FDA finalizes guidance on developing, manufacturing CAR T therapies

The US Food and Drug Administration (FDA) outlined its thinking on what sponsors should consider when submitting premarket applications for chimeric antigen receptor (CAR) T cell products, including recommendations for its non-clinical, clinical, and manufacturing expectations.

The guidance finalizes the agency’s draft version released for comment in March 2022. It also goes into specific expectations depending on whether the CAR T product is derived from autologous or allogeneic cells and provides recommendations on how to conduct analytical comparability studies. (RELATED: FDA drafts guidance on genome editing, CAR T cell therapies, Regulatory Focus 16 March 2022)

“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,” said FDA. “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),” the agency added.

Due to the complexity of CAR T products, FDA acknowledges that their development, manufacture, testing, and clinical assessment may be especially challenging, which requires some extra considerations. The agency said that manufacturing the products requires multiple biological materials and complex multi-step procedures, that can lead to significant variabilities between the different lots of products.

To address such manufacturing complexities, FDA said that it is essential to understand how manufacturing changes can affect the product quality and added that product characterization studies are useful to identify critical quality attributes (CQA). The agency added that critical process parameters (CPPs) can be established by sponsors to ensure that CQAs for every batch of product is consistent.

FDA also points to its January 2020 guidance entitled “Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)” as another good source of information to understand its expectations for gene therapy manufacturing and testing.

FDA noted the challenge posed by non-clinical evaluations of CAR T products, which are necessary for sponsors to move forward with clinical testing.

“Nonclinical testing of CAR T cells can be challenging due to the inherent biological complexity and variability of this product type and the limited availability of suitable animal models to test safety and activity,” said the agency. “A case-by-case nonclinical testing strategy should be applied using in vitro, in silico, and in vivo testing strategies, as appropriate, in conjunction with available nonclinical and clinical data from related products to support use of CAR T cells in a proposed clinical trial.”

Finally, FDA noted that early-phase clinical studies are critical to understanding whether a product is suitable for later-stage trials and manufacturing. The agency said early-stage trials can help it understand several factors, including whether risk mitigation measures are adequate, dose-response relationships are well-established, and how feasible it is to manufacture the products.

“For autologous CAR T cells, early-phase studies also provide information on how long it will take to manufacture the product and whether bridging therapy will or will not be used as an attempt to control the active disease while subjects wait for the CAR T cell treatment,” said FDA. “For allogeneic CAR T cells, early-phase studies can be informative with regards to the risks of graft versus host disease (GVHD).”

“Information gained from these early-phase studies support the development of CAR T cells in later-phase clinical studies and may expedite the clinical development of CAR T cells,” the agency added.

CAR T final guidance

FDA finalizes guidance on developing, manufacturing CAR T therapies

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