FDA announced this week that it intends to extend its enforcement discretion policy regarding investigational new drug (IND) and premarket approval requirements for certain regenerative medicine products through May 2021. In light of the COVID-19 emergency, manufacturers will have six additional months after the initial November 2020 deadline to prepare and submit an IND or marketing application, if an application is required under the regulatory framework for human cell, tissue, and cellular and tissue-based products (HCT/Ps). The enforcement policy remains limited to circumstances where “use of the HCT/P does not raise reported safety concerns or potential significant safety concerns,” and FDA has stated its intent to continue to take action against unapproved HCT/Ps that pose significant safety risks to patients. This announcement signals that FDA continues to focus on HCT/P compliance and is looking ahead to enforcement when the policy expires next year.
Background and Purpose of Enforcement Policy
FDA initially set forth the enforcement policy as part of its final guidance for industry and FDA staff, Regulatory Considerations for Human Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use (November 2017, corrected December 2017) (Minimal Manipulation and Homologous Use final guidance). Issued as part of FDA’s 2017 “comprehensive policy framework for the development and oversight of regenerative medicine products,” the Minimal Manipulation and Homologous Use final guidance was one of four guidance documents intended to clarify aspects of FDA’s tiered, risk-based approach for regulating HCT/Ps. FDA applies a four-part test to determine if an HCT/P is an HCT/P regulated solely under Section 361 of the PHS Act and 21 C.F.R. Part 1271 (often called a “361 HCT/P”), or if it is an HCT/P regulated as a drug, biologic, or device. 361 HCT/Ps are exempt from the IND and premarket review and approval requirements. Additional information about the framework and 2017 guidance documents is available here.
In recent years, many companies have introduced products onto the market based on a self-determination that their products are 361 HCT/Ps or otherwise exempt from FDA’s regulation. When announcing the 2017 guidance documents, FDA recognized that there are “close calls” about what products require premarket approval and issued the policy framework to provide greater clarity to manufacturers (see August 28, 2017 statement here). However, the agency has repeatedly expressed concerns about—and taken enforcement action against—“unscrupulous actors” marketing unproven and unsafe products without approval (e.g., FDA’s August 28, 2017 statement, and a November 15, 2017 statement available here). Under the 2017 policy, FDA planned to exercise limited enforcement discretion for a 36-month period through the end of November 2020. The period was intended to provide companies enough time to engage with FDA to determine whether an IND or marketing approval is needed, and if so, prepare and submit an application.
COVID-19 Challenges Motivated the Extension
On July 20, 2020 FDA revised the Minimal Manipulation and Homologous Use final guidance to extend the enforcement discretion period to May 2021. In a news release announcing the revised guidance, FDA indicated that it is extending the enforcement discretion period due to “the challenges presented by the COVID-19 public health emergency.” More specifically, FDA cited the “unique challenges in recruiting clinical trial participants and carrying out clinical trials” in the Federal Register notice announcing the guidance’s availability. FDA has provided recommendations and answers to frequently asked questions about conducting clinical trials during the pandemic in guidance described here, updated as summarized here.
HCT/Ps with Safety Concerns Remain a Priority
Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research, made clear that this extension is not a moratorium on enforcement actions: “This policy was never intended to provide a cover for bad actors, and we intend to continue to take action against manufacturers and health care providers who are offering unapproved regenerative medicine products that have the potential to put patients at significant risk.” Unapproved products with “reported safety concerns or potential significant safety concerns” remain subject to enforcement under the policy.
Extension May Signal Heightened Enforcement Activity for 2021
FDA’s choice to extend the enforcement discretion policy while agency resources are focused on battling the pandemic may signal an intent by the agency to engage in significant enforcement in this area after May 2021. FDA’s news release points out that the agency has “stepped up its oversight of cellular and related products in recent years.” Rather than allowing the enforcement policy to lapse quietly in November—a time when FDA may not be as well positioned to initiate compliance actions due to the COVID-19 pandemic—the extension could provide FDA additional time to prepare for enforcement activity when agency resources may be less stretched. The extension therefore appears to signal that FDA will meaningfully enforce its requirements when the enforcement discretion period ends.
Options for Engagement with FDA
Manufacturers may obtain a recommendation or decision from FDA regarding the classification of an HCT/P through three mechanisms: (1) requesting a recommendation from the Tissue Reference Group (TRG), or (2) submitting a Request for Designation (RFD) to the Office of Combination Products (OCP); or (3) submitting a Pre-RFD to OCP. The TRG recommendation process is informal, and the Pre-RFD process generates preliminary feedback, while an RFD results in a formal agency decision regarding the classification of the HCT/P. Under the TRG Rapid Inquiry Program (TRIP), now extended until March 31, 2021, “FDA intends to provide preliminary, informal, non-binding responses within one week after receiving an inquiry that contains sufficient detail for evaluation,” as resources permit. The TRIP was instituted in June 2019 because FDA had “seen only modest progress by regulated industry in coming into compliance” with the IND and premarket approval requirements. More information about the TRIP process is available here, and more information (including guidance documents) about the RFD and Pre-RFD processes is available here. Companies can contact the TRG or OCP with questions about each process. For information about IND requirements for biological products, companies may contact the Division of Regulatory Project Management, Office of Tissues and Advanced Therapies, at 240-402-8190 or OTATRPMS@fda.hhs.gov. In a December 2018 update, FDA encouraged manufacturers and health care professionals who have any uncertainty regarding the regulatory status of their products to contact FDA well before the end of the enforcement discretion period.
If you have any questions concerning the material discussed in this client alert, please contact the following members of our Food, Drug, and Device Practice.
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