361 HCT/P Eligibility
TRG TEMPLATE

The TRG Submission Checklist

A successful submission effectively translates your strategy.

The Tissue Reference Group (TRG) is a joint CBER-CDRH group that makes recommendations on whether products meet eligibility criteria enumerated in 21 CFR 1271.10(a) to be regulated as a 361 HCT/P. Such “361 HCT/Ps” do not require pre-market review, and having FDA’s positive feedback on eligibility is a major milestone.

A TRG submission has no mandatory form, and FDA only lists selected information that would be helpful rather than prescriptive templates. The difficulty in putting together a successful submission is reflected in a very high rate of rejections. Nearly 40% of TRG submissions are considered incomplete, and TRG puts them on hold until the company can respond to deficiencies.

Even before you put together the submission, your strategy needs to be rock solid. This means that the first step in any submission is having a clear understanding of your strategy for 361 eligibility and the second step is translating that strategy into clear messaging. A submission that is well-organized, includes the right amount of detail, and anticipates all of FDA’s questions is much more likely to avoid receiving deficiencies.

Reviewers read a submission to confirm a sponsor’s conclusion on regulatory status of their HCT/P.. Every section should make that job easier, and each piece of information should contribute to the conclusion that the product is 361 HCT/P.

Submission Outline

  • Cover Letter: Requestor & representation information — who is asking, for which product, and how to reach you.
  • Executive summary — the product, the intended use, and your conclusion on each of the four criteria, in brief.
  • Product description — manufacturer, trade and common names, tissue source, and a step-by-step account of processing, packaging, and storage.
  • Intended use & labeling — how and by whom the product is used, with the actual labeling and IFU attached.
  • 361 HCT/P eligibility analysis — the core argument: each of the four criteria stated, concluded, and evidenced.
  • Attachments — labeling, inserts, IFU, process flow diagrams, manufacturing process description, and any cited literature.

Component by component

  • Cover Letter Requestor & representation information

The cover letter identifies the product, company, and the formal point of contact. Also, if there are any related submissions, reference this here as well particularly in the case of private labels where TRG can leverage prior submissions.

Cover letters should include basic logistics for the submission and product as well as the submission’s purpose. The request of TRG may seem straightforward, but consider the request in the context of the submission cycle.

Original submissions can include language about agreement on 361 HCT/P eligibility, whereas supplements or re-submission should clearly state that the submission’s purpose is to address TRG’s previously identified deficiencies. Keep the letter to a single page; its job is to route the package, not to argue the case.

Item

Comments

  • Date of Submission
  • Company Name
  • Company Point of Contact
  • Submission Point of Contact, if external consultant
  • Submission Point of Contact’s Email and Phone Number
  • Submission Purpose

Original Submission: “[Company] is seeking TRG’s agreement that [product] is regulated solely under Section 361 of the Public Health Service Act and 21 CFR Part 1271”

Supplement or Resubmission: “[Company] is providing a response to TRG’s deficiencies for [Submission.Number]”

  • If Supplement or Resubmission, TRG’s main concern and the company’s response
  • Product Trade Name

“FDA previously raised questions about the claims in our labeling. We have removed those claims from our labeling.”

  • Product Common Name
  • Product’s abbreviated Intended Use
  • Statement on either prior or related Submissions, as applicable

Option: There are no prior submissions for this product.

Option: This current submission describes an identical product to [Submission.Number], and the purpose of this submission for a White Label.

  • Executive summary

A short overview naming the product and intended use and stating your conclusion on each of the four criteria. It orients the reviewer before the detail and frames how the rest should be read.

Keep it to a few short paragraphs on a single page. State the bottom line first — that the product meets the 361 HCT/P criteria — then list each criterion with a one-line conclusion. A reviewer who reads only the summary should already know what you are claiming and where to find the support for it. Do not introduce facts here that do not reappear, with evidence, in the body.

Item

Comments

  • Company Name
  • Submission Purpose

Original Submission: “[Company] is seeking TRG’s agreement that [product] is regulated solely under Section 361 of the Public Health Service Act and 21 CFR Part 1271”

Supplement or Resubmission: “[Company] is providing a response to TRG’s deficiencies for [Submission.Number]”

  • If Supplement or Resubmission, TRG’s main concern and the company’s response
  • Product Trade Name

Example language: “FDA previously raised questions about the claims in our labeling. We have removed those claims from our labeling.”

  • Product Common Name
  • Product’s abbreviated Intended Use
  • Related Submissions, if applicable

Example language: “This submission is similar to [Submission.Number] except for a new size”

  • Statement on either prior or related Submissions, as applicable

Example language: There are no prior submissions for this product.

Example language: This current submission describes an identical product to [Submission.Number], and the purpose of this submission for a White Label.

  • If Original Submission, an overview of the company’s position for each of the 361 HCT/P eligibility criteria
  • If Supplement or Resubmission, an overview of each of TRG’s questions and a summary of the company’s response for each question

Example language: “FDA issued two deficiencies related to our labeling: one related to claims related to osteogenesis and one related to use of the product in an ectopic site. Our update labeling removes the osteogenesis claim, and adds language directing the user to not use or place at an ectopic site.”

3. Product Description

Describe exactly which product the recommendation will apply to: the manufacturer, any proprietary (trade) names, and the common name(s). TRG’s recommendation is product- and use-specific, so precision matters. This product should include tissue source, recovery, processing, packaging, and storage. A clear, step-by-step description of manufacture and processing from recovery to point of use; packaging, including the range of sizes and configurations; and storage and shipping. This is one of the most closely scrutinized components. A vague description is a leading cause of follow-up questions and delay. A process flow diagram is a strong addition.

Describe each step the tissue actually undergoes — cleaning, cutting, shaping, decellularization, washing, sterilization or disinfection, drying, and any treatment with reagents — and name the reagents used. FDA judges minimal-manipulation based on this description, so conclusory phrasing such as “processed using proprietary methods” invites a request to explain what those methods are. Identify any added reagents and whether they remain in the final product, since that could bear directly on the “not combined with another article” criterion.

Item

Comments

  • Description of the final product and its physical form

Example language: “The product is a square flexible sheet 10 cm by 10 cm and 1 mm thick. It has an off-white color and a slightly rough surface“

  • Product variations

Should address different sizes, shapes, or packaging configurations

  • Donor type

Living or deceased donors

  • Donation type

Allogeneic or autologous

  • Tissue type

E.g., muscle, fascia

  • Tissue processing summary
  • Tissue process diagram

Describe each step the tissue actually undergoes — cleaning, cutting, shaping, decellularization, washing, sterilization or disinfection, drying, and any treatment with reagents — and name the reagents used

  • Packaging
  • Sterility status

Include a statement on whether the product is sterile or aseptically processed

  • Storage conditions

4. Intended Use & labeling

This section should include the intended use Exactly how the product is intended to be used and by whom, the specific intended use(s), and the actual labeling, package inserts, and instruction for use. Labeling is central evidence for homologous use and systemic effect. Ensure that labeling is consistent with the homologous use discussion.

A common reason for a return is a mismatch between the claimed intended use and the homologous-use argument: the analysis asserts the tissue performs the same basic function in the recipient as in the donor, while the labeling promotes a use that goes beyond that function. Reconcile the two before you submit. Provide the labeling as it will actually appear, not a draft of aspirational claims, and make sure every claim in it is one you are prepared to defend as homologous.

Item

Comments

  • Intended use statement

List the intended use in the submission, and ensure it is identical to the intended use statement in the package insert.

  • Package insert

5. 361 HCT/P Eligibility Assessment

This is the core of the submission and should include a discussion for how your device meets all four criteria. Address each as a separate element, in the same structure — state the criterion, state your conclusion, give the supporting evidence.

Item

Comments

  • Minimal Manipulation

Describe processing with the goal of demonstrating that it does not alter the relevant characteristics (the discussion may differ for structural vs. cells/nonstructural tissue).

  • Homologous use only

Valid, scientific rationale for why the product performs the same basic function in recipient as in the donor, supported by labeling and claims.

  • Not combined with another article

Permissible exceptions are water, crystalloids, or a sterilizing/preserving/storage agent.

  • No systemic effect and not metabolism-dependent

Exceptions are limited to autologous / close relative / reproductive uses carve-out.

This section should include a short summary table mapping each criterion to your conclusion and its basis followed by more extensive discussion. The table is a map, not the argument itself, that lets the reviewer see all four conclusions at a glance and points to where each is supported. The full reasoning still belongs in the prose above it. References to FDA Guidance are most helpful when referencing specifics, not general statements. For example, referencing FDA’s Minimal Manipulation and Homologous Use Guidance to support your milling and grinding steps for shaping and sizing your bone products are minimal manipulation is helpful because this same specific example is in the Guidance. However, citing that Guidance for to support that your product’s “processing” is minimal manipulation is not as impactful because lacks specificity.

Using a wound dressing as an example workable form looks like this:

Criterion

Justification

Conclusion

21 CFR 1271.10(a)(1) Minimal manipulation

Our wound dressing is made from amniotic membrane that is washed with a mild detergent to remove blood and rinsed thoroughly in saline to support preservation. The membrane is cut to size and sealed in a Tyvek pouch with saline as a storage media, and then irradiated to sterilize the product. None of these steps fundamentally alter the tissue’s ability to serve as a barrier, since the end product is a sheet. FDA’s Minimal Manipulation and Homologous Use Guidance explicitly describes amniotic sheets as retaining their original relevant characteristics and its ability to serve as a barrier.

Minimally manipulated

Bracketed entries are placeholders; replace them with your product’s specifics. “Met” is shorthand for the conclusion you reach and defend in the prose.

6. Attachments

The supporting documents referenced throughout, such as labeling, inserts, instructions for use; detailed process flow diagrams; and relevant literature.

Attach only what the text actually relies on, label each attachment, and refer to it by that label where you cite it. The aim is that a reviewer never has to guess which document supports a given point. Attachments supplement the argument; they do not replace it. The conclusions and reasoning still belong in the body, with the attachments serving as the evidence behind them.

Submission Logistics

Send a PDF of your TRG submissions by email to the TRG inbox administered through CBER’s tissue office: [email protected].

Submit a single, consolidated PDF rather than a string of separate files, and confirm the current contact and instructions on FDA’s Tissue Reference Group program page before you send. The TRG meets periodically and aims to respond within a defined window described in SOPP 8004; the recommendation is advisory and addresses regulatory status, not the safety or effectiveness of the product. If the TRG needs more information, it will ask — which will likely prolong the review clock — so the time you spend making the package self-contained is time saved on the back end.

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 ↗
  • Regulation — 21 CFR Part 1271 — §1271.10(a), §1271.15. Confirm the current TRG contact and instructions on FDA’s Tissue Reference Group program page before submitting.

Forty percent of submissions get sent back. Yours doesn’t have to.

Deffai prepares TRG submissions from the ground up — drawing on direct experience with what the TRG expects, what triggers requests for more information, and how to frame minimal-manipulation and homologous-use arguments that withstand scrutiny.

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

This guide is general educational information about the components of a TRG submission. It is not legal or regulatory advice and does not substitute for FDA’s guidance, 21 CFR Part 1271, or SOPP 8004, which governs the TRG’s procedures. Regulatory status is fact-specific. Confirm current FDA instructions and consider professional review of your specific product and claims before you submit.