Clinical use of biologics to treat orthopaedic problems has greatly outpaced the evidence. This rise is primarily due to widespread use of “minimally manipulated” autologous therapies that are either blood products or have been interpreted as falling within the Public Health Service Act Section 361 pathway, which does not require premarket approval from the U.S. Food and Drug Administration (FDA).

Concerns over misinformation from direct-to-consumer marketing of unproven treatments have led to recent calls to action from government and scientific agencies, including the National Academy of Sciences and the American Association for the Advancement of Science.

These calls to action are of special relevance to orthopaedics because more than 85 percent of 351 businesses, representing 570 clinics across the country, were marketing “stem cell” treatments for orthopaedic problems. Analyses of these treatments show diverse offerings. Most clinics use autologous, “minimally manipulated” preparations that do not contain clinically significant numbers of stem cells. Widespread use of these cash-for-service, unproven, and poorly described treatments raise concerns for public health and safety.

The Academy collaborated with the National Institutes of Arthritis, Musculoskeletal, and Skin Diseases in holding a symposium on “Optimizing Clinical Use of Biologics in Orthopaedic Surgery” on Feb. 15–17, 2018, at Stanford University. The objectives were the following:

1. establish a clear, collective impact agenda for the clinical evaluation, use, and, optimization of biologics in orthopaedics
2. develop a guidance document on clinically meaningful endpoints and outcome metrics for the evaluation of biologics for common orthopaedic problems

The symposium addressed key issues including poor definition of treatments and mechanisms of action; lack of standardized data and outcomes collection and reporting in existing clinical studies; and minimal evidence to support the myriad of ailments treated with these products. Attendees included leaders from clinical medicine, research, and government. Young investigators, selected through a competitive process, also participated in the event.

The attendees reached consensus regarding the need to clarify terminology surrounding the types of products being used. In particular, they identified the need to clarify “stem cell.” They also discussed the importance of basic division of cell therapies into two categories:

1. uncharacterized: minimally manipulated products, which roughly corresponds to the FDA 361 pathway
2. characterized: evaluated in laboratories and would require FDA 351 clearance

According to many in attendance, products widely marketed and described as stem cells in the United States are uncharacterized, which means that the cellular and protein composition of the administered product are unknown.

Attendees agreed that clear guidelines and standards on the conduct and reporting requirements for clinical studies involving platelet-rich plasma (PRP), as well as characterized and uncharacterized cell products, are needed. Disease-specific biologic targets and clinical outcome are also needed. Prior work arising from a previous AAOS symposium on the minimum information to report for studies evaluating PRP and mesenchymal stem cells were reviewed. Work groups recommended candidate biologic targets and clinical outcome metrics including imaging metrics for treatment of chronic tendon injuries, acute ligament and muscle injuries, knee osteoarthritis, and surgical soft tissue repairs. These initial guidelines are in development.

The use of registries and biorepository-linked registries to generate clinical evidence on the use of biologics in orthopaedics was examined. Several registry models that could provide pathways for obtaining data on practice patterns and early warning of potential issues include the American Joint Replacement Registry, the Kaiser Registry, and the International Cartilage Repair Registry. A biorepository-linked registry similar to what has been established at the Veterans Hospital in Palo Alto, Calif., where samples from the actual PRP administered are stored for later comparison with clinical outcomes was discussed as a model. Adequate participation to yield quality clinical data would require appropriate incentives. For reliable generation of high-quality clinical data, multicenter prospective clinical trials are needed. These trials would involve committed centers with appropriate volume and adequate follow-up, as well as a willingness and ability to follow standardized treatment, imaging, and outcomes data collection protocols.

Finally, a patient panel highlighted the tremendous demand and need for effective treatments to alleviate musculoskeletal pain, particularly from degenerative conditions such as tendinopathy and osteoarthritis. There was agreement that substantial clinical evidence supports classifying Osteoarthritis as a serious condition for which adequate treatment is lacking in concurrence with the position of the Osteoarthiritis Research Society International. Attendees also discussed international models for accelerating regulatory approval for characterized cell therapies. And finally, the potential role of a registry in assisting with postmarket surveillance of products approved through an accelerated process requires additional evaluation.

Constance Chu, MD, is professor and vice chair of research in the Department of Orthopaedic Surgery at Stanford University. She is also the director of the Joint Preservation Center and chief of Sports Medicine at the VA Palo Alto.

References:

1. www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/
2. Sipp D, Caufield T, Kaye J, Barfoot J, Blackburn C, Chan S, De Luca M, Kent A, McCabe C, Munsie M, Sleeboom-Faulkner M, Sugarman J, van Zimmeren E, Zarzeczny A, and Rasko JEJ. Marketing of unproven stem cell–based interventions: A call to action. Science Translational Medicine 05 Jul 2017: Vol. 9, Issue 397, eaag0426. DOI: 10.1126/scitranslmed.aag0426
3. Turner L, Knoepfler P. Selling Stem Cells in the USA: Assessing the Direct-to-Consumer Industry. Cell Stem Cell. 2016 Aug 4;19(2):154-7. doi: 10.1016/j.stem.2016.06.007. Epub 2016 Jun 30.
4. Chu CR, Fortier LA, Williams A, Payne KA, McCarrel TM, Bowers ME, Jaramillo D. Minimally Manipulated Bone Marrow Concentrate Compared with Microfracture Treatment of Full-Thickness Chondral Defects: A One-Year Study in an Equine Model. J Bone Joint Surg Am. 2018 Jan 17;100(2):138-146. doi: 10.2106/JBJS.17.00132
5. www.aaos.org/2018_biologics/
6. LaPrade RF, Dragoo JL, Koh JL, Murray IR, Geeslin AG, Chu CR. AAOS Research Symposium Updates and Consensus: Biologic Treatment of Orthopaedic Injuries. J Am Acad Orthop Surg. 2016 Jul;24(7):e62-78. doi: 10.5435/JAAOS-D-16-00086. www.ncbi.nlm.nih.gov/pubmed/27227987
7. Murray IR, Geeslin AG, Goudie EB, Petrigliano FA, LaPrade RF. Minimum Information for Studies Evaluating Biologics in Orthopaedics (MIBO): Platelet-Rich Plasma and Mesenchymal Stem Cells. J Bone Joint Surg Am. 2017 May 17;99(10):809-819. doi: 10.2106/JBJS.16.00793
8. “Platelet-Rich Plasma (PRP).” OrthoInfo. American Academy of Orthopaedic Surgeons. September 2011. http://orthoinfo.aaos.org/topic.cfm?topic=A00648. Accessed 8/2017.
9. “Osteoarthritis: A Serious Disease.” www.oarsi.org/sites/default/files/docs/2016/oarsi_white_paper_oa_serious_disease_121416_1.pdf