In December 2014, the FDA issued two new draft guidance documents about products that derive from human cells or tissues, usually known as HCT/Ps (from “human cells, tissues, or cellular or tissue-based products”). The documents are currently in draft, and open for comments. They present useful information about the FDA’s approach to regulating this broad and complex category of medical products.
HCT/P Research and the IRB
Neither document mentions IRB responsibilities specifically, but Quorum does receive protocols involving HCT/Ps. Quorum treats HCT/Ps like all other FDA regulated products, cosmetics, foods, live organisms, etc., by conducting an assessment of the need for FDA review (IND or IDE) based on regulatory interpretation. We have identified some common issues in these studies that could assist researchers and institutions in planning any HCT/P research.
- It is important to understand which regulations apply to a particular HCT/P and why
- The requirements around “minimal manipulation” and “homologous use” require particular analysis
- In some cases, study documents (including the protocol and consent) should not include anything beyond the stated (i.e., homologous) uses of the product
- A commercially available HCT/P may be regulated differently if the use per protocol varies from the current commercial labeling
The following is a brief expansion on each of these issues.
The FDA’s Regulation of Human Cellular and Tissue Products
For the FDA, the key question about regulating an HCT/P is whether its creation, use, and activity fall within a particular set of guidelines. These guidelines appear in the Public Health and Safety Act (the PHS Act) and in the Code of Federal Regulations for the FDA under Title 21 CFR 1271. If a product meets the requirements, only the reporting and registration requirements of the PHS Act apply.
If the HCT/P fails any of the four points in 21 CFR 1271, then the FDA considers the product as an HCT/P and as a drug, device, and/or biologic. This means the FDA will apply requirements of the Food and Drug Safety Act (FD&C Act) as well as the PHS Act. In practical terms, this means that the FDA may require an IND or an IDE submission before any research begins. This hierarchal approach reflects what the FDA calls its “tiered, risk-based” strategy toward HCT/Ps.
Here are the requirements for an HCT/P to remain solely under the PHS Act (taken from 21 CFR 1271; emphases added). A product that meets these requirements is referred to as a “361 HCT/P”:
- The HCT/P must be minimally manipulated after removal;
- The HCT/P must be for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent;
- The manufacture of the HCT/P cannot 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
- 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
- The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and:
- Is for autologous use;
- Is for allogeneic use in a first-degree or second-degree blood relative; or
- Is for reproductive use. 
This definition controls how an HCT/P is regulated. The latter two requirements (i.e., mode of manufacture and systemic effect) are largely technical. The first two points, however, can be more subjective and require analysis. These two issues, minimal manipulation and homologous use, were the topics of the draft guidance documents in December.
What is Minimal Manipulation of HCT/P?
The FDA demonstrated the importance of minimal manipulation by dedicating a full guidance document to it.
Here are the CFR’s core requirements for processes that can be considered minimal manipulation of HCT/P:
1) For structural tissue, processing does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement;
2) For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues. (21 CFR 1271.3(f)(1)).
The FDA’s reasoning begins with the assumption that any conversion of tissues or cells is not minimal unless demonstrated otherwise. The role of proving that a process is minimal manipulation therefore falls to anyone – a sponsor, a researcher, or institution – who wants to show that a product qualifies as a 361 HCT/P.
The FDA’s guidance pays particular attention to the idea of altering the relevant characteristics of tissues or cells. Two examples in the discussion provide a good sense of the agency’s thinking.
The FDA compares two HCT/Ps derived from amniotic membranes (Link: http://www.medscape.com/viewarticle/773578_2 ). In one, the process converts the membranes into an HCT/P packaged as sheets; in the other the membranes become a powder. For the FDA, the first HCT/P could represent minimal manipulation because it retains the characteristics of the amniotic membrane (that is, “flat and fibrous”). The second product, however, goes beyond minimal manipulation by changing flat and fibrous into powder. The first HCT/P passes the first requirement to be a 361 HCT/P; the second product does not.
December’s second HCT/P guidance document specifically discuses HCT/Ps developed from human adipose tissue (Link: http://en.wikipedia.org/wiki/Adipose_tissue). The document is specific to these products, but the discussion provides useful insights for any HCT/P. The homologous use requirement means that a product must have a “like for like” purpose; it must serve the same function as the original material did within the body. Applying this definition presents what may seem a narrow range of possibilities. Of the three HCT/P uses below, the FDA considered only one as homologous:
- A product with adipose tissue that helps rebuild bones;
- Adipose tissue used for breast augmentation;
- Adipose tissue used to fill “subcutaneous voids in the face or hands.”
The FDA concluded that only the third use matches the tissue’s original functions, and is the only one that qualifies as homologous. The first two examples would fall outside the scope of a 361 HCT/P.
Research and HCT/P Determinations
For any studies involving a 361 HCT/P, Quorum will expect to see the rationale that places the product’s conversion, use, and activity within the four requirements listed above. The rationale will assist the IRB to two ends:
- To confirm whether the 361 HCT/P category is appropriate (and so not require an IND or IDE submission); and
- To ensure that the protocol and consent form make no claims beyond the product’s labelled (i.e., homologous) use.
To emphasize this second point: for a 361 HCT/P, the protocol and consent can include only statements consistent with a homologous use. Consider one example: a 361 HCT/P derived from an amniotic membrane and used as a wound covering. This is a common and longstanding use of amniotic membrane HCT/Ps, but the FDA does not consider healing a homologous use (See the FDA’s guidance statement from 2014 here: http://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/RegulationofTissues/ucm152857.htm ). Research of a 361 HCT/P derived from amniotic membranes therefore should not include healing as an objective of the research, unless willing to confirm with the FDA whether an IND or IDE may be required.
It might help at this point to consider what kind of HCT/P the FDA does consider as fitting within minimal manipulation and homologous use. The agency provides one example in its adipose tissue guidance. For the FDA, a product that matched both requirements was
- removed by liposuction and not altered in any way other than cleaning (minimal manipulation); and
- used to fill subcutaneous spaces (homologous use).
That was as far as the FDA guidance went in describing a product that clearly met both requirements.
Where to Go with Questions
In 1997 the FDA formed a Tissue Reference Group (TRG) to help with questions about HCT/Ps (Link: http://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/RegulationofTissues/ucm152857.htm). The TRG emphasizes that its guidance is situational, and so serves little use as general precedent. It rarely issues general policy statements; in 2014 it made only two:
- Ground adipose tissue that is defatted and decellularized is more than minimally manipulated and, therefore, is not a 361 HCT/P because the processing alters the original relevant characteristics of the adipose tissue’s utility for reconstruction, repair, or replacement.
- A dehydrated amniotic membrane product for wound covering and healing for dermal ulcers and defects does not meet the criteria for regulation solely under section 361 of the PHS Act because healing of dermal ulcers and defects is a non-homologous use for amniotic membrane.
A representative of the FDA’s Office of Cellular, Tissue, and Gene Therapies told Quorum that the best way to manage any general TRG recommendation is to “accept its plain meaning” and contact the TRG with specifics.
For any research of tissue or cellular-based products, it is important to understand the FDA’s approach toward HCT/P regulation. A thorough analysis of all points in the HCT/P requirements of CFR 1271 is crucial. For studies that involve a 361 HCT/P, and which will not be conducted under an IND or IDE, the IRB submission should contain clear rationale for that categorization, and the study documents should support a clear intent to study only homologous uses that are in-line with the commercial labeling. Please contact Quorum if you have any questions about your HCT/P study.
Useful Links for Studies Involving HCT/Ps
Draft Guidance Document “Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products
 The FDA provides this explanation of what is and what is not an HCT/P:
Examples of HCT/Ps include but are not limited to, bone, ligament, skin, dura mater, heart valve, cornea, hematopoietic stem/progenitor cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, and semen or other reproductive tissue. The following articles are not considered HCT/Ps: (1) Vascularized human organs for transplantation; (2) Whole blood or blood components or blood derivative products subject to listing under 21 CFR Parts 607 and 207, respectively; (3) Secreted or extracted human products, such as milk, collagen, and cell factors, except that semen is considered an HCT/P; (4) Minimally manipulated bone marrow for homologous use and not combined with another article (except for water, crystalloids, or a sterilizing, preserving, or storage agent, if the addition of the agent does not raise new clinical safety concerns with respect to the bone marrow); (5) Ancillary products used in the manufacture of HCT/P; (6) Cells, tissues, and organs derived from animals other than humans; (7) In vitro diagnostic products as defined in 21 CFR 809.3(a); and (8) Blood vessels recovered with an organ, as defined in 42 CFR 121.2 that are intended for use in organ transplantation and labeled “For use in organ transplantation only.” (21 CFR 1271.3(d))
 Guidance for Industry: Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) – Small Entity Compliance Guide, 8/24/2007
 21 CFR §1271.10(a)