Final FDA Guidances on Gene Editing + CAR T-Cell Products Include Society Recommendations

ASGCT recently contributed to positive changes in FDA’s regulation of two genetic therapy modalities. In 2022 the Society commented on two draft guidances that have now been finalized. We are happy to see FDA incorporate many of ASGCT’s recommendations in the final versions of those two guidances: Human Gene Therapy Products Incorporating Human Genome Editing and Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products. 

Human Genome Editing  

This document provides guidance for sponsors who are developing human gene therapy products incorporating genome editing (GE) of human somatic cells. In line with ASGCT's suggestions, FDA made a number of changes to the final guidance:  

• In the opening section of the draft guidance, FDA listed a series of GE technologies that developers might use. ASGCT requested that the final guidance make clear that the list of included technologies is not meant to be comprehensive, so that sponsors aren’t inadvertently discouraged from pursuing new technologies in a rapidly evolving field. FDA edited the section in the final guidance accordingly. 

• ASGCT shared concerns that the draft guidance included overly burdensome and unnecessary recommendations on Chemistry, Manufacturing, and Controls (CMC) for certain GE products. Our comment requested that FDA specify the level of material control needed relative to nature of the materials, frequency of use, and proximity to patients. ASGCT specifically highlighted the case of one-time use plasmids that are differentiated into a Master Cell Bank (MCB), and noted the implication in the draft guidance that “effectively all one-time use plasmids should be made under Good Manufacturing Practices (GMP) for all clinical phases through commercialization, from the very beginning, or the manufacturer risks having to recreate the initial cell, MCB and Working Cell Bank (WCB) at each phase of clinical study as GMP requirements increase.” In the final guidance a new section was added allowing for additional regulatory flexibility for one-time use materials, specifically including MCBs and other starting materials. 

• The section on assessing the activity profile of a GE product was altered in line with ASGCT’s recommendations. The draft noted that sponsors should assess “effects of genetic variation on editing activity across the target population.” ASGCT’s comment pointed out that all drug candidates and approved products can have differential safety and efficacy based on genetic variation, so adding an additional burden of study on GE products specifically would be unwarranted. The line in question was removed in the final guidance. 

• The final guidance includes additional flexibility in the methods sponsors use to identify on- and off-target editing events, in line with ASGCT’s recommendations. The draft specified that those studies should include orthogonal methods and “an unbiased genome-wide analysis…” The Society recommended that sponsors should not be restricted to orthogonal methods, but should have the option to pursue and scientifically justify other approaches. ASGCT also emphasized that no assay is completely unbiased, so calling for one here is inappropriate; in the final guidance, that language is edited to call for “genome-wide analysis… to reduce bias in identification of potential off-target sites.”  

• The final guidance includes significant additional language on the use of surrogate endpoints for GE products, including an explicit statement that the Agency is supportive of accelerated approval for GE products. The draft guidance implied otherwise, which ASGCT strongly objected to.  

CAR T-Cell Products 

This guidance document is focused on ex vivo-manufactured Chimeric antigen receptor (CAR) T cell products, including a lengthy section on CMC. While there are numerous potential uses for CAR Ts, the final guidance specifies that it is meant to apply only for oncology indications. While the final guidance did not change significantly from its draft form, FDA did act on several of ASGCT’s comments:  

• FDA accepted ASGCT's recommendation to remove an unfeasible and clinically irrelevant requirement to evaluate previously administered CAR T cell levels in cellular starting materials. ASGCT noted that if previous CAR cells have an impact on the safety or efficacy of the product, that would be caught as part of existing manufacturing controls.  

• The draft guidance called for vectors to be “well-characterized” prior to the start of clinical trials. ASGCT noted that such a requirement was not aligned with other existing guidance documents. In the final guidance, FDA partially addressed our concern with an edit that says “vector safety and quality should be sufficiently characterized prior to initiation of clinical studies.”   

• FDA also partially addressed ASGCT’s request for regulatory flexibility on specifications and statistical analysis. While language was added noting that different comparability studies may be appropriate at different phases of product development, the final guidance still suggests analysis from sponsors beyond what we believe is necessary to ensure comparability safety and efficacy of an investigational product after a process change. 

• Finally, ASGCT had requested clarity on timelines for communicating with FDA on manufacturing changes. While FDA did not outline a review timeframe in the final CAR T guidance, they did add a note that the issue is likely to be addressed in future guidance.  

ASGCT always appreciates opportunities to engage with FDA and advance the Society’s mission: to advance knowledge, awareness, and education leading to the discovery and clinical application of genetic and cellular therapies to alleviate human disease. We appreciate FDA for thoughtfully considering ASGCT's comments and recommendations.   

Christina is ASGCT's Senior Manager of Government Affairs.

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