FDA Announces Draft Guidances on Genome Editing and CAR T Cell Therapy

The US Food and Drug Administration (FDA) has recently issued two draft guidances addressing the development of gene editing and chimeric antigen receptor (CAR) T cell products. The draft for gene editing provides recommendations on the information that should be provided in investigational new drug (IND) applications for genetic products, including those related to product design, product manufacturing, product testing, preclinical safety assessment, and clinical trial design, while the draft for CAR T cell therapy provides specific recommendations on chemistry, manufacturing and controls (CMC), pharmacology and toxicology, as well as clinical study design regarding CAR T cells. These guidances are also applicable to other transgenic lymphocyte products such as CAR natural killer (NK) cells or T cell receptor (TCR) modified T cells.

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Recommendations for Preclinical and Clinical Studies in the Draft for Gene Editing

In the released document for the draft guidance on gene editing, the FDA states that the benefit-risk profile of each product depends on the proposed indication and patient population, the extent and duration of treatment benefit obtained, and the availability of alternative treatment options. Some specific risks associated with genome editing approaches include off-target editing, unintended consequences of off-target editing, and unknown long-term effects of off-target editing. The guidelines also recommended developers optimize gene-editing components to minimize the possibility of off-target gene modifications.

For preclinical studies, the draft guidance recommends conducting in vitro and in vivo verification of concepts to determine their feasibility and support the scientific basis for the products in clinical trials. Also, preclinical safety studies should be carried out to identify potential risks associated with product administration. In addition, biodistribution studies are one of the suggested ways to provide information on the extent of editing activity in target and non-target tissues. 

FDA believes that the goal of a clinical study should be to address the risks of the product itself, as well as the risks associated with gene editing on the target sequence and off-target editing. The design of a clinical trial should include appropriate patient selection, effective and safe methods of administration (e.g., data-driven dosing), adequate safety monitoring, a proper endpoint, and a long-term safety follow-up of at least 15 years after the initial dose.

Advice on Early Clinical Development of Cancer Treatments

Concerning the draft guidance on CAR T cell therapy, FDA suggests a life-cycle approach to product development, where data can be collected during the process and submitted in a stage-specific manner. FDA points out that applicants can modify the design and manufacturing process or manufacturing facilities for CAR T cells during development or after regulatory approval. However, any modifications involving changes to the structure of the CARs or conversion from an autologous product to an allogeneic product will generally result in the need for submission through a new IND. Each change will be evaluated on a case-by-case basis and should be discussed with the FDA through an IND amendment request or a formal meeting.

The guidance also outlines considerations for preclinical testing of carrier components and cellular components of CAR T cells, as well as in vivo testing. CAR T cells may contain additional components such as suicide genes, detection/selection genes, or immunomodulatory elements in transgenes. Gene editing or gene silencing techniques can also be used to modify CAR T cells to reduce immunogenicity (e.g., for allogeneic CAR T cells) or to increase activity and persistence. New complementary molecules and genetic modifications may require additional preclinical testing to assess the function of specific elements and to examine the safety of the products.

The draft guidance also gives recommendations for early clinical development of CAR T cells for cancer patients. Objectives of the trial should include safety, determination of optimum dose, pharmacokinetic/pharmacodynamic studies, evaluation of efficacy, and selection of appropriate populations for subsequent clinical studies.

Written by Ula Yang/ Translated by Richard Chau

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