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Docket Number: FDA-2021-D-0398 Issued by: Center for Biologics Evaluation and Research In this guidance, we, FDA, are providing recommendations to sponsors developing human gene therapy products incorporating genome editing (GE) of human somatic cells. Specifically, this guidance provides recommendations regarding information that should be provided in an Investigational New Drug (IND) application in order to assess the safety and quality of the investigational GE product, as required in Title 21 of the Code of Federal Regulations 312.23 (21 CFR 312.23). This includes information on product design, product manufacturing and testing, nonclinical safety assessment, and clinical trial design. The FDA Center for Biologics Evaluation and Research (CBER) Office of Therapeutic Products (OTP) hosted a virtual public webinar on Thursday, February 29 at 1:00 p.m. to highlight key considerations in the final guidance.

Docket Number: FDA-2021-D-0404 Issued by: Center for Biologics Evaluation and Research Chimeric antigen receptor (CAR) T cell products are human gene therapy products in which the T cell specificity is genetically modified to enable recognition of a desired target antigen for therapeutic purposes. This guidance is intended to assist sponsors, including industry and academic sponsors, developing CAR T cell products. In this guidance, we, FDA, provide CAR T cell specific recommendations regarding chemistry, manufacturing, and control (CMC), pharmacology and toxicology, and clinical study design. Recommendations specific to autologous or allogeneic CAR T cell products are noted in this guidance. This guidance also provides recommendations for analytical comparability studies for CAR T cell products. While this guidance specifically focuses on CAR T cell products, much of the information and recommendations provided will also be applicable to other genetically modified lymphocyte products, such as CAR Natural Killer (NK) cells or T cell receptor (TCR) modified T cells. These related product types can be highly specialized, and in many cases, considerations beyond those recommended in this guidance would depend on the specific product and manufacturing process. To discuss considerations specific to these related products, we recommend sponsors communicate with the Office of Tissues and Advanced Therapies (OTAT) in the Center for Biologics Evaluation and Research (CBER) before submitting an Investigational New Drug Application (IND) (e.g., by requesting a pre-IND meeting (Ref. 1)).

On December 28, 2023, FDA announced the availability of the draft guidance, Potency Assurance for Cellular and Gene Therapy Products. For a high-level overview of this guidance document, please view this recorded webinarExternal Link Disclaimer featuring Dr. Matthew Klinker, Cell Therapy Branch 2 Chief, Office of Cellular Therapy and Human Tissues, Office of Therapeutic Products, CBER. This draft guidance provides recommendations for developing a science- and risk-based strategy to help assure the potency of a human cellular therapy or gene therapy (CGT) product. A potency assurance strategy is a multifaceted approach that reduces risks to the potency of a product through manufacturing process design, manufacturing process control, material control, in-process testing, and potency lot release assays. The goal of a potency assurance strategy is to ensure that every lot of a product released will have the specific ability or capacity to achieve the intended therapeutic effect.

On August 24, 2023, FDA Announced the comment period for the draft guidance, Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products will be extended to November 13, 2023. For a high-level overview of this guidance document, please view this recorded webinarExternal Link Disclaimer featuring Dr. Andrew Byrnes, Gene Transfer & Immunogenicity Branch Chief, Office of Gene Therapy CMC, Office of Therapeutic Products, CBER. The management of manufacturing changes presents many challenges for human cellular therapy or gene therapy (CGT) products due to the complexity of these products. We, FDA, are providing you, sponsors of Investigational New Drug Applications (INDs) and applicants of Biologics License Applications (BLAs) for CGT products, with recommendations regarding product comparability and the management of manufacturing changes for investigational and licensed CGT products. The purpose of this guidance is to provide FDA’s current thinking on 1) management and reporting of manufacturing changes for CGT products based on a lifecycle approach, and 2) comparability studies to assess the effect of manufacturing changes on product quality.

Docket Number: FDA-2021-D-0776 Issued by: Center for Biologics Evaluation and Research The purpose of this guidance is to provide recommendations to sponsors interested in studying multiple versions of a cellular or gene therapy product in an early-phase clinical trial for a single disease. Sponsors have expressed interest in gathering preliminary evidence of safety and activity using multiple versions of a cellular or gene therapy product in a single clinical trial. Although multiple versions of a product can be studied together in a single clinical trial, each version of the product is distinct and is generally submitted to FDA in a separate investigational new drug application (IND). The objective of these early-phase clinical studies is to guide which version(s) of the product to pursue for further development in later-phase studies. Thus, these studies are not intended to provide primary evidence of effectiveness to support a marketing application and generally are not adequately powered to demonstrate a statistically significant difference in efficacy between the study arms. In this guidance, we, FDA, provide recommendations for studies that evaluate multiple versions of a cellular or gene therapy product, including how to organize and structure the INDs, submit new information, and report adverse events. This guidance finalizes the draft guidance of the same title dated September 2021.

Docket Number: FDA-2020-D-2101 Issued by: Center for Biologics Evaluation and Research This guidance provides recommendations to sponsors developing human gene therapy (GT) products for neurodegenerative diseases affecting adult and pediatric patients. Neurodegenerative diseases are a heterogeneous group of disorders characterized by progressive degeneration of the structure and function of the central nervous system or peripheral nervous system. These diseases vary in etiology, prevalence, diagnosis, and management, and include genetic as well as age-related diseases. This guidance focuses on considerations for product development, preclinical testing, and clinical trial design. This guidance finalizes the draft guidance of the same title dated January 2021.

Docket Number: FDA-2019-D-5392 Issued by: Center for Biologics Evaluation and Research Office of the Commissioner, Office of Clinical Policy and Programs, Office of Orphan Products Development This guidance provides FDA’s current thinking on determining sameness of human gene therapy products under FDA’s orphan drug regulations for the purpose of orphan-drug designation and orphan-drug exclusivity. This guidance is intended to assist stakeholders, including industry and academic sponsors who seek orphan-drug designation and orphan-drug exclusivity, in the development of gene therapies for rare diseases. This guidance focuses specifically on factors that FDA generally intends to consider when determining sameness for gene therapy products and does not address sameness determinations for other types of products. This guidance finalizes the draft guidance of the same title dated January 2020.

Docket Number: FDA-2020-D-1137 Issued by: Center for Biologics Evaluation and Research FDA plays a critical role in protecting the United States from threats such as emerging infectious diseases, including the Coronavirus Disease 2019 (COVID-19) pandemic. FDA is committed to providing timely guidance to support response efforts to this pandemic. FDA is issuing this guidance to provide manufacturers of licensed and investigational cellular therapy and gene therapy (CGT) products with risk-based recommendations to minimize potential transmission of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This guidance is intended to supplement the recommendations to drug and biological product manufacturers provided in FDA’s “Good Manufacturing Practice Considerations for Responding to COVID-19 Infection in Employees in Drug and Biological Products Manufacturing; Guidance for Industry” issued in June 2020 (Ref. 1) (June 2020 GMP Guidance). The recommendations in this guidance specifically consider the source material (cells and/or tissues) recovered from donors and how the CGT product will be manufactured (e.g., cell expansion in culture, viral reduction steps, formulation).

Docket Number: 2008-D-0205 Issued by: Center for Biologics Evaluation and Research 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. We, FDA, are providing you, 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.

Docket Number: FDA-2018-D-2173 Issued by: Center for Biologics Evaluation and Research We, FDA, are providing you, a sponsor who is developing a human gene therapy product (GT Product), recommendations regarding the design of long term follow-up studies (LTFU observations) for the collection of data on delayed adverse events following administration of a GT product. Often, GT products are designed to achieve therapeutic effect through permanent or long-acting changes in the human body. As a result of long term exposure to an investigational GT product, study subjects may be at increased risk of undesirable and unpredictable outcomes that may present as delayed adverse event(s). To understand and mitigate the risk of a delayed adverse event, subjects in gene therapy trials may be monitored for an extended period of time, which is commonly referred to as the “long term follow-up” (LTFU) period (of a clinical study). LTFU observations are extended assessments that continue some of the scheduled observations of a clinical trial past the active follow-up period, and are an integral portion of the study of some investigational GT products. LTFU observations are important to monitor long term safety of GT products. For GT products that present long term risks to subjects, LTFU/surveillance plan(s) should also be put in place post-licensure for monitoring of delayed adverse events (for details we refer you to section VI. of this document). Not all GT products will require LTFU observations; a risk assessment should be performed by a sponsor based on several factors as outlined in this guidance.

Docket Number: FDA-1999-D-0081 Issued by: Center for Biologics Evaluation and Research The potential pathogenicity of replication competent retrovirus (RCR) requires vigilant testing to exclude the presence of RCR in vector-based human gene therapy products (Ref. 1). We, the FDA, are 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.

Docket Number: FDA 2018-D-2238 Issued by: Center for Biologics Evaluation and Research This guidance provides recommendations to sponsors developing human gene therapy (GT) products for the treatment of hemophilia including clinical trial design and related development of coagulation factor VIII (hemophilia A) and IX (hemophilia B) activity assays, including how to address discrepancies in factor VIII and factor IX activity assays. This guidance also includes recommendations regarding preclinical considerations to support development of GT products for the treatment of hemophilia. Additional clinical and preclinical recommendations are available in other guidances (Refs. 1 and 2). This guidance does not provide recommendations for products for the treatment of hemophilia C (factor XI deficiency) or for the treatment of any bleeding disorders other than hemophilia A and B, because of the unique nature of those bleeding disorders. This guidance finalizes the draft guidance of the same title dated July 2018.

Docket Number: FDA-2018-D-2258 Issued by: Center for Biologics Evaluation and Research This guidance provides recommendations to sponsors developing human gene therapy (GT) products intended to treat a rare disease in adult and/or pediatric patients regarding the manufacturing, preclinical, and clinical trial design issues for all phases of the clinical development program. Such information is intended to assist sponsors in designing clinical development programs for such products, where there may be limited study population size and potential feasibility and safety issues, as well as issues relating to the interpretability of bioactivity/efficacy outcomes that may be unique to rare diseases or to the nature of the GT product itself. This guidance finalizes the draft guidance of the same title dated July 2018.