The FDA released draft guidance focused on using next-generation sequencing and bioinformatics to evaluate safety for genome-edited gene therapy products. The document centers on nonclinical studies designed to assess off-target editing risk and loss of genome integrity before investigators move into human trials and, later, biologics license applications. The agency describes how sponsors can build sequencing strategies into safety packages and submit the resulting data as part of INDs, aiming for more standardized methods across programs. The guidance also aligns with the FDA’s broader frameworks for accelerating development of individualized therapies for ultra-rare diseases and prior gene therapy guidance. Regulators are signaling that the sequencing approach should be tailored to the types of edits and the lengths of DNA segments involved—for example, short on- and off-target changes may support a short-read strategy—while maintaining a risk-minimization focus. For biotech teams, the guidance effectively raises the bar for how gene-editing programs will demonstrate genomic safety using measurable, reportable NGS workflows that can withstand regulatory review.