What's the Difference Between a Biologic and a Cell Therapy? A Beginner's Guide to FDA Regulation

What This Article Covers

If you've been researching stem cell treatments, you've probably noticed something confusing: some cell therapies go through years of clinical trials and cost hundreds of thousands of dollars, while others are offered same-day at a local clinic for a few thousand dollars, with no mention of FDA approval at all. This isn't a marketing quirk — it reflects two genuinely different legal categories under U.S. law, nicknamed “351” and “361” after the sections of the Public Health Service Act that define them. Understanding this one distinction is arguably the single most useful piece of knowledge a newcomer can have before evaluating any stem cell or cell therapy claim, because it tells you what kind of evidence — if any — actually stands behind the product being offered.

How the FDA Splits Cell Products Into Two Buckets

The Public Health Service Act gives the FDA two very different ways to regulate a “human cell, tissue, or cellular or tissue-based product” (the FDA's formal term, abbreviated HCT/P). Which bucket a product falls into depends not on what it's called or where it's offered, but on how it was made and how it's used.

Section 361 products are regulated solely under the FDA's public-health authority, codified in the regulations at 21 CFR Part 1271. This is a lighter-touch framework: no premarket review, no clinical trials, no FDA approval required before the product reaches a patient. To qualify for this pathway, a product must meet all four criteria spelled out in 21 CFR 1271.10(a): minimal manipulation (processing that doesn't alter the tissue's original relevant characteristics or the cells' biological characteristics); homologous use only (the product must perform the same basic function in the recipient it performed in the donor); no combination with other articles (with narrow exceptions like water, crystalloids, or sterilization agents); and either no systemic effect and no dependence on living-cell metabolism, or use that is autologous (a patient's own cells given back to that same patient), reproductive, or between close blood relatives.

If a product meets all four, the FDA doesn't require a Biologics License Application (BLA) — it's overseen mainly through facility registration, donor-eligibility screening, and manufacturing rules under Part 1271. A related but distinct carve-out, the “same surgical procedure” exception under 21 CFR 1271.15(b), exempts certain tissue removed from and reimplanted into the same patient during a single procedure without outside processing.

Section 351 products are everything that doesn't meet those criteria — which, in practice, includes most modern engineered cell and gene therapies. These are regulated as biological drugs under Section 351 of the Public Health Service Act, meaning the manufacturer must file a BLA and prove safety and effectiveness through the full clinical trial pipeline before the FDA will approve the product. Once approved, manufacturers must also follow current good manufacturing practice rules under 21 CFR Parts 210, 211, and 600–680.

The clearest illustration of a 351 product is CAR-T cell therapy. Kymriah (tisagenlecleucel), approved by the FDA on August 30, 2017, was the first CAR T-cell therapy ever approved in the United States, followed by Yescarta (axicabtagene ciloleucel) later that year. Both required full BLAs, years of clinical trials, and are manufactured under strict, FDA-inspected conditions — because engineering a patient's T-cells to express a chimeric antigen receptor is about as far from “minimal manipulation” as a cell product can get.

Why This Distinction Actually Matters to You as a Patient

Here's the empowering part: this isn't just regulatory trivia. It's a direct, practical signal you can use. A product regulated under 351 has, by definition, been reviewed by the FDA for safety and effectiveness in the specific condition it's approved to treat. A product offered under a 361 claim has not been reviewed for effectiveness at all — the FDA has only confirmed (or, in many disputed cases, has not confirmed) that it qualifies for the narrow exemption in the first place.

This is exactly why it's reasonable — and smart — to ask any clinic offering a stem cell procedure a direct question: “Is this product FDA-approved, or is it being offered under the 361/same-day exemption?” A clinic offering a legitimate, minimally-manipulated, same-day, autologous procedure should be able to explain that framework clearly. Hesitation, vague answers, or claims that a product is “FDA-registered” (registration is not the same as approval — it just means a facility told the FDA it exists) are worth treating as a red flag.

It's also worth being clear-eyed about what a 361 exemption does and doesn't mean. It is a manufacturing and public-health classification, not a certification of safety or efficacy for a given disease. Being unregulated in the “premarket approval” sense does not mean a 361 product is equivalent, in evidence quality or demonstrated safety, to an FDA-approved biologic — the two categories exist precisely because the underlying products carry different risk profiles and different evidentiary bars.

When the Line Gets Contested: Real Enforcement Cases

The 351/361 boundary isn't just theoretical — the FDA has repeatedly gone to court over clinics that classified their products as 361-exempt when the agency believed they didn't qualify.

The most significant recent example is United States v. California Stem Cell Treatment Center, Inc., decided by the Ninth Circuit Court of Appeals on September 27, 2024. The case centered on stromal vascular fraction (SVF) — a mixture of stem cells and other cells extracted from a patient's own fat tissue, then re-injected to treat conditions like arthritis. The clinic argued this qualified for the “same surgical procedure” exception, since the tissue was removed from and returned to the same patient. The Ninth Circuit disagreed, unanimously holding that SVF itself is a “drug” under federal law: because the fat tissue is significantly processed (enzymatically broken down to isolate the cells) before being reinjected, the resulting product is no longer the same tissue that was removed, so the same-surgical-procedure exception doesn't apply. Reporting on the case notes this ruling aligned the Ninth Circuit with prior decisions from the D.C. Circuit and Eleventh Circuit, reinforcing across multiple courts that clinics can't sidestep BLA requirements simply by performing extraction and reinjection in one visit.

The FDA has also issued warning letters directly over 361 misclassification. In a warning letter dated January 17, 2025, the FDA cited Chara Biologics, Inc. of Chatsworth, California, for marketing umbilical-cord-derived products (CharaCore and CharaOmni) that it said failed to meet the minimal-manipulation and homologous-use criteria — processing turned the umbilical cord “from a conduit into a flowable form,” and the products were marketed for conditions like Parkinson's disease, Alzheimer's disease, multiple sclerosis, and ALS that go well beyond the tissue's original function. Because the products didn't qualify for the 361 exemption, the FDA treated them as unapproved new drugs and unlicensed biologics requiring a BLA the company didn't have, and separately cited manufacturing and record-keeping violations under Part 1271.

Cases like these are useful for patients precisely because they show the exemption is not self-executing. A clinic calling its product “361-compliant” is making a legal claim, not stating a settled fact — and the FDA has shown it will challenge that claim in court and through direct enforcement when it believes the criteria aren't met.

How to Use This Framework When Evaluating a Clinic or Product

None of this requires you to become a regulatory lawyer. A few grounded, practical habits go a long way: ask directly which pathway the product uses — a straightforward answer (“this is your own bone marrow, minimally processed, reinjected during the same procedure, under the same-surgical-procedure exception”) is a good sign, while marketing language without a clear regulatory answer is not. Understand that “FDA-registered” is not “FDA-approved” — facility registration under Part 1271 is a baseline administrative requirement and says nothing about whether the specific product has been reviewed for safety or effectiveness. Check whether the treatment is part of a registered clinical trial under an FDA Investigational New Drug (IND) application — legitimate research should not require you to pay for participation the way a commercial “treatment” would. Remember that the FDA itself states no regenerative medicine product is currently approved for many commonly advertised uses, including most orthopedic, neurological, cardiovascular, and anti-aging claims. And if something goes wrong, report it — the FDA's MedWatch program exists specifically to capture adverse events from products like these, and it's one of the ways enforcement actions like the ones above get started.

Bottom Line

The 351/361 distinction is the FDA's basic sorting mechanism for cell and tissue products, and it maps directly onto a question every patient should feel entitled to ask: has this specific product been reviewed and approved based on clinical evidence, or is it being offered under a narrow manufacturing exemption that says nothing about whether it actually works? Engineered, non-homologous, or heavily processed products — like CAR-T therapies — sit squarely in the 351/BLA category and carry the weight of full FDA review behind them. Minimally manipulated, homologous, same-day autologous procedures can legitimately sit in the 361 category — but that classification is a legal claim the FDA has shown, through cases like California Stem Cell Treatment Center and warning letters like the one issued to Chara Biologics, it will contest when a clinic gets it wrong. Knowing which bucket a product claims to be in — and asking the clinic to explain why — is one of the simplest, most concrete ways to protect yourself before pursuing any stem cell or cell-based treatment.