FDA decides which pathway applies by testing a product against the criteria in 21 CFR 1271.10(a). Say a product meets all of them. Then only two things govern it. One is section 361 of the Public Health Service Act. The other is the rules in 21 CFR Part 1271. It needs no premarket review. Now say it fails any of them, and no exception under 21 CFR 1271.15 applies. Then it is regulated as a drug, device, and/or biological product. That falls under the Federal Food, Drug, and Cosmetic Act and/or section 351 of the PHS Act. FDA’s guidance states that premarket review will then be required.
What are human cells, tissues, and cellular and tissue-based products (HCT/Ps)?
FDA’s July 2020 guidance points to the definition in 21 CFR 1271.3(d). HCT/Ps are items that contain or consist of human cells or tissues. They are meant to be implanted, transplanted, infused, or transferred into a human recipient.
That definition is the gate before the pathway question. If a product is not human cells or tissue, this framework does not cover it at all. That is why the same rule book cannot be stretched over every category a clinic might offer.
What are the four criteria for a 361 HCT/P?
Minimal manipulation
Start with structural tissue. Here, minimal manipulation means processing that keeps the tissue’s original key traits. Those are the traits that make it useful for rebuilding, repair, or replacement. For cells or nonstructural tissue, the processing must not change their key biological traits.
Homologous use
The HCT/P must be meant for homologous use only. That intent shows in the maker’s labeling, advertising, or other signs of its objective intent. Homologous use means repair, rebuilding, replacement, or adding to a recipient’s cells or tissues. The HCT/P must do the same basic job in the recipient as in the donor.
The remaining two criteria
The third criterion limits what the HCT/P may be mixed with. Only water, crystalloids (simple salt solutions), or an agent for sterilizing, preserving, or storage is allowed. And the addition must not raise new clinical safety concerns.
The fourth deals with effects on the whole body. One way to pass: the HCT/P has no systemic effect. It also does not depend on the metabolic activity of living cells. If it does, its use must be limited. It must be autologous (your own cells), allogeneic use in a first- or second-degree blood relative, or reproductive use.
Registration and listing is a separate paragraph
Registering with FDA and listing each HCT/P are required by 21 CFR 1271.10(b). These duties fall on the sites that make qualifying products. They follow from qualifying under section 361. They are not one of the four tests a product must pass to get there.
What happens when a product does not qualify under section 361?
Some HCT/Ps are regulated as drugs or biological products. FDA expects every site making them to have one of two things in effect: an approved biologics license application or an investigational new drug application. An approved BLA is required to sell such a product legally. During development, it may be given for clinical use in humans only under an IND.
This is the real difference between the two lanes. It is not about paperwork. It decides whether a product may legally be sold at all.
Why does the 361 versus 351 pathway matter to patients?
The word “orthobiologic” covers products that fall into different legal categories. Marketing language rarely shows you the difference. Regen.MD’s position is that patients should be able to ask the question directly. You should not have to guess 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? Does that processing keep it inside the minimal manipulation definition?
- Is the intended use in my case homologous? Does it do the same basic job 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, made from your own body. They include intra-articular and tendon PRP in leukocyte-poor and leukocyte-rich forms. They include intraosseous and subchondral PRP. They also include bone marrow aspirate concentrate, Lipogems, and intradiscal orthobiologics. Legal category depends on the specific product as made and used. 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 framed as the practice positions it: a bridge therapy prior to arthroplasty. Surgery is provided when conservative measures have been exhausted, never as the first option. The Regen.MD approach to terrain-first care sets out the order of those decisions.
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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.
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Frequently Asked Questions
What is the practical difference between a 361 HCT/P and a 351 product?
Say an HCT/P meets all the criteria in 21 CFR 1271.10(a). Then only section 361 of the Public Health Service Act and 21 CFR Part 1271 govern it. It needs no 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. Then premarket review will be required. Raise that difference when you compare the orthobiologic services at Regen.MD with anything else you have been offered.
Does the injection route change the regulatory pathway?
No. The category depends on the product as made and on its intended use. It does not depend on whether it goes into a joint, a tendon, a bone, or a disc. The route is a clinical choice based on your anatomy and your findings. That is what the review of the conditions evaluated at Regen.MD is for.
If a clinic says its product is FDA-registered, does that mean FDA approved it?
Those are different things. Site registration and product listing are required under 21 CFR 1271.10(b) for makers. They are not a finding that FDA reviewed or approved the product. The Regen.MD patient library is a good place to get your terms 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 cover them. At Regen.MD, we talk about them as topics for care and teaching. We do not sell them as products. See physician-directed peptide therapy for how that separate subject is handled.
What does homologous use mean?
Homologous use means the cells or tissue do the same basic job in the recipient that they did in the donor. That job is repair, rebuilding, replacement, or adding to the recipient’s own cells or tissues. It is one of the four criteria in 21 CFR 1271.10(a). It is judged by the maker’s labeling, advertising, and other signs of its objective intent.
Under what law are HCT/Ps regulated?
Say an HCT/P meets all four criteria in 21 CFR 1271.10(a). Then only section 361 of the Public Health Service Act and the rules in 21 CFR Part 1271 govern it. One that fails any criterion, with no exception under 21 CFR 1271.15, is regulated differently. It is treated as a drug, device, and/or biological product. That falls under the Federal Food, Drug, and Cosmetic Act and/or section 351 of the Public Health Service Act.
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).