Bone Morphogenetic Protein: The State of the Evidence for On-Label and Off-Label Use
Disposition of Comments
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.|
|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.|
|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.
|Baker, Ray MD||NASS||Results||
|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|
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||
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.