FDA Guidance on CMC for Human Gene Therapy: Chemistry, Manufacturing & Control and Related Documents
Human gene therapy seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use. FDA is providing sponsors of human gene therapy Investigational New Drug Applications (INDs), recommendations regarding chemistry, manufacturing, and control (CMC) information submitted in an IND. The purpose of this guidance is to inform sponsors how to provide sufficient CMC information required to assure product safety, identity, quality, purity, and strength (including potency) of the investigational product (21 Code of Federal Regulations (CFR) 312.23(a)(7)(i)). This guidance applies to human gene therapy products and to combination products that contain a human gene therapy in combination with a drug or device.
Potency Tests for Cellular and Gene Therapy Products
The FDA is issuing this guidance to provide you, manufacturers of cellular and gene therapy (CGT) products, with recommendations for developing tests to measure potency. These recommendations are intended to clarify the potency information that could support an Investigational New Drug Application3 (IND) or a Biologics License Application4 (BLA). Because potency measurements are designed specifically for a particular product, this guidance does not make recommendations regarding specific types of potency assays, nor does it propose acceptance criteria for product release. This guidance is intended to supplement related documents (Refs. 1 through 12) and does not replace or supersede any currently published guidance documents, with the exception that this guidance finalizes the draft guidance entitled “Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products” dated October 2008 (October 9, 2008, 73 FR 59635).
Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use
FDA has published guidance to human cells, tissues, and cellular and tissue-based product (HCT/P) manufacturers, healthcare providers, and FDA staff, with our current thinking on the criteria under Title 21 of the Code of Federal Regulations (CFR) Part 1271, specifically the 21 CFR 1271.10(a) criterion of minimal manipulation and the 21 CFR 1271.10(a)(2) criterion of homologous use.
Potency Tests for Cellular and Gene Therapy Products
The FDA is issuing this guidance to provide you, manufacturers of cellular and gene therapy (CGT) products, with recommendations for developing tests to measure potency. These recommendations are intended to clarify the potency information that could support an Investigational New Drug Application3 (IND) or a Biologics License Application4 (BLA). Because potency measurements are designed specifically for a particular product, this guidance does not make recommendations regarding specific types of potency assays, nor does it propose acceptance criteria for product release. This guidance is intended to supplement related documents (Refs. 1 through 12) and does not replace or supersede any currently published guidance documents, with the exception that this guidance finalizes the draft guidance entitled “Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products” dated October 2008 (October 9, 2008, 73 FR 59635).
Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up
The potential pathogenicity of replication-competent retrovirus (RCR) requires vigilant testing to exclude the presence of RCR in vector-based human gene therapy products. The FDA is providing you, sponsors of retroviral vector-based human gene therapy products, recommendations regarding the testing for RCR during the manufacture of retroviral vector-based gene therapy products, and during follow-up monitoring of patients who have received retroviral vector-based gene therapy products. Recommendations include the identification and amount of material to be tested as well as general testing methods. In addition, recommendations are provided for monitoring patients for evidence of retroviral infection after administration of retroviral vector-based gene therapy products.
The potential pathogenicity of replication-competent retrovirus (RCR) requires vigilant testing to exclude the presence of RCR in vector-based human gene therapy products. The FDA is providing you, sponsors of retroviral vector-based human gene therapy products, recommendations regarding the testing for RCR during the manufacture of retroviral vector-based gene therapy products, and during follow-up monitoring of patients who have received retroviral vector-based gene therapy products. Recommendations include the identification and amount of material to be tested as well as general testing methods. In addition, recommendations are provided for monitoring patients for evidence of retroviral infection after administration of retroviral vector-based gene therapy products.
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Recommendations for Microbial Vectors Used for Gene Therapy
The FDA is providing investigational new drug application (IND) sponsors, with recommendations concerning IND submissions for microbial vectors used for gene therapy (MVGTs) in early-phase clinical trials. MVGTs meet the definition of “biological product” in section 351(i) of the Public Health Service (PHS) Act (42 U.S.C. 262), when such products are applicable to the prevention, treatment, or cure of a disease or condition of human beings. This guidance focuses on the chemistry, manufacturing, and control (CMC) information that you should submit in an IND for MVGTs and provides an overview of preclinical and clinical considerations for these products.
Recommendations for Microbial Vectors Used for Gene Therapy
The FDA is providing investigational new drug application (IND) sponsors, with recommendations concerning IND submissions for microbial vectors used for gene therapy (MVGTs) in early-phase clinical trials. MVGTs meet the definition of “biological product” in section 351(i) of the Public Health Service (PHS) Act (42 U.S.C. 262), when such products are applicable to the prevention, treatment, or cure of a disease or condition of human beings. This guidance focuses on the chemistry, manufacturing, and control (CMC) information that you should submit in an IND for MVGTs and provides an overview of preclinical and clinical considerations for these products.
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Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products
The Center for Biologics Evaluation and Research (CBER)/Office of Cellular, Tissue, and Gene Therapies (OCTGT) is issuing this guidance to provide you, sponsors of virus or bacteria-based gene therapy products (VBGT products)1 and oncolytic viruses or bacteria (oncolytic products) with recommendations on how to conduct shedding studies during preclinical and clinical development. For purposes of this guidance, the term “shedding” means release of VBGT or oncolytic products from the patient through one or all of the following ways: excreta (feces); secreta (urine, saliva, nasopharyngeal fluids etc.); or through the skin (pustules, sores, wounds). Shedding is distinct from biodistribution because the latter describes how a product is spread within the patient’s body from the site of administration while the former describes how it is excreted or released from the patient’s body. Shedding raises the possibility of transmission of VBGT or oncolytic products3 from treated to untreated individuals (e.g., close contacts and health care professionals). This guidance represents FDA’s current thinking on how and when shedding data should be collected for VBGT and oncolytic products during preclinical and clinical development and how shedding data can be used to assess the potential for transmission to untreated individuals.
Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant Viral or Microbial Products
The FDA issued this guidance to provide you, investigational new drug application (IND) sponsors and applicants for a biologics license application (BLA) or a supplement to a BLA (BLA supplement), with recommendations on considerations when assessing whether to submit an Environmental Assessment (EA) for gene therapies, vectored vaccines, and related recombinant viral or
microbial products (GTVVs).1 This guidance also contains recommendations as to what information should be included in an EA and what you can expect once an EA is filed. This guidance finalizes the draft guidance of the same title dated June 2014. This guidance also supplements the guidance entitled “Guidance for Industry: Environmental Assessment of Human Drug and Biologics Applications” dated July 1998, (July 27, 1998, 63 FR 40127) (1998 Guidance) and supersedes the recommendations for GTVVs in section IV.B.1 “Assessing Toxicity to Environmental Organisms” in the 1998 Guidance.
Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products
The Center for Biologics Evaluation and Research (CBER)/Office of Cellular, Tissue, and Gene Therapies (OCTGT) is issuing this guidance to provide you, sponsors of virus or bacteria-based gene therapy products (VBGT products)1 and oncolytic viruses or bacteria (oncolytic products) with recommendations on how to conduct shedding studies during preclinical and clinical development. For purposes of this guidance, the term “shedding” means release of VBGT or oncolytic products from the patient through one or all of the following ways: excreta (feces); secreta (urine, saliva, nasopharyngeal fluids etc.); or through the skin (pustules, sores, wounds). Shedding is distinct from biodistribution because the latter describes how a product is spread within the patient’s body from the site of administration while the former describes how it is excreted or released from the patient’s body. Shedding raises the possibility of transmission of VBGT or oncolytic products3 from treated to untreated individuals (e.g., close contacts and health care professionals). This guidance represents FDA’s current thinking on how and when shedding data should be collected for VBGT and oncolytic products during preclinical and clinical development and how shedding data can be used to assess the potential for transmission to untreated individuals.
Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant Viral or Microbial Products
The FDA issued this guidance to provide you, investigational new drug application (IND) sponsors and applicants for a biologics license application (BLA) or a supplement to a BLA (BLA supplement), with recommendations on considerations when assessing whether to submit an Environmental Assessment (EA) for gene therapies, vectored vaccines, and related recombinant viral or
microbial products (GTVVs).1 This guidance also contains recommendations as to what information should be included in an EA and what you can expect once an EA is filed. This guidance finalizes the draft guidance of the same title dated June 2014. This guidance also supplements the guidance entitled “Guidance for Industry: Environmental Assessment of Human Drug and Biologics Applications” dated July 1998, (July 27, 1998, 63 FR 40127) (1998 Guidance) and supersedes the recommendations for GTVVs in section IV.B.1 “Assessing Toxicity to Environmental Organisms” in the 1998 Guidance.
Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products
The FDA is issuing this guidance to assist you, establishments making donor eligibility determinations, with complying with the requirements in Title 21 Code of Federal Regulations, part 1271, subpart C (21 CFR part 1271, subpart C) (Ref. 1). The regulations under 21 CFR part 1271, subpart C set out requirements for determining donor-eligibility, including donor screening and testing, for donors of human cells, tissues, and cellular and tissue-based products (HCT/Ps).
The FDA is issuing this guidance to assist you, establishments making donor eligibility determinations, with complying with the requirements in Title 21 Code of Federal Regulations, part 1271, subpart C (21 CFR part 1271, subpart C) (Ref. 1). The regulations under 21 CFR part 1271, subpart C set out requirements for determining donor-eligibility, including donor screening and testing, for donors of human cells, tissues, and cellular and tissue-based products (HCT/Ps).
Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use
FDA has published guidance to human cells, tissues, and cellular and tissue-based product (HCT/P) manufacturers, healthcare providers, and FDA staff, with our current thinking on the criteria under Title 21 of the Code of Federal Regulations (CFR) Part 1271, specifically the 21 CFR 1271.10(a) criterion of minimal manipulation and the 21 CFR 1271.10(a)(2) criterion of homologous use.