The FDA has released a draft guidance on the safety assessment of gene editing as part of the agency’s framework for accelerating the development of therapies for ultra-rare diseases. The April 2026 draft guidance emphasizes the need for next-generation sequencing (NGS) to conduct these assessments, which will be used to evaluate a therapy for off-target gene editing effects.
The FDA announced the guidance in an April 14 press release urging developers of gene editing therapies to engage the agency early in the development process. FDA commissioner Marty Makary said the final version of the guidance will provide sponsors with clear, scientifically grounded recommendations for evaluating a gene editing therapy’s off-target editing risk with the aid of NGS systems. Makary emphasized the importance of gene therapies in the agency’s efforts to improve the prospects for these patients by stating, “we are serious about moving this ball forward.”
The FDA’s Center for Biologics Evaluation and Research issued the guidance with a 90-day comment period, which is scheduled to end July 14, 2026. The guidance addresses non-clinical studies that will be important in obtaining FDA approval for clinical trials for these therapies. The FDA said the draft guidance is complementary to the January 2024 final guidance for human gene therapy products that employ gene editing. The scope of the January 2024 guidance includes several gene editing technologies, including but not limited to CRISPR-Cas9, and addresses both ex vivo and in vivo genome modification.
The April 2026 draft guidance states that recent advances in the field of gene editing have led to the development of technologies that can also modify the epigenome or cleave sequences of RNA. Consequently, the scope of the guidance includes any therapeutic developments that act on the epigenome or the RNA transcriptome. The FDA acknowledged that sponsors already use NGS-based methods to assess off-target effects, and hence the guidance would not seem to signal a significant additional uptake of sequencing equipment. Nonetheless, several sources predict double-digit compound annual growth rates for NGS sales over the next eight to 10 years.
Sponsors can use sequencing to evaluate only short stretches of DNA base pairs if the developmental therapy’s target is captured entirely within a limited number of pairs. Conversely, the FDA indicated it would expect to see sequencing for longer series of pairs when the large insertions or deletions are the target of the therapy.
The guidance states that the amount of input material can be adjusted to allow detection of off-target editing events at a lower frequency or edit rate than the on-target rate. Sponsors can rely to some extent on relevant information from peer-review journals to corroborate the presumed frequency of off-target events, although in-house testing may be required to characterize the rate of events presumed to occur at a low rate.
In some instances, the FDA will expect to see confirmatory testing for the results of the NGS analysis of the gene therapy’s safety profile, although sponsors will have several options. Among these are probe-based sequence enrichment and targeted sequence amplification, but the draft guidance states that the sponsor may not be required to conduct confirmatory testing for each off-target site. CBER director Vinay Prasad said in the FDA press release that the final version of the guidance will provide a roadmap for comprehensive gene therapy safety assessment as part of an effort to “work collaboratively with the scientific community” to bring gene editing therapies to the patients who are most at need.
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