July 17, 2026 —
The pharmaceutical industry has broadly supported the U.S. Food and Drug Administration’s draft guidance on using next-generation sequencing, or NGS, to assess the safety of investigational human genome editing therapies. However, industry groups have requested additional clarity on off-target editing analysis, site nomination methods, and expectations following manufacturing changes.
The FDA released the draft guidance in April 2026. It focuses on NGS-based methods used in nonclinical studies to support the initiation of clinical trials for investigational human genome editing products. The agency received more than 30 comments by the submission deadline.
Industry groups including the Biotechnology Innovation Organization, or BIO, the Pharmaceutical Research and Manufacturers of America, or PhRMA, and Eli Lilly welcomed the guidance as an important step toward a more predictable and science-based regulatory framework for genome editing therapies.
PhRMA said the draft guidance provides valuable recommendations on applying NGS technologies to evaluate potential off-target editing and genome integrity risks. BIO also supported the FDA’s risk-based approach, noting that the guidance provides direction on sequencing modality selection, bioinformatics transparency, variant-aware analysis, and chromosomal integrity assessment.
A key area of requested clarification relates to off-target editing analysis for in vivo genome editing products. The guidance recommends using cell types representative of the intended target tissue and editing conditions that achieve the intended on-target editing rate. If appropriate cells are unavailable or difficult to use in vitro, sponsors may justify alternative approaches.
BIO and Lilly said the guidance should more clearly define when non-target tissues need to be included in off-target analyses. For in vivo products with strong tissue tropism and limited exposure outside the intended tissue, companies argued that testing non-target cell types at saturating in vitro concentrations may have limited translational relevance.
Industry commenters also requested clarification on off-target site nomination methods. The draft guidance lists in silico methods, biochemical assays, and cell-based assays as potential approaches for identifying candidate off-target sites. BIO and Lilly recommended that the FDA explicitly state that all three approaches are not always required and that modality-appropriate combinations may be acceptable.
This point is especially relevant as genome editing technologies diversify beyond traditional nuclease-based systems. For base editors, nickase-based systems, epigenome editors, and transcriptome editors, different nomination tools may provide different levels of sensitivity and relevance depending on the mechanism of action.
Another major area of feedback involves chemistry, manufacturing, and controls, or CMC, expectations after manufacturing changes. The draft guidance states that additional off-target analysis may be needed if major process changes affect editor activity or on-target editing rates in a way that could alter the off-target profile.
The Alliance for Regenerative Medicine and PhRMA requested more detail on what level of analysis would be expected following manufacturing changes, particularly during late-stage development, scale-up, and preparation for a Biologics License Application. Industry groups said sponsors would benefit from clearer principles for bridging studies between clinical and commercial processes.
PhRMA also encouraged the FDA to ensure timely access to INTERACT and pre-IND meetings for sponsors developing novel genome editing products. While the draft guidance encourages early regulatory engagement on off-target study plans, PhRMA noted that sponsors have reported challenges obtaining timely opportunities to discuss genome editing-specific questions.
Overall, the comments reflect broad support for the FDA’s effort to establish NGS-based safety expectations for genome editing therapies, while highlighting the need for flexibility as editing technologies, delivery platforms, and manufacturing processes continue to evolve.
