April 14, 2026 —
The U.S. Food and Drug Administration has released new draft guidance outlining how sponsors can apply next-generation sequencing (NGS) technologies in nonclinical studies to evaluate safety risks associated with gene therapy and genome editing products. The guidance is intended to support regulatory submissions, including investigational new drug (IND) applications and biologics license applications (BLAs).
Developed by the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research, the document builds on earlier 2024 guidance addressing development considerations for human gene therapies incorporating genome editing. The agency emphasizes that development programs must account not only for risks related to the gene therapy product itself, but also for genome editing–specific risks such as off-target modifications and unintended genomic alterations.
The draft guidance highlights that genome editing approaches—whether applied ex vivo or in vivo using mRNA or DNA-based delivery systems—carry inherent risks, including unintended edits and chromosomal rearrangements that may disrupt normal cellular function. As a result, the FDA recommends comprehensive analytical strategies to assess off-target editing events and evaluate genomic integrity.
Central to this framework is the use of appropriate NGS methodologies. The agency advises sponsors to align sequencing strategies with the type of genomic changes being assessed. Short-read sequencing may be sufficient for detecting small DNA modifications, while long-read sequencing technologies may be necessary to characterize larger structural changes. Additionally, sufficient sequencing depth and input material are required to detect low-frequency off-target events, which often occur at rates below intended edits.
Sponsors are also encouraged to provide supporting data demonstrating the sensitivity and adequacy of their sequencing approaches, including in-house validation data or evidence from peer-reviewed literature. The guidance further suggests the use of targeted sequencing or genome-wide NGS approaches to detect rare chromosomal translocations and quantify associated risks.
Overall, the FDA’s guidance reflects a continued push to integrate advanced genomic technologies into regulatory science, providing a clearer pathway for developers to evaluate safety and advance innovative gene and genome editing therapies.
