Laxmaiah Manchikanti, Christopher J Centeno1, Sairam Atluri2, Sheri L Albers3, Shane Shapiro4, Gerard A Malanga5, Alaa Abd-Elsayed6, Mairin Jerome7, Joshua A Hirsch8, Alan D Kaye9, Steve M Aydin10, Douglas Beall11, Don Buford12, Joanne Borg-Stein13, Ricardo M Buenaventura14, Joseph A Cabaret15, Aaron K Calodney16, Kenneth D Candido17, Cameron Cartier18, Richard Latchaw3, Sudhir Diwan19, Ehren Dodson20, Zachary Fausel1, Michael Fredericson21, Christopher G Gharibo22, Mayank Gupta23, Adam M Kaye, Nebojsa Nick Knezevic24, Radomir Kosanovic25, Matthew Lucas25, Maanasa V Manchikanti26, R Amadeus Mason27, Kenneth Mautner28, Samuel Murala25, Annu Navani29, Vidyasagar Pampati30, Sarah Pastoriza1, Ramarao Pasupuleti31, Cyril Philip32, Mahendra R Sanapati33, Theodore Sand34, Rinoo V Shah, Amol Soin35, Ian Stemper36, Bradley W Wargo37, Philippe Hernigou38. 1. Centeno-Schultz Clinic. 2. Tri State Spine Care Institute. 3. Radiology Research and Consultation. 4. Department of Orthopedic Surgery, Mayo Clinic. 5. Department of Physical Medicine and Rehabilitation, Rutgers School of Medicine, NJ Medical School, Newark, NJ, and Partner, New Jersey Regenerative Institute, Cedar Knolls, NJ. 6. Department of Anesthesiology University of Wisconsin, School of Medicine and Public Health, Madison, WI. 7. Interventional Orthopedics, Centeno-Schultz Clinic. 8. Massachusetts General Hospital and Harvard Medical School, Boston, MA. 9. LSU Health Science Center, New Orleans. 10. Manhattan Spine and Pain Medicine, New York, NY, and Hofstra-North Shore/LIJ School of Medicine, New York, NY. 11. Clinical Radiology of Oklahoma, Edmond, OK. 12. The Texas Orthobiologic Institute. 13. Department of Physical Medicine & Rehabilitation, Harvard Medical School. 14. Pain Relief of Dayton, Centerville, OH, and Clinical Associate Professor, Department of Surgery, Wright State University School of Medicine, Dayton, OH. 15. Genesis Pain Specialist. 16. Precision Spine Care, Tyler, TX. 17. Department of Anesthesiology, Advocate Illinois Masonic Medical Center and Professor of Clinical Surgery and Anesthesia, University of Illinois College of Medicine. 18. Dr. Attaman PLLC. 19. Advanced Spine on Park Avenue. 20. Research & Development, Regenexx, LLC. 21. Department of PMR Sports Medicine, Stanford University. 22. Department of Anesthesiology, Perioperative Care and Pain Medicine, New York University Langone Health, New York, NY. 23. Neuroscience Research Center, LLC. 24. Vice Chair for Research and Education, Department of Anesthesiology and Pain Management, Advocate Illinois Masonic Medical Center, Clinical Associate Professor of Anesthesiology and Surgery at University of Illinois, Chicago, IL. 25. Pain Management Centers of America. 26. University of Kentucky, Lexington KY. 27. Department of Orthopaedics & Family Medicine, Emory Orthopaedics, Sports, Spine. 28. Department of Orthopaedics, Emory University. 29. Comprehensive Pain Management Center, Campbell, CA. 30. Pain Management Centers of America, Paducah, KY. 31. Center for Pain Management. 32. Advocate Illinois Masonic Medical Center. 33. Pain Management Centers of America, Evansville, IN. 34. Cellular Therapies & Regulatory, Gallant Pet, Inc. 35. Ohio Pain Clinic. 36. Regenexx, LLC. 37. Department of Interventional and Non-Interventional Pain Management, OrthoSouth Surgery Center. 38. Orthopedic Surgery, University of Paris Est.
Abstract
BACKGROUND: The use of bone marrow concentrate (BMC) for treatment of musculoskeletal disorders has become increasingly popular over the last several years, as technology has improved along with the need for better solutions for these pathologies. The use of cellular tissue raises a number of issues regarding the US Food and Drug Administration's (FDA) regulation in classifying these treatments as a drug versus just autologous tissue transplantation. In the case of BMC in musculoskeletal and spine care, this determination will likely hinge on whether BMC is homologous to the musculoskeletal system and spine. OBJECTIVES: The aim of this review is to describe the current regulatory guidelines set in place by the FDA, specifically the terminology around "minimal manipulation" and "homologous use" within Regulation 21 CFR Part 1271, and specifically how this applies to the use of BMC in interventional musculoskeletal medicine. METHODS: The methodology utilized here is similar to the methodology utilized in preparation of multiple guidelines employing the experience of a panel of experts from various medical specialties and subspecialties from differing regions of the world. The collaborators who developed these position statements have submitted their appropriate disclosures of conflicts of interest. Trustworthy standards were employed in the creation of these position statements. The literature pertaining to BMC, its effectiveness, adverse consequences, FDA regulations, criteria for meeting the standards of minimal manipulation, and homologous use were comprehensively reviewed using a best evidence synthesis of the available and relevant literature. RESULTS/Summary of Evidence: In conjunction with evidence-based medicine principles, the following position statements were developed: Statement 1: Based on a review of the literature in discussing the preparation of BMC using accepted methodologies, there is strong evidence of minimal manipulation in its preparation, and moderate evidence for homologous utility for various musculoskeletal and spinal conditions qualifies for the same surgical exemption. Statement 2: Assessment of clinical effectiveness based on extensive literature shows emerging evidence for multiple musculoskeletal and spinal conditions. • The evidence is highest for knee osteoarthritis with level II evidence based on relevant systematic reviews, randomized controlled trials and nonrandomized studies. There is level III evidence for knee cartilage conditions. • Based on the relevant systematic reviews, randomized trials, and nonrandomized studies, the evidence for disc injections is level III. • Based on the available literature without appropriate systematic reviews or randomized controlled trials, the evidence for all other conditions is level IV or limited for BMC injections. Statement 3: Based on an extensive review of the literature, there is strong evidence for the safety of BMC when performed by trained physicians with the appropriate precautions under image guidance utilizing a sterile technique. Statement 4: Musculoskeletal disorders and spinal disorders with related disability for economic and human toll, despite advancements with a wide array of treatment modalities. Statement 5: The 21st Century Cures Act was enacted in December 2016 with provisions to accelerate the development and translation of promising new therapies into clinical evaluation and use. Statement 6: Development of cell-based therapies is rapidly proliferating in a number of disease areas, including musculoskeletal disorders and spine. With mixed results, these therapies are greatly outpacing the evidence. The reckless publicity with unsubstantiated claims of beneficial outcomes having putative potential, and has led the FDA Federal Trade Commission (FTC) to issue multiple warnings. Thus the US FDA is considering the appropriateness of using various therapies, including BMC, for homologous use. Statement 7: Since the 1980's and the description of mesenchymal stem cells by Caplan et al, (now called medicinal signaling cells), the use of BMC in musculoskeletal and spinal disorders has been increasing in the management of pain and promoting tissue healing. Statement 8: The Public Health Service Act (PHSA) of the FDA requires minimal manipulation under same surgical procedure exemption. Homologous use of BMC in musculoskeletal and spinal disorders is provided by preclinical and clinical evidence. Statement 9: If the FDA does not accept BMC as homologous, then it will require an Investigational New Drug (IND) classification with FDA (351) cellular drug approval for use. Statement 10: This literature review and these position statements establish compliance with the FDA's intent and corroborates its present description of BMC as homologous with same surgical exemption, and exempt from IND, for use of BMC for treatment of musculoskeletal tissues, such as cartilage, bones, ligaments, muscles, tendons, and spinal discs. CONCLUSIONS: Based on the review of all available and pertinent literature, multiple position statements have been developed showing that BMC in musculoskeletal disorders meets the criteria of minimal manipulation and homologous use. KEY WORDS: Cell-based therapies, bone marrow concentrate, mesenchymal stem cells, medicinal signaling cells, Food and Drug Administration, human cells, tissues, and cellular tissue-based products, Public Health Service Act (PHSA), minimal manipulation, homologous use, same surgical procedure exemption.
BACKGROUND: The use of bone marrow concentrate (BMC) for treatment of musculoskeletal disorders has become increasingly popular over the last several years, as technology has improved along with the need for better solutions for these pathologies. The use of cellular tissue raises a number of issues regarding the US Food and Drug Administration's (FDA) regulation in classifying these treatments as a drug versus just autologous tissue transplantation. In the case of BMC in musculoskeletal and spine care, this determination will likely hinge on whether BMC is homologous to the musculoskeletal system and spine. OBJECTIVES: The aim of this review is to describe the current regulatory guidelines set in place by the FDA, specifically the terminology around "minimal manipulation" and "homologous use" within Regulation 21 CFR Part 1271, and specifically how this applies to the use of BMC in interventional musculoskeletal medicine. METHODS: The methodology utilized here is similar to the methodology utilized in preparation of multiple guidelines employing the experience of a panel of experts from various medical specialties and subspecialties from differing regions of the world. The collaborators who developed these position statements have submitted their appropriate disclosures of conflicts of interest. Trustworthy standards were employed in the creation of these position statements. The literature pertaining to BMC, its effectiveness, adverse consequences, FDA regulations, criteria for meeting the standards of minimal manipulation, and homologous use were comprehensively reviewed using a best evidence synthesis of the available and relevant literature. RESULTS/Summary of Evidence: In conjunction with evidence-based medicine principles, the following position statements were developed: Statement 1: Based on a review of the literature in discussing the preparation of BMC using accepted methodologies, there is strong evidence of minimal manipulation in its preparation, and moderate evidence for homologous utility for various musculoskeletal and spinal conditions qualifies for the same surgical exemption. Statement 2: Assessment of clinical effectiveness based on extensive literature shows emerging evidence for multiple musculoskeletal and spinal conditions. • The evidence is highest for knee osteoarthritis with level II evidence based on relevant systematic reviews, randomized controlled trials and nonrandomized studies. There is level III evidence for knee cartilage conditions. • Based on the relevant systematic reviews, randomized trials, and nonrandomized studies, the evidence for disc injections is level III. • Based on the available literature without appropriate systematic reviews or randomized controlled trials, the evidence for all other conditions is level IV or limited for BMC injections. Statement 3: Based on an extensive review of the literature, there is strong evidence for the safety of BMC when performed by trained physicians with the appropriate precautions under image guidance utilizing a sterile technique. Statement 4: Musculoskeletal disorders and spinal disorders with related disability for economic and human toll, despite advancements with a wide array of treatment modalities. Statement 5: The 21st Century Cures Act was enacted in December 2016 with provisions to accelerate the development and translation of promising new therapies into clinical evaluation and use. Statement 6: Development of cell-based therapies is rapidly proliferating in a number of disease areas, including musculoskeletal disorders and spine. With mixed results, these therapies are greatly outpacing the evidence. The reckless publicity with unsubstantiated claims of beneficial outcomes having putative potential, and has led the FDA Federal Trade Commission (FTC) to issue multiple warnings. Thus the US FDA is considering the appropriateness of using various therapies, including BMC, for homologous use. Statement 7: Since the 1980's and the description of mesenchymal stem cells by Caplan et al, (now called medicinal signaling cells), the use of BMC in musculoskeletal and spinal disorders has been increasing in the management of pain and promoting tissue healing. Statement 8: The Public Health Service Act (PHSA) of the FDA requires minimal manipulation under same surgical procedure exemption. Homologous use of BMC in musculoskeletal and spinal disorders is provided by preclinical and clinical evidence. Statement 9: If the FDA does not accept BMC as homologous, then it will require an Investigational New Drug (IND) classification with FDA (351) cellular drug approval for use. Statement 10: This literature review and these position statements establish compliance with the FDA's intent and corroborates its present description of BMC as homologous with same surgical exemption, and exempt from IND, for use of BMC for treatment of musculoskeletal tissues, such as cartilage, bones, ligaments, muscles, tendons, and spinal discs. CONCLUSIONS: Based on the review of all available and pertinent literature, multiple position statements have been developed showing that BMC in musculoskeletal disorders meets the criteria of minimal manipulation and homologous use. KEY WORDS: Cell-based therapies, bone marrow concentrate, mesenchymal stem cells, medicinal signaling cells, Food and Drug Administration, human cells, tissues, and cellular tissue-based products, Public Health Service Act (PHSA), minimal manipulation, homologous use, same surgical procedure exemption.
Authors: Rajesh N Janapala; Laxmaiah Manchikanti; Mahendra R Sanapati; Srinivasa Thota; Alaa Abd-Elsayed; Alan D Kaye; Joshua A Hirsch Journal: J Pain Res Date: 2021-09-10 Impact factor: 3.133