benefit to these patients and likely result in a reduced need for revision surgeries. Also not addressed in this assessment are patients who have had bone graft harvested previously and therefore have limited availability of autograft bone. Under these circumstances, allograft bone offers insufficient fusion potential and the compassionate use of BMP is appropriate. Another group not discussed in this review are patients who for religious or cultural reasons or for concerns over the risk of transmission of infectious agents refuse cadaveric allograft yet still have a need for bone graft during surgery. Unfortunately, many of these clinical situations arise with such a low frequency that generating valid medical evidence may prove difficult if not impossible.	The language was taken from the FDA Approval Summary We agree with Dr. Rutka, but identified no study that specifically addressed these patient factors. Again, we agree with Dr. Rutka. BMP would seem to provide a good alternative for patients with these characteristics, but studies addressing these issues were not identified.

¹Names are alphabetized by last name. Those who did not disclose name are labeled "Anonymous Reviewer 1," "Anonymous Reviewer 2," etc..
² Affiliation is labeled "NA" for those who did not disclose affiliation.
³ If listed, page number, line number, or section refers to the draft report.
⁴ If listed, page number, line number, or section refers to the final report.

Page last reviewed September 2012

Internet Citation: Bone Morphogenetic Protein: The State of the Evidence for On-Label and Off-Label Use: Disposition of Comments. September 2012. Agency for Healthcare Research and Quality, Rockville, MD. http://archive.ahrq.gov/research/findings/ta/comments/misccomments/bmpetab2.html