CAR T-Cell Development Considerations Guide
FDA has posted a guidance entitled “Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products.” The document provides recommendations regarding chemistry, manufacturing, and control, pharmacology and toxicology, and clinical study designs for oncology indications (including hematologic malignancies and solid tumors). It also provides recommendations for analytical comparability studies for CAR T cell products.
The agency notes that while the guidance focuses on CAR T cell products, some of the information and recommendations provided may apply to other genetically modified lymphocyte products, such as CAR Natural Killer cells or T cell receptor-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,” the guidance says.
FDA’s guidance also acknowledges the challenges related to the development, manufacture, testing, and clinical assessment of CAR T cells. “Careful design and appropriate testing of the CAR transgene and delivery vector are critical to product safety, specificity, and function,” it says. “CAR T cell manufacturing involves multiple biological materials and complex multi-step procedures, which are potential sources of variability among product lots. Thus, control of the manufacturing process and appropriate in-process and lot release testing are crucial to ensure CAR T cell safety, quality, and lot-to-lot consistency.”
Additionally, the agency notes that changes to the manufacturing process are common during product development. “It is essential to understand the effects of such changes on product quality,” it says. “Comprehensive product characterization studies are valuable for identifying relevant critical quality attributes (CQAs) that can be assessed during manufacture, at lot release, and in comparability and stability studies to assure safety and efficacy. Critical process parameters (CPPs) can then be established through process qualification, to ensure consistent CQAs for every manufactured batch.”
Regarding nonclinical testing of CAR T cells, the guidance says this too 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. 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. Well-designed early-phase clinical studies are critical to establish safety of the product, adequacy of risk mitigation measures, dose-response relationship, differences in optimal dose based on differences in indication, preliminary evidence of efficacy, and feasibility of manufacturing.”