What is FDA’s Tissue Reference Group?

For many products, the review center is clear: biologics in CBER, drugs in CDER, and devices in CDRH. For others, it’s more complicated: human cells, tissues, and cellular and tissue-based products can be regulated as drugs, devices, biologics, or combination products. This impacts who reviews them and how they’re regulated.

Under a risk-based regulatory framework for regenerative medicine products, FDA allows low risk human cell and tissue products to be marketed without the formal marketing review in an NDA, BLA, or 510(k). It’s easy to assume that FDA will readily agree that your product fits into this “361 HCT/P” pathway, but many companies have a frustrating FDA experience.

Before you build a commercial strategy, submit anything to FDA, or ship a single unit, you need to understand FDA’s decision-making: what an HCT/P is, how FDA’s review centers are organized, what “361” actually requires, how the same tissue can end up regulated as a device, a biologic, or a combination product, and who inside FDA makes the call.

01 · THE STARTING POINT

What is an HCT/P?

FDA regulates human cells, tissues, and cellular and tissue-based products — HCT/Ps — under 21 CFR Part 1271. An HCT/P is broadly defined as an article containing or consisting of human cells or tissues intended for implantation, transplantation, infusion, or transfer into a human recipient.

Common examples include allografts, demineralized bone matrix, skin grafts, corneas, heart valves, amniotic membrane products, cord blood, and reproductive tissues. Notably excluded are vascularized organs, whole blood and blood components, and most secreted or extracted products.

02 · THE MAP

How FDA is organized and where tissue fits

FDA reviews medical products through three product centers, each with its own governing regulations, review pathways, and review culture. Knowing which center owns your product tells you almost everything about the road ahead, because the centers do not run on the same rules.

CDER: the Center for Drug Evaluation and Research reviews most drugs and some biological products, from small molecules and polypeptides to large therapeutic proteins. Drug products generally reach the market through a New Drug Application (NDA), or an Abbreviated New Drug Application (ANDA) for generics, after clinical study under an Investigational New Drug application (IND).

CBER: the Center for Biologics Evaluation and Research reviews biological products: vaccines, blood and blood components, allergenics, and cell, gene, and tissue therapies. HCT/Ps live here. Within CBER, the Office of Therapeutic Products (OTP), the expanded office that replaced the former Office of Tissues and Advanced Therapies (OTAT), handles cell therapies, gene therapies, and tissue-based products. Most applicants deal with OTP if their products are 351 undergoing licensure through a Biologics License Application (BLA) following a clinical study under an IND.

CDRH: the Center for Devices and Radiological Health reviews medical devices through 510(k) premarket notification, the De Novo route for novel low-to-moderate-risk devices, or Premarket Approval (PMA) for the highest-risk devices. Some tissue-containing and tissue-derived products are regulated here as devices. Most sponsors interact with one of the Office of Health Technologies (OHT1-8), which are organized based on clinical indication.

Center

What it reviews

How products reach market

CDER

Most drugs and some biologics; includes small molecule and polypeptides drugs, and therapeutic protein biologics

NDA (ANDA for generics) or drugs, BLA for biologics; IND for clinical study

CBER

Vaccines, blood and blood products, allergenics, and cell, gene & tissue therapies; drugs and devices related to biologics

BLA under PHS Act §351; IND for clinical study. 510(k)/De Novo/PMA for devices, and NDA for drugs (361 HCT/Ps need none of these.)

CDRH

Medical devices, including some tissue-containing or tissue-derived products

510(k), De Novo, or PMA; IDE for clinical study

There’s nuance to these assignments: CDER reviews certain BLAs, and CBER also reviews some NDAs, 510(k)s, and PMAs, and all three review combination products. Nowhere on the premarket side, however, will you find 361 HCT/Ps. CBER oversees it under Part 1271 through registration, donor eligibility, and good tissue practice, but not a marketing application. A **non-**361 product, by contrast, could be pulled into one of the three centers depending on how it is best appropriately regulated.

WHY THE TRG STRADDLES TWO CENTERS

The Tissue Reference Group is a joint CBER and CDRH body for exactly this reason. Tissue products frequently sit on the line between being regulated as a “biologic” and “device,” and the question of which center owns a product, or whether it escapes premarket review altogether as a 361, is precisely what the TRG was created to answer.

03 · THE FORK IN THE ROAD

Two pathways: “361” vs. “Non-361” (or “351”)

Part 1271 sorts all these cell and tissue products into two major regulatory pathways based on risk. The side you land on changes everything about your timeline, cost, and route to market.

361 HCT/PS · LOWER RISK

361 HCT/Ps must meet all four criteria under §1271.10(a), and are marketed without premarket review. No BLA, IND, or 510(k), just FDA registration. The Agency’s oversight focuses on communicable-disease control: registration, donor eligibility, Current Good Tissue Practice (cGTP), adverse-reaction reporting, and labeling. 361 products include conventional allografts, bone, demineralized bone matrix, skin, corneas, and sheet-form amniotic membrane.

NON-361 (OFTEN “351”) · HIGHER RISK

HCT/Ps that fail any one of the four criteria and the product is regulated as a drug, biologic, or device. Typically, this means a biologic submitted as a BLA under Section 351 of the PHS Act, and all of Part 1271 also applies. “351 products” include expanded stem cells, CAR-T, and other substantially manipulated tissue.

A 361 regulatory status recommendation means a faster, cheaper, and streamlined path to market. A non-361 classification potentially means years of clinical development and millions in regulatory cost. A single criterion failure is all it takes to shift from one to the other.

04 · THE TEST

The four criteria, in plain language

All four criteria in 21 CFR 1271.10(a) must be satisfied to be 361. FDA’s detailed interpretation of the first two criteria lives in its Minimal Manipulation and Homologous Use guidance.

• Minimal manipulation. Processing does not alter the original relevant characteristics of structural tissue, or the relevant biological characteristics of cells/nonstructural tissue. Cutting bone into dowels qualifies; demineralizing it into a gel does not. With no evidence of minimal manipulation, FDA defaults to assuming it’s more than minimal and the burden of proof is yours.
• Homologous use only. The product performs the same basic function in the recipient as it did in the donor, usually evidenced by labeling, advertising, indications, and intended use. Claims about neurological, cardiac, or anti-aging benefits fall squarely outside homologous use. Be aware that homologous use is more than just claims, and you must ensure your product truly serves a homologous function.
• Not combined with another article. Narrow exceptions for water, crystalloids, or sterilizing/preserving/storage agents that raise no new safety concern. Adding a synthetic scaffold, growth factors, or a drug disqualifies it.
• No systemic effect / not metabolism-dependent or the carve-out. Either the product has no systemic effect and does not depend on living-cell metabolism for its primary function; or it does, but is limited to autologous use, allogeneic use in a first- or second-degree blood relative, or reproductive use.

Miss any one, and it is not a 361. The product is then regulated under the FD&C Act and/or Section 351 of the PHS Act, which is most often as a biologic requiring premarket approval (BLA) or as a medical device requiring premarket notification (510(k) submission).

05 · BEYOND THE TISSUE PATHWAY

When cells and tissues are regulated articles requiring premarket review

Human cells and tissues are increasingly used as components in, or paired with, other regulated articles. There are three main ways for medical products that contain cells or tissue to be regulated.

As a biologic. When an HCT/P fails any of the four criteria, more-than-minimal manipulation, a non-homologous claim, or dependence on living-cell metabolism outside the carve-out, it can be regulated as a biological product. For example, expanded mesenchymal stromal cells, culture-expanded chondrocytes, and substantially processed tissue marketed for a new function are typically studied under an IND and licensed through a BLA, reviewed by CBER’s Office of Therapeutic Products.

As a device. Some tissue-derived and tissue-containing products are regulated as medical devices by CDRH. When processed tissue is combined with a structural material and the product’s primary action is mechanical or scaffolding rather than biological, the product can be a device, or a device-led combination product, cleared or approved through CDRH. Examples include bone void fillers composed of human demineralized bone matrix and either carriers for handling properties or ceramics that are regulated as a device, and wound dressings made of human-derived material.

As a combination product. When a product has two or more regulated components, it is a combination product under 21 CFR 3.2(e). The Office of Combination Products (OCP) assigns a lead center based on the product’s primary mode of action (PMOA), which is the single mode expected to make the greatest contribution to the therapeutic effect. A biologic-led combination is led by CBER; a device-led one by CDRH.

Product shape

Typical lead center

Marketing pathway

Cells or tissue as the active product

CBER (OTP)

BLA, after IND

Tissue combined with a device or structural material

CDRH — or CBER if biologic-led

510(k) / De Novo / PMA, or BLA

Combination product (e.g., cells + scaffold, tissue + drug)

Assigned by OCP via primary mode of action

Lead center’s pathway; ideally a single application

Of course, there’s nuance too in the PMOA, and where center jurisdiction is genuinely unclear, you can obtain a non-binding recommendation in a Pre-Request for Designation (RFD) submitted to OCP under 21 CFR Part 3, which is a more formal determination that is distinct from the informal, advisory recommendation that the TRG provides.

06 · WHO DECIDES

What the Tissue Reference Group is and does

The Tissue Reference Group (TRG) is FDA’s standing body for advising a company whether a specific HCT/P meets the four criteria enumerated in 21 CFR 1271.10(a). It is a working group of representatives from CBER and CDRH, with input from each Center’s product jurisdiction officer. Its procedures are governed by SOPP 8004.

It gives companies a single reference point on how an HCT/P is regulated: whether it meets §1271.10(a), whether a §1271.15 exception applies, and, if it is not a 361, which Center and regulations apply instead.

TWO THINGS TO INTERNALIZE EARLY

Submission is voluntary. Companies can make their own determination, but payers such as CMS and the Defense Health Agency increasingly may request a TRG recommendation. Marketing without CMS remains an option, but companies that get it wrong risk a warning letter.

A recommendation is informal and non-binding, based on the information known at the time. A negative read is not a final verdict, and a favorable letter is not a license. The only binding determination comes from a Request for Designation to the Office of Combination Products under 21 CFR Part 3.

The criteria FDA actually applies during review don’t always read the way you’d expect from the guidance documents alone.

In the absence of clear Guidance from FDA, submitting to TRG requires careful planning and execution. Many companies are surprised and frustrated when TRG doesn’t give them the response they expect. A good thoughtful strategy will save you time and money.

FDA sources & references

• SOPP 8004 — Tissue Reference Group: procedures, timing, and responsibilities. fda.gov ↗
• Guidance — Regulatory Considerations for HCT/Ps: Minimal Manipulation and Homologous Use (Guidance for Industry and FDA Staff, July 2020). fda.gov ↗
• Guidance — Same Surgical Procedure Exception under 21 CFR 1271.15(b): Q&A (Guidance for Industry, November 2017). fda.gov ↗
• FDA centers — Overview of CBER, CDER, and CDRH and CBER’s Office of Therapeutic Products (OTP), which oversees HCT/Ps. fda.gov ↗
• Combination products — Office of Combination Products: jurisdiction, primary mode of action, and the Request for Designation process. fda.gov ↗
• Regulation — 21 CFR Part 1271 — esp. §1271.10(a) (criteria), §1271.15 (exceptions), §1271.20 (if criteria not met); 21 CFR Part 3 (combination products); Sections 361 & 351 of the PHS Act.

If you’re working with HCT/Ps, don’t guess.

Deffai evaluates your product against the same analytical framework the TRG uses internally — and tells you where your 361 position will hold up, and where it won’t.

Johnny Lam, PhD — Head of Regulatory Strategy · Laura Rose, PhD — Cofounder & Chief Regulatory Officer

This document is general educational information about FDA’s regulation of HCT/Ps. It is not legal or regulatory advice and does not create an attorney–client or consulting relationship, nor does it substitute for FDA’s guidance, 21 CFR Part 1271, or SOPP 8004. HCT/P regulatory status is highly product- and indication-specific. TRG recommendations are informal, non-binding, and based on the information presented. Confirm current FDA procedures and consider professional review of your specific product and claims before acting.