---
title: How FDA's 2026 Genome Editing Drafts Connect on Off-Target Methods
description: FDA's June and October 2026 drafts on prior knowledge and individualized genome editing, and how they link to the April NGS draft on off-target methods.
---

<https://www.countagen.com/countagen-insights>

# [How FDA's 2026 Genome Editing Drafts Connect on Off-Target Methods](https://www.countagen.com/countagen-insights/fda-2026-genome-editing-drafts-off-target-methods)

 Written by [Countagen Team](https://www.countagen.com/countagen-insights/author/countagen-team) | Nov 14, 2026, 1:09:11 PM

FDA issued two more draft guidances on genome-edited products in 2026 that our earlier posts didn't cover. *Leveraging Prior Knowledge in the Development of Human Gene Therapy Products Incorporating Genome Editing* came out on June 2, 2026 (docket FDA-2026-D-1257). *Individualized Human Genome Editing Products: Considerations for BLA Submission and Postapproval Management* followed on October 27, 2026 (docket FDA-2026-D-11783). Both link back to the April 2026 draft on NGS-based safety assessment (docket FDA-2026-D-1255), which we covered in September. This post looks at what the two newer drafts say about off-target methods, and how FDA connects the three.

Three caveats first:

- **All three are drafts.** Each is marked "not for implementation". FDA's guidances "do not establish legally enforceable responsibilities", and "should" means recommended, not required (June §I; October §I).
- **Different scope.** 
    - The April draft covers genome-edited gene therapy products, ex vivo and in vivo (§III).
    - The June draft covers the same products and spans CMC, nonclinical and clinical knowledge (§I). This post covers only its off-target section (§III.B.2).
    - The October draft is limited to individualized products for a monogenic disease caused by known pathogenic variants, where every product variant in the BLA aims at the same editing outcome (§I). It doesn't cover the design of clinical studies (§I).
- **Comment periods.** April's closed on July 14, 2026 and June's on September 1, 2026. The October draft is open for comments until November 27, 2026.

## What the June draft says about off-target methods

The June draft is about "prior knowledge": public or platform knowledge that may be leveraged so a sponsor doesn't have to generate all of its data from scratch (§I, §II). Its off-target material sits in one subsection, "Leveraging Bioinformatics Knowledge" (§III.B.2).

It starts from the default. Off-target and genomic integrity data are recommended for each drug product, "but this data may be considered for leveraging in some circumstances". Study designs, methods, analysis tools and sequencing technologies may be "more broadly appropriate" to leverage across product types (§III.B.2).

What the draft says may be considered for leveraging:

- **Methods.** For editors with an identical mechanism of action, "a specific set of methods for the nomination and confirmation of off-target sites for one drug product may be considered for leveraging for a similar safety assessment of other drug products" (§III.B.2.a.i). The same applies to genomic integrity methods.
- **Assay parameters,** where the intended on-target edit rates are similar: the amount of starting material, concentrations of editing components, culture methods and the use of appropriate controls (§III.B.2.a.ii).
- **The NGS strategy.** The draft's example is an NGS-based confirmatory testing method "implemented at a certain sequencing depth and with specific sequence quality acceptance criteria" for one product (§III.B.2.b.i). The draft doesn't give a depth or the criteria; they are the sponsor's own.
- **Analysis pipelines,** for data from the same off-target assay, with parameters such as target sequence and mismatches changed per product. The draft's example is a GUIDE-seq analysis pipeline, where the input target sequence differs between products (§III.B.2.c.i). Individual tools for quality assessment, trimming and alignment, and depth and quality metrics, may also be leveraged (§III.B.2.c.ii–iii).

Leveraging the off-target *data* is narrower.

- **Identical setup.** Off-target data for a gRNA may be considered for leveraging if a product uses a gRNA and an editor in a specific cell type identical to those of another clinical program (§III.B.2.d.i).
- **Same gRNA, different editor.** If the gRNA is identical but the editor differs and prefers common PAM sequences, computationally nominated sites may be leveraged. Confirmatory testing is then done in samples edited with the intended editor, and editor-specific testing may still be needed (§III.B.2.d.iii).
- **Different gRNAs.** "It is generally not scientifically appropriate to leverage off-target assessment data across products using different guide RNAs or sequence recognition components" (§III.B.2.e.i).
- **Different target sites.** On-target outcome data and genomic integrity results are likewise generally not appropriate to transfer between products that edit different sites (§III.B.2.e.ii–iii).

So the draft treats methods and results differently. The way off-target sites are found and checked may carry across products. The results generally don't, unless the guide, the editor and the cell type are the same.

## What the October draft says about off-target methods

The October draft introduces the **individualized feature space (IFS)**: the allowable limits of variation for a product's genome editing components (§III).

- **What an IFS describes.** For a product whose only variable feature is the gRNA spacer, the IFS describes which spacer sequences are allowed. One example is any spacer that targets a defined class of pathogenic variants in a specified gene, with the same editing outcome (§II).
- **Criteria attached to it.** The IFS should come with explicit in vitro safety and activity criteria, "for example, acceptable off-target editing and a minimum acceptance criterion for on-target editing" (§III).

On safety, the draft is specific about off-target work for each variant (§V.B):

> "The unique gRNA spacer sequence for each product variant creates a distinct off-target editing profile; therefore, applicants should assess the off-target editing risk for each gRNA/editor combination. Applicants should assess unintended editing activities for each product variant using pre-defined next-generation sequencing (NGS)-based methods. These methods may be leveraged across product variants."

The same paragraph asks for:

- **The right cells.** The assessment should be done in "appropriate target human cells and other human cell types selected based on data obtained from prior nonclinical biodistribution studies, as applicable" (§V.B).
- **A protocol with the BLA.** "A protocol detailing the specific methods (e.g., NGS-based nomination, confirmatory testing, etc.) for in vitro assessment of the safety of product variants should be submitted with the BLA" (§V.B).
- **What the results cover.** Unintended outcomes at the on-target site, off-target editing activity and genomic rearrangement events. For every identified and confirmed off-target site, the BLA or supplement should include the empirical, in silico or sequence homology data and a risk assessment of its clinical significance (§V.B).

After approval, new variants are added by supplement (§VI.A):

- **What the supplement contains.** In vitro activity data showing that each new variant reaches the intended edit at or above a threshold established in clinical studies. In vitro safety data "including comprehensive on-target and off-target editing analyses", showing that off-target profiles stay within acceptable limits.
- **Clinical data.** In most cases, variants within the established IFS can be added on in vitro data without additional clinical data (§VI).
- **A protocol agreed in advance.** FDA recommends a postapproval change management protocol that describes, in advance, the in vitro activity and safety data to be generated for each new variant and how they will be evaluated (§VI.A).
- **Expanding the IFS.** Widening the IFS itself is a prior approval supplement (§VI.B).

## How the drafts connect

FDA draws the connection itself, in the off-target paragraph of the October draft (§V.B):

- **Footnote 20 → April draft.** The "pre-defined next-generation sequencing (NGS)-based methods" cite the April draft. That is where confirmation is its own step: 
    - It names "probe-based sequence enrichment, targeted sequence amplification, and/or other equivalent methods" (§VI.D).
    - It asks for depth that detects events at rates "usually lower than the on-target edit rate", with the sponsor supporting the adequacy of that depth (§IV).
    - It sets no numeric threshold.
- **Footnote 21 → June draft.** "These methods may be leveraged across product variants" cites the June draft.
- **Footnote 22 → February draft.** The sentence on choosing human cell types from biodistribution data cites a fourth document: FDA's February 2026 draft on the Plausible Mechanism Framework for individualized therapies (docket FDA-2026-D-1256). For genome editing products, that draft had already said: 
    - off-target studies "should use NGS-based methods to facilitate detection and reporting of low frequency off-target editing events";
    - where data leveraging is anticipated, off-target risk "should be evaluated for each product variant" (§III.B).

Taken together:

- **April** describes how nominated off-target sites are confirmed for a product.
- **June** describes when those methods, their parameters and their pipelines may be leveraged across products, and where the results may not.
- **October** applies both to individualized products: an off-target assessment for each gRNA/editor combination, with pre-defined NGS methods that may be leveraged across variants and a protocol submitted with the BLA.

Comments on the October draft can be submitted to docket FDA-2026-D-11783 at regulations.gov until November 27, 2026.

If you're planning an off-target package and want to talk through the confirmation step, [get in touch](https://www.countagen.com/contact).

### Sources

- FDA, "Individualized Human Genome Editing Products: Considerations for BLA Submission and Postapproval Management," draft guidance for industry, October 2026 (docket FDA-2026-D-11783) — [fda.gov](https://www.fda.gov/regulatory-information/search-fda-guidance-documents/individualized-human-genome-editing-products-considerations-bla-submission-and-postapproval); Federal Register notice, October 28, 2026 — [federalregister.gov](https://www.federalregister.gov/documents/2026/10/28/2026-21954/individualized-human-genome-editing-products-considerations-for-bla-submission-and-postapproval)
- FDA, "Leveraging Prior Knowledge in the Development of Human Gene Therapy Products Incorporating Genome Editing," draft guidance for industry, June 2026 (docket FDA-2026-D-1257) — [fda.gov](https://www.fda.gov/regulatory-information/search-fda-guidance-documents/leveraging-prior-knowledge-development-human-gene-therapy-products-incorporating-genome-editing); Federal Register notice, June 3, 2026 — [federalregister.gov](https://www.federalregister.gov/d/2026-11054)
- FDA, "Safety Assessment of Genome Editing in Human Gene Therapy Products Using Next-Generation Sequencing," draft guidance for industry, April 2026 (docket FDA-2026-D-1255) — [fda.gov](https://www.fda.gov/regulatory-information/search-fda-guidance-documents/safety-assessment-genome-editing-human-gene-therapy-products-using-next-generation-sequencing)
- FDA, "Considerations for the Use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause," draft guidance for industry, February 2026 (docket FDA-2026-D-1256) — [fda.gov](https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-use-plausible-mechanism-framework-develop-individualized-therapies-target-specific)

[View full post](https://www.countagen.com/countagen-insights/fda-2026-genome-editing-drafts-off-target-methods)

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