The U.S. Food and Drug Administration (FDA) has issued new guidance for regenerative medicine manufacturers and healthcare providers. At the core of the guidance are two central interpretations: 1) the FDA’s current interpretation of the minimal manipulation and homologous use criteria set forth in 21 CFR Part 1271; and 2) the FDA’s current view on the same surgical procedure exception under 21 CFR 1271.15(b). Additionally, the FDA issued a notice to all interested stakeholders that the FDA intends to initiate increased discretionary enforcement over the next 36 months for human cell and tissue-based products. Given these developments, healthcare companies and providers impacted by this guidance are strongly encouraged to ensure compliance with the FDA’s new interpretations.
This guidance applies to human cells, tissues, and cellular and tissue-based products (HCT/Ps). HCT/Ps are defined in 21 CFR 1271.3(d) as articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. HCT/Ps can be derived from bone, ligament, skin, blood, cornea, semen, or reproductive tissue. Regulations for HCT/Ps were originally enacted in the Public Health Service (PHS) Act with the purpose of preventing the introduction and transmission of infectious diseases from tissue to tissue.
The FDA has classified the guidance as non-binding recommendations. This simply means the agency is giving its current thinking on a topic. However, despite this declaration, healthcare companies and providers should still proceed with caution and comply fully with the FDA’s opinions, as an agency’s interpretation of statutes and regulations within its purview are given great deference.
Minimal Manipulation and Homologous Use
HCT/Ps that are 1) minimally manipulated, 2) intended for homologous use, and 3) not combined with other articles are regulated solely under Section 361 of the PHS Act. In other words, this means these products are considered part of the practice of medicine and most importantly, outside the FDA’s jurisdiction. If these criteria are not met, the products are more stringently regulated and subject to premarket evaluation by the FDA.
The phrase “minimal manipulation” refers to the processing of tissue and is generally defined as processing that does not alter the biological characteristics of the tissue. The provision of 21 CFR 1271.3(f) provides two definitions for structural (e.g., bone, skin, adipose tissue, and ligament) and non-structural tissue (e.g., reproductive cells, cord blood, lymph nodes, and peripheral tissue). In the new guidance, the FDA indicates that if information does not exist to show that the processing meets the definition then the processing is more than minimal manipulation.
Homologous use is defined as the repair or replacement of cells or tissues with an HCT/P that performs the same basic function in the recipient as in the donor. In the new guidance, the FDA clarifies that the agency generally considers HCT/Ps to be for homologous use if 1) the cells or tissues are identical to the donor and perform one or more of the same functions as in the donor (e.g., a heart valve is transplanted to replace a non-performing heart valve) or 2) if the cells or tissues are not identical but perform one or more of the same functions as in the donor (e.g., pericardium is used as a wound cover for spinal cord tissue defects).
Same Surgical Procedure Exception
Under specific circumstances, a healthcare provider may qualify for an exception from the requirements of 21 CFR part 1271. Section 1271.15(b) states that a provider is not required to comply with the requirements if an establishment only removes HCT/Ps from an individual and implants HCT/Ps into the same individual during the same surgical procedure. In the new guidance, the FDA makes clear that cells or tissues that are removed and implanted into the same individual without intervening processing steps (i.e., beyond rinsing, cleaning, sizing, or shaping) meet the narrow exception. One area of contention related to this exception is whether any types of procedures consisting of more than a single operation could be considered the same surgical procedure. The guidance provides clarification. Under limited circumstances, surgical removal and subsequent implantation of autologous HCT/P may be considered the same procedure even though the removal and implantation are not performed on the same day. As an example, the FDA mentions a craniotomy or craniectomy that involves rinsing or cleaning and temporary storage pending implantation.
The field of regenerative medicine is an intricate and fast developing area. The FDA has said it intends to use discretionary enforcement in the coming months to focus on products with higher risk for transmission of diseases and on predatory companies who use the exceptions to evade regulation and harm the public with treatments backed by little scientific evidence. Given the FDA’s latest position on these issues, it is important for manufacturers and providers to engage counsel in order to remain compliant in this ever changing regulatory environment.