On November 16, 2017, FDA announced a comprehensive regenerative medicine policy framework to provide additional clarity regarding existing and future tissue regulation. This framework includes a final guidance document establishing FDA’s interpretation of integral terms relating to regulation of certain tissue products, as well as draft guidances regarding the statutory designation of regenerative medicine advanced therapies (RMATs) authorized under the 21st Century Cures Act.
As readers may already be aware, human cells, tissues, and cell- and tissue-based products (HCT/Ps) that meet certain criteria set forth in 21 C.F.R. § 1271.10 are subject to regulation solely under Section 361 of the Public Health Service Act (PHSA), the intent of which is simply to prevent the introduction, transmission, and spread of communicable diseases. Accordingly, there is no premarket review of these products for safety and efficacy. Rather, Section 361 HCT/Ps are subject only to limited controls that are intended to minimize infectious disease risks. Because of the absence of premarket review, a product regulated solely under Section 361 has, essentially, an expedited pathway to market. By contrast, an HCT/P that does not meet the criteria for regulation solely under Section 361 will typically be regulated by FDA as a biological product requiring FDA premarket approval under Section 351 of the PHSA (and may also be subject to the drug provisions of the Federal Food, Drug, and Cosmetic Act). Two central elements of the criteria that determine whether a product is a Section 361 HCT/P or a Section 351 biological product are (i) whether the product has been “minimally manipulated” and (ii) whether the product is intended for “homologous use.” Given the desirable path to market for 361 HCT/Ps, fulfilling these criteria can be a critical factor in how, or even if, an HCT/P is marketed.
Recognizing that homologous use and minimal manipulation are closely-related concepts, FDA consolidated the draft guidance policies regarding both criteria into a single, final guidance document, Regulatory Considerations for Human Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use. The guidance establishes guardrails within which tissue products must remain in order to qualify for regulation as a 361 HCT/P. As a benefit to readers, we have highlighted certain policies in the guidance that we believe are of particular interest:
- Determining whether an HCT/P is minimally manipulated turns on whether it is a structural or non-structural tissue in the donor;
- Tissues cannot be both structural and nonstructural;
- Machining does not always constitute minimal manipulation of structural tissues; and
- Processing that alters the cellular or extracellular matrix components may or may not be minimal manipulation, depending on the tissue type, because such processing may or may not alter the original relevant characteristics of that particular tissue type.
- The use of bone products to repair or reconstruct bone is generally considered homologous;
- Promoting amniotic membrane for uses other than as a protective barrier or as a covering will generally cause it to fall outside the scope of a 361 HCT/P; and
- Secreted body fluid, including amniotic fluid, is generally ineligible to qualify as a 361 HCT/P.
Stakeholders are generally pleased that FDA has finalized draft guidances regarding minimal manipulation and homologous use, which have remained pending since December 2014 and October 2015, respectively. The final policy provides predictability regarding qualification as a 361 HCT/Ps that has been, to date, murky at best. Certain institutions, such as the Alliance for Regenerative Medicine (ARM), have already applauded FDA for the recent efforts. In a statement dated November 16, 2017, ARM commended the agency for its continued commitment to safe and effective patient therapies, as well as clarity provided regarding the RMAT designation.
Other industry participants will face challenges with implementing FDA’s minimal manipulation and homologous use policies, with respect to products that are already being marketed. Certain claims can be revised in response to FDA’s policy on homologous use to bring the products into compliance. For example, FDA made clear in the guidance that amniotic tissue would not be considered as intended for homologous use when marketed for wound healing, but the same tissue would be considered as intended for homologous use when sold as a wound covering. Therefore, revising the claims for a product may allow it to escape regulation as a biological product. The agency’s position on what constitutes minimal manipulation, however, may impact manufacturers to a greater extent. A marketed tissue that is not minimally manipulated likely cannot avoid regulation by mere labeling changes, and could instead require modifications to tissue processing protocols that must subsequently be validated under cGTPs in order to qualify as a 361 HCT/P. As an additional layer of complexity, the 36-month enforcement grace period afforded by the guidance for marketed HCT/Ps to come into compliance with the current paradigm is only provided for cells and tissues that are intended for autologous use, which may leave numerous allograft manufacturers scrambling to assemble an intelligent regulatory and marketing strategy.
FDA’s final guidance interpreting “minimal manipulation” and “homologous use” provides a degree of regulatory certainty that was long overdue with respect to products that could qualify as 361 HCT/Ps. Interestingly, jurisdictional decisions made by FDA’s Tissue Reference Group, which have until now been one of the primary sources of insight into the agency’s thinking regarding the applicability of these terms, appear to have been eliminated from FDA's website, concurrently with publication of the final Guidance. Their removal likely indicates FDA’s view that any precedent the agency provided has been superseded by the new Guidance, which, unlike the product-specific TRG decisions, is intended to have broad applicability. Regardless of whether stakeholders agree with the interpretations set forth in the Guidance, it appears to represent a commitment from FDA to grapple with and resolve challenging tissue product regulatory issues and, by providing greater certainty about how HCT/Ps are regulated, should help level a formerly uneven playing field. FDA’s draft guidances regarding the RMATs may serve as the next meaningful opportunity for interested parties to influence tissue product regulation and pathways to market. FDA’s RMAT draft guidance proposes five expedited pathways to market for certain tissue products and provides a comment period that expires February 15, 2018.