In a move welcomed by industry, the Food and Drug Administration (FDA) has granted six additional months of enforcement discretion to manufacturers of certain human cell, tissue, or cellular or tissue-based products (HCT/Ps). Manufacturers now have until May 2021 to comply with the FDA guidance, "Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use," issued in November 2017 ("HCT/P Guidance"). Since its release nearly three years ago, industry has been hard-pressed to comply with the policies announced in the HCT/P Guidance. The FDA stated that extension of the enforcement discretion period is attributed to challenges presented by the COVID-19 public health emergency. The agency intends that the additional 180 days "will provide manufacturers and potential sponsors an additional six months to determine if they need to submit an Investigational New Drug (IND) or marketing application and, if such an application is needed, to prepare and submit the application, as appropriate."
Under section 361 of the Public Health Service Act, HCT/Ps that meet certain criteria are subject only to limited controls that are intended to minimize infectious disease risks—they are not required to undergo premarket review for safety or efficacy. These criteria primarily include whether a product has been minimally manipulated, is intended for homologous use, and does not depend on the metabolic activity of living cells to achieve its primary function. In the HCT/P Guidance, the FDA significantly scaled back how these concepts apply to HCT/Ps, including those that were on the market before the guidance was issued.
For many HCT/Ps currently on the market, the guidance's policies triggered the need to develop regulatory-grade data and submit premarket approvals. The FDA initially granted 36 months for manufacturers to come into compliance, a timeframe that seemed ambitious even three years ago. Many nimble companies that began preparing for regulatory submissions soon after the guidance's release were still challenged by the previous November 2020 compliance deadline. The FDA clarified that during the enforcement discretion period, the agency would continue to take enforcement action against higher-risk products. Though the clarification was helpful, the FDA's interpretation of "higher-risk" has seemed to expand as the enforcement discretion period progressed. Recent FDA violation letters have cited types of HCT/Ps that were generally not mentioned in similar letters issued at the beginning of the enforcement discretion period.
Many stakeholders have adapted to this risk by routinely monitoring and evaluating recent FDA Warning Letters and Untitled Letters to get a better sense of how the agency may enforce in the future. The FDA has issued approximately 15 unique Warning Letters and Untitled letters during the enforcement discretion period. Targets of these actions include manufacturers, suppliers, and clinics across a diverse geography. This indicates that even though a six-month reprieve has been granted, it is not absolute as the FDA remains active during the enforcement discretion period. Indeed, the FDA issued an Untitled Letter citing the HCT/P Guidance as recent as July 22, 2020.
Simultaneous with managing post-market risk, HCT/P manufacturers are expected to develop premarket applications for their products and proactively engage with the agency to discuss plans for regulatory approval. In a May 2019 news release, the FDA stated, "We intend to step up our oversight of those sponsors who have not engaged the regulatory process in the proper development of their stem cell products…" Many stakeholders have used the expectation for discussions to interface with the FDA on prospect of accelerated regulatory review of an eventual application, such as through a regenerative medicine advanced therapy (RMAT) designation. Since 2017, the FDA has granted RMAT designation to more than 50 products, providing each with actions to facilitate development and expedite review of the product, intensive guidance on efficient development beginning as early as Phase I, organizational commitment involving senior managers, and/or the ability to satisfy applicable post-approval requirements through patient registries. The FDA generally expects that RMAT justifications include some level of clinical evidence, which may be beyond the current development program or financial ability for many companies. These manufacturers may still benefit from the Tissue Reference Group Rapid Inquiry Program (TRIP), under which the FDA intends to provide preliminary, informal, non-binding assessments to manufacturers about how their products are regulated. The additional time provided by the extended enforcement discretion period allows companies to consider RMAT designation, TRIP, and other regulatory opportunities.
Further, the enforcement discretion extension was provided in response to the COVID-19 pandemic which may not be adequately resolved by May 2021. It is therefore possible that the enforcement discretion period will be extended again if the FDA deems it appropriate.