Disposition of Comments
Project ID: BMPE0109
Table 2: Public Review Comments
Anonymous Reviewer 1
|| 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.
|| 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.
||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.
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.
|| 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.
|| 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 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.
|| Complete, extensive and pertinent to the text of the body. The
references were complete and no obvious omissions were made in the reference
|| 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
- 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
- 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.
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.
||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
||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.
||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
||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.
||Introduction, Background, Methods
- Clarifications on BMP formulations, dose, and FDA status
- 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.)
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
- 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.
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
|Rutka, James, MD, PhD
- 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
- 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.