Getting Products to Market: Understanding and Navigating the Regulatory Pathway

Abstract

Orthobiologics are products that include growth factors, stem cells, and matrices that are designed to alleviate symptoms and improve function in the setting of musculoskeletal injury. In the United States, biologics are regulated by the Food and Drug Administration’s (FDA)’s Center for Biologics Evaluation and Research (CBER). In 1997, the CBER established a tiered regulatory framework for the management of human cells, tissues, cellular, and tissue-based products based on perceived risk. Products are separated into those exempted from regulation, those seen as low risk (section 361 products), and those seen as higher risk (section 351 products). The distinctions between section 361 and 351 products are primarily based on the extent to which they are manipulated, used for a nonhomologous purpose, combined with other products, and elicit a systemic effect. Higher risk products require more concrete data supporting product safety and efficacy derived from an investigational new drug application or independent device exemption. Under current regulations, blood products, including platelet-rich plasma (PRP), are exempt and therefore do not follow the FDA’s traditional regulatory pathway and do not have to demonstrate safety and efficacy. Nevertheless, nearly all PRP preparation devices have gained FDA 510(k) clearance for producing PRP intended to be mixed with bone graft to improve graft handling properties. Although PRP can be used by practitioners in other ways (including injection and as additions to tissue scaffolds), these constitute off-label usage. Similarly, mesenchymal stem cells are precursors to cartilage, bone, and other connective tissue cell lines and also have powerful anti-inflammatory and immunomodulatory effects. Although mesenchymal stem cells can be harvested from a number of different tissues including bone marrow, adipose, and synovium, harvest sites vary in their abundance of stem cells and regulatory constraints. Though autologous chondrocyte implantation was successful in making it through the approval process as cultured cells, it is telling that no similar product has been approved since that time. Although the principle objective of the CBER is to ensure safety and efficacy in the use of human cells, tissues, cellular, and tissue-based products, their regulation of orthobiologics has led to an increased abundance of products that enter the market through the 361 pathway.