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upon the metabolic activity of living cells for primary function (with certain exceptions).Last year, FDA issued three draft guidance documents intended to assist industry in understanding how FDA applies the regulation.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),

By Jeffrey K. Shapiro & Charlene Cho –In the emerging world of regenerative medicine, there is a stark dichotomy in the level of regulation applied to products derived from human cells and tissues, or what FDA calls “human cells, tissue or cellular and tissue‑based products” (HCT/Ps).If an HCT/P meets certain requirements, it is eligible for regulation solely under section 361 of the Public Health Service (PHS) Act. A “361 HCT/P” does not undergo any premarket review by FDA prior to marketing. 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. In practice, many of the HCT/Ps in regenerative medicine that do not qualify as 361 HCT/Ps are regulated as biologics subject to section 351 of the PHS Act or “351 HCT/Ps.” A 351 HCT/P requires approval of a biologics license application (BLA), typically supported by significant clinical data gathered under an Investigational New Drug (IND) exemption. The IND/BLA process is perhaps the most burdensome a

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

t to regulation.Second, US Stem Cell Clinic argued that an HCT/P re-implanted into a patient meets the regulatory definition of “such HCT/P” if it is “like or similar” to the HCT/P removed from the patient. The Eleventh Circuit disagreed. Instead, the court adopted FDA’s interpretation that “such HCT/P” refers to “the antecedent HCT/P removed from the patient in its original form.” The Eleventh Circuit agreed with FDA and the District Court that the SVF procedure does not fall within the “same surgical procedure” exception “because the biological material implanted into the patient is not the same as that removed.” 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. However, the Eleventh Circuit ruled that the 361 HCT/P exception does not apply because the HCT/P in this case is not “intended for homologous use only.”“Homologous use” is “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.” 21 C.F.R. § 1271.3(c). US Stem Cell Clinic argued that SVF meets the “homologous use” criterion of a “361 HCT/P” because SVF was intended to perform the same basic regenerative function both before and after the procedure. However, the District Court determined that the Clinic intended that the SVF treat a “litany of illnesses in the recipient,” which is not the “same basic

processes can be restructured to align with the exemptions. Where appropriate, manufacturers should prioritize engaging with FDA and initiating concrete steps toward preparing marketing applications. They should also ensure that, in the meantime, their HCT/Ps are used only under an IND. Alternately, manufacturers may consider winding down operations, particularly if the likelihood of obtaining an approval or qualifying for an exemption proves infeasible. If manufacturers choose to continue existing operations without taking corrective action, they operate at risk of FDA enforcement.1 21 C.F.R. § 1271.3(d).2 FDA, Guidance for Industry, Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use at 3–4 (July 2020), https://www.fda.gov/media/109176/download [hereinafter ”HCT/P Guidance”]; seealso 21 U.S.C. § 355(a); 42 U.S.C. § 262(a); 21 C.F.R. Part 1271.3 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.6 See 21 C.F.R. § 1271.15(b).7 See HCT/P Guidance, at 22 n.32.8 FDA, Press Release, FDA Announces Comprehensive Regenerative Medicine Policy Framework (Nov. 15, 2017), https://www.fda.gov/news-events/press-announcements/fda-announces-comprehensive-regenerative-medicine-policy-framework.9 Melissa Mendoza, Deputy Director, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research, Address at the Food and Drug Law Institute: Key Issues in Regenerative Medicine Regulation and Approval (May 18, 2021).10 Id.; see also Peter Marks, Advancing the Development of Safe and Effective Regenerative Medicine Products, U.S. Food & Drug Admin. (Apr. 21, 2021), https://www.fda.gov/news-events/fda-voices/advancing-development-safe-and-effective-reg

t preventing the transmission of communicable disease. Such a product is not subject to additional regulation by FDA as a device, drug, or biologic under the Food, Drug, and Cosmetic Act (FDCA).This discussion will focus on the requirement that a 361 HCT/P be labeled and advertised only for homologous use. We will look first at the basic regulatory definition and guidance. Then, we will ask the specific question of whether advertising the clinical effects (performance characteristics) of an HCT/P 361 is compatible with meeting the homologous use requirement.Homologous UseThe regulation defines homologous use to mean “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.” 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.” 66 Fed. Reg. 5447, 5457 (Jan. 19, 2001).In addition, as a general matter, FDA indicated that the homologous use test merely would be a coarse screen for unproven uses: “We intend to interpret ‘nonhomologous’ narrowly. Examples of uses that would be considered nonhomologous include: The use of dermis as a replacement for dura mater . . . and the use of cartilage in the bladder.” Id. And: “For example, promotion of an HCT/P for an unproven therapeutic use, such as curing cancer, would clearly make it inappropriate to regulate the HCT/P [as a

he “same surgical procedure,” it is exempt from FDA regulation. Instead, the court adopted FDA’s view that the clinic’s separation of stromal and vascular cells from surgically-removedadipose (fat) tissue disqualified the procedure from this exception.The court held that the exception only applies to a procedure where the human cell, tissue, or cellular or tissue-based product (HCT/P) that is implanted into a patient includes “all” of “the antecedent HCT/P removed from the patient in its original form.” The case is a critical ruling supporting FDA’s increasing enforcement against stem cell clinics. 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. However, if the HCT/P does not meet all of those criteria, the product is deemed a “351 HCT/P,” meaning that it constitutes a “biological product” requiring FDA review and licensure under Section 351 of the PHSA. In that case, it is also a “drug” subject to regulation under the Federal Food, Drug, and Cosmetic Act (FDCA), as well as the PHSA.Since 2015, FDA has been documenting violations of current Good Manufacturing Practice (cGMP) for tissue products by US Stem Cell Clinic. The agency ultimately issued a warning letter to the company in August 2017, which we analyzed here. In response to the letter, the clinic claimed that FDA’s cGMP regulations are not applicable because the clinic’s SVF treatment f