Frequently Asked Questions

HCT/Ps are defined in 21 CFR 1271.3(d) as articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.

SEC. 361. [264] (a) The Surgeon General, with the approval of the Secretary is authorized to make and enforce such regulations as in his judgment are necessary to prevent the introduction, transmission, or spread of communicable diseases from foreign countries into the States or possessions, or from one State or possession into any other State or possession. For purposes of carrying out and enforcing such regulations, the Surgeon General may provide for such inspection, fumigation, disinfection, sanitation, pest extermination, destruction of animals or articles found to be so infected or contaminated as to be sources of dangerous infection to human beings, and other measures, as in his judgment may be necessary.

SEC. 351. [262] (a) (1) No person shall introduce or deliver for introduction into interstate commerce any
biological product unless—

  • (A) a biologics license under this subsection or subsection (k) is in effect for the biological product; and
  • (B) each package of the biological product is plainly marked with—
    • (i) the proper name of the biological product contained in the package;
    • (ii) the name, address, and applicable license number of the manufacturer of the biological product; and
    • (iii) the expiration date of the biological product.

(2)(A) The Secretary shall establish, by regulation, requirements for the approval, suspension, and revocation of biologics licenses.
(B) PEDIATRIC STUDIES.—A person that submits an application for a license under this paragraph shall submit to the Secretary as part of the application any assessments required under section 505B of the Federal Food, Drug, and Cosmetic Act.
(C) The Secretary shall approve a biologics license application—

  • (i) on the basis of a demonstration that—
  • (I) the biological product that is the subject of the application is safe, pure, and potent; and
  • (II) the facility in which the biological product is manufactured, processed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent; and
  • (ii) if the applicant (or other appropriate person) consents to the inspection of the facility that is the subject of the application, in accordance with subsection (c).

(D) POSTMARKET STUDIES AND CLINICAL TRIALS; LABELING; RISK EVALUATION AND MITIGATION STRATEGY.—A person that submits an application for a license under this paragraph is subject to sections 505(o), 505(p), and 505–1 of the Federal Food, Drug, and Cosmetic Act.
(E)(i) The Secretary may rely upon qualified data summaries to support the approval of a supplemental application, with respect to a qualified indication for a drug, submitted under this subsection, if such supplemental application complies with the requirements of subparagraph (B) of section 505(c)(5) of the Federal Food, Drug, and Cosmetic Act.

Section 351 of the PHS Act governs biological products that do not meet the criteria to be regulated solely under Section 361 of the PHS Act. Products regulated under Section 351 are regulated similarly to drugs or devices which must have an IND in effect or acquire pre-market approval to be commercially marketed. In contrast, Section 361 governs HCT/Ps that meet all four criteria listed in 21CFR 1271.10(a). Products that fall under section 361 do not need an IND or premarket approval to be sold because if they retain their primary functions and are used in homologous fashion, they are considered a known quantity and thus would not warrant further investigation.

(a) An HCT/P is regulated solely under section 361 of the PHS Act and the regulations in this part if it meets 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; and
  • (4) 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:
      • (a ) Is for autologous use;
      • (b ) Is for allogeneic use in a first-degree or second-degree blood relative; or
      • (c ) Is for reproductive use.
      • (b) If you are a domestic or foreign establishment that manufactures an HCT/P described in paragraph (a) of this section:
        • (1) You must register with FDA;
        • (2) You must submit to FDA a list of each HCT/P manufactured; and
        • (3) You must comply with the other requirements contained in this part.

[66 FR 5466, Jan. 19, 2001, as amended at 69 FR 68681, Nov. 24, 2004]

[Code of Federal Regulations]
[Title 21, Volume 8]
[Revised as of April 1, 2020]
[CITE: 21CFR1271.10]

Because of the unique nature of HCT/Ps, FDA proposed and in 2005 implemented a tiered, risk-based approach to the regulation of HCT/Ps. Although FDA is authorized to apply the requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and the Public Health Service Act (PHS Act) to those products that meet the definition of drug, biologic, or device, under this tiered, risk-based approach, those HCT/Ps that meet specific criteria or fall within detailed exceptions do not require premarket review and approval.

It is not necessary to submit an RFD for every product. We recommend submitting an RFD when the classification of a product or the Agency Center to which it should be assigned is unclear or in dispute. Sponsors are encouraged to submit an RFD as soon as they have sufficient information for FDA to make a decision regarding classification or assignment of a product.

The RFD should be submitted before filing any investigational or marketing application for the product. This will avoid a potential stay of the review clock if the classification or assignment of the product under review is determined to be unclear or in dispute during the review process. See 21 CFR 3.10. This will also help you avoid expending unnecessary time and resources, by ensuring that whatever of the appropriate type and to the appropriate Agency component. If you have classification or assignment questions regarding multiple related products or product families that have different configurations, ingredients, and/or proposed uses or indications, we recommend submitting a separate RFD for each product.

  1. For structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement;
  2. For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues.

As defined in 21 CFR 1271.3(c), homologous use means 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. This criterion reflects the Agency’s conclusion that there would be increased safety and effectiveness concerns for HCT/Ps that are intended for a nonhomologous use, because there is less basis on which to predict the product’s behavior, whereas HCT/Ps for homologous use can reasonably be expected to function appropriately (assuming all of the other criteria are also met).

Yes. Homologous use for any given tissue type depends on the function(s) of that tissue in the donor. Below are two FDA examples of structural tissue and a description of their original relevant characteristics. For homologous application, the end product (after processing) must maintain its original relevant characteristics in order to perform the same basic function(s) as it did in the donor.

Example 10-1: Original relevant characteristics of bone relating to its utility to support the body and protect internal structures include strength, and resistance to compression. Milling, grinding, and other methods for shaping and sizing bone may generally be considered minimal manipulation when they do not alter bone’s original relevant characteristics relating to its utility to support the body and protect internal structures.

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.

Yes, if a product does not have objective evidence of minimal manipulation (that the tissue maintains its ability to perform the same basic function(s) as it did in the donor), the FDA assumes that the product does not meet this criteria.

Please note that if information does not exist to show that the processing meets the definition of minimal manipulation, FDA considers the processing of an HCT/P to be “more than minimal manipulation” that cannot qualify for regulation solely under section 361 of the PHS Act and 21 CFR Part 12718.

The FDA gives individual examples of both homologous and non-homologous use as well as minimal manipulation and more than minimal manipulation.

Homologous Use Examples

Example 19-1: Sources of hematopoietic stem/progenitor cells (HPCs) include cord blood, peripheral blood, and bone marrow.24 The basic functions of HPCs include forming and replenishing the lymphohematopoietic system.

  • a. HPCs from mobilized peripheral blood are intended for transplantation into an individual with a disorder affecting the hematopoietic system that is inherited, acquired, or the result of myeloablative treatment. This is homologous use because the peripheral blood product performs the same basic function of reconstituting the hematopoietic system in the recipient.
  • b. HPCs from bone marrow are intended for infusion into an artery with a balloon catheter for the purpose of limiting ventricular remodeling following acute myocardial infarction. This is not homologous use because limiting ventricular remodeling is not a basic function of bone marrow.
  • c. HPCs from cord blood are intended for intravenous infusion to treat cerebral palsy purportedly through the repair of damaged tissue in the brain through paracrinesignalingordifferentiationintoneuronalcells. Thisisnothomologous use because there is insufficient evidence to support that repair of neurologic tissue through paracrine signaling or differentiation into neuronal cells is a basic function of these cells in the donor.

Example 19-2: The basic functions of the cornea include protecting the eye and serving as its outermost lens. A corneal graft is transplanted to a patient with corneal blindness. This is homologous use because a corneal graft performs the same basic functions in the donor as in the recipient.

Example 19-3: The basic functions of a vein or artery include serving as a conduit for blood flow throughout the body. A cryopreserved vein or artery is used for arteriovenous access during hemodialysis. This is homologous use because the vein or artery is supplementing the vessel as a conduit for blood flow.

Example 19-4: The basic functions of amniotic membrane include serving as a selective barrier for the movement of nutrients between the external and in utero environment, protecting the fetus from the surrounding maternal environment, and serving as a covering to enclose the fetus and retain fluid in utero.

  • a. Amniotic membrane is used for bone tissue replacement to support bone regeneration following surgery to repair or replace bone defects. This is not a homologous use because bone regeneration is not a basic function of amniotic membrane.
  • b. An amniotic membrane product is used for wound healing and/or to reduce scarring and inflammation. This is not homologous use because wound healing and reduction of scarring and inflammation25 are not basic functions of amniotic membrane.
  • c. An amniotic membrane product is applied to the surface of the eye to cover or offer protection from the surrounding environment in ocular repair and reconstruction procedures. This is homologous use because serving as a covering and offering protection from the surrounding environment are basic functions of amniotic membrane.26

Example 19-5: The basic functions of pericardium include covering, protecting against infection, fixing the heart to the mediastinum, and providing lubrication to allow normal heart movement within chest. Autologous pericardium is used to replace a dysfunctional heart valve in the same patient. This is not homologous use because facilitating unidirectional blood flow is not a basic function of pericardium. The use of an HCT/P from adipose tissue for the repair, reconstruction, replacement, or supplementation of adipose tissue would be considered a homologous use. In these situations, FDA would consider the HCT/P from adipose tissue to be performing the same basic function in the recipient as in the donor. In contrast, the use of an HCT/P from adipose tissue for the treatment of a degenerative, inflammatory, or demyelinating disorder would generally be considered a non-homologous use.

Example 19-6: The basic functions of adipose tissue include providing cushioning and support for other tissues, including the skin and internal organs, storing energy in the form of lipids, and insulating the body.

  • a. Adipose tissue is used to fill voids in the face or hands (e.g., for cosmetic reasons). This is homologous use because providing cushioning and support, is a basic function of adipose tissue.27
  • b. An HCT/P from adipose tissue is used to treat musculoskeletal conditions such as arthritis or tendonitis by regenerating or promoting the regeneration of articular cartilage or tendon. This is generally not considered a homologous use because regenerating or promoting the regeneration of cartilage or tendon is not a basic function of adipose tissue.
  • c. An HCT/P from adipose tissue is used to treat neurological disorders such as multiple sclerosis by limiting the autoimmune reaction and promoting remyelinization. This is generally not considered a homologous use because limiting the autoimmune reaction and promoting remyelinization are not basic functions of adipose tissue.
  • d. Adipose tissue is used for transplantation into the subcutaneous areas of breast for reconstruction or augmentation procedures. This is homologous use because providing cushioning and support is a basic function of adipose tissue

 

Minimal Manipulation Examples

Structural tissues may be processed by various machining and other mechanical methods to change the size or shape of the HCT/P. Such processing can be either minimal manipulation or more than minimal manipulation depending on whether the processing alters the original relevant characteristics of the structural tissue relating to its utility for reconstruction, repair, or replacement.

Example 10-1: Original relevant characteristics of bone relating to its utility to support the body and protect internal structures include strength, and resistance to compression. Milling, grinding, and other methods for shaping and sizing bone may generally be considered minimal manipulation when they do not alter bone’s original relevant characteristics relating to its utility to support the body and protect internal structures.

  • a. A manufacturer performs threading and other mechanical machining procedures to shape bone into dowels, screws, and pins. The HCT/Ps are generally considered minimally manipulated because the processing does not alter the bone’s original relevant characteristics relating to its utility to support the body and protect internal structures.
  • b. A manufacturer grinds bone to form bone chips and particles. The HCT/Ps would generally be considered minimally manipulated because the processing does not alter the bone’s original relevant characteristics relating to its utility to support bodily structures.15
  • c. A manufacturer exposes bone to acid at elevated temperature to demineralize bone and dissolve collagen in order to form a gel. The HCT/P is generally considered more than minimally manipulated because the processing alters the bone’s original relevant characteristics relating to its utility to support the body and protect internal structures.

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.

  • a. 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.
  • b. 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.

Example 10-3: Original relevant characteristics of fascia lata, relating to its utility to cover muscle and aid in movement, generally include its strength, flexibility, and its fibrous, sheet-like configuration. A manufacturer grinds sheets of fascia lata into 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 cover muscle and aid in movement.

Example 10-4: The original relevant characteristics of skin relating to its utility to serve as a protective covering generally include its large surface area, keratinized, water-resistant epithelial layer (epidermis), and dense, strong, and flexible connective tissue layer (dermis).

  • a. A manufacturer processes skin by mechanical meshing and cryopreservation and packages it in sheets as meshed skin. The HCT/P generally is considered minimally manipulated because the processing does not alter the original relevant characteristics of the skin relating to its utility as a protective covering.
  • b. A manufacturer processes skin by removing the epidermis and then grinding the dermis into particles. The HCT/P generally is considered more than minimally manipulated because the processing alters the original relevant characteristics of skin related to its utility as a protective covering

HCT/Ps may perform multiple functions and FDA acknowledges that structural tissues contain cells. 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. HCT/Ps that physically support or serve as a barrier or conduit, or connect, cover, or cushion are generally considered structural tissues for the purpose of applying the HCT/P regulatory framework.

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.28F29 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.

Yes! Regenative Labs is responsible for all steps in the manufacturing process that take place after recovery, including the processing, storage, labeling, packaging, and distribution of any human cell or tissue products manufactured and marketed by Regenative Labs.

Donors are thoroughly screened for risk factors and clinical evidence of relevant communicable diseases. A careful medical and social history is collected in advance to ensure the donor meets all eligibility requirements. These tissues undergo extensive and comprehensive medical, social, and blood testing before processing. Only tissue cleared after this stringent screening regimen is processed and re-tested under standards established by the American Association of Tissue Banks (AATB) and FDA requirements. Every precaution is taken to eliminate the potential risk of infectious diseases through comprehensive testing following the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and 42 CFR Part 493 and the FDA. Regenative Labs verifies each step of the manufacturing process to ensure the most stringent safety standards are met and maintained, from start to finish.

Yes, Regenative Labs has collaborated with Baylor University to create mass spectrometry reports detailing the structural components of Wharton’s jelly before and after processing.

No, there have not been any violations or adverse reactions reported in conjunction with Regenative Labs’ products. In fact, the last FDA inspection resulted in the rare issuance of form 482, meaning that there were no adverse observations reported.

Regenative Labs produces birth tissue products regulated under Section 361 of the PHS Act, such as amniotic membrane discs/patches (AmnioText™) intended to be used in homologous fashion as a covering or barrier and Wharton’s jelly (ProText™, CryoText™, SecreText™), umbilical cord-derived tissue intended to be used in homologous fashion to provide cushioning and structural support to the site of a defect.

Regenative Labs processes Wharton’s jelly to maintain its original, relevant characteristics relating to its ability to repair, replace, or supplement missing or damaged tissue. Our Wharton’s jelly products are cut and reduced to a size that sufficiently maintains its basic structural function(s) and that can flow through a syringe. We work with a number of universities to study the structural properties of Wharton’s jelly in the donor and verify that those same properties are present in the end product produced by Regenative Labs.

**Ask for our objective scientific proof from Baylor College of Medicine

ProText™ is our coded (and payable) Wharton’s jelly product that is intended to be used in a homologous fashion to repair, replace, or supplement missing or damaged tissue by providing cushioning and structural support directly to the site of a defect. This product has seen Medicaid/Medicare coverage in ten of the thirteen MAC regions. Regenative Labs’ Wharton’s jelly products can be applied straight to the site of the defect in soft tissue or cartilage using a syringe. See Q4246 on pg. 63 of CMS decision.

Wharton’s jelly has a shelf life of 5 years when the product is appropriately stored between -40 and -80 degrees Celsius. Regenative Labs’ facility houses multiple SO-LOW ultra-low freezers for product storage, including an entire freezer where each new batch is quarantined until sterility results are received and the product is cleared for distribution. For physicians wishing to purchase and store products locally, we offer cryogenic-tanks that can store nearly 150 vials.

Regenative Labs houses more than a dozen certified tissue bank auditors and analyzes relevant regulatory information with great diligence. Our specialized industry knowledge is put to good use in our physician teachable training, which provides answers directly from 21CFR 1271 and a comprehensive quiz to test your knowledge. This training is totally free to Physician Partners of Regenative Labs.

Disassociated amniotic membrane products that have been processed into a flowable product do not fall under Section 361 of the PHS act because they are more than minimally manipulated. The FDA describes the basic function for amniotic membrane to be acting as a barrier, so when it is produced in a liquid (or flowable) form, it clearly does not maintain its utility to serve as a barrier and thus the processing is considered more than minimal manipulation.

This may cause one to question how Regenative Labs’ Wharton’s jelly products, which are processed in a similar fashion, meet the minimal manipulation criteria while amniotic flowables do not. The FDA does not list the primary functions of Wharton’s jelly, but they are well-documented in clinical literature as providing cushioning and support, protecting the umbilical vein and arteries from mechanical stress. Unlike Amniotic membrane, Wharton’s jelly can retain its ability to perform its primary function when processed into a flowable product.

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. Therefore, to assess whether a processing step alters the original relevant characteristics of a structural tissue relating to its utility for reconstruction, repair, or replacement, you should consider the effects of the processing on the properties that contribute to the specific tissue’s function in the donor, for each type of tissue you manufacture.

Generally, products used in an IND cannot be sold commercially because there is not sufficient evidence of its safety and efficacy to treat or cure a specific disease or condition. When a study collects enough data to establish statistical significance for safety and efficacy, an approved new drug is established by the FDA and the product can begin commercial sale.

The FDA keeps a comprehensive database of all registered tissue establishments and products in Human Cell and Tissue Establishment Registration (HCTERS). This online database allows you to search for FDA registration by product name and by company name.

A note from Regenative Labs

Note: Italicized words are direct quotes. Non-italicized words are our commentary. Questions with direct quotes will have the citation number listed in the question. Answers containing direct quotes from more than one source will have the citations listed in the order that they are quoted.

Works Cited

  1. https://www.fda.gov/media/109176/download
  2. https://www.govinfo.gov/content/pkg/COMPS-8773/pdf/COMPS-8773.pdf
  3. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/how-write-request-designation-rfd#IID