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On 28 January 2020, the US FDA released six (6) final guidance documents on Gene Therapy (GT) products.

Two (2) of them provide FDA recommendations on the development of GT products used for the treatment of hemophilia and Retinal Disorders. The other three (3) are more procedural, they provide FDA recommendations on CMC content of IND for GT, development of GT product for rare diseases, long term follow-up after administration of Human Gene Therapy Products, and testing of retroviral vector-based therapies. A summary of each guidance is provided here below.

Human Gene therapy for Hemophilia

  1. 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 pre-clinical considerations to support development of GT products for the treatment of hemophilia.

Human Gene Therapy for Retinal Disorders

2. This guidance provides recommendations to sponsors developing human gene therapy (GT)  products for retinal disorders affecting adult and pediatric patients.  These disorders vary in etiology, prevalence, diagnosis, and management, and include genetic as well as age-related diseases.  These disorders manifest with central or peripheral visual impairment and often with progressive visual loss. 

It focuses on issues specific to GT products for retinal disorders and provides recommendations related to product development, pre-clinical testing, and clinical trial design for such GT products

Human Gene Therapy for Rare Diseases

3. 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, pre-clinical, 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. 

Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)

4. This guidance provides sponsors of human gene therapy Investigational New Drug Applications (INDs), recommendations regarding chemistry, manufacturing, and control (CMC) information submitted in an IND. 

The guidance provides information on required CMC information 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.

Long Term Follow-up After Administration of Human Gene Therapy Products

5. This guidance provides sponsor who are 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 during the clinical study “long term follow-up” (LTFU) and after the clinical study through LTFU observations. 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.

Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up

6. This guidance provides 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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