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A Letter from the CEO

Jun 15, 2021

Regenative Labs to-date produces the first and only Wharton’s jelly allograft to be recognized as a 361 HCT/P by any government body (pg. 63 see here) and has been preparing for the end of the FDA’s discretionary enforcement period on 361 HCT/Ps since its foundation, however, it is important to note that there continues to be broad marketing of unapproved products considered regenerative medicine therapies that are intended for non-homologous use(s), such as treating or curing of a wide range of diseases or medical conditions. In a June 3rd letter entitled Important Consumer and Patient Information about Regenerative Medicine Therapies, the FDA was absolutely right to point out that unapproved “stem cells”, stomal vascular fraction (fat-derived cells), umbilical cord blood, and/or cord blood stem cells, amniotic fluid, Wharton’s jelly, ortho-biologics, and exosomes that do not meet the same-day surgical exemption or the 361 criteria must have an IND in effect or an approved biologics license to be marketed legally. By making claims of curing or treating a disease or medical condition, an HCT/P manufacturer self-classifies its product(s) as a 351 drug immediately, without respect to whether the HCT/P(s) meets other requirements to be regulated under section 361 of the PHS act.

 

Human Cell and Tissue products (HCT/Ps) are typically regulated by the Center for Biologics Evaluation and Research (CBER). The FDA has expressed that all HCT/P manufacturers must adhere to its guidance and indicated that action would be taken against any company not in compliance. The FDA’s regulatory authority over HCT/Ps stems from the Federal Food, Drug, and Cosmetic Act (FDCA) and the Public Health Service Act (PHS). Some HCT/Ps do not require premarket approval and are regulated under section 361 of the PHS and 21 CFR 1271.10(a), and therefore are not regulated as a drug. To qualify for premarket approval exemption, HCT/Ps in this category must meet all of the following criteria:

 

  1. The HCT/P is minimally manipulated;
  2. The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent;
  3. The manufacture of the HCT/P does not 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;
  4. and Either:
    i) 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
    ii) The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and:
  1. Is for autologous use;
  2. Is for allogeneic use in a first-degree or second-degree blood relative; or
  3. Is for reproductive use.

 

Minimal manipulation determination for both structural and nonstructural/cellular-based products under 21 CFR 1271 relates to how the HCT/P is processed. Before a minimal manipulation determination can be made, the HCT/P must be classified as either structural tissue or cellular/nonstructural tissue. This classification is determined based on the function of the HCT/P in the donor before any recovery or processing takes place. While some structural tissues may undergo processing that alters the cellular or extracellular matrix components without altering the original relevant characteristics of the tissue, the same processing may alter the original relevant characteristics of a different structural tissue.

 

When evaluating whether processing of an HCT/P meets the regulatory definition of minimal manipulation, a clinician must consider whether their supplier of HCT/Ps alters the original relevant characteristics of the tissue which relate to its utility to repair, replace, or supplement missing or damaged tissue.

 

Examples of both structural and nonstructural tissues have been provided by the FDA. Structural tissue types that have been processed in a way that compromises their utility for the same basic function or functions as originally observed in the donor tissue (homologous use) do not meet the criteria for a 361 product.

 

FDA Example 10-2: Original relevant characteristics of amniotic membrane relating to its utility to serve as a barrier generally include the tissue’s physical integrity, tensile strength, and elasticity.

  1. A manufacturer processes amniotic membrane to preserve it and package it in sheets. The HCT/P generally is considered minimally manipulated because the processing does not alter the original relevant characteristics of the HCT/P relating to its utility to serve as a barrier.
  2. A manufacturer grinds and lyophilizes amniotic membrane and packages it as particles. The HCT/P generally is considered more than minimally manipulated because the processing alters the original relevant characteristics of the HCT/P relating to its utility to serve as a barrier.

Please Note* Regenative Labs has demonstrated its attention to detail and willingness to comply with FDA regulations/updates by proactively removing our disassociated amniotic membrane product, AmnioText flowable, from the market despite receiving a Level II HCPCS code. However, we will continue to offer AmnioText patches & discs as 361 HCT/Ps.

 

After determining that the HCT/P maintains its utility to repair, replace, or supplement missing or damaged tissue, a clinician may then ask: Does the HCT/P have to be used in the same anatomic location to perform the same basic function(s)?

 

An HCT/P may perform the same basic function or functions even when it is not used in the same anatomic location where it existed in the donor. A transplanted HCT/P could replace missing tissue, or repair, reconstruct, or supplement tissue that is missing or damaged, either when placed in the same or different anatomic location, as long as it performs the same basic function(s) in the recipient as in the donor.

 

(FDA) Example 20-1: The basic functions of skin include covering, protecting the body from external force, and serving as a water-resistant barrier to pathogens or other damaging agents in the external environment. The dermis is the elastic connective tissue layer of the skin that covers, provides support, and protects the body from mechanical stress.

  1. An acellular dermal product is used for supplemental support, protection, reinforcement, or covering for a tendon. This is homologous use because, in both anatomic locations, the dermis provides support and protects the soft tissue structure from mechanical stress.
  2. An acellular dermal product is used for tendon replacement or repair. This is not homologous use because serving as a connection between muscle and bone is not a basic function of dermis.

Wharton’s jelly is a structural connective tissue that performs the basic functions of supporting and protecting the structural integrity of the umbilical cord and protecting the umbilical vein and arteries from mechanical stress. Regenative Labs Wharton’s jelly allografts are minimally manipulated, processed to preserve the original relevant characteristics as observed in the donor, and are intended for homologous use only and not intended to treat any disease or condition. A minimally manipulated allogeneic Wharton’s jelly connective tissue is used to supplement the recipient’s connective tissue for repair, replacement, and reconstruction of voids, gaps, or defects involving connective tissue in the torso or extremities, or for implantation of connective tissue into facial wrinkles to supplement a recipient’s tissues, are all examples of homologous use because, in all locations, the HCT/P is supplementing the recipient’s connective tissue and performs a structural function for the purpose of supporting the body or protecting internal structures.

 

A clinician may then wonder: Can a structural tissue regulated under section 361 of the PHS contain living cells? 

The FDA has indicated that an HCT/P that either has systemic effect or depends upon the metabolic activity of living cells for its primary function would not be appropriately regulated solely under section 361 of the PHS Act, and therefore will be regulated as a drug, device, and/or biological product. Cells or tissues such as pancreatic islet cells, which have effects on many different organs throughout the body through the secretion of insulin, are appropriately characterized by the term “systemic effect.” Neurons for implantation in the brain would fall into the category of HCT/P’s that depend upon the metabolic activity of living cells for their primary function. In contrast, some HCT/P’s (such as corneas, skin, or osteochondral allografts) may contain living cells, but do not depend on them for their primary function, which is structural (Registration and Listing; Final Rule).

 

HCT/Ps may perform multiple functions and the FDA acknowledges that structural tissues contain cells. The FDA also acknowledges that some manufacturers assert that an HCT/P has both a structural and cellular/nonstructural function. However, under the regulations, HCT/Ps are considered either structural tissues or cells/nonstructural tissues (see section III.B).

 

Wharton’s jelly is a structural connective tissue, and while this tissue contains cells, none of its native cell populations contribute to its primary structural function when processed to comply with 21 CFR 1271.10(a) of the PHS Act.

 

As your partner in facilitating predictable patient outcomes, we want you to know that allogeneic 361 human tissue grafts and transplants will continue to be available for you patients from respectable tissue banking establishments that adhere to FDA regulations and guidance. Allogeneic human tissue grafts, or allografts, have been in use since the early 19th century and by 1941, the US Navy began to embrace tissue banking after observing the utility of skin grafts on burn and wound patients in the service. From there, tissue banking became commonplace and by the end of the 1980s, there were over 300 tissue banks in the United States, leading to FDA guidance in 1993 with the introduction of stop-gap regulation 21 CFR 1270 of the PHS Act. Today, over 1 million patients in the US benefit from allogeneic grafts or transplants every year. Allografts that would today be 361 HCT/Ps represent the very genesis of and basis for tissue banking and shall continue to improve the lives of patients across nearly every scope of practice well into the future.

 

We are excited to see the tissue banking industry moving in the right direction and look forward to new expanded guidance documents from the FDA as this sector continues to flourish under their care. We eagerly anticipate any new updates from the FDA and will continue our standing as the leader in FDA 361 HCT/P regulatory compliance.

 

If you have any questions, please feel free to email me personally at [email protected], or set an appointment by calling 800-891-3452. I look forward to hearing from you.

 

Best regards,

Tyler C. Barrett

Chief Executive Officer

 

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