hopes to foster new and innovative treatment options for patients, while creating a clearer regulatory framework that will allow for greater enforcement ability against those that fall outside of the framework.The two new draft guidance documents, which will be the subject of a future blog post, are intended to aid the effort to bring innovative, safe, and effective products to patients as efficiently as possible:Expedited Programs for Regenerative Medicine Therapies for Serious Conditions (“Expedited Programs for RMAT”).Evaluation of Devices Used with Regenerative Medicine Advanced Therapies (“Devices Used with RMAT”).The two final guidance documents describe the Agency’s approach to regulating HCT/Ps:Regulatory Considerations for Human Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use—Guidance for Industry and Food and Drug Administration Staff (November 2017) (“Regulatory Considerations Guidance”).Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception—Guidance for Industry (November 2017) (“SSP Guidance”). FDA regulations at 21 C.F.R. Part 1271, previous draft guidance documents, and untitled letters establish the Agency’s approach to regulating HCT/Ps. In short, some HCT/Ps are exempt from premarket approval and are subject to regulation solely under section 361 of the Public Health Service Act (“PHS Act”) (so‑called “361 HCT/Ps”) whereas others require premarket approval (i.e., as a drug, device, or biologic) (so‑called “351 HCT/Ps”). Both 361 HCT/Ps and 351 HCT/Ps are subject to FDA requirements (at Part 1271) for registration and listing, donor-eligibility, current good tissue practices, and other requirements intended to prevent transmission of communicable diseases. Still others – those that are the subject of the “same surgical procedure” exception – are exempt from both premarket approval requirements and the requirements of Part 1271. (This regulatory regime is ou

aging 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-regenerative-medicine-products.11 See 82 Fed. Reg. 54290, 54291–92 (Nov. 17, 2017); HCT/P Guidance at 22 n.32.12

ction 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 falls under FDA’s “same surgical procedure” exception to the HCT/P regulations. 21 C.F.R. § 1271.15(b). This provision states that FDA’s regulation does not apply if “you are an establishment that removes HCT/P’s from an individual and implants such HCT/P’s into the same individual during the same surgical procedure.” Bringing this issue to court, FDA successfully asserted that the SVF implanted into the clinic’s patients does not constitute “such HCT/P” removed from the patient due to the processing steps applied to the SVF, meaning the defendant was not covered by the exception.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 court disagreed. Instead, it adopted FDA’s interpretation that “such HCT/P” refers to “the antecedent HCT/P removed from the patient in its original form” (emphasis added). The clinic further asserted that in its procedures, the “unit of HCT/P”, i.e., SVF cells implanted into the patient, “remain largely unchanged” from the SV

the manufacturer can avoid the time-consuming and costly premarket review and approval process:The HCT/P is minimally manipulated;The HCT/P is objectively marketed for intended uses in the recipient that are consistent with its normal function in the donor’s body (i.e., homologous uses);The HCT/P is not combined with another article (with some limited exceptions); andThe HCT/P either: (1) does not have a systemic effect and is not dependent on the metabolic activity of living cells for its primary function; or(2) does have a systemic effect or is dependent on the metabolic activity of living cells for its primary function, and is for: (a) use in the same individual who was the source of the tissue or cells;(b) use in an individual who is a first- or second-degree blood relative of the donor of the tissue or cells; or(c) reproductive use.These are commonly known as “361 HCT/Ps.” HCT/Ps that do not meet the above criteria – and do not fall into one of the enumerated exceptions under 21 CFR § 1271.15 – are considered to be drugs, devices, and/or biological products regulated under Section 351 of the PHS Act and the Federal Food, Drug, & Cosmetic Act (FDCA). While 361 HCT/Ps are not required to undergo any FDA premarket review or approval, HCT/Ps considered to be drugs, devices, and/or biological products must satisfy the FDCA’s premarketing requirements.As aforementioned, this is a risk-based regulatory framework. The FDA has deemed that HCT/P products which meet these four criteria are exempt from premarketing requirements because they present a limited public health risk. In contrast, HCT/Ps that fail to meet these criteria must undergo clinical trials and FDA premarket review and approval in order to gain confidence in their clinical safety and effectiveness. FDA has explained that, for example, when an HCT/P is taken from the donor’s body and more than minimally altered during processing, there is less certainty that the cell or tissue will function the same in the recipient’s

ropriate 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 (fda.gov)

e surgical procedure” and “361 HCT/P” exceptions to regulation under the Federal Food, Drug, and Cosmetic Act (FDCA) and the Public Health Service Act (PHSA). In June 2019, a Florida district court ruled in favor of FDA, and enjoined the clinic from offering its stem cell therapy to patients.As we summarized (here), the district courtfoundthat the population of stromal and vascular cells in US Stem Cell Clinic’s therapy, known as stromal-vascular fraction (SVF), requires FDA approval of a New Drug Application (NDA) or a Biologics License Application (BLA) before it can be commercially marketed. The court also found that the therapy was adulterated and misbranded because of the clinic’s manufacturing procedures and that its promotion violated statutory requirements.“Same surgical procedure” exceptionOn appeal with the Eleventh Circuit, US Stem Cell Clinic again argued it is exempt from regulation under the FDCA because the procedure falls into the “same surgical procedure” exception at 21 C.F.R. § 1271.15(b). This provision states that FDA’s regulation does not apply if “you are an establishment that removes HCT/P’s from an individual and implants such HCT/P’s into the same individual during the same surgical procedure.” Arguing before the District Court, FDA had successfullyassertedthat the SVF implanted into the clinic’s patients does not constitute “such HCT/P” removed from the patient due to the processing steps applied to the SVF in this case, meaning US Stem Cell Clinic was not covered by this exception.In prefacing its analysis, the Eleventh Circuit notably explained that it was not merely offering judicial deference to FDA, saying it was “giving the agency’s view no special weight.” The court said that although “[t]here was a time when a court faced with a regulation that seemed ‘impenetrable on first read’ might simply ‘wave the ambiguity flag’ and defer to the agency’s interpretation,” this is the case “[n]o longer.” Rather, the court “carefully consider[ed] the text, structure,

Not all HCT products are regulated by both the FD&C Act and the PHS Act. According to the 2017 guidelines, certain HCT products will be regulated only by the PHS Act, so long as they meet the following criteria pursuant to 21 CFR 1271.15(b) and 1271.10(a):The product is “minimally manipulated,” which means: For structural tissue, processing does not alter the original characteristics of the tissue relating to the tissue’s use for reconstruction, repair or replacement; andFor nonstructural tissues (e., cells), processing does not alter the relevant biological characteristics of cells or tissuesThe manufacturers’ “objective intent” is that the product is intended for homologous use onlyThe manufacture of the product does not involve the combination of the cells or tissues with another article, with limited exceptionsThe product either does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function, or if the product does have a systemic effect and is dependent upon metabolic activity of the cells for its primary function, the product must be for: Autologous (obtained from the same individual) useAllogenic (involving tissues or cells that are genetically dissimilar

One of the first warning letters of 2018 was issued to a manufacturer of a human cell, tissue, and cellular and tissue-based product (HCT/P) that the Food and Drug Administration said was regulated as a drug, and as a biological product, and required a biologics license because it did not meet the definitions of minimal manipulation and homologous use. The meanings of these two terms are the subject of a new guidance FDA issued in November 2017. The guidance, Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use (Guidance), provides clarification on these two criteria that are used to determine how an HCT/P will be regulated by FDA. FDA also issued another HCT/P guidance, Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception, which covers another HCT/P regulatory exception, at the same time. We are not covering the Same Surgical Exception guidance in this article. Because both guidances cover various aspects of adipose tissue regulation, the agency withdrew the previous adipose tissue draft guidance titled: Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) from Adipose Tissue: Regulatory Considerations. Adipose tissue regulation will be discussed in more detail below.Background HCT/Ps are biologic products typically regulated by the Center for Biologics Evaluation and Research (CBER). FDA’s regulatory authority over HCT/Ps stems from both the Federal Food, Drug, and Cosmetic Act (FDCA) and the Public Health Service Act (PHSA). Some HCT/Ps do not require premarket approval and are regulated only under section 361 of the PHSA and 21 CFR Part 1271. In order to avoid regulation as a new drug requiring premarket approval, an HCT/

those regulated solely under section 361 of the [PHS Act] and part 1271 of title 21, Code of Federal Regulations”;The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; andPreliminary clinical evidence indicates the drug has the potential to address an unmet medical need.The effect of designation means that FDA must take actions to expedite development and review of the drug, including early interactions to discuss the potential for accelerated approval. In addition, a designated drug may be eligible for priority review or accelerated approval under current FDA regulatory standards, and if approved under accelerated approval, would be subject to a confirmatory study.The final guidance documents, which were addressed in a previous accompanying blog post (here), are:Regulatory Considerations for Human Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use;Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception.The two new draft guidances, which are the subject of this blog post, are intended to aid in bringing innovative, safe, and effective products to patients as efficiently as possible:Expedited Programs for Regenerative Medicine Therapies for Serious Conditions (“Expedited Programs for RMAT”);Evaluation of Devices Used with Regenerative Medicine Advanced Therapies (“Devices Used with RMAT”).Draft Guidance #1: Expedited Programs for Regenerative Medicine TherapiesThe “Expedited Programs for RMAT” draft guidance (RMAT draft guidance) describes several established programs, including Fast Track designation, Breakthrough Therapy designation, accelerated approval, and priority review designation, all of which are detailed in the more generally applicable guidance document entitled “Expedited Programs for Serious Conditions – Drugs and Biologics,” (May 2014) (see previous coverage here) as well as the newly established RMAT designati

All stakeholders will now keenly await the announced guidance documents to understand how FDA will implement this new regulatory framework.1See 21 C.F.R. Part 1271.2See FDA, Draft Guidance for Industry and FDA Staff: Homologous Use of HCT/Ps (Oct. 2015); FDA Draft Guidance for Industry and FDA Staff: Minimal Manipulation of HCT/Ps (Dec. 2014); FDA, Draft Guidance for Industry: HCT/Ps from Adipose Tissue: Regulatory Considerations (Dec. 2014); FDA, Draft Guidance for Industry: Same Surgical Procedure Exception under 21 CFR 1271.15(b) (Oct. 2014).3 FDA, Public Hearing; Request for Comments – Draft Guidances Relating to the Regulation of HCT/Ps (Docket No. FDA-20150D-3719).MoreSidley Austin LLP provides this information as a service to clients and other friends for educational purposes only.