361 HCT/P Warning Letters

Low risk human cells, tissues, and cellular and tissue-based products (HCT/P) can be marketed as “361 products” without the formal marketing review in an NDA, BLA, or 510(k). Companies can make their own determination based on FDA’s criterion and with the help of FDA Guidance documents, but FDA’s interpretation of the eligibility criteria often differs. Since these products don’t undergo premarket review, that difference in interpretation of 361 HCT/P eligibility plays out in post-market compliance actions.

Understanding how FDA, and specifically CBER, makes decisions and takes action on compliance cases helps companies contextualize the risk associated with a self-determination of 361 eligibility.

01 · PASSIVE SURVEILLANCE

How FDA Keeps Tabs on 361 HCT/P Marketing

FDA and CBER specifically does not currently perform any systemic, active surveillance of 361 HCT/Ps: compliance is mostly reactive and focuses on reviews of allegations of improper marketing. Company whistle-blowers, competitors, healthcare providers, and patients can all submit allegations, which can also be submitted anonymously. When reviewing an allegation, CBER looks at all marketing materials including websites, labeling, and brochures. Just because it isn’t on the company’s website doesn’t mean it’s safe: FDA compliance reviews have included posts from company personnel on LinkedIn and even social media. Proactive surveillance is generally limited to spot checks of companies with a history of untitled or warnings, which is why it’s best to avoid scrutiny in the first place.

02 · FDA ACTION

What Happens Behind the Scenes

Whether the result of an allegation from industry or proactive surveillance, all allegations are evaluated by a CBER reviewer who makes a recommendation on FDA’s next steps. FDA’s decision can be that there is a violation, that there is no violation, or that the reviewer needs more information to make a recommendation.

CBER has a toolbox of compliance actions, and requesting more information typically comes via an It Has Come To Our Attention (IHCTOA) Letter or a directed inspection. A preliminary violative finding can lead to an Untitled Letter, and subsequent unresolved violations can escalate to a Warning Letter when the company and review team are generally unable to resolve the issue. Untitled and Warning Letters are more likely to have an additional review from FDA’s Office of Chief Counsel (OCC), which means letters have been scrutinized for their ability to withstand a legal challenge before they’re issued.

03 · A DIFFERENT APPROACH

361 HCT/P Compliance Patterns

FDA’s pattern of compliance escalation is common for products that undergo a premarket review (e.g., 510(k), De Novo, PMA, or BLA/NDA). In contrast, 361 HCT/P allegations do not have the escalation, and CBER frequently reviews and makes decisions on violative marketing claims with no prior notification or opportunity for the sponsor to resolve. This means that CBER will frequently issue warning letters without any warning.

After issuance, these warnings are published on FDA’s website with a delay of days to weeks. This means that letter is immediately visible to your investors, employees, and patients. And once you’re on CBER’s radar in this way, it’s hard to escape, even for different products. That warning letter is likely to be cited in all subsequent review memos, which primes the review team to scrutinize your product, manufacturing, and labeling more closely than you may want.

FDA’s position on claims may feel unpredictable when many websites list clearly violative claims: the passive surveillance combined with FDA’s lengthy review times contribute to a considerable lag between claims and action. However, silence from the FDA doesn’t mean that claims are acceptable.

NO WARNING BEFORE THE WARNING

If you are incorrect in your 361 assessment and market an ineligible product, you will receive no prior notice before FDA sends a warning letter. It is publicly posted for anyone to see, and CBER will internally cite it for many years to come in their internal review memos.

04 · HIGH RISK AREAS

Where Companies Fail

Although CBER’s jurisdiction covers a very diverse set of products, CBER’s warning letters overwhelmingly target companies in 361 HCT/P space. More than 80% of CBER’s warning letters are for products that FDA determines to not meet the criteria for 361 HCT/P. Companies most often get into trouble with homologous use and minimal manipulation, fewer companies have difficulty with combination and systemic effects.

361 HCT/P ELIGIBILITY CRITERION

% OF LETTERS

RISK LEVEL

Homologous use

90%

CRITICAL

Minimal manipulation

81%

CRITICAL

Combination

13%

Moderate

Systemic effect / metabolic

6%

Lower

Although FDA’s Guidance covered homologous use and minimal manipulation, this compliance trend reflects the layers of internal review logic and precedent that aren’t captured in any public resource. That institutional knowledge is the difference between a clean path to market and a year-long delay, an unfavorable determination, or a warning letter.

05 · 1271.10(a)(1)

Homologous Use

FDA interprets homologous use as the product performing the same basic function in the recipient as in the donor. The product does not need to be used in the same anatomic location: pericardium used as a covering for dura mater defects is homologous because both serve as coverings. However, the intended use must be homologous as evidenced by labeling, advertising, and other claims. The push for market dominance can lead companies to stretch claims, and products marketed to include claims of treating neurological diseases, cardiac conditions, or general anti-aging fall squarely outside homologous use.

06 · 1271.10(a)(2)

Minimal Manipulation

FDA’s assessment heavily depends on tissue type. For structural tissues that physically support, serve as barriers, or connect, cover, or cushion, minimal manipulation means processing that does not alter the “original relevant characteristics.” Cutting bone into dowels qualifies; demineralizing it into a gel does not. For cells and non-structural tissues (those serving metabolic, hematopoietic, immune, or endocrine functions), minimal manipulation means processing that does not alter the “relevant biological characteristics” such as differentiation state and proliferation potential. Density-gradient separation can qualify; cell expansion does not.

07 · BUSINESS IMPACT

What a Warning Letter Costs You

A 361 warning letter is rarely just a regulatory inconvenience. Because these letters are posted to FDA’s public database, often within a days or weeks of issuance, the damage begins the moment the letter goes live. Investors performing diligence, hospital purchasing committees, distributors, and competitors can all find it with a single search, and it can stay on FDA’s website for years even if it’s been resolved via close out letter.

The substance of the letter compounds the exposure. An HCT/P warning letter typically asserts that the product is not a 361 product at all, but an unapproved biological product or drug that cannot be lawfully marketed without an IND and a BLA. In effect, FDA is telling you, your customers, and the market that your commercial premise is invalid. Revenue tied to the cited product is suddenly at risk, and continuing to ship it after the letter exposes the company to enforcement.

The letter itself is an advisory action, but FDA explicitly reserves the right to pursue seizure, injunction, import refusal, civil money penalties, consent decrees, and, in serious cases, criminal prosecution if violations persist. Even short of those actions, a posted letter raises the scrutiny on everything you do next, from future submissions to export certificate requests, and it can stall financing rounds, partnerships, and acquisitions while counterparties wait to see how it resolves.

THE LETTER OUTLIVES THE PRODUCT

Even if you correct every violation, the warning letter stays publicly posted. That compliance activity follows other Agency interactions as well and primes the FDA review team for increased scrutiny of the violative product and other products.

06 · THE FIRST 15 DAYS

After the Letter Arrives

The clock starts immediately. FDA warning letters generally request a written response within 15 working days of issuance. That window is short, and how you use it shapes everything that follows.

Your next interactions with FDA can either resolve this easily, or lead to further escalation of FDA’s actions, and you need the right people on your team. The skillset necessary to resolve these high profile and potentially contentious interactions are not common, and most companies who receive Warning Letters do not have this expertise in house. Getting the right expertise on your side is the most significantly beneficial action you can take.

The critical tasks are to read every cited violation carefully, map out FDA’s concerns, and propose a response to each one. Your regulatory expert should be involved in each of these steps. Together, you and your regulatory expert should ensure that you understand all of FDA’s violations and are proposing an active response that will resolve FDA’s underlying concern.

For 361 HCT/Ps, the issue is usually the product’s regulatory status, driven by your product’s claims. The “fix” may mean revising labeling and marketing, halting distribution of an ineligible product, or committing to an IND/BLA pathway. Any of these decisions touch the whole business, so all the more reason to have your regulatory expert closely involved in the process.

07 · MARKET CONFIDENTLY

How to Avoid FDA Scrutiny

With the absence of prior notification before Warning Letters and the long-term impact on your entire company’s FDA interactions, the best approach is to avoid scrutiny in the first place. Since CBER’s Warning Letters typically relate to 361 HCT/P regulatory status eligibility and claims, this is where you should focus your attention. CBER’s Tissue Reference Group is FDA’s designated body for evaluating whether a specific HCT/P meets the four criteria enumerated in 21 CFR 1271.10(a) to be regulated as a 361 HCT/P. Although it doesn’t ask for all marketing materials, TRG does need labeling in order to conduct its review. Submission is voluntary, but gives you confidence that your assessment is aligned with FDA’s.

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

FDA sources & references

• Source data — FDA Warning Letters database ↗
• 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 ↗
• Regulation — 21 CFR Part 1271 — §1271.10(a), §1271.15, §1271.20; FD&C Act §501(a); Sections 351 & 361 of the PHS Act.

Talk to the people who wrote the playbook.

Before you invest in a TRG submission or build a commercial strategy around 361 status, find out whether your position holds up — using the same framework and institutional knowledge the TRG applies internally.

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

This document is intended for educational purposes only and does not constitute legal or regulatory advice. Data and statistics referenced are based on publicly available FDA enforcement records, an analysis of 31 FDA warning letters posted since 2021, and the perspective of a former FDA Tissue Reference Group reviewer. HCT/P regulatory status is highly product- and indication-specific; TRG recommendations are informal and non-binding. Confirm current FDA procedures and consider professional review before acting.