FDA decides which pathway applies by testing a product against the criteria in 21 CFR 1271.10(a). Meet all of them and the product is regulated solely under section 361 of the Public Health Service Act and the regulations in 21 CFR Part 1271, without premarket review. Fail any of them, with no exception available under 21 CFR 1271.15, and the product is regulated as a drug, device, and/or biological product under the Federal Food, Drug, and Cosmetic Act and/or section 351 of the PHS Act — and FDA’s guidance states that premarket review will be required.
First question: is it an HCT/P at all?
FDA’s July 2020 guidance points to the definition in 21 CFR 1271.3(d): HCT/Ps are articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.
That definition is the gate before the pathway question. Products that are not human cells or tissues are not answered by this framework at all, which is why the same regulatory vocabulary cannot be stretched across every category a clinic might offer.
The four criteria in 21 CFR 1271.10(a)
Minimal manipulation
For structural tissue, minimal manipulation means processing that does not alter the original relevant characteristics of the tissue relating to its utility for reconstruction, repair, or replacement. For cells or nonstructural tissues, it means processing that does not alter the relevant biological characteristics of the cells or tissues.
Homologous use
The HCT/P must be intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent. Homologous use is defined as 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.
The remaining two criteria
The third criterion limits what the HCT/P may be combined with: nothing beyond water, crystalloids, or a sterilizing, preserving, or storage agent, and only where the addition does not raise new clinical safety concerns.
The fourth addresses systemic effect. Either the HCT/P has no systemic effect and does not depend on the metabolic activity of living cells, or, if it does, its use is confined to autologous use, allogeneic use in a first- or second-degree blood relative, or reproductive use.
Registration and listing is a separate paragraph
Registration with FDA and listing each HCT/P are requirements in 21 CFR 1271.10(b), placed on the establishments that manufacture qualifying products. They are obligations that follow from qualifying under section 361, not one of the four tests a product must pass to get there.
What happens when a product falls outside 361
FDA expects every establishment manufacturing HCT/Ps regulated as drugs or biological products to have an approved biologics license application or an investigational new drug application in effect. An approved BLA is required to lawfully market such a product, and during development it may be distributed for clinical use in humans only under an IND.
This is the concrete difference between the two lanes. It is not a paperwork distinction; it determines whether a product may lawfully be marketed at all.
Why this matters when you are comparing offers
The word “orthobiologic” covers products that land in different regulatory categories, and marketing language rarely makes the difference visible. Regen.MD’s position is that patients should be able to ask the question directly rather than infer it from a brochure.
Questions worth bringing to a physician-led evaluation
- Is this product an HCT/P as defined in 21 CFR 1271.3(d)?
- Does it meet all four criteria in 21 CFR 1271.10(a), or is it regulated under section 351?
- How is it processed, and does that processing keep it within the minimal manipulation definition?
- Is the intended use in my case homologous — the same basic function in me as in the donor?
- If it is a 351 product, is there an approved BLA, or is this being offered under an IND?
Where this sits at Regen.MD
Regen.MD works with autologous preparations: intra-articular and tendon PRP in leukocyte-poor and leukocyte-rich variants, intraosseous and subchondral PRP, bone marrow aspirate concentrate, Lipogems, and intradiscal orthobiologics. Regulatory classification depends on the specific product as manufactured and used, and it is a fair question to put to any physician, including this one.
What does not change with the pathway is the clinical standard. Regen.MD does not claim that any orthobiologic regrows or regenerates cartilage; for advanced knee osteoarthritis, PRP is discussed framed as the practice positions it, a bridge therapy prior to arthroplasty. Surgery is provided when conservative measures have been exhausted, never as the opening option. The Regen.MD approach to terrain-first care sets out how those decisions are sequenced.
Find out what is actually driving your pain
Regen.MD begins with a physician-led Clinical Evaluation — a review of your history, imaging, and metabolic data, and a written terrain roadmap. Evaluation is contingent upon review of your data.
Questions? Call (314) 295-3000 or text (314) 886-5902.
Frequently Asked Questions
What is the practical difference between a 361 HCT/P and a 351 product?
An HCT/P meeting all the criteria in 21 CFR 1271.10(a) is regulated solely under section 361 of the Public Health Service Act and 21 CFR Part 1271, without premarket review. One that does not meet all of them, with no exception under 21 CFR 1271.15, is regulated as a drug, device, and/or biological product and premarket review will be required. That distinction is worth raising when you compare the orthobiologic services at Regen.MD against anything else you have been offered.
Does the injection route change the regulatory pathway?
No. The classification turns on the product as manufactured and on its intended use, not on whether it is delivered intra-articularly, into tendon, intraosseously, or intradiscally. The route is a clinical decision made against your anatomy and your findings, which is what the conditions evaluated at Regen.MD assessment is for.
If a clinic says its product is FDA-registered, does that mean FDA approved it?
Those are different things. Establishment registration and product listing are requirements under 21 CFR 1271.10(b) that apply to manufacturers; they are not a finding that FDA reviewed or approved the product. The Regen.MD patient library is a reasonable place to get your vocabulary straight before you sit down with anyone selling a procedure.
Do peptides fall under this framework?
No. Peptides are not human cells or tissues, so the HCT/P framework does not describe them, and at Regen.MD they are discussed as clinical and educational subjects rather than sold as products. See physician-directed peptide therapy for how that separate subject is handled.
Sources
- U.S. Food and Drug Administration, Center for Biologics Evaluation and Research and Center for Devices and Radiological Health. 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. July 2020. https://www.fda.gov/media/109176/download (HCT/P definition at 21 CFR 1271.3(d); minimal manipulation definitions at 21 CFR 1271.3(f); homologous use definition at 21 CFR 1271.3(c); statement that a product failing the criteria with no 1271.15 exception is regulated as a drug, device, and/or biological product under the FD&C Act and/or section 351 of the PHS Act, with premarket review required).
- Electronic Code of Federal Regulations. 21 CFR 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? https://www.ecfr.gov/current/title-21/section-1271.10 (the four criteria in paragraph (a); the registration and listing requirements in paragraph (b)).
- U.S. Food and Drug Administration. Questions and Answers Regarding the End of the Compliance and Enforcement Policy for Certain Human Cells, Tissues, or Cellular or Tissue-based Products (HCT/Ps). https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/questions-and-answers-regarding-end-compliance-and-enforcement-policy-certain-human-cells-tissues-or (FDA expectation of an approved BLA or an IND in effect for HCT/Ps regulated as drugs or biological products; approved BLA required to lawfully market).