Safety Assessment of Genome Editing in Human Gene Therapy Products Using Next-Generation Sequencing; Draft Guidance for Industry

The commenter, representing Simon Fraser University's Computational Biology Lab, proposes four specific quantitative reporting elements to be added to the draft guidance on genome editing safety assessments. They argue that the current guidance lacks specific statistical forms for "completeness" and "sensitivity," and they provide a methodology to account for off-target candidate universe completeness, structural-variant detection floors, sequencing-depth adequacy, and bioinformatics reproducibility.

The Alliance for Regenerative Medicine (ARM) supports the FDA's draft guidance on the safety assessment of genome editing in human gene therapy products. They recommend refining the guidance to ensure it remains risk-based, modality-specific, and proportionate to the biological risk of different editing technologies.

Dr. Kay C. Wiese, representing Simon Fraser University's Computational Biology Lab, proposes four specific quantitative reporting elements to be added to the draft guidance. The author argues for more rigorous disclosure of off-target nomination completeness, structural-variant detection floors, sequencing-depth adequacy, and bioinformatics reproducibility to address current qualitative gaps in the draft.

The American Society of Gene & Cell Therapy (ASGCT) supports the draft guidance on NGS-based safety assessment of human genome editing products. They request additional clarity on assay performance principles, emerging editing modalities, and specific parameters for off-target and chromosomal integrity analysis to ensure consistent implementation across the industry.

SeQure, a contract research organization, supports the draft guidance and suggests specific improvements regarding minimum sensitivity for off-target confirmation, the inclusion of optical genome mapping for structural variations, and the recommendation of insertion site analysis for certain payloads. They also advocate for high-throughput biochemical assays to account for human genetic variation and editor-specific nomination strategies.

A group of scientists and researchers from various biotechnology and technology development companies (including Pacific Biosciences, Praxis Molecular Solutions, Catalent, Sangamo Therapeutics, and Form Bio) expressed broad support for the FDA's draft guidance on NGS-based genome editing safety assessments. They recommend specific technical enhancements, such as establishing a limit of detection (LoD) for assays, requiring explicit bioinformatics version control, and encouraging validation against reference datasets.

PhRMA, representing leading biopharmaceutical companies, supports the FDA's draft guidance on genome editing safety assessments. They advocate for a risk-based, "fit-for-purpose" regulatory framework that provides more clarity on analytical thresholds, off-target site filtering, and specific requirements for different editing modalities to ensure regulatory predictability and innovation.

ProtaGene, a contract research organization (CRO), supports the FDA's draft guidance on safety assessments for genome-edited human gene therapy products. They argue for greater clarity regarding sequencing technology selection, assay performance expectations, the use of clinically relevant cell models, and more comprehensive evaluations of genome integrity and integration site analysis.

Eli Lilly and Company supports the draft guidance as a positive step toward predictable, science-based regulation for genome editing. They provide specific recommendations to improve clarity on off-target analysis, variant-aware analysis, and long-term follow-up requirements for non-integrating products.

The Biotechnology Innovation Organization (BIO) supports the FDA's draft guidance on safety assessments for genome editing products, praising its forward-looking approach and clarity. They request specific clarifications and refinements regarding biodistribution-driven scope, modality-specific requirements (especially for base and nickase editors), and standardized reporting for chromosomal integrity and variant-aware analysis.