Human cells or tissues intended for implantation, transplantation, infusion, or transfer into the body are collectively regulated by the U.S. Food and Drug Administration (FDA) as “human cell, tissue, and cellular and tissue-based products.” Typically, biologic products are regulated with a Biologics Licensing Application (BLA), requiring premarket review and approval prior to marketing. However, a subset of these products are exempt from premarket review provided they meet established eligibility requirements. This subset is known as HCT/Ps, or 361-HCT/Ps.¹ The FDA’s HCT/P regulation is multifaceted, and some of the eligibility criteria for exemption from premarket review are considered unclear by industry, leaving some areas of the regulation open to interpretation. Manufacturers have been using these vague definitions to justify biologics marketing under the HCT/P pathway since the approach is more attractive (faster and less costly) than the BLA regulatory pathway.

To understand FDA’s current positioning on what constitutes a HCT/P, the agency has drafted and released a series of guidance documents to provide additional clarification of these concepts and definitions, complete with relevant examples. With the release of these guidance documents, however, comes an increase in FDA oversight of HCT/Ps with a grade period ending in November 2020. With the significant cost and time associated with the BLA pathway, manufacturers should revisit their product designations to assess whether they meet HCT/P requirements or if drug designation is required. This article is intended to help clarify FDA’s HCT/P requirements and explain how tightened regulation of these products will impact industry.

HCT/P Regulation Overview
HCT/Ps are regulated by 21 CFR, Parts 1270 and 1271, and the Public Health Service Act (PHS Act), Section 361. These regulations are designed to prevent the introduction, transmission, and spread of communicable disease through the transfer of cells and tissues between donors and recipients. Under these regulations, infectious disease testing, donor screening, and record-keeping are required for all cellular and tissue products.¹

Per 21 CFR 1271, regulation of HCT/Ps requires the establishment register with FDA (Form 3356) with annual renewal and a filed listing of all HCT/P products manufactured. To comply with the regulation, HCT/Ps must undergo donor screening and testing for communicable disease, and manufacturers must follow current Good Tissue Practices (cGTP). Due to their nature, additional adverse reaction reporting requirements apply, along with stringent HCT/P product labeling mandates.2 One of the key benefits of the HCT/P regulatory pathway is that it allows manufacturers to self-designate and does not require FDA premarket review before product commercialization.2 This premarket review exemption, however, leaves the manufacturer responsible for maintaining the proper internal documentation demonstrating its product meets all HCT/P regulatory pathway criteria. This documentation will likely be reviewed by FDA as part of any facility audits.

Products meeting the criteria established in 21 CFR 1271 are subject to regulation by the PHS Act, Section 361. Products not meeting HCT/P requirements and not qualifying for any exceptions outlined in 21 CFR 1271(15) are regulated as a drug, device, and/or biological product under the Food, Drug and Cosmetic Act and/or PHS Act, Section 351.¹ This pathway requires clinical studies and BLA submission, which substantially increase the time and cost required to market the product. Compared with HCT/P directives, BLA applications require substantial safety and efficacy evidence through bench, animal, and clinical trials. With FDA’s tiered, risk-based approach to HCT/P regulation, manufacturers are able to cut both costs and time to market.

HCT/P Requirements
HCT/Ps regulated by Section 361 of the PHS Act must meet the following requirements, established by 21 CFR 1271 (Chart).


Through numerous guidance documents, FDA has defined several products that are considered HCT/Ps per the aforementioned criteria, in addition to several products that could be mistaken as HCT/Ps, but are ultimately excluded from regulation under Section 361.¹

HCT/P Interpretations
FDA established the Tissue Reference Group (TRG) to help manufacturers determine product designation and correctly interpret the aforementioned criteria. A working group with drug, device, and biologics representatives, the TRG determines eligibility of novel cell and tissue products and publicizes its ruling. Additionally, FDA has issued several guidance documents to help industry interpret the criteria, including recent guidance addressing HCT/P manufacturing in light of new disease risks and technological advances, such as Zika and West Nile virus.^3,4

Some criteria used to define HCT/Ps in 21 CFR 1271 have been deemed by industry as unclear and ill-defined, leaving the requirements open to interpretation. FDA has provided explanations of these terms but has not yet issued a guidance that clearly defines “systemic effect” and “metabolic activity.” Consequently, manufacturers are able to interpret these specific criteria in their own way in product classifications.⁵ The FDA guidance “Regulatory Considerations of Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use (December 2017)” clarifies the agency’s position on “minimal manipulation” and “homologous use” in HCT/Ps.¹

Minimal Manipulation
A key requirement in HCT/P regulation is that the product be “minimally manipulated,” and FDA interprets this term differently for structural and nonstructural tissues. In structural tissues like skin, bone, and adipose material, “minimally manipulated” denotes processing that maintains the tissue’s original characteristics—i.e., those relevant to the structure, such as strength and flexibility. Amniotic membrane (preserved in packaged sheets), for example, is considered an HCT/P by the FDA, as it is minimally manipulated but still retains its original relevant structural characteristics. Shaping harvested bone into dowels is also considered minimal manipulation because the original relevant characteristics have not been altered. Conversely, exposing bone to acid during demineralization is considered “more than minimal manipulation,” since the process alters the bone’s original relevant characteristics.¹

In nonstructural tissues such as hematopoietic stem cells and lymph nodes, minimal manipulation refers to processing that does not change the relevant biological characteristics of cells or tissues (those pertaining to cell function). An example of such manipulation would be hematopoetic stem cells that have been concentrated before transplantation. In this case, the processing has not altered the biological characteristics. Culturing these cells to drive differentiation, on the other hand, is considered “more than minimal manipulation.”¹

Since processing can potentially alter a product’s original characteristic as well as raise safety and efficacy concerns, manufacturing procedures and their impact should be considered at every step in production.

Homologous Use
The term “homologous use” has also lead to some confusion among manufacturers in determining the appropriate product classification. Homologous use refers to the repair, reconstruction, replacement, or supplementation of cells or tissues with an HCT/P that performs the same basic function(s) in the recipient as it does in the donor. FDA considers an HCT/P to be for homologous use when it repairs, reconstructs, replaces, or supplements recipient cells that are identical to the donor cells and performs one or more of the same basic functions performed by the donor cells. For instance, excised adipose tissue can be used to fill voids in the face or hands for cosmetic purposes and still maintain HCT/P status, since adipose tissue provides cushioning and support for other tissues. If the cell origin is not identical to the intended use in the recipient, the HCT/P must still perform one or more of the same basic functions. Case in point: A heart valve can replace another heart valve because the same basic function is preserved. Alternatively, transfer of hematopoetic stem cells from the bone marrow into an artery to limit ventricular remodeling is not considered homologous use, as this intended role is not a basic function of bone marrow cells.¹

FDA does not require the HCT/P be harvested from the same anatomic location as the recipient implantation. Bone, for example, can be harvested, demineralized, and used for the supplementation of recipient bone and still be considered a homologous use. Homologous use is critical for HCT/Ps, as non-homologous use can raise potential safety and efficacy concerns.1

HCT/P Regulations – What’s to Come
The HCT/P pathway is more appealing to companies, as it saves time and money (no premarket approval) as compared with the BLA regulatory route. As such, manufacturers have potentially been classifying and marketing products that may not fully meet HCT/P requirements. To address the potential safety and efficacy concerns resulting from the flux of these products into the U.S. market, FDA released a series of guidance documents that address the interpretation of HCT/P regulations. In a December 2017 guidance, FDA vowed over the next 36 months to “exercise enforcement discretion under limited conditions” regarding BLA premarket approval requirements for certain HCT/Ps.1 The FDA also promised to significantly increase HCT/P oversight to ensure all HCT/Ps meet all applicable requirements.

The issuance of this guidance was soon followed by a press release by FDA in December 2018, noting that time is running out for manufacturers to come into compliance, with the November 2020 deadline quickly approaching. While what “enforcement discretion under limited conditions” will entail is still unknown, FDA followed the press release with a “To Whom It May Concern” letter issued to manufacturers producing stem cell products with vague, general indications in December 2018. As stated by former FDA Commissioner Scott Gottlieb within the press release, “The letters we’re issuing today…are a reminder that there’s a clear line between appropriate development of these products and practices that sidestep important regulatory controls needed to protect patients.”6 Overall, the purpose of both the guidance documents and press release is to open a channel of communication between HCT/P manufacturers and FDA, providing industry with FDA’s current position on HCT/P requirement interpretation and the best path forward to ensure compliance with the relevant regulations.

The agency stated that it will be providing manufacturers ample time to determine if a marketing application is required for their products, providing 36 months before full enforcement is enacted. FDA also indicated which HCT/Ps are of most interest, stating that higher risk devices, such as those administered through intravenous injection or aerosol inhalation, will be the first products to come under review. By providing this information prior to the November 2020 deadline, manufacturers will have time to meet with and discuss any questions or concerns regarding product designation with FDA and plan accordingly. 

References

1. “Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use” FDA Guidance. December 2017.
2. Title 21 of the Code of Federal Regulations, Part 1270 and 1271
3. “Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products; Guidance for Industry” FDA Guidance. Updated May 2018.
4. “Use of Nucleic Acid Tests to Reduce the Risk of Transmission of West Nile Virus from Living Donors of Human Cells, Tissues, and Cellular and Tissue-Based Product s (HCT/Ps) ; Guidance for Industry” FDA Guidance. Updated May 2017.
5. Gadiock, P. “HCT/P Regulation – 351 vs 361 Products” (2017). Arent Fox, LLP. Presentation. 
6. FDA News Release. “FDA sends warning to company for marketing dangerous unapproved stem cell products that put patients at risk and puts other stem cell firms, providers on notice.” December 20, 2018.

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Lindsay Kleinwaks, Ph.D., is a regulatory affairs associate at MCRA LLC, primarily focusing on developing regulatory strategies and submissions for the FDA, and international regulatory agencies. She has an extensive experience developing IDEs, 510(k)s, and clinical evaluation reports, with a focus in orthopedic devices. Kleinwaks also assists clients with understanding FDA’s interpretations of HCT/P designation requirements. She graduated from Drexel University with a doctorate degree in microbiology and immunology, with a concentration in molecular biology.