Jun 11, 2015

FDA Regulation of HCT/Ps – Impact of New Guidances on Manufacturers and Users

Axinn, Veltrop & Harkrider LLP

What does the Food and Drug Administration (FDA) consider to be “minimal manipulation” and how are human cells, tissues and tissue-based products (HCT/Ps) made from adipose tissue regulated by FDA?  These questions were addressed in two draft guidances issued by FDA in late December of 2014.  The first, Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) from Adipose Tissue: Regulatory Considerations (1), focuses on how adipose tissue is defined and thus how adipose-based HCT/Ps are regulated by FDA.  The second, Minimal Manipulation of Human Cells, Tissues and Tissue-Based Products (2), focuses on the types of cell and tissue processing that would be considered more than minimal manipulation, resulting in the regulation of the cell or tissue-based product as a drug, biologic or medical device.  Although they are not yet final, these guidances shed light on FDA’s current thinking and may signal that FDA will make it more difficult for products to be regulated solely under Section 361.  Not only will such a position by FDA impact development of new HCT/Ps, but it could threaten the regulation status of currently marketed HCT/Ps. 

Historically, HCT/Ps were covered solely by Section 361 of the Public Health Service Act (PHSA).  (3)  When so regulated, HCT/Ps do not require premarket approval or regulation as a drug, biologic or medical device and thus are not required to invest in expensive clinical trials that are vetted by FDA.  Today, qualification for regulation solely under Section 361 requires that the HCT/P be no more than minimally manipulated.  (4)  Recently, however, there is increasing public pressure for FDA to play a more active role in the growing HCT/P market.  The December draft guidances were part of FDA’s effort to shed some clarity on the definition of minimal manipulation for any HCT/P and the regulation of adipose-based HCT/Ps. 
FDA’s current thoughts on adipose tissue regulation

As with any HCT/P, those made from adipose tissue can be regulated solely under Section 361 by satisfying each criterion listed in 21 C.F.R. § 1271.10(a).  In general, the tissue must be only minimally manipulated during processing, created for an homologous use, cannot be used in combination with other cells or tissue and cannot depend on the metabolic activity for its primary function unless it is for autologous use or use in a first or second degree blood relative. (4)  In its adipose tissue guidance, FDA provides explanations and examples under each criterion for regulation solely under Section 361 and discusses regulation as a biologic if the criteria are not met. (1)

As an initial matter, FDA has categorized adipose tissue as a structural tissue.  (1 at p. 3, 2 at p. 5)  The determinations of homologous use and minimal manipulation flow from this characterization.  For example, because adipose tissue is considered structural, the basic functions of adipose tissue in the donor is to provide cushioning and support.  (2 at p. 5)  Any use of adipose-based HCT/Ps that does not provide cushioning and support in the recipient is not considered an homologous use.  Thus, adipose tissues, which can include stem cells, for treating bone and joint disease are not an homologous use.  (1 at p. 5)

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FDA provides definitions and examples of minimal manipulation of adipose tissues that are also echoed in the second draft guidance, Minimal Manipulation of Human Cells, Tissues and Tissue-Based Products.  And, because FDA generally considers adipose tissue to be a structural tissue and not a cell/nonstructural tissue, minimal manipulation means that the processing does not alter the original characteristics of the tissue (i.e., characteristic present in the tissue in the donor) relating to the tissue’s utility for reconstruction, repair or replacement.  Thus, adipose tissue that has been decellularized can result in two products – the decellularized tissue and the cells themselves – neither of which meet the definition of minimal manipulation.  (1 at p. 3-4, 2 at p. 8)  In fact, based on the information provided in both guidances, minimal manipulation of adipose tissue includes only aliquoting, rinsing, removal of macroscopic debris or freezing.  (1 at p. 4)

Did FDA change the definition of minimal manipulation?

On its face, the draft Minimal Manipulation of Human Cells, Tissues and Tissue-Based Products guidance does not change the definition of minimal manipulation.  In general, the guidance reiterates the regulations provision that the definition of minimal manipulation depends on whether the tissue is classified as a structural tissue or as cells/nonstructural tissue.  (2 at p. 3)  The draft guidance does, however, indicate that the classification is determined by the main function of the cells and tissues in the donor.  (2 at p. 4)  Some have commented that this is a departure from the language of 21 C.F.R. § 1271 and that it borders on changing the definition of minimal manipulation. 

Regardless, the structural/nonstructural distinction greatly impacts what types of processing goes beyond minimal manipulation.  As discussed above, minimal manipulation of structural tissue focuses on the original, i.e., donor, as regards to biological characteristics.  Minimal manipulation of cells/nonstructural tissue, however, means that the processing does not alter the relevant biological characteristics of cells or tissue without reference to “original.”

Thus, once a tissue is characterized as “structural,” even its isolated cells must provide the same “structural” function in the receipt as in the donor.  (2 at p. 8)  Interestingly, one example of nonstructural tissue is bone marrow aspirate, but there is no analogous nonstructural example of lipoaspirate.  Instead, adipose tissue is flatly characterized as structural, which as discussed above, impacts the ability to comply with minimal manipulation and homologous use.  This classification presents an incongruous distinction between stem cells derived from bone marrow, which can qualify as minimally manipulated, while those stem cells derived from adipose tissue may not.

Industry view on draft guidances

The official comment period for both guidances ended on February 23, 2015.  About 60 comments were submitted by a wide variety of interested parties.  A review of these comments indicates that, although many believe regulation as a drug, biologic or medical device is appropriate for certain HCT/Ps, they also believe there are still issues that should be discussed regarding the characterization as structural or nonstructural tissue and how that characterization “inappropriately” determines what processes can be considered as minimal manipulation.  The comments suggest that these guidances represent scientifically flawed reasoning at best and impose new burdens on developing new products or even the continued marketing of existing products at worst.

For example, some take issue with FDA’s belief that a tissue must be characterized as either structural or nonstructural without allowing that some tissues may exhibit both functions.  Allowing that a tissue may be both structural and nonstructural may allow products such as ground amnion to achieve minimal manipulation status.  Also, if adipose tissue can be classified as both structural and nonstructural, there is an opportunity for adipose-derived stem cells to achieve minimal manipulation status similar to stem cells derived from bone marrow aspirate.

Another cause for concern is that basing the structural/nonstructural tissue dichotomy on the main function in the donor does not focus enough on how that tissue is to perform in the recipient.  Thus, some have suggested that the function in the recipient should determine which characteristics are relevant and what processing can be considered minimal manipulation.    


The recent guidances indicate that FDA is tightening its regulatory authority over HCT/Ps by making it more difficult to demonstrate minimal manipulation, thus requiring some HCT/Ps to seek premarket approval as a drug, biologic or medical device.  In addition, currently marketed HCT/Ps may be re-evaluated and determined to no longer qualify for regulation solely under Section 361.  Given the number of comments and concerns expressed by industry, FDA may elect to re-open the comment period, hold public workshops on the issues raised and/or hold meetings with HCT/P industry leaders.  Thus, there may still be an opportunity to voice an opinion and participate in the ultimate decision on how HCT/Ps are defined and regulated.   

(1) Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) from Adipose Tissue: Regulatory Considerations: Draft Guidance for Industry (December 2014)

(2) Minimal Manipulation of Human Cells, Tissues and Tissue-Based Products: Draft Guidance for Industry and Food and Drug Administration Staff (December 2014)

(3) Codified at 42 U.S.C. § 264

(4) See  21 C.F.R. § 1271.10(a) for additional criteria for regulation solely under Section 361

Stacie L. Ropka, Ph.D. is Counsel at Axinn, Veltrop & Harkrider LLP, where she is active in patent litigation and advises clients on biologics, stem cells and other tissue-based therapies/diagnostics.  sropka@axinn.com  860-275-8166

Chad A. Landmon is Chair of Axinn, Veltrop & Harkrider LLP’s FDA and Intellectual Property Practice Groups, where he actively litigates and advises clients on FDA and patent matters, including those involving biologics, stem cells, drugs and tissue-based products. clandmon@axinn.com  860-275-8170

Axinn regularly advises clients on matters regarding stem cells and other tissue-based therapies.  http://www.axinn.com/ with offices in New York, Washington D.C. and Connecticut.

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