FDA Issues Draft Guidance on CAR T-Cell Development and Study Design

The FDA has issued a draft guidance related to the development of new chimeric antigen receptor (CAR) T-cell therapy products to provide clarity on special requirements for development, study design, and investigational new drug (IND) applications to improve safety for CAR T-cell products.

The guidance from the FDA includes recommendations for preclinical and clinical study development as well as for chemistry, manufacturing, and control (CMC) elements. These recommendations outline how developers, manufacturers, and clinical trial designers for CAR T cell products can ensure safety and comply with FDA requirements for approval.

“We recognize that the development, manufacture, testing, and clinical assessment of CAR T cells is challenging. Careful design and appropriate testing of the CAR transgene and delivery vector are critical to product safety, specificity, and function,” the FDA stated in the draft guidance.1

The recommendations for preclinical development emphasized the main components of CAR T-cell products that must be investigated for safety and efficacy. They also described additional components that product may include in the transgene, including suicide genes, detection/selection genes, or immunomodulatory elements.

For early-phase clinical trials, a primary objective should be safety assessment; other objectives include dosage, pharmacokinetics, and evidence of clinical activity or efficacy. Study design must include plans for cytokine release syndrome (CRS) monitoring and management since CRS is the most significant and dangerous CAR T cell-related adverse event.

Long-term follow-up is also advised, especially for integrated vectors that may persist. In addition to the vector type, the disease type and the persistence of the CAR T cells should be considered. For studies using integrated vectors, the FDA recommends 15 years of follow-up.

Special planning is required for studies of allogeneic cell products due to the need for immunological matching of the donor and recipient and the risk of graft-vs-host disease (GVHD). Dose management and study stopping plans should incorporate GVHD as a concern.

The CMC guidance also discussed recommendations for ensuring safety in manufacturing CAR T cell products. Biological vectors should not have additional transgene expression and are unlikely to have immunogenic effects that could harm patients, taking into account that animal models may not accurately predict human antigen responses.

Reagents and other biological agents need to be monitored for quality and safety and sourced from reliable locations to avoid contamination. Manufacturers are advised to use vendor qualification programs and certificates to ensure quality, safety, and potency of ancillary materials used for CAR T-cell production.

The FDA recommends that assays are designed in early stages of CAR T cell development and a variety of assays are used. “Validation of analytical procedures is usually not required for IND submissions for phase 1 studies; however, we recommend providing information that demonstrates appropriate control of the test methods,” the draft guidance stated. Changes to assays should be accompanied by a risk assessment.

The FDA advises that changes may be made to the CAR T cell product during development, but changes to the CAR construct or changing from an autologous to allogeneic cell-based product would require a new IND application. For this reason, comparability assessments and risk assessments should be considered for any significant changes to the product.

While nonbinding, these recommendations represent the position of the FDA and may impact the approval process of CAR T cell products. The FDA stated that some of its recommendations may also be applicable to similar products such as CAR Natural Killer cells or T cell receptor–modified T cells in addition to CAR T-cell therapy.

_Reference:

_{1. Considerations for the development of chimeric antigen receptor (CAR) T cell products. FDA. Published March 15, 2022. Accessed March 18, 2022. https://bit.ly/3wfNMKj}