Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use Guidance for Industry and Food and Drug Administration Staff

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Biologics Evaluation and Research

Center for Devices and Radiological Health

Office of Combination Products

November 2017

https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM585403.pdf

We, FDA, are providing you, human cells, tissues, and cellular and tissue-based product (HCT/P) manufacturers, healthcare providers, and FDA staff, with our current thinking on the criteria under Title 21 of the Code of Federal Regulations (CFR) Part 1271, specifically the 21 CFR 1271.10(a)(1) criterion of minimal manipulation and the 21 CFR 1271.10(a)(2) criterion of homologous use. The interpretation of the minimal manipulation and homologous use criteria and definitions of related key terms have been of considerable interest to industry stakeholders since the criteria and definitions were first proposed. 1 This guidance is intended to improve stakeholders’ understanding of the definitions of minimal manipulation in 21 CFR 1271.3(f) and homologous use in 21 CFR 1271.3(c). It will also facilitate stakeholders’ understanding of how the regulatory criteria in 21 CFR 1271.10(a)(1) and (2) apply to their HCT/Ps.2 In addition, we are informing manufacturers, healthcare providers, and other interested persons that over the next 36 months, we intend to exercise enforcement discretion under limited conditions with respect to the investigational new drug (IND) application and premarket approval (biologics license application (BLA)) requirements, for certain HCT/Ps. This guidance finalizes the document entitled “Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps); Draft Guidance for Industry and Food Administration Staff” dated December 2014, and “Homologous Use of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps); Draft Guidance for Industry and FDA Staff” dated October 2015. This guidance also finalizes certain material related to adipose tissue that was included in draft guidance entitled “Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) from Adipose Tissue: Regulatory Considerations; Draft Guidance for 1 “Establishment Registration and Listing for Manufacturers of Human Cellular and Tissue-Based Products” 63 FR 26744 at 26748-26749 (May 14, 1998). (Tissue Registration and Listing; Proposed Rule) 2 This guidance does not address the classification and/or assignment of HCT/Ps that do not meet the criteria for regulation solely under section 361 of the Public Health Service (PHS) Act and 21 CFR Part 1271. Contains Nonbinding Recommendations 2 Industry” dated December 2014 (Adipose Draft Guidance). This material, together with the material related to adipose tissue included in the final guidance entitled “Same Surgical Procedure Exception under 21 CFR 1271.15(b); Questions and Answers Regarding the Scope of the Exception” dated November 2017, supersedes the Adipose Draft Guidance. Accordingly, we do not intend to finalize the Adipose Draft Guidance, which is now withdrawn. Finally, this guidance supersedes the document entitled “Minimal Manipulation of Structural Tissue (Jurisdictional Update); Guidance for Industry and FDA Staff” dated September 2006 (2006 Guidance). FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe FDA’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word “should” in FDA’s guidances means that something is suggested or recommended, but not required.

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.3 Because of the unique nature of HCT/Ps, FDA proposed and in 2005 implemented a tiered, risk-based approach to the regulation of HCT/Ps. Although FDA is authorized to apply the requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and the Public Health Service Act (PHS Act) to those products that meet the definition of drug, biologic, or device, under this tiered, risk-based approach, those HCT/Ps that meet specific criteria or fall within detailed exceptions do not require premarket review and approval. In developing the tiered, risk-based approach the agency focused on public health and regulatory concerns, including how transmission of communicable disease can be prevented; what processing controls are necessary to prevent contamination that could result in an unsafe or ineffective product, and to preserve integrity and function so that the products will work as they are intended; and how clinical safety and effectiveness can be assured. The tiered, risk-based approach is contained in a set of regulations commonly referred to as the “tissue rules,” issued by FDA through notice and comment rulemaking, under the communicable disease authority of section 361 of the PHS Act 3 Examples of HCT/Ps include, but are not limited to, bone, ligament, skin, dura mater, heart valve, cornea, hematopoietic stem/progenitor cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, and semen or other reproductive tissue. The following articles are not considered HCT/Ps: (1) Vascularized human organs for transplantation; (2) Whole Blood or blood components or blood derivative products subject to listing under 21 CFR Parts 607 and 207, respectively; (3) Secreted or extracted human products, such as milk, collagen, and cell factors, except that semen is considered an HCT/P; (4) Minimally manipulated bone marrow for homologous use and not combined with another article (except for water, crystalloids, or a sterilizing, preserving, or storage agent, if the addition of the agent does not raise new clinical safety concerns with respect to the bone marrow); (5) Ancillary products used in the manufacture of HCT/P; (6) Cells, tissues, and organs derived from animals other than humans; (7) In vitro diagnostic products as defined in 21 CFR 809.3(a); and (8) Blood vessels recovered with an organ, as defined in 42 CFR 121.2 that are intended for use in organ transplantation and labeled “For use in organ transplantation only.” (21 CFR 1271.3(d)) Please note, the regulatory status of products identified as not being HCT/Ps is beyond the scope of this guidance. Contains Nonbinding Recommendations 3 (42 U.S.C. 264). These regulations explain the types of HCT/Ps that do not require premarket approval; and the registration, manufacturing, and reporting steps that must be taken to prevent the introduction, transmission, and spread of communicable disease by these HCT/Ps. These regulations can be found in 21 CFR Part 12714 . In 21 CFR 1271.10, the regulations identify the criteria for regulation solely under section 361 of the PHS Act and 21 CFR Part 1271. An HCT/P is regulated solely under section 361 of the PHS Act and 21 CFR Part 1271 if it meets all of the following criteria (21 CFR 1271.10(a)): 1) The HCT/P is minimally manipulated; 2) The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent; 3) The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P; and 4) Either: i) The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or ii) The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and: a) Is for autologous use; b) Is for allogeneic use in a first-degree or second-degree blood relative; or c) Is for reproductive use. If an HCT/P does not meet the criteria set out in 21 CFR1271.10(a), and the establishment that manufactures the HCT/P does not qualify for any of the exceptions in 21 CFR 1271.155 , the HCT/P will be regulated as a drug, device, and/or biological product under the FD&C Act, and/or section 351 of the PHS Act (42 U.S.C. 262), and applicable regulations, including 21 CFR Part 1271, and premarket review will be required.

Minimal Manipulation Section 1271.10(a)(1) (21 CFR 1271.10(a)(1)) provides that one of the criteria for an HCT/P to be regulated solely under section 361 of the PHS Act and the regulations in Part 1271 is that the HCT/P is minimally manipulated. As defined in 21 CFR 1271.3(f), minimal manipulation means: 4 See “Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment Registration and Listing;” Final Rule, 66 FR 5447 (January 19, 2001); “Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products;” Final Rule, 69 FR 29786 (May 25, 2004); “Current Good Tissue Practice for Human Cell, Tissue, and Cellular and Tissue-Based Product Establishments; Inspection and Enforcement;” Final Rule, 69 FR 68612 (November 24, 2004). 5 See the “Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception; Guidance for Industry” dated November 2017 available at: https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/T issue/UCM419926.pdf Contains Nonbinding Recommendations 4 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; 2) For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues. FDA discussed these terms in the preamble to the HCT/P Establishment Registration and Listing final rule6 and the 2006 Guidance. However, we have received requests from stakeholders to provide additional guidance that explains our current thinking related to meeting the criterion in 21 CFR 1271.10(a)(1). This guidance supersedes the 2006 Guidance. Please note that if information does not exist to show that the processing meets the definition of minimal manipulation, FDA considers the processing of an HCT/P to be “more than minimal manipulation” that cannot qualify for regulation solely under section 361 of the PHS Act and 21 CFR Part 1271. 7 Homologous Use Section 1271.10(a)(2) (21 CFR 1271.10(a)(2)) provides that one of the criteria for an HCT/P to be regulated solely under section 361 of the PHS Act and the regulations in Part 1271 is that the “HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent.” As defined in 21 CFR 1271.3(c), homologous use means the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor. This criterion reflects the Agency’s conclusion that there would be increased safety and effectiveness concerns for HCT/Ps that are intended for a non-homologous use, because there is less basis on which to predict the product’s behavior, whereas HCT/Ps for homologous use can reasonably be expected to function appropriately (assuming all of the other criteria are also met)8 . In applying the homologous use criterion, FDA will determine what the intended use of the HCT/P is, as reflected by the labeling, advertising, and other indications of a manufacturer’s objective intent, and will then apply the homologous use definition. FDA has received many inquiries from manufacturers about whether their HCT/Ps meet the minimal manipulation and/or homologous use criteria. Additionally, transplant and healthcare providers often need to know this information about the HCT/Ps that they are considering for use in their patients. This guidance provides examples of different types of HCT/Ps and how the regulations in 21 CFR 1271.10(a)(1) and (2) apply to them, and provides general principles that can be applied to HCT/Ps that may be developed in the future. In some of the examples, the 6 “Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment Registration and Listing” 66 FR 5447 at 5457 (January 19, 2001). (Tissue Registration and Listing; Final Rule). 7 See the proposed rule, “Establishment Registration and Listing for Manufacturers of Human Cellular and TissueBased Products” 63 FR 26744 at 26748-26749 (May 14, 1998). (Tissue Registration and Listing; Proposed Rule) 8 “Proposed Approach to Regulation of Cellular and Tissue-Based Products,” dated February 28, 1997 62 FR 9721 (March 4, 1997) page 19. (1997 Proposed Approach). Contains Nonbinding Recommendations 5 HCT/Ps may fail to meet more than one of the four criteria in 21 CFR 1271.10(a).

1271. REGULATORY SCOPE AND COMPLIANCE POLICY A. Scope of FDA’s Regulation of HCT/Ps As noted in the Background section of this document, this guidance only applies to products and establishments that are subject to FDA’s regulations in 21 CFR Part 1271. Establishments that meet the same surgical procedure exception in 21 CFR 1271.15(b) are not subject to FDA’s regulations in 21 CFR Part 1271. This guidance also does not apply to products that fall outside the definition of HCT/P in 21 CFR 1271.3(d). For example, platelet rich plasma (PRP, blood taken from an individual and given back to the same individual as platelet rich plasma) is not an HCT/P under Part 1271 because it is a blood product. Accordingly, FDA does not apply the criteria in 21 CFR 1271.10(a) to PRP, and PRP is outside the scope of this guidance.