Yesterday (January 29), the U.S. Food and Drug Administration (FDA) finalized two guidance documents to help biopharmaceutical companies accelerate approvals: one is gene-edited genes**, and the other is CAR-T cell products manufactured in vitro.
The final 19-page version of the genome editing guidance clearly illustrates the FDA's support for the use of accelerated approval, as previously signaled by the FDA** such as Peter Marks: that the FDA supports the use of accelerated approval for GE's "gene editing" products and encourages manufacturers to discuss the potential eligibility of GE products for such programs early in clinical trial development, including proposed surrogate endpoints or intermediate clinical endpoints.
The differences between the March 2022 draft and the final version also include the clarification of recommendations for single-use gene-edited components (e.g., "the degree of information and detection of transgenic components may be reduced" when manufacturing master cell banks), which is an expectation based on results analysis and not a consideration for non-clinical studies with the toxicity potential of the target.
At the same time, the 36-page final guide to CAR-T** development provides specific recommendations on chemical manufacturing and control, pharmacology and toxicology, and clinical study design.
Changes to the March 2022 draft include clarifying the scope of the guidelines, increasing focus on cancer indications, recommendations for the production of cell naïve material from patients who have previously received CAR-T cells, details of the potency of CAR-T cells expressing multiple genetic elements, stability studies, and clinical monitoring.
While these recommendations are specific to CAR-T cell products, most of the guidelines 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 guidelines, the FDA also labels and distinguishes differently between allogeneic and autologous **.
Recognizing the difficulty of developing, producing, and testing CAR-T cells, the FDA wrote in the guidance that the manufacturing process involves "complex multi-step procedures that may be potential for variability between different batches of product."
Given this variability, the FDA says control of the production process and proper intermediate process testing and batch release testing are critical. In addition, FDA emphasizes the importance of characterization data obtained in the early stages of research that is used to guide release criteria in subsequent development phases to ensure consistency.
The recommendations in the guidelines also include a non-clinical trial component, which FDA believes is necessary, but can be challenging due to the inherent biological complexity and variability of such products, as well as the limited availability of suitable animal models for testing safety and activity. With these challenges in mind, the FDA recommends a case-by-case testing strategy, combined with existing non-clinical and clinical knowledge of the product in question, to support the use of CAR-T cells in the proposed trial.
Clinical recommendations cover considerations for early oncology trials evaluating CAR-T**, including safety assessment and monitoring recommendations.
The BIO organization commented on a sentence in the draft: "Well-designed early clinical studies are critical to establishing the safety of the product, the effectiveness of risk mitigation measures, the dose-response relationship, the optimal dose difference based on indication differences, preliminary evidence of efficacy, and manufacturing feasibility." But the FDA kept that phrase in the final document, with only minor adjustments to the risk mitigation section.
The FDA also provides some examples of appropriate clinical trial discontinuation—criteria for discontinuing a study based on the incidence of certain adverse events (AES), such as an expected significant increase in severe AES, an unexpectedly severe AES, or any death within 30 days of CAR-T cell administration.
These safety recommendations were made during months of investigation into the possibility of patients developing secondary T-cell carcinoma after receiving CAR-T drugs**. As of the end of 2023, the FDA recorded 22 cases of T-cell carcinoma after receiving CAR-T products**, with about one-third of those cases still under investigation as of last week. CAR insertion was detected in all three cases of malignant clones performed for gene sequencing, suggesting that CAR-T** may be a potential causative factor.