Q&A: What Information Is Required for 361 HCT/P Products to Obtain HCPCS Codes?

Recent requirements imposed by the Centers for Medicare and Medicaid Services (CMS) related to skin substitutes have raised questions related to whether key wound care products have received appropriate review by the Food and Drug Administration (FDA) and, as such, can be legally marketed within the United States. This set of frequently asked questions (FAQs) is intended to provide additional clarity regarding their regulatory status under both CMS and the Food and Drug Administration (FDA or Agency).

Note: “Skin substitutes” is a commonly used term but an inaccurate one to describe these products since they do not actually “substitute” for human skin. With input from the Alliance of Wound Care Stakeholders, ASTM has adopted the term “Cellular and/or Tissue based products (CTPs)” as a more accurate terminology for this category. However, the term “skin substitutes” continues to be used in many regulatory documents.

Q:

How does the FDA approve skin substitutes?

A:

Skin substitutes—a term that includes split thickness skin, dermis, and amnion products—are currently regulated by the FDA as either (1) devices or (2) 361 Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P), which are also known as “361 HCT/P” as they are regulated under Section 361 of the Public Health Service Act. For devices, the Agency will provide documentation clearly indicating the product’s regulatory classification. There is no parallel documentation for a 361 HCT/P.

It is, however, possible to obtain an informal designation of a product’s 361 HCT/P status. To accomplish this, the tissue bank or other manufacturer will need to request from the FDA specific documentation related to the product’s regulatory status. Please note that the FDA does not formally approve but does have oversight of 361 HCT/Ps.

Q:

What is a “361 HCT/P”?

A:

Unlike drugs and medical devices, which require FDA clearance/approval to be distributed, for a 361 HCT/P, a manufacturer must register with the FDA and provide a list of HCT/Ps recovered or distributed, paving the way for an inspection by the Agency. As such, a 361 HCT/P may be marketed without formal FDA approval if the product meets four key standards. The two standards that are most relevant to skin substitutes are (1) that the product be marketed for a homologous use (i.e., how the product is described by the manufacturer and whether the marketed function and indications for use it performs are the same in the recipient as in the donor); and (2) that the product be minimally manipulated (i.e., how the manufacturer processes the product before marketing and whether such processing changes the original relevant characteristics of the tissue)¹.

According to the FDA, most split thickness skin, dermis, and amniotic membranes perform a barrier function in the donor and recipient and, as such, it is a homologous use. Some relevant examples of minimal processing steps include antibiotic disinfection, decellularization, cryopreservation, sterilization, meshing, or cutting the grafts into smaller sheets to cover a wound.

Q:

What documentation is CMS requesting for most, if not all, skin substitutes before granting an HCPCS code?

A:

Starting in 2020, several entities requesting HCPCS codes for most, if not all, skin substitutes received this message from CMS, along with an initial denial for the code:

After review of FDA’s guidance, it does not appear to CMS that [insert name of product] is suitable for registration as an HCT/P. CMS refers the applicant to the FDA’s Tissue Reference Group or the Office of Combination Products to obtain written feedback regarding how the product is appropriately regulated. After obtaining the FDA’s written feedback, the applicant is welcome to submit a complete HCPCS code application in a subsequent coding cycle. Information for submitting questions to the TRG is located at:
https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products/tissue-reference-group  

Thus, recently, CMS has taken the position that, for some skin substitutes, prior to receiving an HCPCS code for payment purposes, the manufacturer must first receive documentation from the FDA that the product is appropriately marketed for distribution in the United States.

Q:

What guidance is CMS referring to?

A:

CMS is likely referring to the FDA final guidance, titled Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue- Based Products: Minimal Manipulation and Homologous Use, which was originally released in November 2017 and most recently updated in July 2020 to further extend the enforcement discretionary period (more below). The final 2017 guidance clarified the regulatory status of several key tissue products.

Q:

When does FDA’s guidance go into effect?

A:

Given that the 2017 guidance did clarify the regulatory status of several key tissue products, the Agency opted to have an enforcement discretionary period (most recently extended through May 31, 2021), provided that there is not otherwise a safety issue with the tissue products. As such, the requirements including regulatory changes related to the final 2017 guidance do not go into effect until June 1, 2021.

Q:

What are the implications for skin substitutes that may have changed as a result of the FDA guidance?

A:

With respect to dermis, the guidance document includes several examples that clarify the use of dermis as a skin substitute is appropriate (Example 11-3; Example 20-1), provided that it is not ground (Example 10-4). According to the FDA, grinding results in the tissue being more than minimally manipulated.

With respect to amnion, the guidance document also includes several examples that clarify the use of amnion as a skin substitute is appropriate as a cover (Example 11-2 and Example 19-2), provided that it is not ground (Example 10-2) and not utilized for “wound healing” or to “reduce scarring and inflammation” (Example 19-2). According to the Agency, those are clinical effects that the tissue does not perform in the donor.

Q:

If a product is registered with the FDA as a 361 HCT/P, is that enough documentation to confirm its status as a 361 HCT/P?

A:

Unfortunately, no. While it is important to confirm that processers of skin substitutes have registered their products with the FDA (which can be done here), the Agency has further opined that “FDA acceptance of an establishment registration and HCT/P listing does not constitute a determination that an establishment is in compliance with applicable rules and regulations or that the HCT/P is licensed or approved by FDA.”

Q:

How can a manufacturer receive documentation from the FDA that a product is a 361 HCT/P?

A:

The FDA does not require 361 HCT/Ps to receive documentation of 361 status from the Agency before marketing the product. Per the guidance document, if a manufacturer would like documentation confirming that a product is a 361 HCT/P, then there are two main ways to do so: (1) request a determination from the Tissue Reference Group (TRG) or (2) file a Request for Designation (RFD).

Q:

How long does it take for a manufacturer to receive documentation from the FDA that a product is a 361 HCT/P?

A:

That depends. For a TRG determination, the FDA’s Standard Operating Policy and Procedure (SOPP) states that the goal of the TRG is to respond within 60 days of receipt, provided enough detail has been provided within the manufacturer’s submission. The FDA includes a goal of 60 days as part of the RFD process as well. However, with the pandemic and other circumstances, the Agency turnaround time may be longer.

Q:

As a payer (like CMS), can I request a 361 HCT/P determination directly from the FDA?

A:

No. Given that a payer would not be aware of all of the key manufacturing steps or marketing information related to the product, a payer would not likely receive a TRG determination or an RFD, given that the Agency would likely determine that enough detail was not provided in the submission.

Q:

As a payer (like CMS), can I receive the documentation related to a 361 HCT/P directly from the manufacturer?

A:

Yes. However, given that this documentation is not required by the FDA, if that documentation is not already on file, then it may be months before the documentation is available, given the lead time to develop the TRG or RFD submissions, for the Agency to respond, and other contingencies.

Marc Pearce is the President & CEO of the American Association of Tissue Banks (AATB).

1 . The other two standards are (1) The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P; and
(2) Either:
(i) The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or
(ii) The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and:
(a) Is for autologous use;
(b) Is for allogeneic use in a first-degree or second-degree blood relative; or
(c) Is for reproductive use.