Addressing the Challenges of Human Tissues and Cell Products Regulation

Regulatory oversight of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) is complicated. This article highlights what sponsors, investigators, and Institutional Review Boards (IRBs) need to know about how these distinct products are regulated.

Introduction

Clinical investigations to gather data to support new drug, biologic, and device approvals generally require the protocol and other documents to be submitted to the FDA prior to starting the trial. A Human Cells, Tissues, and Cellular and Tissue-Based Product (HCT/P) can be a biologic or device or have a separate and distinct regulatory classification. If an HCT/P meets specific regulatory criteria, it can be studied in clinical investigations without prior FDA review if there is appropriate Institutional Review Board (IRB) oversight. While the sponsor must interpret the regulatory language and make the determination regarding whether an FDA submission is required in these cases, there is also a burden on the reviewing IRB to ensure that the regulatory requirements are being met appropriately.

The nuanced details of the regulations for HCT/Ps make determining whether a given clinical investigation of an HCT/P product requires prior FDA review complicated. Providing the necessary information for the IRB to confirm the sponsor’s assessment of the regulatory classification in the IRB submission will increase the efficiency of a high-quality review and ensure that the study will be in compliance for a possible FDA inspection later.

Background

The definition of an HCT/P is established in the regulations as “articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.”¹ In the regulations, this definition is followed by two lists; a list of examples of products that are considered HCT/Ps, including stem cells from peripheral and cord blood and bone, and a numbered list of products that are not considered HCT/Ps, including blood components and bone marrow for homologous use (in certain situations). The similarities in the examples of products that are and are not considered HCT/Ps point to the difficulties in classification. Many products commonly considered to be HCT/Ps are not on either list, such as products from chorion or amnion, further requiring close attention to the regulatory classification.

FDA takes a risk-based approach to regulate HCT/Ps through significantly different pathways. If the HCT/P does not meet a set of specific requirements listed in 21 CFR 1271.10(a), the HCT/P is regulated as a device or biological product. This means FDA premarket approval – including FDA review prior to starting a clinical investigation – is required. On the other hand, no premarket approval is required for an HCT/P that meets these requirements, and no FDA review is necessary prior to starting a clinical investigation. An HCT/P subject only to regulation under section 361 of the Public Health Service Act (42 USC 264) is often referred to as a “361 HCT/P.”² The unified system for listing the HCT/Ps requirements and for registering HCT/Ps establishments is found in the regulations at 21 CFR § 1271.3.

The set of specific requirements for a 361 HCT/P includes five parts, each with specific elements. Therefore, a determination of which products require FDA review is made by analyzing each of these regulatory requirements in 21 CFR 1271.10(a): minimal manipulation, homologous use, manufacturing and storage agents, systemic effects, and registration. Because of the nuance involved in most of the requirements, IRBs analyzing their use require specific product information and knowledge to ensure proper analysis.

Requirements

The IRB must have certain information to assess each of the five requirements in 21 CFR 1271.10(a). Again, if the product being tested meets these five requirements, an FDA review of the product is not required. Only one requirement — manufacturing registration — is easily verified. In contrast, the other four requirements necessitate significant analysis. Understanding the requirements and the parameters of each of those analyses provides a useful outline to ensure that sponsors and investigators provide the appropriate information in their IRB applications and protocol documents.

A. Minimal Manipulation

The first requirement is that the product must be “minimally manipulated,”⁴ which is defined in the regulations based on the tissue:

1. “For structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement; and
2. For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues.”⁵

The first step is therefore to determine whether the main function of the HCT/P in the donor is structural or not. Of note, structural tissue can be composed of both structural components (such as collagen or hydroxyapatite) and cells. If cells are part of the structural tissue included in this criterion, removing those cells can be considered more than minimal manipulation.

B. Homologous Use

The second requirement is that the product must be intended for homologous use only. This means the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues is being performed with an HCT/P that performs the same basic function in the recipient as in the donor. This can follow from the prior structural/non-structural separation but requires a different analysis as it focuses on the use of the product.

When HCT/Ps are marketed, the limitation to homologous use needs to be “reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent.”⁶ In the research setting, this means that the specific use of the product for the trial must match the same basic function, and the objectives of the research must be for the research to show that the product performs the same basic function. For example, if a study is designed to test if a structural product does more than perform the same basic function in the recipient, this requirement would not be met.

C. Manufacture

The third requirement involves manufacturing.⁷ The manufacture of the HCT/P cannot involve the combination of the cells or tissues with another article, such as a drug. Water, crystalloids, or a sterilizing, preserving, or storage agent are allowed provided that the addition of the agent does not raise new clinical safety concerns with respect to the HCT/P. The amount, kind, and history of use of the additional article impact this assessment.

Unless the HCT/P is manufactured under an investigational device exemption (IDE) or investigational new drug (IND) application, the fourth requirement is that the HCT/P manufacturer must be registered with the FDA.^8,9 The agency maintains these registrations in a publicly accessible database.¹⁰ Documents included with the IRB submission should link to that registration or clearly identify the manufacturer so that the IRB can confirm that the manufacturer is properly registered.

D. Systemic Effects

The fourth criterion is more complicated. To meet it, the product must meet either of two sub-requirements.¹¹ The first sub-requirement is the simpler of the two, that the HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function. From IRB experience and a review of the literature, most HCT/P products fall into this first category. The conclusion of systemic effect and dependence on metabolic activity might follow from a homologous use analysis, but not necessarily.

If the product does not meet the first sub-requirement and it does have a systemic effect, it must fit into one of the following specific use situations: autologous use, allogenic use in a first-degree or second-degree blood relative, or reproductive use.

Review and Analysis

Because of the complexity of the definitions and classifications of HCT/Ps above, combined with the rapid development of new HCT/Ps, sponsors, investigators, and IRBs will require an understanding of how the regulatory requirements are applied. For example, the Tissue Reference Group provides clarification for specific products in a public listing.¹² An example from the FY 2015 Update:

• A dehydrated chorioamniotic membrane in sheet form, used as a wound cover, is regulated as an HCT/P under section 361 of the PHS Act and 21 CFR 1271.
• A tissue product consisting of cryopreserved chorionic small sheets is more than minimally manipulated because the processing alters the membrane’s original relevant characteristics and therefore, is not regulated as an HCT/P under section 361 of the PHS Act.

To further improve understanding of the same issues, FDA provided more insight in a guidance document.¹³ First, this guidance on minimal manipulation and homologous use specifically notes that if information does not exist to show that the minimal manipulation and homologous use requirements are met, an HCT/P would be considered a biologic or device. The implication is that the default position is that prior FDA review is required. Then, FDA guidance provides further insight into minimal manipulation and homologous uses in several examples.

For minimal manipulation, example 14-1 in the guidance specifically addresses stromal vascular fraction (SVF), which is created from processing adipose tissue. Adipose tissue processing involves enzymatic or mechanical procedures for cell isolation, instead of merely aliquoting, rinsing, removing macroscopic debris, and freezing. That processing is more than minimal manipulation. Therefore, an SVF product would need FDA review prior to being marketed or studied. This example is on point as SVF is being studied in chronic inflammatory diseases, ischemic diseases, orthopedic procedures, a treatment for obesity, and other applications.^{14, 15}

For homologous use, example 19-6 in the guidance lists uses of adipose tissue. Treating inflammatory conditions such as arthritis or tendonitis by regenerating or promoting the regeneration of articular cartilage or tendons is generally not considered a homologous use. Regenerating or promoting the regeneration of cartilage or tendons is not a basic function of adipose tissue, which is a structural tissue. Similarly, the example of adipose tissue’s use for breast plastic surgery augmentation is not considered as homologous use, since “the primary function of breast tissue is producing milk.” However, adipose tissue’s cosmetic use to fill voids in the face and hands is homologous use because “providing cushioning and support is a basic function of adipose tissue.”¹³

Other Considerations

Depending on the study, study designs could include comparators that would also require consideration of other regulations. Products that could serve as a comparator or control arm for an HCT/P could include biologics, devices, drugs, or a combination of products. A study using a drug as a comparator would need to additionally follow the regulations under 21 CFR 312 for the clinical study of drugs, and a study using a device would follow the regulations under 21 CFR 812 for the clinical study of medical devices. A common issue for studies that compare HCT/Ps to 510(k) cleared devices is that the cleared device needs to either have been used in specific accordance with its labeling or meet the non-significant risk definition and follow the requirements for an abbreviated IDE.^16,17 Additionally, devices used in the creation of the product may be subject to FDA device regulations in addition to consideration for the use of the product created.

With their shortened process to market, HCT/P products are reasonably studied in post-market research designs. All FDA-regulated clinical investigations require IRB review, and informed consent of the participant, and documentation of consent or a waiver of consent or documentation of consent.¹⁸ Study designs that include collection of data from existing records would fall under these requirements.

Conclusions

In a submission for IRB review, sponsors and investigators of HCT/Ps who believe that FDA review is not necessary for the product should explicitly address the specifics of how the product fulfills each of the criteria under 21 CFR 1271.10 so that the IRB can confirm this conclusion. HCT/Ps may fall outside these specific requirements based on relatively small differences in use, processing, and manufacture. A product classified as cellular tissue might have structural properties, and structurally classified products might have cellular properties. The same tissue may or may not require prior FDA review depending on the labelling or specific use in a study. With the FDA guidance on minimal manipulation and homologous use pointing toward the default position that a product requires FDA review until proven otherwise, the rationale for the product meeting the criterion of being minimally manipulated and for homologous use would especially benefit from a detailed description.

The issues around these products appear to be increasing in complexity as science progresses. Following the leaps of creative scientific discovery, biotechnology’s advances will continually outpace attempts to codify them. Matching the study of the product to the appropriate regulatory pathway provides regulators and scientists investigating new therapies with many challenges.¹⁹ Despite the nuance and uncertainty, HCT/Ps deserve careful attention to maximize their promise while ensuring regulatory compliance. Clear and effective communication, with explicit rationales and an understanding of the regulatory framework, are the tools to ensure a high-quality, timely review by an IRB. Using these tools will accelerate the scientific advancement of human health while ensuring that the risks of progress never outweigh the value of human life.

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References

1. 21 CFR Part 1271, Human cells, Tissues, and Cellular and Tissue-Based Products, Subpart A, General provisions, § 1271.3: How does FDA define important terms in this part?
2. Guidance for Industry: Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) – Small Entity Compliance Guide.  https://www.fda.gov/media/70689/download. Last updated November 2022. Accessed 3 Aug 2024.
3. Compliance Program Guidance Manual. Inspection of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps). Division of Inspections & Surveillance, HFM-650, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research, Food and Drug Administration  https://www.fda.gov/media/73949/download Last updated October 8, 2015. Accessed 3 Aug 2024.
4. 21 CFR Part 1271, Human cells, Tissues, and Cellular and Tissue-Based Products, Subpart A, General provisions, § 1271.10: Are my HCT/P’s regulated solely under section 361 of the PHS Act and the regulations in this part, and if so what must I do? (a) (1).
5. 21 CFR Part 1271, Human cells, Tissues, and Cellular and Tissue-Based Products, Subpart A, General provisions, § 1271.3 How does FDA define important terms in this part? (f).
6. 21 CFR Part 1271, Human cells, Tissues, and Cellular and Tissue-Based Products, Subpart A, General provisions, § 1271.10: Are my HCT/P’s regulated solely under section 361 of the PHS Act and the regulations in this part, and if so what must I do? (a)(2).
7. 21 CFR Part 1271, Human cells, Tissues, and Cellular and Tissue-Based Products, Subpart A, General provisions, § 1271.10: Are my HCT/P’s regulated solely under section 361 of the PHS Act and the regulations in this part, and if so what must I do? (a) (3).
8. U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research. Guidance for Industry Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps). Small Entity Compliance Guide. August 2007.
9. 21 CFR Part 1271, Human cells, Tissues, and Cellular and Tissue-Based Products, Subpart A, General provisions, § 21 CFR 1271 Subpart B–Procedures for Registration and Listing 1.
10. https://www.accessdata.fda.gov/scripts/cber/CFAppsPub/tiss/index.cfm Accessed 3 Aug 2024.
11. 21 CFR Part 1271, Human cells, Tissues, and Cellular and Tissue-Based Products, Subpart A, General provisions, § 1271.10: Are my HCT/P’s regulated solely under section 361 of the PHS Act and the regulations in this part, and if so what must I do? (a)(4).
12. U.S. Food and Drug Administration. Tissue Reference Group.  https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products/tissue-reference-group.  Content current as of 1/11/2023. Accessed 3 Aug 2024.
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14. Casteilla L, Planat-Benard V, Laharrague P, Cousin B. Adipose-derived stromal cells: Their identity and uses in clinical trials, an update. World J Stem Cells. 2011 Apr 26;3(4):25-33. doi: 10.4252/wjsc.v3.i4.25.
15. Pak J, Lee JH, Kartolo WA, Lee SH. Cartilage Regeneration in Human with Adipose Tissue-Derived Stem Cells: Current Status in Clinical Implications. Biomed Res Int. 2016;2016:4702674. Epub 2016 Jan 6. doi:10.1155/2016/4702674.
16. 21 CFR Part 812, Investigational Device Exemptions §812.2, Applicability.
17. 21 CFR Part 812, Investigational Device Exemptions §812, Applicability, 2(b).
18. 21 CFR Part 50, Protection of Human Subjects and Part 56, Institutional Review Boards.
19. Brittany P. Dodson and Aaron D. Levine. Challenges in the translation and commercialization of cell therapies. BMC Biotechnol. 2015; 15: 70. Published online 2015 Aug 7. doi: 10.1186/s12896-015-0190-4. PMCID:PMC4528687.