On October 30, 2015, the Food and Drug Administration (FDA) issued a draft guidance document, Homologous Use of Human Cells, Tissues, and Cellular and Tissue-Based Products (the Homologous Use Guidance), discussing FDA’s interpretation of homologous use and how to apply regulatory criteria for human cells, tissues, and cellular and tissue-based products (HCT/Ps).1 Though FDA does not appear to have changed its definition of homologous use, the guidance provides broader insight into FDA's thoughts on how to determine whether an HCT/P is to be used for or is intended for homologous use. The guidance also includes a series of examples to demonstrate when products would or would not be regulated as HCT/Ps for homologous use. Most of what FDA states in the guidance is unsurprising and is consistent with how FDA has interpreted and applied the HCT/P regulations in recent years. What is most significant is what FDA does not say, inviting comments.
HCT/Ps, as defined in 21 C.F.R. § 1271.3(d), are articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. To be regulated as an HCT/P subject to regulation solely under section 361 of the PHS Act and 21 C.F.R. Part 1271, an HCT/P must meet the criteria in 21 C.F.R. §1271.10(a). To meet these criteria, an HCT/P must be minimally manipulated; be intended for homologous use; not be combined with other articles except specified types of ingredients; and either not have a systemic effect nor depend on the metabolic activity of living cells, or be intended for autologous use or for allogeneic use in a first-degree or second-degree blood relative. If an HCT/P does not meet these criteria, the HCT/P will be regulated as a drug, device, and/or biological product.
FDA defines homologous use as “the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor, including when such cells or tissues are for autologous use.”2 FDA notes in the guidance that the agency generally considers an HCT/P to be intended for a homologous use when it is used to repair, reconstruct, replace, or supplement:
- recipient cells/tissues that are identical to donor cells/tissues and perform one or more of the same basic functions in the recipient as the cells/tissues performed in the donor; or
- recipient cells/tissues that are not identical to the donor’s cells but perform one or more of the same basic functions in the recipient as the cells/tissues performed in the donor.3
Generally, FDA states that, if an HCT/P is intended for use as an unproven treatment for a myriad of diseases or conditions, the agency will not consider the HCT/P to be intended only for a homologous use.4
FDA attempts to add some clarity to its interpretation of Part 1271 by providing general definitions and examples of “repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues”5:
- Repair: The physical or mechanical restoration of tissues, including by covering or protecting.
- Reconstruction: Surgical reassembling or re-forming.
- Replacement: Substitution of a missing tissue or cell.
- Supplementation: To add to or complete.
That brief discussion invites comments and elaboration. For example, in illustrating its definition of “replacement,” FDA states that the term includes “the replacement of donor hematopoietic stem/progenitor cells in a recipient with a disorder affecting the hematopoietic system that is inherited, acquired, or the result of myeloablative treatment.” That language raises questions about the scope of disorders that would be covered, and about the relationship between the homologous use prong and the systemic effect prong. It implies that such “replacement” might not constitute a “systemic effect” that would limit transplantation of the hematopoietic stem/progenitor cells to autologous or close-relative use under 21 C.F.R. § 1271.10(a)(4).
In the new guidance, FDA also states that to meet the definition of “same basic function or functions,” an HCT/P would generally be expected to perform the same function in the body of the donor that would be expected to be performed in the recipient. Not all the functions would have to be performed for the HCT/P to fall in the regulatory category of homologous use.6
Again, the draft guidance invites questions about what it does not say. For example, on one hand, the guidance declares that using an amniotic membrane product “for wound healing of dermal ulcers and defects” would not qualify as homologous use “because wound healing of dermal lesions is not a basic function of amniotic membrane.”7 On the other hand, the guidance also states that “a homologous use for a structural tissue would generally be to perform a structural function in the recipient, for example, to . . . serve as a barrier or conduit, or connect, cover, or cushion.”8 Further, the guidance also acknowledges that basic functions of amniotic membrane include “covering, protecting, serving as a selective barrier for the movement of nutrients between the external and in utero environment, and to retain fluid in utero.”9 FDA did not explain whether a company may market an amniotic tissue-derived product to serve as a cover or barrier and to retain fluid in dermal lesions, even if the obvious result will be to aid in wound healing.
Finally, the draft guidance also confirms that an HCT/P is intended for homologous use when its labeling, advertising, or other indications of the manufacturer’s objective intent refer to only homologous uses for the HCT/P. When an HCT/P’s labeling, advertising, or other indications of the manufacturer’s objective intent refer to non-homologous uses, the HCT/P would not meet the homologous use criterion. The manufacturer’s objective intent is determined by the expressions of the manufacturer or its representatives or may be shown by the circumstances surrounding the distribution of the article. What is particularly significant is that FDA did not elaborate on what circumstances surrounding the distribution, independent of specific communications by the marketing company, could render use to be non-homologous.
On the same date that FDA issued the draft guidance, the agency also proposed a public hearing and re-opened the comment period on three related draft guidances:
- Human Cells, Tissues, and Cellular and Tissue-Based Products from Adipose Tissue: Regulatory Considerations; Draft Guidance for Industry;
- Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products; and
- Same Surgical Procedure Exception: Questions and Answers Regarding the Scope of the Exception.
These actions suggest that FDA may revisit certain critical definitional issues that could affect which HCT/Ps are regulated solely under section 361 of the Public Health Service Act and 21 C.F.R. Part 1271. For that reason, all interested parties should consider submitting comments. Comments on the new draft guidance, as well as on the three re-opened draft guidances, can be submitted electronically at http://www.regulations.gov and are due by April 29, 2016.