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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Tissue Reference Group

The Tissue Reference Group (TRG) was created as specified in the "Proposed Approach to the Regulation of Cellular and Tissue-based Products" published by FDA in February of 1997. The purpose of the TRG is to provide a single reference point for product specific questions received by FDA (either through the Centers, or from the Office of Combination Products) concerning jurisdiction and applicable regulation of human cells, tissues and cellular and tissue-based products (HCT/Ps).

The TRG is composed of three representatives from the Center for Biologics Evaluation and Research (CBER) and three from the Center for Devices and Radiological Health (CDRH), including the product jurisdiction officer at each Center. An executive secretary handles administrative functions for the TRG. A liaison from the Office of Combination Products and from the Office of the Chief Counsel attends meetings. Other FDA staff attend meetings as needed to discuss issues related to HCT/Ps in their area of expertise.

The TRG provides recommendations to the Centers and through the Centers to the Office of Combination Products, which then communicates with the sponsor. These recommendations are based on the information known at the time and are subject to change.

If you have questions or wish to send a request for recommendation to the Tissue Reference Group, please contact the Executive Secretary for the Tissue Reference Group, Division of Human Tissues, Office of Cellular, Tissue, and Gene Therapies at 301-827-5363, by FAX at 301-827-2844, or by email at TissueReferenceGroup@fda.hhs.gov. Submissions to the TRG can be emailed or mailed to the Tissue Reference Group, at the Center for Biologics Evaluation and Research (CBER), Office of Cellular, Tissue and Gene Therapies (OCTGT), Food and Drug Administration, 1401 Rockville Pike, HFM-775, Rockville, MD 20852-1448.

To facilitate review of your inquiry by the TRG, you may want to include the following:

  • Your name and contact information, and if applicable, the name and contact information of the party you represent
  • Manufacturer of product
  • The way the product is to be used
  • Source of the product
  • A clear, step by step, description of how the product is processed from the time of recovery to the point of use

NOTE: The TRG may request additional or clarifying information if it is needed to make a recommendation.


TRG Annual Reports

Please keep in mind that updates to the TRG Annual Reports are stated in general terms in order to avoid revealing confidential information protected from disclosure. The TRG's recommendations are based on specific facts, which may not be provided in the updates. For these reasons, it may not be appropriate to generalize broadly from the updates. If you have questions about your specific product, please contact TissueReferenceGroup@fda.hhs.gov

FY 2013 Update

The Tissue Reference Group made recommendations concerning the application of 21 CFR Part 1271.1, 1271.15, and 1271.20 to 4 HCT/Ps.

  • An allogeneic bone product composed of frozen cortical bone milled into micron-sized granules and used as a bone void filler is regulated solely under section 361 of the PHS Act and 21 CFR part 1271.
  • An allogeneic, decellularized adipose tissue matrix product is more than minimally manipulated and therefore not a 361 HCT/P because the processing alters the original, relevant characteristics of the adipose tissue's utility for reconstruction, repair or replacement.
  • The use of a human dermis product in breast reconstruction procedures where the dermis is used to form an extension of the submuscular pocket for placement of a breast implant or tissue expander constitutes non-homologous use and therefore is not a 361 HCT/P.
  • Bone marrow-derived mesenchymal stem cells expanded in culture are more than minimally manipulated and therefore not a 361 HCT/P.

FY 2012 Update

The Tissue Reference Group made recommendations concerning the application of 21 CFR Part 1271.1, 1271.15, and 1271.20 to 8 HCT/Ps.

  • A human amniotic membrane product for wound covering, and containing viable cells that are retained in the product to support and promote soft tissue repair and wound healing, is not regulated solely under section 361 of the Public Health Service Act because it is dependent upon the metabolic activity of living cells for its primary function and is not for autologous or allogeneic use in a first-degree or second-degree relative.
  • A human amniotic membrane product used for bone tissue replacement to support bone regeneration following surgery to repair or replace bone defects is non-homologous use and therefore is not a 361 HCT/P.
  • Allogeneic, processed acellular dermis, rolled or folded to serve as a structural support and placed in defects following breast conservation treatment, is non-homologous use and therefore is not a 361 HCT/P.
  • Adipose-derived mesenchymal stern cells product used as a bone graft substitute for the repair, replacement, or reconstruction of musculoskeletal defects is not a 361 HCT/P because it is dependent upon the metabolic activity of living cells for its primary function and is not intended for autologous use or allogeneic use in a first or second degree blood relative.
  • Microbiota isolated from fecal matter of a donor is not an HCT/P, as defined under 21 CFR 1271.3(d).
  • An allograft bone product – either in a mineralized or demineralized form – intended for bone repair or replacement and regulated solely under section 361 of the Public Health Service Act is still regulated solely under section 361 of the Public Health Service Act if soaked in antibiotic during processing for the purpose of reducing the bioburden of the allograft.
  • A solubilized collagen product prepared from autologous tissue would not be considered an HCT/P because secreted or extracted human products, including collagen, is not an HCT/P, as defined under 21 CFR 1271.3(d).
  • A cell selection process that results in activation of the T-Cell Receptor (TCR) does not meet the definition of minimal manipulation, as defined in 21 CFR 1271.3(f), because TCR activation alters the relevant biological characteristicsof the selected cell population.
     

FY 2011 Update

The Tissue Reference Group made recommendations concerning the application of 21 CFR Part 1271.1, 1271.15, and 1271.20 to 5 HCT/Ps.

  • An allograft peroneus tendon product that is used for Anterior Cruciate Ligament (ACL) reconstruction meets the criteria for regulation as a 361 HCT/P.
  • Use of an allogeneic peritoneal membrane product in guided bone regeneration and guided tissue regeneration dental procedures is a non¬ homologous use.
  • The use of demineralized bone matrix for repair, reconstruction, replacement, or supplementation of cartilage tissue does not meet the definition of homologous use because bone does not perform the same basic function as cartilage tissue.
  • A cartilage allograft that is homogenized is more than minimally manipulated because the processing alters the structural and mechanical characteristics of the tissue relating to its utility for the reconstruction, repair or replacement of cartilage and would not be considered a 361 HCT/P.
  • An allogeneic, cryopreserved vein or artery that has not been decellularized and is used for arteriovenous access during hemodialysis is considered to be an HCT/P solely regulated under section 361 of the Public Health Service Act (supersedes FY2003 recommendation).

 

FY 2010 Update

The Tissue Reference Group made recommendations concerning the application of 21 CFR Part 1271.1, 1271.15, and 1271.20 to 3 HCT/Ps.

  • A fascia lata allograft used for the repair of Anterior Cruciate Ligament (ACL) defects would not be considered a 361 HCT/P because this would be a non-homologous use.

  • Allogeneic adipose-derived stem cells seeded onto a bone scaffold for filling, augmenting or repair of pathologically or surgically created bony voids is considered a biological product, and not a 361 HCT/P, because the product is dependent upon the metabolic activity of living, unrelated allogeneic cells for its primary function.
  • Allogeneic demineralized cortical human bone consisting of alternating large and small sections for use in orthopedic repair, replacement and reconstruction applications for filling or augmenting bony voids or gaps involving the extremities, cranium, and spinal column; and for augmentation for posterior lateral fusions in the spinal column is considered a 361 HCT/P. 

FY 2009 Update

The Tissue Reference Group made recommendations concerning the application of 21 CFR Part 1271.1, 1271.15, and 1271.20 to 4 HCT/Ps.

  • Allogeneic retinal pigment epithelium and neurosensory cell layer for the treatment of patients with retinal degenerative diseases is considered a biological product subject to investigational new drug applications (INDs) and biologic license applications (BLAs), and not a 361 HCT/P because the product is dependent upon the metabolic activity of living (allogeneic) cells for its primary function (systemic effect).
  • Allogeneic orthopedic tissue for replacement of knee ligaments is not a 361 HCT/P because the product is processed with a solution that contains an anti-inflammatory drug. The anti-inflammatory drug in the processing solution is not a sterilizing, preserving, or storage agent as described in 1271.10(a)(3) (combination with another product).
  • Product containing tendon tissue, cancellous bone, and a polyester suture for use in ligament reconstruction is regulated as a medical device, and not a 361 HCT/P. The Tissue Reference Group made the same recommendation in the past, as stated in the FY 2002 Update below.
  • Addition of a manufacturing hold stage whose purpose is solely an improvement in the processing efficiency and flexibility, during manufacturing of various cardiovascular tissues previously determined to be 361 HCT/Ps does not change the regulatory status of these tissues.

FY 2008 Update

The Tissue Reference Group made recommendations concerning the application of 21 CFR Part 1271.1, 1271.15, and 1271.20 to 7 HCT/Ps.

  • Allogeneic freeze-dried, irradiated human peritoneal membrane used as a soft tissue wound covering is considered a 361 HCT/P.
  • Allogeneic placental-derived extracellular matrix and hematopoietic progenitor cells contained in the placental vasculature of the same donor used for repair, replacement and/or reconstruction of bone defects is considered a biological product, and not a 361 HCT/P because of the non-homologous use, combination with another article and a systemic effect.
  • An HCT/P where an antimicrobial considered to be a sterilizing, preserving, or storage agent per 1271.10(a)(3) is added to a solution used in the processing of the HCT/P to improve the solution’s antimicrobial properties is considered a 361 HCT/P.
  • Allogeneic demineralized cancellous bone advertised for filling of osteochondral defects is considered a medical device and not a 361 HCT/P because use for filling osteochondral defects in the cartilage constitutes a non-homologous use.
  • Autologous adipose tissue enzyme digested and processed for urinary incontinence and treatment of impotence is considered a biological product and not a 361 HCT/P because this is a non-homologous use. The tissue is recovered during one surgical procedure, then processed, and therefore the HCT/P is not exempt from the regulations under 21 CFR Part 1271.15(b).
  • Decellularized allogeneic fascia lata and pericardium used as wound coverings for dura mater defects are considered 361 HCT/Ps.This use is considered an homologous use.
  • Allogeneic demineralized bone matrix combined with human collagen derived from the same donor is a medical device. Processing of the carrier alters the original relevant characteristics of the demineralized bone matrix and this constitutes more than minimal manipulation.

FY 2007 Update

The Tissue Reference Group made recommendations concerning the application of 21 CFR Part 1271.1-, 1271.15, and 1271.20 to four HCT/Ps

  • Allogeneic cryopreserved amniotic membrane powder is more than minimally manipulated because processing alters the original relevant characteristics of the tissue relating to its utility for ocular repair and would not be considered a 361 HCT/P
  • Allogeneic osteochondral allograft preloaded in an applicator for surgical repair is considered a 361 HCT/P
  • Allogeneic osteochrondral allograft copackaged with single use drill sleeve/guide is considered a 361 HCT/P
  • Allogeneic dehydrated acellular osteochondral tissue, machined to specific dimensions for repair of osteochondral defects is considered a 361 HCT/P

FY 2006 Update

The Tissue Reference Group made recommendations concerning the application of 21 CFR Part 1271.10, 1271.15, and 1271.20 to six HCT/Ps

  • Allogeneic processed acellular dermis advertised for glenoid coverage, protection or cushioning would not be considered a 361 HCT/P because these would be non-homologous uses.
  • Allogeneic decellularized, human dermis when extracted to create a solubilized collagen preparation would not be considered a 361 HCT/P because the original relevant characteristics of the dermis related to its utility are altered by the processing and this constitutes more than minimal manipulation.
  • Allogeneic demineralized bone matrix combined with cross-linked osteoinductive demineralized bone matrix carrier from the same donor is a medical device because the processing of the carrier alters the original relevant characteristics of the demineralized bone matrix and this constitutes more than minimal manipulation.
  • Allogeneic demineralized bone matrix combined with a gelatinous carrier made by further processing of demineralized bone matrix from the same donor is a medical device because the processing to produce the carrier alters the original relevant characteristics of the demineralized bone matrix and this constitutes more than minimal manipulation.
  • Allogeneic decellularized dehydrated amniotic membrane advertised for improved wound healing of venous ulcers on the leg in conjunction with compression therapy is considered to be a biological product subject to investigational new drug applications (INDs) and biologic license applications (BLAs) because processing would have a meaningful bearing on how the tissue performs, thereby altering the original relevant characteristics of the HCT/P and constituting more than minimal manipulation.
  • Umbilical cord stem cells treated with enzyme to increase engraftment are considered biological products and are subject to INDs and BLAs because this processing constitutes more than minimal manipulation.

FY 2005 Update

The Tissue Reference Group made recommendations concerning the application of 21 CFR Part 1271.10, 1271.15, and 1271.20 to two HCT/Ps

  • A polymer scaffold with expanded, autologous urothelial and bladder smooth muscle cells for augmentation of diseased, damaged or otherwise non-functional bladders is considered a biological product.
  • Allogeneic dehydrated and decellularized amniotic membrane is considered to be a minimally-manipulated 361 HCT/P when the product is intended to be used as a wound covering. When intended for wound repair or wound healing, additional characteristics of the HCT/P are relevant (e.g., the presence of cytokine-containing cells). Since dehydration and decellularization alter these relevant characteristics, dehydration and decellularization constitute more than minimal manipulation and the product, when intended for wound repair or wound healing, would not be considered a 361 HCT/P (clarification of 2003 recommendation).

FY 2004 Update

The Tissue Reference Group made recommendations concerning the application of 21 CFR Part 1271.10, 1271.15, and 1271.20 to five HCT/Ps

  • Allogeneic processed acellular dermis with restricted advertising for supplemental support, protection, reinforcement or covering of tendon or periosteum is considered a 361 HCT/P (revision of FY 2003 recommendations). Replacement or direct repair of a rotator cuff tendon or periosteum, or bioactivity of the acellular dermis would be non-homologous uses, and when advertised as such, the product could not be considered a 361 HCT/P.
  • Allogeneic decellularized urinary bladders for replacement of damaged bladder tissue is not considered a 361 HCT/P because they are more than minimally manipulated.
  • Allogeneic decellularized cryopreserved pulmonary conduit tissue for pulmonary repair and reconstruction is considered a device because they are more than minimally manipulated.
  • Demineralized bone combined with decellularized dermis and promoted for revascularization, cell adhesion and repopulation with bone forming cells is not considered a 361 HCT/P because this is a non-homologous use.
  • Decellularized particulate human placental connective tissue matrix intended to replace or supplement damaged or inadequate integumental tissue is considered a 361 HCT/P.

FY 2003 Update

The Tissue Reference Group made recommendations concerning the application of 21 CFR Part 1271.10, 1271.15, and 1271.20 to ten HCT/Ps:

  • Allogeneic bone marrow used to induce tolerance in kidney transplant recipients is considered a 351 biological product because this is a non-homologous use.
  • Allogeneic decellularized dermis (and particulate dermis), and fascia are considered to be 361 HCT/ Ps
  • Cultured allogeneic skin cells applied with gauze are considered a 351 biological product because they are more than minimally manipulated.
  • Autologous olfactory mucosa for use in spinal defect repair is considered a 351 biological product because this is a non-homologous use.
  • Autologous cultured epithelial cells isolated from skin biopsies and processed by a contract manufacturer are considered to be 351 biological products because they are more than minimally manipulated.
  • Allogeneic decellularized arteries, veins and valve conduits are considered devices because they are more than minimally manipulated, i.e., processing has altered the original relevant characteristics of the tissue relating to the tissue's utility for reconstruction, repair or replacement.
  • Allogeneic veins or arteries intended for use as arteriovenous access for hemodialysis are considered devices because this is a non-homologous use.1
  • Allogeneic processed acellular dermis for rotator cuff tendon replacement and repair is not considered a 361 HCT/P because this is a non-homologous use.
  • Allogeneic processed acellular dermis for replacement and repair of damaged periosteum is not considered a 361 HCT/P because this is a non-homologous use.
  • Allogeneic dehydrated and decellularized amniotic membrane is considered a 361 HCT/P if the product's advertising is restricted to homologous use for a wound covering. Wound repair or wound healing would be non-homologous uses, and when advertised as such, the product could not be considered a 361 HCT/P.

    1. This recommendation has been reconsidered. Please see the FY2011 periodic update. 

     

FY 2002 Update

The Tissue Reference Group made recommendations on the application of 21 CFR 1271.10, 1271.15 and 1271.20 to nine HCT/Ps:

  • Allogeneic and autologous nerves combined with fibrin sealant and neurotrophic factors and/or autologous cells and also cultured with bovine collagen for use in regeneration of spinal nerves are considered to be combination products.
  • Allogeneic or autologous ligaments cultured with bone marrow stromal cells on silk for use in anterior cruciate ligament reconstruction are considered to be combination products.
  • Bone and tendon allograft combined with a polyester suture, (which is a regulated device) for use in ligament reconstruction is regulated as a device.
  • Hematopoietic stem cells from first and second degree blood relatives for induction of tumor regression in cancer patients are considered to be biological products because this intended use is considered a non-homologous use.
  • Demineralized bone combined with handling agents such as glycerol, sodium hyaluronate, calcium sulfate, gelatin, or collagen are regulated under the device authorities.
  • Processed dermis for the treatment of chronic eardrum perforations are considered to be section 361 HCT/Ps.
  • Autologous cultured skin fibroblasts for skin defects such as wrinkles and acne scars are considered biological products because they are more than minimally manipulated.
  • Allogeneic, cryopreserved, cultured epidermal cells attached to a gauze backing for use as an interactive wound and burn dressing are considered to be combination products.
  • Autologous keratinocytes combined with processed acellular dermis to treat oral defects are considered to be biological products.

FY 2001 Update

The Tissue Reference Group made recommendations on the application of 21 CFR 1271.10, 1271.15 and 1271.20 to seven HCT/Ps:

  • Allogeneic ex vivo cultured adipose cells are considered to be biologic products subject to investigational new drug applications (INDs) and biologic license applications (BLAs).
  • Allogeneic particulate acellular dermis is considered to be a section 361 HCT/P.
  • Allogeneic machined cortical bone dowels are considered to be section 361 HCT/P.
  • Allogeneic demineralized bone combined with gelatin is considered to be a device that must be evaluated for safety and efficacy for the intended use.
  • Allogeneic acellular dermal matrix combined with minced autologous skin during surgery is considered to be a section 361 HCT/P.
  • Allogeneic acellular dermis used as an urethral sling to treat female urinary stress incontinence due to intrinsic sphincter deficiency or urethral hypermobility is considered to be a section 361 HCT/P.
  • Allogeneic amniotic membrane for ocular repair is considered to be a section 361 HCT/P (reverses FY2000 decision). Amniotic membrane cultured with stem cells for ocular repair is considered to be a biologic product subject to INDs and BLAs.

FY 2000 Update

The Tissue Reference Group made recommendations on the regulatory approach to be applied to three new products.

  • An ex-vivo cultured cartilage and periosteum tissue product is considered a biologic product.
  • A particulate fascia lata product administered in a syringe is considered a tissue under the current regulations at 21 CFR Part 1270.
  • Amniotic membrane promoted for ocular surface reconstruction is considered a tissue under the current regulations at 21 CFR Part 1270, but the intended use would be non-homologous when 21 CFR Part 1271 becomes effective.

FY 1999 Update

The Tissue Reference Group made recommendations on the regulatory approach to be applied to two new products.

  • One involved processing by methods that changed tissue function or characteristics with a metabolic mode of action and hence the product was considered a biologic.
  • One consisted of ex vivo expanded hematopoietic stem cells and hence is considered a biologic product.

FY 1998 Update

  • During FY 98, the TRG has developed its standard operating procedures (CBER-SOPP 8004, effective date 7/28/98).
  • Ten recommendations have been made concerning new products and how they would be regulated under 21 CFR Part 1270 (Final Rule for Human Tissue Intended for Transplantation). Of these,
    • Three involved processing by methods that did not change the tissue function or characteristics, and hence, the products were tissues;
    • Two involved processing by methods that did change tissue function or characteristics, and hence the products were devices;
    • Two involved bone combined with regulated products, and hence were devices;
    • Three involved expanded cells combined with regulated devices, and hence were devices.
  • There was also one request for an interpretation, under the proposed approach, of the regulation of a product when promoted for a non-homologous use.

 

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Contact FDA

(800) 835-4709
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