FDA drafts guidance on genome editing, CAR T cell therapies

Regulatory NewsRegulatory News | 16 March 2022 |  By 

The US Food and Drug Administration (FDA) has issued two draft guidances addressing the development of human gene therapy products that incorporate genome editing of human somatic cells and chimeric antigen receptor (CAR) T cell products.
Incorporating genome editing
In the draft guidance on human gene therapy products that incorporate human genome editing, FDA offers recommendations on the information that should be included in an investigational new drug (IND) application. The draft guidance, issued on 15 March by FDA’s Center for Biologics Evaluation and Research (CBER), provides information on component design, component manufacture and testing, product manufacture and testing, and preclinical and clinical studies.
“FDA evaluates human [genome editing] products using a science-based approach weighing the benefits and risks of each product,” the agency wrote. “The benefit-risk profile for each product depends on the proposed indication and patient population, the extent and duration of therapeutic benefit achieved, and the availability of alternative therapeutic options. Some of the specific risks associated with [genome editing] approaches include off-target editing, unintended consequences of on- and off-target editing, and the unknown long term effects of on- and off-target editing.”
FDA recommends that product sponsors use a design platform that is most applicable to their genomic target and the type of intended modification. The IND should include a description of the design and screening processes and a rationale for that approach. FDA also recommends that the IND include the sequences of the genome editing components. “We recommend sponsors optimize the [genome editing] components to reduce the potential for off-target genome modification, to the extent possible,” according to the draft guidance.
Genome editing components can be administered in vivo or used to modify cells ex vivo. When components are administered in vivo in the form of DNA, RNA, and/or protein via nanoparticles, FDA considers the genome editing components to be the active pharmaceutical ingredients or drug substances. When in its final formulation for in vivo administration, a genome editing component is generally considered a drug product, FDA wrote. If the genome editing component is used to modify cells ex vivo, the component quality is considered “critical” for the manufacture of the final product.
The IND should contain a detailed description of the manufacturing process, the testing plan, and the analytical procedures used for testing. The draft guidance spells out the specific manufacturing and testing data needed for each type of genome editing product.
For preclinical studies, the draft guidance recommends performing in vitro and in vivo proof of concept studies to establish feasibility and support the scientific rationale for the product in a clinical trial. FDA also recommends preclinical safety studies that can identify potential risks associated with the administration of the product. Finally, the agency recommends biodistribution studies, which can provide information on the extent of editing activity in target and non-target tissues.
In clinical studies, the goal for sponsors should be to address risk from the product itself, as well as risks associated with on- and off-target editing associated with the genome editing. Clinical trial design should include appropriate patient selection, an efficient and safe approach to administration (such as data-based dosing), adequate safety monitoring, appropriate endpoints, and long-term safety follow-up of at least 15 years after first administration.
CAR T cell product development
In the draft guidance issued on CAR T cell product development, FDA offers insights on chemistry, manufacturing and control (CMC) elements; pharmacology and toxicology; clinical study design; and recommendations that are specific to autologous or allogeneic CAR T cell products.
“The emphasis for CMC in all phases of development is product safety and manufacturing control,” FDA stated in the newly issued draft guidance. “We recommend that CAR T cells be developed following a life cycle approach where information may be gathered over the course of product development and submitted in a stage-appropriate manner.”
FDA noted that sponsors will make changes to the CAR T cell design and manufacturing process or the manufacturing facility during development or after approval. However, changes that involve the CAR construct or changing from an autologous to an allogeneic product would generally result in a new product that would need to be submitted via a new IND. Each change is assessed on “case-by-case basis” and should be communicated with the agency through an IND amendment requesting advice or a formal meeting request.
The guidance also outlines preclinical testing considerations for the vector component and the cellular component of CAR T cell, as well as in vivo testing, and the additional tests that may be needed for CAR T cells with modifications. “CAR T cells can include additional components in the transgene, such as suicide genes, detection/selection genes, or immunomodulatory elements. Gene editing or gene silencing techniques may also be used to modify the CAR T cells to reduce immunogenicity (e.g., for allogeneic CAR T cells) or increase activity or persistence,” FDA wrote. “Additional preclinical testing may be needed for novel accessory molecules and genetic modifications to evaluate functionality of the specific elements and safety of the investigational product. 
The draft guidance also offers considerations for the early-phase clinical development of CAR T cells in patients with cancer. The objective of this early clinical testing should include safety, determination of optimal dosage, pharmacokinetic/pharmacodynamic studies, evaluation of efficacy, and selection an appropriate population for later further clinical studies, according to FDA.
Draft guidance on human gene editing products

Draft guidance on CAR T cell products


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