Comment from Christopher Freeman
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Summary: Christopher Freeman supports the FDA's efforts to establish a rigorous framework for genome editing safety but argues that the guidance should be more flexible for rare and ultra-rare diseases. He recommends a "fit-for-purpose" approach that accounts for limited biological samples, emphasizes non-animal methods, and prioritizes the functional relevance of off-target findings over simple enumeration.
I appreciate the opportunity to comment on FDA-2026-D-1255, Safety Assessment of Genome Editing in Human Gene Therapy Products Using Next-Generation Sequencing. I support the Agency’s efforts to establish a rigorous and science-based framework for evaluating off-target editing and genomic integrity. At the same time, we encourage FDA to ensure that this framework is sufficiently flexible to accommodate the realities of rare and ultra-rare disease development, including conditions such as POLG-related disorders. In these settings, limitations in biological samples, disease-relevant models, and clinical data availability make it challenging to meet uniformly high expectations for replication, sequencing depth, and exhaustive off-target characterization. I recommend that FDA explicitly adopt a fit-for-purpose, context-driven approach that aligns safety expectations with disease severity, feasibility constraints, and the totality of available evidence.
I further recommend that the guidance more clearly incorporate the role of non-animal methods (NAMs), including patient-derived iPSC and organoid models, as primary tools for off-target assessment, and that it emphasize interpretation of functional and clinical relevance rather than enumeration of off-target events alone. Additional clarification is also needed regarding emerging large-payload genome editing technologies, integration with the Plausible Mechanism Framework, and the use of iterative, lifecycle-based safety assessment strategies. We have provided detailed comments and specific recommendations in the attached document and appreciate FDA’s consideration of these points as it finalizes the guidance.