How Might Regulations on Human Cell, Tissue and Cellular, and Tissue-based Products (HCT/Ps) Affect Your Practice?

Podiatrists are likely very familiar with human cell, tissue and cellular, and tissue-based products (HCT/Ps). For example, studies exist that focus on injectable placental allografts as potential treatment modalities for tendinous pathologies and arthritic conditions affecting the foot and ankle.^1-4 A pilot study of injectable placental allograft to treat tendinitis of the foot and ankle in 10 patients reported elimination of pain in 8 patients at 4 weeks following a single injection.¹ Two larger retrospective case series that looked at treating chronic foot and ankle tendonitis with injected micronized dehydrated human amnion/chorion membrane also reported a significant reduction in pain and increase
in function.^2,3

One study reported symptom resolution in 66 percent of patients and improvement in the remaining 34 percent of patients with chronic Achilles tendinopathy 45 days following injection of a placental allograft.² Seventy-two percent of patients also reported no pain at 45 days following treatment. The second study³ looked at 40 patients with chronic tendinopathy and noted a significant reduction in pain, a reduced need for pain medication, and an increased ability to perform activities of daily living at 1-, 2-, and 3-months following injection. Another report on micronized dehydrated human amnion/chorion membrane in the treatment of plantar fasciitis also resulted in a significant decrease in pain and improved functional outcomes compared to placebo at three months following a single injection.⁴ These outcomes led to the rapid adoption of these products in podiatry. Despite reported positive outcomes, injectable placental allografts are no longer available for commercial use per Food and Drug Administation (FDA) guidance. This article aims to provide a high-level overview of the regulations surrounding HCT/Ps and how those regulations determine what grafts are available for commercial use.

Defining HCT/Ps and Their Associated Regulations

Regulation of HCT/Ps intends to help prevent the introduction, transmission, and spread of communicable diseases from donor to recipient.^5,6 The marketing and regulation of HCT/Ps for commercial use varies based on specific criteria. These products can either be:

• 361 HCT/Ps requiring no pre-market authorization;

• 351 HCT/Ps, which are biological drugs; or

• medical devices regulated under the Food Drug and Cosmetic act.⁷

Human cell, tissue and cellular, and tissue-based products designated as 361 HCT/Ps fall under the Code of Federal Regulations, 21 CFR 1271, and Section 361 of the Public Health Service Act (PHSA).⁵ These products meet the criteria outlined in the 21 CFR 1271.10⁸ and the FDA Guidance Document on Homologous Use and Minimal Manipulation,⁷ which state that the final products are:

1.  minimally manipulated;

2.  intended for homologous use only;

3. not combined with other cells or tissues during manufacturing; and

4. does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or

5. if the HCT/P does have a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, it is for:

a.  autologous use;

b. allogeneic use in a first-degree or second-degree blood relative; or

c. reproductive use.⁷

A Closer Look at Specific Regulatory Points

Minimal manipulation of a 361 HCT/P refers to the processing of the final allograft product so that there is no alteration of “original relevant characteristics” of the cells or tissues.⁷ The definition of minimal manipulation differs based upon the categorization of the tissue or cells as “structural tissue” or “cells or nonstructural tissue.”⁷ Minimal manipulation of structural tissue is defined as tissue processing that “does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement.” Allografts derived from bone, skin, and placenta have designation as structural tissues.⁷ Minimal manipulation of these allografts requires that they maintain their original relevant characteristics – physical integrity, tensile strength, flexibility, elasticity, cushioning, covering, compressibility, and ability to respond to friction and shear.^5,7

Examples of minimally manipulated structural tissues are machined bone dowels, placental allografts maintained in sheet-form, and decellularized human dermal matrices maintained in sheet form, with or without meshing or fenestration of the graft. Processing in this way retains the original structural characteristics of the tissue of origin.⁵ Bone subjected to processing to demineralize it and produce it into a gel and placental or skin-derived allografts ground into a paste or micronized are not considered “minimally manipulated” as these tissue processing methods alter the “original relevant structural characteristics” of the tissue, specifically their ability to cover and protect.⁵

For “cells or nonstructural tissue,” minimal manipulation is defined as tissue processing that “does not alter the relevant biological characteristics” of the cells or tissue.^5,7 An example of minimal manipulation of “cells or nonstructural tissue” is concentrating hematopoietic stem cells before transplantation. This processing does not alter the cells’ “relevant biological characteristics.” An example of tissue processing of “cells or nonstructural tissue” not considered “minimally manipulated” is the culturing of cells to expand their numbers and promote cellular differentiation as this processing method has the potential to alter the “relevant biological characteristics” of the original cells utilized.⁵

Homologous use of a 361 HCT/P refers to the allograft being used so that it performs the same basic function in the recipient as it did in the donor.^5,7 “Structural tissues” and “cells or nonstructural tissues” do not need to be identical to the recipient’s cells or tissues to be meet the criteria of homologous use. If the 361 HCT/P performs the same basic primary function in the recipient as they did in the donor, this meets the criterion.⁷ Performance of the allograft in the same capacity in the recipient as in the donor helps ensure its safety and effectiveness due to the ability to better predict the behavior of the graft once implanted in the recipient.⁷ For structural tissues, homologous use means that the allograft will repair, reconstruct, or replace tissues. The primary functions of structural tissues are to serve as a barrier, connection, conduit, cover, cushion, or support.⁷

An example of homologous use would be the utilization of adipose tissue to fill atrophied areas in the face or hands as the tissue functions to provide cushioning and support to the area.⁵ Another example is the replacement of a damaged heart valve with an allograft valve as the allograft is functioning in the same capacity in the recipient as it did in the donor. Regarding skin and placental-derived tissues, categorized as structural tissues, their primary function must serve as a cover or barrier to the external environment to meet the criterion of homologous use.^5,7 Thus, skin and placental-derived tissues ground, made into a paste, micronized, or otherwise processed to alter the capacity of the tissue to serve as a structural barrier or cover to the external environment render the final product unable to function in a homologous use capacity.⁷

In this case, the graft would be considered a biological drug and must go through the 351 regulatory pathway to availability for commercial use. Homologous use requires that the allograft will supplement the recipient’s cells or tissues for cells and nonstructural tissues.⁷ An example of homologous use of cells and nonstructural tissues is a transfusion because the concentrated hematopoietic stem cells supplement a deficiency of the same type of cells. In contrast, administration of bone marrow aspirate into the heart to limit ventricular remodeling is not considered homologous use as this is not a primary function of cells derived from bone marrow.⁵

How Do These Regulations Impact Your Practice?

As 361 HCT/Ps are minimally manipulated (processed to maintain their original structural or biological relevant characteristics) and intended for homologous use only (functioning in the same capacity in the recipient as in the donor) their behavior once implanted is more predictable. This is akin to the surgical saying of replacing “like for like.” Establishments involved in HCT/P recovery, donor screening and tissue, processing, packaging, labeling, storing, and/or distributing HCT/Ps must register with the FDA and complete and document screening and testing for infectious communicable diseases to determine donor eligibility before tissue release for use and monitor reported adverse events.^5,6 Allografts that do not meet the criteria as a 361 HCT/P must seek FDA approval for commercial marketing as either a biologic, drug, or medical device.^5,7 These pathways require companies to demonstrate product safety and effectiveness due to the reduced ability to predict product behavior once implanted in the recipient, as the product is more than minimally manipulated and/or not functioning in a homologous use capacity.⁵

While these guidelines have been in place for several years, the FDA exercised discretion in enforcing these guidelines giving manufacturers a specified period to comply with these guidelines before enforcing them.⁵ This period expired May 31, 2021, leading to the removal of non-compliant products from the market, ie, allografts that did not meet the criteria to be regulated as a 361 HCT/P and had not obtained FDA approval for commercial use as a biological drug or medical device. These products included micronized placental allografts for injection and paste-like skin-derived allografts.⁹ Injectable placental allografts may still be available in operating rooms and podiatrists’ offices if they were purchased prior to May 31, 2021, and their expiration date has not yet been exceeded. However, these products cannot currently be marketed for commercial use unless they have obtained FDA approval as a biological drug or medical device or the institution, surgeon, and indication for use are under an FDA approved Investigation New Drug (IND) application and the patient is a subject enrolled in a clinical trial. Placental allografts in sheet-form, cryopreserved skin, and acellular dermal matrices continue to be regulated as 361 HCT/Ps, as they meet the outlined criteria and are available for commercial use.

Concluding Thoughts

This high-level overview of HCT/P regulations aims to provide podiatrists with a generalized understanding of how these products are regulated and recent changes to product availability. All allograft donors contributing to the derivation of HCT/P products must undergo screening beforehand, helping prevent the spread of communicable diseases.^5,6 Pathways to market vary based on tissue processing methods and the intended function of the final product. Those products that meet criteria to be classified as 361 HCT/Ps continue to be available for commercial use. Examples of 361 HCT/Ps include bone, ligaments, tendons, fascia, cartilage, corneas, sclera, veins, and arteries – except for preserved umbilical cord veins, pericardium, dura mater, heart valves, hematopoietic stem cells derived from peripheral or umbilical cord blood, semen, oocytes, embryos, and placental membrane. They all must maintain their original relevant structural characteristics and serve as a protective cover or barrier. Products that do not meet the criteria to be regulated as 361 HCT/Ps must obtain FDA approval or clearance for use as a biological drug or medical device. Until receiving FDA approval, products such as injectable placental allografts and paste-like skin-derived allografts remain unavailable for commercial use in the United States. 

Valerie Marmolejo, DPM, MS, CTBS, MWC is the Western Region, Clinical Wound Specialist for LifeNet Health.
She is also a certified Medical Writer with Scriptum Medica.

1.Lullove E. A flowable placental tissue matrix allograft in lower extremity injuries: a pilot study. Cureus. 2015;7(6):e275. doi: 10.7759/cureus.275.

2.Spector J, Hubbs B, Kot K, Istwan N, Mason D. Micronized dehydrated amnion chorion membrane (mdHACM) injection in the treatment of chronic Achilles tendinitis: a large retrospective case series. J Am Podiatr Med Assoc. 2021:19-170. Online ahead of print. doi: 10.7547/19-170.

3.Gellhorn AC, Han A. The use of dehydrated human amnion/chorion membrane allograft injection for the treatment of tendinopathy or arthritis: a case series involving 40 patients. PM R. 2017;9(12):1236-1243. doi: 10.1016/j.pmrj.2017.04.011.

4.Cazzell S, Stewart J, Agnew PS, et al. Randomized controlled trial of micronized dehydrated human amnion/chorion membrane (dHACM) injection compared to placebo for the treatment of plantar fasciitis. Foot Ankle Int. 2018;39(10):1151-1161. doi: 10.1177/1071100718788549.

5.Kleinwaks L. The ABCs of HCT/Ps. Navigating the complex regulatory pathway of human cell and tissue products. Orthopedic Design Technology. https://www.odtmag.com/issues/2019-05-24/view_features/the-abcs-of-hctps/. Published May 23, 2019. Accessed February 3, 2022.

6.Williams MO. The regulation of human tissue in the United States: a regulatory and legislative analysis. Food and Drug Law Journal. 1997;52(4):409-428. Available at: http://www.jstor.org/stable/26659888 . Accessed February
3, 2022.

7.U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research, Center for Devices and Radiological Health, Office of Combination Products. Regulatory considerations for human cells, tissues, and cellular and tissue-based products: minimal manipulation and homologous use guidance for industry and Food and Drug Administration staff. July 2020. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/regulatory-considerations-human-cells-tissues-and-cellular-and-tissue-based-products-minimal . Accessed February 3, 2022.

8.HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS, 21 C.F.R. § 1271 Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=1271 . Accessed February 8, 2022.

9.Great Practices. FDA requiring many amnion fluid injectables to be withdrawn by May 31, 2021. Available at: https://great-practices.com/fda-requiring-many-amnion-fluid-products-to-be-withdrawn-by-may-31-2021/ . Accessed February 3, 2022.

10.US Food and Drug Administration. FDA Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P’s) Product List. Available at:  https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products/fda-regulation-human-cells-tissues-and-cellular-and-tissue-based-products-hctps-product-list. Published February 1, 2018. Accessed February 3, 2022