On Label and Off-Label Use of Bone Morphogenetic Proteins (BMPs)

CMS evidence review | evidence_type=MEDCAC Meeting | record_type=medcac_meeting | document_id=55 | meeting_date=2010-09-22

The Centers for Medicare and Medicaid Services (CMS) has called this meeting to consider the currently available evidence regarding the clinical benefits and harms of on-label and off -label use of BMPs. More than 20 BMPs have been identified, but only BMPs -2, -4, -6 and -7 have been shown to have 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 now produced using recombinant DNA technology. Currently, two recombinant BMPs have some form of FDA approval and are commercially available in the United States: rhBMP-2 and rhBMP-7. The on-label 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. There have also been a number of reports of adverse events associated with the use of BMPs.

Actions Taken: June 17, 2010 CMS announces MEDCAC meeting. Those interested can register at http://www.cms.gov/apps/events/event.asp?id=602&Kw=&Mh=NoMonth&cboOrder=date&Yr=NoYear&type=2 July 28, 2010 Posted FR notice, questions to panel and appendix . August 25, 2010 We will be broadcasting the meeting via Webinar. You must register for the Webinar portion of the meeting at https://webinar.cms.hhs.gov/bmp/event/registration.html (Updated Link) by 5 p.m. EDT, Friday, September 17, 2010. September 10, 2010 Posted technology assessment . September 20, 2010 Posted agenda , roster and speaker list . September 24, 2010 Posted scoresheet [PDF, 38KB] from meeting. November 2, 2010 Posted minutes [PDF, 137KB] and transcript [PDF, 689KB] from meeting. Agenda: Federal Register Notice Agenda Medicare Evidence Development & Coverage Advisory Committee September 22, 2010 7:30 AM - 4:30 PM CMS Auditorium Clifford Goodman, PhD, Chair Saty Satya-Murti, MD, Vice Chair Tamara Syrek Jensen, JD, Deputy Director, Coverage and Analysis Group Maria Ellis, Executive Secretary 7:30 - 8:00 AM Registration 8:00 - 8:15 AM Opening Remarks— Maria Ellis/Tamara Syrek Jensen, JD/Clifford Goodman, PhD 8:15 - 8:25 AM CMS Presentation of Voting Questions - Deirdre O’Connor 8:25 - 8:50 AM Julie Glowacki, PhD , Professor of Orthopedic Surgery, Harvard Medical School, Professor of Oral & Maxillofacial Surgery, Harvard School of Dental Medicine, Orthopedic Research, Brigham and Women’s Hospital 8:50 - 9:50 AM TA Presentation: Thomas Ratko, PhD , Associate Director, Blue Cross Blue Shield Association, Technology Evaluation Center, EPC, Washington, DC 9:50 - 10:05 AM BREAK 10:05 - 10:50 AM Scheduled Public Comments (Refer to Speaker List) Public attendees, who have contacted the executive secretary prior to the meeting, will address the panel and present information relevant to the agenda. Speakers are asked to state whether or not they have any financial involvement with manufacturers of any products being discussed or with their competitors and who funded their travel to this meeting. 10:50 - 11:05 AM Open Public Comments Public Attendees who wish to address the panel will be given that opportunity 11:05 - 12:00 PM Questions to Presenters 12:00 - 1:00 PM LUNCH (on your own) 1:00 - 2:00 PM Initial Open Panel Discussion: Dr. Goodman 2:00 - 3:00 PM Formal Remarks and Voting Questions The Chairperson will ask each panel member to state his or her position on the voting questions 3:00 - 4:00 PM Final Open Panel Discussion: Dr. Goodman 4:00 - 4:30 PM Closing Remarks/Adjournment: Tamara Syrek Jensen & Dr. Goodman Issue: The Centers for Medicare and Medicaid Services (CMS) has called this meeting to consider the currently available evidence regarding the clinical benefits and harms of on-label and off -label use of BMPs. More than 20 BMPs have been identified, but only BMPs -2, -4, -6 and -7 have been shown to have 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 now produced using recombinant DNA technology. Currently, two recombinant BMPs have some form of FDA approval and are commercially available in the United States: rhBMP-2 and rhBMP-7. The on-label 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. There have also been a number of reports of adverse events associated with the use of BMPs. Minutes: Download meeting minutes [PDF, 137KB] Other Material: Transcript 1 Panel Voting Questions: MEDCAC –September 22, 2010 On-Label and Off-Label use of Bone Morphogenetic Proteins (BMPs) Voting Questions For all voting questions, the clinically meaningful health outcomes of interest for CMS are pain, patient function and adverse events related to use of BMPs. For explanation of premarket approval (PMA) and humanitarian device exemption (HDE) on-label use of BMPs, see the attached appendix that summarizes the FDA actions and public health notification on BMPs. Off-label use is defined as any use for other than the manner or specific indications in the FDA approval. Some examples of off-label use in the lumbar spine would be: if infuse bone graft were used with a device other than the approved devices, if infuse bone graft were used for more than one level in the lumbar spine, if infuse/mastergraft or OP-1 were used in a primary lumbar fusion procedure as opposed to the approved revision fusion procedure. For the voting questions, use the following scale identifying level of confidence - with 1 being the lowest or no confidence and 5 representing a high level of confidence. 1 — 2 — 3 — 4 — 5 Low Intermediate High Confidence Confidence Confidence How confident are you that there is adequate evidence to determine whether or not the use of BMPs in each of the following indications improves at least one of the clinically meaningful health outcomes? On-label use in Lumbar spine ( FDA Ref. LS and LS HDE) Open tibial fracture ( FDA Ref. T) Recalcitrant long bone nonunions (FDA Ref. LB) Off-label use in Cervical spine Lumbar spine All other Note: Questions 2 -6 should be addressed only for those indications where the panel is confident that there is adequate evidence (mean vote of 2.5) to consider the question. How confident are you that there is adequate evidence to determine that the use of BMPs in the lumbar spine for each of the indications identified below improves at least one of the clinically meaningful health outcomes? FDA PMA on-label use (FDA Ref. LS) FDA HDE on-label use (FDA Ref. LS HDE) Off-label use How confident are you that the evidence is adequate to conclude that the use of BMPs for FDA HDE on-label use in recalcitrant long bone non-unions improves at least one of the clinically meaningful health outcomes? (FDA Ref. LB) How confident are you that the evidence is adequate to conclude that the use of BMPs for FDA PMA approved on-label use for the treatment of acute, open tibial fractures improves at least one of the clinically meaningful health outcomes? (FDA Ref. T ) How confident are you that the evidence is adequate to conclude the off-label use of BMPs in the cervical spine improves at least one of the clinically meaningful health outcomes? How confident are you that these conclusions are generalizable to: the Medicare patient population? community based settings? Discussion Questions In the absence of evidence based guidelines, what types of research are needed to address evidence gaps so that physicians can appropriately counsel patients on the risks and benefits of the use of BMPs? Download Scoresheet [PDF, 38KB] Roster: MEDCAC ROSTER September 22, 2010 Clifford Goodman, PhD CHAIR Senior Vice President The Lewin Group Saty Satya-Murti, MD, FAAN VICE CHAIR Health Policy Consultant Ray Baker, MD Clinical Professor Director of Interventional Pain Services Department of Anesthesiology University of Washington Kevin J. Bozic, MD, MBA Associate Professor in Residence University of California, San Francisco School of Medicine Department of Orthopaedic Surgery and Institute for Health Policy Studies Helen Darling, MA National Business Group on Health Charles Davis, IIII, MD, PhD Chief, Hip and Knee Joint Arthroplasty Penn State Hershey Bone and Joint Institute The Pennsylvania State University College of Medicine Jeffrey G. Jarvick, MD, MPH Professor Radiology & Neurosurgery University of Washington Susan Kendig, JD, MSN Coordinator, Woman’s Health Nurse Practitioner Program Associate Teaching Professor College of Nursing University of Missouri-St. Louis Raj Rao, MD Professor of Orthopaedic Surgery and Neurosurgery Medical College of Wisconsin Invited Guest Speaker Julie Glowacki, PhD Professor of Orthopedic Surgery Harvard Medical School Professor of Oral & Maxillofacial Surgery Harvard School of Dental Medicine Orthopedic Research Brigham and Women’s Hospital CMS Liaison Tamara Syrek-Jensen, JD Deputy Director Coverage and Analysis Group Executive Secretary Maria Ellis Coverage and Analysis Group Courtland G. Lewis, MD Orthopaedic Associates of Hartford, PC Robert McDonough, MD, JD Head, Clinical Policy Research & Developemnt Medical Policy & Program Administration National Medical Services Aetna, Inc. J. Sanford Schwartz, MD Professor of Medicine, Health Management & Economics University of Pennsylvania Andrew Sloan, MD, FACS Staff Neurosurgeon, Department of Neurosurgery University Hospitals of Cleveland Robert L. Steinbrook, MD Adjunct Associate Professor of Medicine and Community and Family Medicine Dartmouth Medical School Industry Representative Peter Juhn, MD, MPH President Therapeutic Resource Centers Medco Health Solutions, Inc. Guest Panel Members John S. Kirkpatrick, M.D., F.A.C.S. Professor and Chair Department of Orthopaedics & Rehabilitation University of Florida College of Medicine Edward Kim, MD, MBA Head, Multiple Sclerosis, Neuroscience and Psychiatry Evidence Based Medicine Novartis Pharmaceuticals Corporation Speaker List: Medicare Evidence Development & Coverage Advisory Committee September 22, 2010 SPEAKER LIST *7 MINUTES PER SPEAKER* Brian K. Kwon, MD, PhD, FRCSC , Associate Professor, Department of Orthopaedics, University of British Columbia R. Patrick Jacob, MD, FACS , Dunspaugh-Dalton Chair, Cranial and Spine Surgery, Department of Neurosurgery, University of Florida - Representing: American Association of Neurological Surgeons/Congress of Neurological Surgeons Richard Kuntz, MD , Senior Vice President of Strategy and Scientific Operations, Medtronic, Inc. William G. De Long, Jr., MD , Chief of Orthopaedic Surgery for St. Luke’s Hospital & Health Network, Bethlehem, PA - Representing: American Academy of Orthopaedic Surgeons Christopher M. Bono, MD , Chair, Professional Economic and Regulatory Committee, NASS, Associate Professor of Orthopaedic Surgery, Harvard Medical School, Chief, Orthopaedic Spine Service, Brigham and Women’s Hospital; William Mitchell, MD, Director, Health Policy Council, NASS, Board of Directors, NASS, Neurosurgeon, Coastal Spine - Representing: North American Spine Society Summary Of Fda Actions On Bmps: Appendix Summary of FDA Actions on BMPs Question Reference Date Infuse (rhBMP -2) OP-1 (rhBMP -7) Indications LS Lumbar Spine Anterior July 2, 2002 Approved PMA for Infuse Bone Graft/LT Cage (P000058) – Medtronic Sofamor Danek Spinal fusion procedures in skeletally mature patients with degenerative disc disease at one level from L4-S1 via anterior open or anterior laparoscopic approach. DDD confirmed by patient history, function deficit and/or neurological deficit and radiographic studies. May have up to Grade I. Spondylolisthesis at involved level. Should have had at least six months of nonoperative treatment prior to surgery with Infuse Bone Graft/LT Cage device. December 1, 2003 Approval for the inclusion of additional fusion cage component designs for use with the InFuse Bone Graft Component. The device as modified will include the previous device, along with InFuse Bone Graft/Inter Fix Threaded Fusion Device and Inter Fix RP Threaded Fusion Device. (P000058/S004) – Medtronic Sofamor Danek All indications are the same as the approval for the Infuse Bone Graft/LT Cage, except that these devices are only approved to be implanted via an anterior open approach. July 29, 2004 Approval for 1) the extension of the levels of use, 2) modification of the indications, 3) change in storage temperature limit and 4) revisions to instruction for use. Infuse Bone Graft –LT Cage Lumbar tapered fusion device (P000058/S002) – Medtronic Sofamor Danek Extended levels of use from L4-S1 to L2-S1. Modified indications to allow the device to be used in subjects who may have retrolisthesis in conjunction with DDD. Note; There are additional supplemental approvals to P000058 not listed here that deal with things other than indications for use, such as packaging, minor design modifications, storage temperature, etc. LS HDE Lumbar Spine Posterolateral April 7, 2004 Approved HDE (H020008) Stryker Biotech Indicated for use as an alternative to autograft in compromised patients requiring revision posterolateral (intertransverse) lumbar spinal fusion, for whom autologous bone and bone marrow harvest are not feasible or are not expected to promote fusion. Examples of compromising factors include osteoporosis, smoking and diabetes. October 10, 2008 Approved HDE for Infuse/mastergraft posterolateral revision device. (H040004) – Medtronic Sofamor Danek This device is indicated for repair of symptomatic, posterolateral spine pseudarthrosis. This device is intended to address a small subset of patients for whom autologous bone and/or bone marrow harvest are not feasible or are not expected to promote fusion. These patients are diabetics and smokers. This device is indicated to treat two or more levels of the lumbar spine where previous fusion has failed. LB Long Bone October 17, 2001 Approved HDE (H010002) – Stryker Biotech As alternative to autograft in recalcitrant long bone nonunions where use of autograft is unfeasible and alternative treatments have failed. T Tibia April 30, 2004 INFUSE PMA (P000054) – Wyeth Pharmaceuticals, Inc. Approved for treating acute, open tibial shaft fractures that have been stabilized with IM nail fixation after appropriate wound management. INFUSE Bone Graft must be applied within 14 days after the initial fracture. Prospective patients should be skeletally mature. Sinus March 9, 2007 INFUSE Bone Graft PMA (P050053) – Medtronic Sofamor Danek Indicated as an alternative to autogenous bone graft for sinus augmentations, and for localized alveolar ridge augmentations for defects associated with extraction sockets. July 1, 2008 FDA issued a public health notification regarding BMP in cervical spine fusion. The FDA warned of life-threatening complications associated with BMP when used in the cervical spine. BMP is not approved for use in the cervical spine. March 31, 2009 *FDA- Orthopedic and Rehab Devices Panel advised not to approve Stryker OP-1 (P060021) for posterolateral lumbar spinal fusion in adult patients with degenerative spondylolisthesis. *Stryker submitted an application with the FDA for OP-1 Putty spinal product and hoped for approval by late 2007. FDA requested additional data which significantly delayed the company’s expectation for approval. FDA convened an advisory committee to review this issue and did not recommend approval (2009). No further action by FDA.