Clarification of Registration Requirements Designed to Help Industry
In November 2017, FDA issued a series of guidance documents aimed at clarifying the definition, use and regulation of regenerative medicine products and HCT/Ps, including two pathways to accelerate development timelines through early feedback and expedited review.
HCT/Ps, which consist of human cells or tissues, are intended for implantation, transplantation, infusion or transfer from one location to another in the same person, or from a donor to another human recipient. Examples of such products include adipose tissue, bone, ligament, skin, dura mater, hematopoietic stem/progenitor cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix and reproductive tissues. The regulatory framework for HCT/Ps is established in Sections 351 and 361 of the Public Health Service (PHS) Act, and 21 CFR Part 1271.
FDA has been challenged on how to regulate these products and has developed comprehensive guidance documents that expand on the fundamental criteria of minimal manipulation and homologous use.
An HCT/P will be regulated as a tissue (i.e., not considered a drug/biologic/device) if it meets certain criteria listed in 21 CFR 1271 for minimal manipulation, homologous use and its intended use is NOT based on predominantly metabolic or other biochemical roles in the body such as hematopoietic, immune, and endocrine functions unless the recipient is a first degree relative.
Many of these tissue products are regulated solely under Section 361 of the PHS Act and, therefore, do not require premarket authorization from FDA, which means that they are not required to demonstrate evidence of clinical safety and efficacy before being sold in the marketplace. Examples of such HCT/Ps often used in orthopedics include certain preparations from bone marrow, adipose tissue, blood, amnion and dermis. To be considered a “361 HCT/P,” the product must meet all of the criteria as outlined in the guidance, and HCT/Ps that do not are regulated as drugs, biologicals or devices, based primarily on the degree of manipulation, intended use and the expected level of biochemical action as part of an intended therapy.
By contrast, HCT/Ps subject to Section 351 of the PHS Act and the applicable 21 CFR regulations must have premarket clearance, license or approval by FDA, which typically requires long and arduous development, qualification and human clinical trials to measure safety and efficacy. Examples of such 351 HCT/Ps include culture-expanded chondrocytes for cartilage repair; ground and lyophilized amniotic membrane for modulating inflammation such as in the case of osteoarthritis; any purified stem cell preparation from fat, marrow, blood or other tissue; and any combination of a tissue with another material. Interpreting and applying these criteria can be challenging, and therefore, it is important to communicate with FDA early in the development process to verify shared understanding of the regulatory requirements.
