The long and winding road for bone morphogenic proteins (BMPs) is about to reach its next destination: the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC). Most recently the journey has led BMPs through the FDA’s orthopedic panel, which resulted in a recommendation of approval for Medtronic’s Amplify.
MEDCAC Consideration
The MEDCAC committee is meeting in Baltimore on September 22 to consider whether or not adequate evidence exists to determine the clinical benefits and harms of on- and off-label uses of BMPs. This marks the committee’s first meeting to consider an orthopedic device since 2006.
Infuse/Medtronic
Specifically, the committee will look at Medtronic’s Infuse [rhBMP-2] and Stryker’s OP-1 [rhBMP-7], the only BMPs the FDA has approved as being safe and effective. Now CMS wants to determine if enough evidence exists to decide if the materials are reasonable and necessary.
OP-1/StrykerMore than 20 BMPs have been identified, but, says CMS (Centers for Medicare and Medicaid Services), only BMPs -2, -4, -6 and -7 have been shown to offer significant osteogenic properties. The main physiologic role of BMP is to promote differentiation of mesenchymal cells into chrondrocytes and osteoblasts, to promote differentiation of osteoprogenitors into osteoblasts, and to influence skeletal pattern formation.
Human BMPs are currently produced using recombinant DNA technology. CMS says the on- and off-label use of BMPs has rapidly grown since becoming clinically available in 2001. There are reports stating that up to 85% of BMP use is for off-label indications, mostly in the spine. However, a number of reports of adverse events associated with the use of BMPs have been reported.
Steven Phurrough, M.D./U.S. Government
Phurrough’s Prognostication
Steven Phurrough, M.D., is the former director of the agency’s Coverage and Analysis Group (CAG). It was under his watch that a list of potential topics for coverage determinations, including BMPs, was announced in 2008. Phurrough told OTW that his group had met with other parts of CMS for several years discussing BMP and recognized the limited amount of information on them.
“That led to its selection for inclusion on this list, ” said Phurrough.
Phurrough said CAG usually announces potential topics that are being considered from internally generated requests on a quarterly basis, and allows interested stakeholders to comment on these topics. The purpose of these announcements, he added, provides advance notice regarding potential topics that CMS is considering. The agency wanted to “create a more transparent and predictable NCD [National Coverage Determination] process, ” added Phurrough.
Why Now?
Why are BMPs on the radar now? Phurrough said, “CMS schedules MEDCACs for two major reasons: One, to support an NCD or two, to bring to the public’s attention areas where evidence is weak. CMS obviously believes that the level of evidence for use of BMP needs to be publically addressed.”
Medtronic and Stryker took their opportunity in 2008 to notify Phurrough that neither company wanted the agency to consider a NCD. There are usually only three outcomes after a MEDCAC meeting. One, the agency does nothing and continues to let local carriers decide on coverage. Two, the agency issues a negative NCD, as it did for lumbar artificial discs, then reimbursement dries up. Or three, the agency issues an NCD that requires local carriers to pay for treatments and procedures, as is the case for fusion.
What does Phurrough think will happen this time? He says he believes this MEDCAC meeting falls into the category of weak evidence and CMS is “attempting to bring to full light the state of evidence for BMP.”
Phurrough concluded:
I don’t believe that this will result in an NCD.
Phurrough, now COO/Senior Clinical Director for the Center for Medical Technology Policy in Baltimore, advises companies to “keep the reimbursement agency’s needs in mind as you design trials for regulatory approval. Don’t assume that access to the market for a limited indication will always result in access for all indications.”
Evidence of Improvements and Harm
Here is what CMS had to say about BMPs, as the agency detailed the specific questions it will ask committee members to answer on September 22.
“Members of the BMP family are potentially useful as therapeutics in areas such as spinal fusion. [Infuse] and [OP-1] have been shown in clinical studies to be beneficial in the treatment of a variety of bone-related conditions including delayed union and non-union…Certain off-label uses in cervical spine fusion may be associated with life-threatening complications. Is the evidence adequate to demonstrate health improvements in the Medicare population?”
Off-Label Warnings
In July 2008, the FDA issued a warning that it had received at least 38 reports of complications in the last four years, relating to the use of Infuse in cervical spine fusion.
Mike McCormack, Senior Manager, Reimbursement Planning for Medtronic’s Spinal and Biologics division, addressed the use of Infuse in the cervical spine in September 2008 in a public comment to Phurrough and his coverage group.
McCormack wrote that the first warning to doctors about the off-label use of Infuse was in 2004.
“As you know, because the FDA does not regulate the practice of medicine, physicians may use an FDA-approved product for off-label indications if they believe it is in the best interest of their patients.”
He noted that the majority of safety problems linked to Infuse use in the cervical spine may be due to inappropriate dosing and that using the exact volume concentration of Infuse used in lumbar interbody spine fusion may be too high of a dose for the cervical spine.
McCormack wrote that prospective studies are ongoing and designed to ensure appropriate dosage. He added that as Medtronic identifies appropriate dosages, the company believes it is important that CMS “not restrict access to rhBMP-2 for those patients that may derive benefit from it. At this time, we believe that it would be premature to initiate the NCD process on this issue.”
Stryker also notified Phurrough’s coverage group that the company wanted to “help CMS appreciate” that OP-1 need not proceed to an NCD.
Medical Society Conclusions
But perhaps the most detailed response to the Coverage Group’s request for input on NCD topics came from the Professional Society Coalition Task Force made up of the American Association of Neurological Surgeons (AANS), Congress of Neurological Surgeons (CNS), North American Spine Society (NASS), Scoliosis Research Society (SRS), and Spine Arthroplasty Society (SAS).
The task force noted in 2008 that data suggest that routine BMP use for elective anterior cervical spine surgery does not seem to be warranted. “While appropriate dosage has been proposed as a primary factor to ensure safety, the current literature is conflicted regarding this issue…There is an overwhelming paucity of data evaluating the use of BMP in the posterior cervical spine, making any recommendation regarding its routine use difficult.”
However, the task force wrote, “While the indications for the use of BMPs in spinal surgery in the Medicare population are not fully defined, substantial evidence exists supporting the efficacy and cost effectiveness of BMP in the anterior lumbar interbody fusion. Moderate and increasing evidence is being developed for its use in posterolateral fusions compared to ICBG [Iliac Crest Bone Graft]. Posterolateral fusion, in conjunction with decompression for stenosis or deformity correction, in spondylolisthesis, or degenerative scoliosis, is the most common spinal fusion technique performed in the Medicare population.”
The task force believes that BMPs are, “a reasonable and safe alternative to ICBG in anterior interbody lumbar fusion. For posterior spinal fusion, there is moderate and increasing evidence that BMP is also beneficial. We also believe that ongoing additional investigation will contribute to refinements in dose, carriers and site specific applications for these valuable biologic technologies.”
In the anterior cervical spine, the group said the evidence is limited and there remain unanswered safety concerns and the group “does not support its [BMPs] broad use except in ongoing research trials.”
Coverage Advice
In a somewhat surprising set of conclusions, since CMS only asked about the available medical evidence, the task force offered the following unsolicited coverage advice to the Phurrough coverage group.
Anterior Lumbar Fusions—Recommend coverage in Medicare and non-Medicare patients without severe osteoporosis.
Posterior/Lateral Lumbar Fusion—Delay decision pending publication of upcoming literature.
Posterior Interbody Fusion—Literature is insufficient to make recommendation. Further study should be encouraged.
Anterior Cervical Spine—The use of BMP should not be covered/approved for routine use in the cervical spine. The use of BMP for complex, revision, or salvage situations may be appropriate in certain cases. Such cases should be considered on an individual basis. Further study should be encouraged.
Posterior Cervical/Thoracic Spine—Literature is insufficient to make recommendation. Further study should be encouraged.
We hear from sources that this same coalition is developing another joint response. NASS Council Director William Mitchell, M.D., told OTW that NASS was “in the process of reviewing the BMP literature and will be preparing our findings to present to MEDCAC.”
MEDCAC Voting
The testimony before MEDCAC will be followed by a vote. Committee members will show their confidence on a scale from 1 to 5 as to whether or not there is adequate evidence to determine whether the use of BMPs for a list of indications “improves at least one of the clinically meaningful health outcomes.” To answer whether there are clinically meaningful health outcomes, CMS will center their focus on the criteria of: pain, patient function and adverse events.
The long and winding road for BMPs may lead to a homecoming. We’ll be there and leave the light on for you.
