Tissue Reference Group Annual Reports
One of the Tissue Action Plan task groups is the Tissue Reference Group (TRG). 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 six representatives: three from CBER and three from the Center for Devices and Radiological Health (CDRH). Also attending meetings is a liaison from the Office of Combination Products and the executive secretary. The TRG was created in February 1997, and currently meets twice a month.
The TRG gives recommendations to the Centers and through the Centers to the Office of Combination Products, which then communicate with the sponsor. These recommendations are based on the information known at the time and are subject to change.
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
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.
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).
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.
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.
- 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.
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.
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.
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.
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.
- 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.