This status is advantageous, because an HCT/P regulated exclusively under Part 1271 does not have to undergo premarket review of any kind. The four criteria in 21 C.F.R § 1271.10(a) are: (i) minimal manipulation, (ii) homologous use, (iii) not combined with another article (with certain exceptions), and (iv) not having a systemic effect and not dependent upon the metabolic activity of living cells for primary function (with certain exceptions).Last year, FDA issued three draft guidance documents intended to assist industry in understanding how FDA applies the regulation.

In addition, the GMP deviations relating to sterility assurance, described below, likely amplified the agency’s concern about the risks associated with the routes of administration. The agency determined that Atcell is not only an HCT/P subject to section 361 of the Public Health Service Act (42 USC 264), but also constitutes a biological product requiring licensure because it fails to meet the criteria 21 CFR 1271.10(a). Among FDA’s reasons for that determination were the following: The manufacturer’s objective intent, as reflected by the labeling, advertising or other indications, was to treat patients for a variety of serious or life-threatening diseases or conditions, including Parkinson’s disease, amyotrophic lateral sclerosis (ALS), stroke, multiple sclerosis (MS), and anoxic brain injury.

In November of 2017, FDA published its enforcement discretion policy regarding HCT/Ps that don’t meet all four criteria under 21 CFR 1271.10(a):To give manufacturers time to determine if they need to submit an IND or marketing application in light of this guidance and, if such an application is needed, to prepare the IND or marketing application, for the first 36 months following issuance of this guidance FDA generally intends to exercise enforcement discretion with respect to the IND and the premarket approval requirements for HCT/Ps that do not meet one or more of the 21 CFR 1271.10(a) criteria, provided that use of the HCT/P does not raise reported safety concerns or potential significant safety concerns.FDA has believed for some time that numerous HCT/P manufacturers don’t meet all four criteria for regulation solely under 21 CFR Part 1271, and they have been hoping that the publication of the 2017 Guidance on Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue Based Products: Minimal Manipulation and Homologous Use, together with the 36 months of enforcement discretion (with 22 months remaining),

Once marketed, under 21 C.F.R. Part 1271, such products must comply with donor screening and eligibility requirements, as well as labeling, adverse event/manufacturing deviation reporting to FDA and product handling (Good Tissue Practice) requirements.To qualify as a 361 HCT/P, a product must meet the following requirements in 21 CFR 1271.10(a):Be minimally manipulated;Be intended for homologous use (as reflected in labeling and advertising); Not be manufactured by combining cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent;Not have a systemic effect and not be dependent upon the metabolic activity of living cells for its primary function, with certain limited exceptions.If any of these requirements are not met, the HCT/P is still subject to regulation under 21 C.F.R. Part 1271, but in addition is likely subject to biologic, drug or medical device regulation.

As a result, the product was adulterated and misbranded. The court agreed with the FDA that Regenerative’s product did not satisfy the “minimal manipulation” requirement for exemption under 21 C.F.R. § 1271.10, which provides that the product is not regulated as a drug or biologic under the FDA regulations, because the mixture altered the biological characteristics of the resultant cell population through its culturing process. The court disagreed with Regenerative and explained that the FDA was not attempting to regulate the practice of medicine.

ignation, for sponsors of regenerative medicine therapies; andEvaluation of Devices Used with Regenerative Medicine Advanced Therapies,describing FDA’s current thinking about devices used in the recovery, isolation and delivery of regenerative medicine advanced therapies (RMATs).FDA’s decision to make HCT/P promotion the subject of their first untitled letter of 2023 signals the agency’s continued push to keep a close eye on HCT/Ps and regenerative medicine in general.As this field continues to advance and more products begin to hit the market, it appears FDA will not be shy about making sure HCT/Ps are properly classified and undergo appropriate premarket review. Manufacturers developing products in this area should take care to properly follow FDA’s regenerative medicine guidance when determining an approval and marketing strategy for their product.FOOTNOTES Untitled letter available here: March 1, 2023 Untitled Letter – Thomas Advanced Medical LLC (fda.gov).See 21 CFR 1271.3(d).See 21 CFR 1271.10(a) Guidance available here: 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, (fda.gov).Id.Id. Framework available here: Framework for the Regulation of Regenerative Medicine Products | FDA Guidance available here: 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, (fda.gov). Guidance available here: Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception; Guidance for Industry (fda.gov) Guidance available here: Expedited Programs for Regenerative Medicine Therapies for Serious Conditions; Guidance for Industry (fda.gov) Guidance available here: Evaluation of Devices Used with Regenerative Medicine Advanced Therapies; Guidance for Industry (fd

The court cited a history of FDA treating “such HCT/Ps” as meaning HCT/Ps in their original form that have not been subjected to significant processing.“361 HCT/P” exceptionThe clinic also argued on appeal that it is exempt from regulation under the FDCA and PHSA because the procedure falls into the “361 HCT/P” exception, whereby an HCT/P meeting four criteria (set forth in 21 C.F.R. § 1271.10(a)) is deemed a “361 HCT/P,” meaning that it is regulated solely under Section 361 of the Public Health Service Act (PHSA) and its implementing regulations in 21 C.F.R. Part 1271. Being deemed a “361 HCT/P” subjects a therapy to a lighter regulatory burden.

3 See 42 U.S.C. §§ 262(a) and 264; 21 C.F.R. § 601.2(a).4 See 21 C.F.R. § 1271.10(a); HCT/P Guidance, at 3.5 FDA, Guidance for Industry, Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception at 3 (Nov. 2017), https://www.fda.gov/media/89920/download.

In determining whether a product is “intended” for homologous use, FDA considers only “the labeling, advertising, or other indications of the manufacturer’s objective intent.” 21 C.F.R. § 1271.10(a)(2).In the preamble to the regulation, FDA clarified that homologous use does not require use of tissue in its native anatomic location: “a use of a structural tissue may be homologous even when it does not occur in the same location as it occurred in the donor. For example, the use of bone for repair, replacement, or reconstruction anywhere in the skeleton of the recipient (including the vertebral column) would be considered homologous use.

It also clarifies FDA’s authority to regulate SVF therapies in particular, and bolsters FDA’s effort to gain more control over the HCT/P field more broadly.FDA has published regulations governing HCT/Ps under which certain of such products are subject to a standard generally lower than that applying to drugs and biological products. Specifically, if an HCT/P meets four criteria set forth in 21 C.F.R. §1271.10(a), then it is deemed a “361 HCT/P,” meaning that it is regulated solely under Section 361 of the Public Health Service Act (PHSA) and its implementing regulations in 21 C.F.R. Part 1271. Section 361 authorized FDA to issue regulations to prevent the transmission of communicable diseases.