FDA emphasizes available information in final CAR-T guidance while acknowledging lack of precedent

FDA emphasizes available information in final CAR-T guidance while acknowledging lack of precedent

Amid a high-profile CAR-T safety probe, the FDA has released final industry guidance for developers in the space built on the backbone of available information while simultaneously acknowledging a lack of precedent in the space.

The guidance (PDF) follows a March 2022 draft release that received feedback from industry players such as the Biotech Innovation Organization (BIO), urging (PDF) the FDA to take a closer look at the role of manufacturing processes, refine early-stage trial guidelines and define how the guidelines apply to other therapies beyond CAR-T.

The federal agency responded in the final Jan. 29 edition, noting that while the recommendations specifically focus on CAR-T cell products, much of the guidance can be applied to other genetically modified lymphocyte products, such as CAR natural killer (NK) cells or T cell receptor (TCR) modified T cells.

Throughout the guidance, the FDA also denotes differing specifications for allogenic versus autologous therapies.

The agency recognized the challenging nature of developing, manufacturing and testing CAR-T cells, writing that manufacturing involves “complex multi-step procedures, which are potential sources of variability among product lots.” Because of this variability, the FDA said control of the manufacturing process and appropriate in-process and lot release testing is vital. The agency also underscored the importance of characterization data taken during early studies to inform release criteria used in later development to safeguard consistency.

The recommendations also cover nonclinical testing, which the FDA dubbed as necessary but potentially challenging given “the inherent biological complexity and variability of this product type and the limited availability of suitable animal models to test safety and activity.” Considering those challenges, the FDA recommends a case-by-case testing strategy combined with available nonclinical and clinical knowledge from related products to support use of CAR-T cells in a proposed trial.

Clinical recommendations covered considerations for early-stage oncology trials assessing CAR-Ts, including safety evaluation and monitoring recommendations.

BIO took issue with the draft sentence, “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.” But the FDA kept the wording in the final document, with slight changes to the risk mitigation measures segment.

The biotech organization had argued that the word “establish” gave too much weight to the early trials given the complexity and novelty of the products and often small patient populations. Instead, BIO asked the FDA to soften the wording by adding “begin to establish,” particularly when referring to product safety or optimal dosing—an ask the federal agency did not acquiesce to.

The FDA recommended using a detailed monitoring plan based on available information to protect patient safety. For products with limited prior human experience available, the FDA suggests staggered enrollment to minimize the possibility of patient exposure to unacceptable toxicities.

The agency also included examples of appropriate stopping rules—criteria for halting a study based on the incidence of certain adverse events (AEs)—such as a jump in expected severe AEs, unexpected severe AEs or any death within 30 days after CAR-T cell administration.

The safety recommendations come amid a months-long agency investigation into the risk of patients developing secondary T-cell cancers after receiving a CAR-T drug. By the end of 2023, the FDA had recorded 22 cases of T-cell cancers following treatment with a CAR-T product, with about a third of those cases still under investigation as of last week. CAR insertion, which indicates a possible contribution from the CAR-T therapy, was detected in the malignant clone in each of the three cases for which genetic sequencing was performed.

The FDA also released final gene editing guidelines specifically targeting the best safety and quality processes when undergoing the Investigational New Drug application process for investigational gene therapy products. The guidance follows draft documents posted in March 2022, recommendations the industry found par for the course.

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