Biologics Symposium

AAOS Tackles Controversies Surrounding the Use of Biologics in Orthopaedic Surgery

Constance R. Chu, MD

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 have been brought to market through 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 a recent study showed that more than 85 percent of 351 businesses, which represent 570 clinics across the country, were marketing “stem cell” treatments for orthopaedic problems. Analyses of these treatments show a diversity of offerings with most clinics using 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 (NIAMS) and held a think tank symposium on “Optimizing Clinical Use of Biologics in Orthopaedic Surgery” on Feb. 15–17. 2018, at Stanford University to accomplish the following objectives:

  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. Leaders from clinical medicine, research, and government, as well as young investigators selected through a competitive process, 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 categorization of cell therapies into two categories of “uncharacterized” roughly corresponding to the FDA 361 pathway and “characterized,” which would require FDA 351 clearance. According to many in attendance, products widely marketed and described as stem cells in the United States are uncharacterized.

Attendees also reached an agreement on the need to establish and accept clear guidelines and standards on the conduct and reporting requirements for clinical studies involving platelet rich plasma (PRP) as well as characterized and uncharacterized stem Cells. It was determined that biologic targets and clinical outcome metrics need to be disease specific. 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. Adequate participation would require appropriate incentives. For reliable generation of high-quality clinical data, it was determined that multicenter prospective clinical trials involving committed centers with appropriate volume and adequate follow-up, as well as willingness and ability to follow standardized treatment, imaging, and outcomes data collection protocols, were needed.

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.

Symposium Group Photo WEB

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