On December 17 and December 24, 2014, the Food and Drug Administration (FDA or the agency) published two related, human tissue-focused draft guidance documents, one on “Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products”1(Minimal Manipulation Guidance) and a second addressing “Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) from Adipose Tissue: Regulatory Considerations” (Adipose Tissue Guidance)2. The draft guidances are intended to clarify the FDA approaches for determining whether a product or specific materials derived from the human body will be regulated as a HCT/P solely under section 361 of the Public Health Service Act (PHS Act) and the regulations codified at 21 C.F.R. Part 1271 (referred to as “361 HCT/Ps”), or as a drug, device, or biologic subject to premarket review and regulated under Section 351 of the PHS Act and/or the Federal Food, Drug and Cosmetic Act (FDCA).

The draft guidances attempt to guide manufacturers in applying the analysis outlined in 21 C.F.R. 1271.10 for assessing which HCT/P products are regulated solely under section 361 of the PHS Act by further defining key terms, including what constitutes “minimal manipulation” per 21 C.F.R 1271.10 (a)(1) and 21 C.F.R 1271.3(f).      As explained below, these clarifying guidances appear to provide the FDA with expanded discretion in defining the types of HCT/Ps subject to more stringent regulation and premarket review by the agency, as opposed to the postmarket requirements that apply to 361 HCT/Ps. As currently drafted, the guidances create a presumption in favor of a product being considered a drug, medical device, or biologic, rather than a 361 HCT/P. Additionally, the guidances propose to incorporate the agency’s own, new definitions of key, previously undefined regulatory terms, which are likely to present significant implications for the HCT/P processors. We strongly encourage interested parties to review these potential impacts and submit comments to the agency. For full consideration prior to issuance of the final guidances, comments should be submitted by February 23, 2015.

Change in approach to minimal manipulation?

In the Minimal Manipulation Guidance, the FDA describes its current thinking regarding what types of processing of a HCT/P amounts to minimal manipulation, and would satisfy one of the criteria for regulation as a 361 HCT/P. Importantly, as noted in both draft guidances, the FDA intends to employ a presumption that any processing will amount to more than minimal manipulation unless information exists—as demonstrated by the manufacturer—to show that the processing meets the definition of minimal manipulation.3

This presumption, although iterated in the 1998 proposed rule that first outlined registration and listing requirements for HCT/Ps4 was not established as a requirement in the GTP final rule5, and represents a departure from prior agency practice in assessing the status of HCT/Ps based on what tissue characteristics are relevant based on each HCT/P’s intended use. Specifically, in its 2006 jurisdictional update on minimal manipulation6, which will be replaced by the draft guidance, this presumption was not referenced. Rather, the agency noted that it would determine whether processing amounts to minimal manipulation “based on the data and information before it” and after “consideration of all the potential effects, both positive and negative, of the alteration of a particular characteristic on the utility of the tissue for reconstruction, repair or replacement7.” In the simplest terms, the FDA now expects manufacturers to prove that there has been no impact, rather than having the burden of showing that a specific practice has an impact.

For purposes of assessing whether processing alters the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement, such that the processing would amount to more than minimal manipulation, both draft guidances define, by the agency’s proposed standards, a priori, what these relevant characteristics are for certain types of tissues. For example, for structural tissues, the FDA has noted that examples include strength, flexibility, cushioning, covering, compressibility, and response to friction and shear. As such, separating structural tissues to extract or separate cells in a manner that does not alter the remaining structural tissue’s relevant characteristics would still constitute only minimal manipulation, as the term has been defined by the agency.

In another example, in the Adipose Tissue Guidance, the FDA defines adipose tissue and the agency’s definition of its relevant characteristics. Per the guidance, the FDA generally considers adipose tissue to be a structural tissue, and its relevant characteristics for reconstruction, repair, or replacement relate to its utility to cushion and support the other tissues of the subcutaneous layer (subcutaneum) and skin. Across the two draft guidances, the agency has also defined the original relevant characteristics of skin, ligament, and cartilage tissues, and provided examples of processing that would alter these relevant characteristics, such that the processing would amount to more than minimal manipulation.

Importantly, this approach to determining the original relevant characteristics of the tissue represents an additional, significant departure from agency practice. In these draft guidances, the FDA has outlined the relevant characteristics for a specific tissue type, which will, in most cases, be applied across the board by the agency in addressing the question of minimal manipulation. As such, certain processes will almost always alter the original relevant characteristics of a tissue and will virtually always amount to more than minimal manipulation if performed on a certain type of tissue.

For example, the FDA has provided examples of processing that amount to more than minimal manipulation of adipose tissue because such processing alters the relevant characteristics stated in the guidance. These include:

  1. Processing to isolate non-adipocyte or nonstructural components from adipose tissue (with or without subsequent cell culture or expansion), because this processing entirely removes the connective tissue and structural components of the adipose tissue. For example, isolating stromal vascular fraction, a potential source of adipose-derived stromal/stem cells, for clinical therapeutic purposes would be more than minimal manipulation.
  2. Processing to remove cellular components to obtain the decellularized extracellular matrix portion of adipose tissue, because removal of these cells leaves very little bulk and alters the ability of the adipose tissue to provide cushioning and support. For example, by this logic, treating adipose with acid/detergent, washing, decellularizing, and grinding the tissue to obtain a homogenous fibrous tissue suspension would be more than minimal manipulation.

In past practice, the FDA previously addressed questions of minimal manipulation on a case-by-case basis, assessing the intended use of a proposed HCT/P and the relevant characteristics of the product for these uses, to determine whether the processing has altered the original relevant characteristics to accomplish these intended uses, such that the processing amounts to minimal manipulation. In essence, what characteristics of a tissue are relevant depended in part on the tissue itself and in part on the intended use of the processed tissue. For example, stiffness, elasticity, and strength might be relevant characteristics for bone dowels, but not demineralized bone. Similarly, porous microstructures that allow cellular and fluid infiltrates would likely be relevant characteristics for both intact and demineralized structural tissues, but their relevance required some, case-by-case, or use-by-use understanding of the product’s purpose. This approach is reflected in the preamble to the final rule, which notes that the Tissue Reference Group will serve as a liaison for communicating with manufacturers regarding individual questions related to the FDA's application of the definition of minimal manipulation to particular tissues.

Under the approach outlined in these two draft guidance documents, the FDA has intimated that specific tissues have specific relevant characteristics independent of their use. As such, it is likely that many HCT/P products will be considered more than minimally manipulated and, thus, subject to regulation beyond section 361 of the PHS and 21 C.F.R. Part 1271, irrespective of how they are processed. As such, these draft guidances could render more HCT/Ps subject to regulation as drugs, devices, or biologics under Section 351 of the PHS, the FDCA, and the applicable regulations. These products would be subject to the more stringent regulatory requirements of these authorities, including premarket review requirements.

FDA Imposes Definitions of Key, Previously Undefined Terms

In addition to defining the relevant characteristics of certain tissues, the Minimal Manipulation Guidance also defines regulatory terms that were previously undefined in FDA regulations or guidance. The guidance defines cells or nonstructural tissues for the first time as those that serve predominantly metabolic or other biochemical roles in the body, e.g., hemapoietic, immune, or endocrine functions. Examples of these types of HCT/Ps include oocytes, cord blood, amniotic fluid, bone marrow aspirate, lymph nodes, parathyroid glands, peripheral nerve, and pancreatic tissue. Importantly, by defining cells or nonstructural tissues in this way, the agency has created a presumption that these HCT/Ps act biologically and that those biological activities are the relevant characteristics of the cells or tissues. As a result, these products would apparently be regulated as drugs, devices, or biologics, unless intended for autologous use in the donor, allogeneic use in a first- or second-degree blood relative, or reproductive use, unless a sponsor could show definitively that no such biological activities were present. Such wide reaching implementation of new regulatory terms with such significant impact on stakeholders seems to be a process that should not be attempted solely through the guidance review process.

As a corollary to creating a new, more inclusive definition for cells and non-structural tissues, the agency has narrowed and refined its definition of structural tissue. As outlined in the Minimal Manipulation guidance, structural tissues would be viewed only as tissues that physically support or serve as a barrier or conduit, or connect, cover, or cushion in the donor. Examples provided include bone, skin, amniotic membrane, blood vessels, adipose tissue, articular and non-articular cartilage, and tendons/ligaments. Although the relevant characteristics of cells and nonstructural tissues are not discussed, it can be inferred from this definition that these characteristics would not include the ability to serve as a barrier/conduit, or connect, cover, or cushion the donor. It remains to be seen if the agency believes the examples of cells and nonstructural tissues provided in the guidance could ever be deemed a structural tissue, for example, if serving a structural purpose in the recipient.

In the Adipose Tissue Guidance, the agency also seeks to define the basic functions of adipose tissue, for purposes of determining whether an adipose tissue product satisfies the homologous use prong of the 361 HCT/P analysis. In addition, the FDA states that adipose requires the presence of both its extracellular matrix and its cellular components to behave structurally, so that any action to separate the components will automatically involve more than minimal manipulation. As it has in the Minimal Manipulation Guidance, the FDA has taken upon itself the ability to define what is and what is not a tissue’s relevant characteristic, without any grounding in the tissue’s eventual use in recipients.

The FDA also seeks to define what uses are homologous uses. For example, the FDA states that cosmetically filling voids in the subcutaneous space would be considered a homologous use, because supporting the subcutaneum is a basic function of adipose tissue. Meanwhile, adipose tissue used to treat bone and joint disease, or for breast augmentation, would not be considered homologous use, because these are not basic functions of adipose tissue. This later discussion seems especially incongruous because breast tissue contains significant amounts of adipose. Autologous fat transfer to augment deficiencies in specific areas (including the breasts or elsewhere for either reconstructive or aesthetic purposes) is a routine procedure. Under the GTP Final Rule, the FDA indicated that the determination of homologous use and the regulations would focus “on the objective intent of the HCT/P’s manufacturer for a nonhomologous use,“ and agreed with commenters that such uses would normally be determined “narrowly” and “by the promotion, labeling, and objective intent of the manufacturer8.”

The draft guidances are silent about how the agency will treat tissues that serve both structural and non-structural uses in the donor. Under the approach in the GTP Final Rule, and as the FDA has interpreted the HCT/P regulations historically, the manufacturer’s objective intent would govern. If the manufacturer intended its HCT/Ps to be used only for structural purposes, and marketed its HCT/Ps accordingly, then the HCT/Ps would be treated strictly as structural tissue, even if the HCT/P retained cells with biological activity when transplanted into the patient. The agency’s silence on this issue could be read as confirming the FDA’s historical approach, but clarifying the agency’s position explicitly would help eliminate potential uncertainty in the healthcare industry.

Summary and opportunity for comment

Ultimately, the approach outlined in these draft guidances—including the presumption that processing amounts to more than minimal manipulation and the agency’s defining of relevant characteristics for certain tissue types—indicates that the agency will seek to more stringently regulate HCT/P products in the future. Specifically, under this proposed approach, new and narrowed definitions, and shifting of burden, fewer HCT/P products likely would be considered 361 HCT/Ps. As a result, more HCT/P products would be subject to regulation under Section 351 of the PHS Act and/or the FDCA. Such products would be considered drugs, devices, or biological products subject to premarket review requirements, among others.