Genome Editing Draft Shows How FDA Guidance Documents Work

The Food and Drug Administration issued draft guidance on April 14 for companies developing gene therapies that use genome editing. According to the agency's announcement, the document, "Safety Assessment of Genome Editing in Human Gene Therapy Products Using Next-Generation Sequencing," gives recommendations on sequencing strategies, sample selection, analysis parameters and reporting for evaluating off-target editing and loss of genome integrity. It applies to products edited outside the body and to those that edit cells inside the patient, and is meant to support nonclinical studies submitted with investigational new drug applications and biologics license applications.

FDA said comments must be submitted within 90 days of the notice's publication in the Federal Register, and that it will consider comments before finalizing the guidance. That sequence, and the word "draft," follow a set of rules that govern how FDA tells industry what it expects.

What a guidance is, and is not

FDA's procedures for guidance are written in its good guidance practices regulation, 21 CFR 10.115. It defines guidance documents as documents for FDA staff, applicants and the public that describe the agency's interpretation of or policy on a regulatory issue.

The regulation is direct about their force: "Guidance documents do not establish legally enforceable rights or responsibilities. They do not legally bind the public or FDA." A company may use a different approach, as long as that approach complies with the relevant statutes and regulations, and FDA says it is willing to discuss alternatives. At the same time, guidances represent the agency's current thinking, so FDA employees may depart from them only with appropriate justification and supervisory concurrence.

Every guidance must prominently display a statement of its nonbinding effect. The listing for the genome editing draft carries the label "Not for implementation. Contains non-binding recommendations." It names CBER's Office of Therapeutic Products as the issuing office and gives docket number FDA-2026-D-1255 for comments.

Draft, comment, final

The regulation sorts guidance into two levels. Level 1 documents set out initial interpretations of statutes or regulations, more than minor changes in policy, complex scientific issues or highly controversial issues. Everything else, mostly existing practices and minor changes, is Level 2.

For a Level 1 guidance, FDA publishes a Federal Register notice that a draft is available, posts it online and invites comment. It may also hold public meetings or take the draft to an advisory committee. After the comment period, the agency reviews the comments, prepares a final version that incorporates changes when appropriate, announces it in the Federal Register and then implements it. FDA can also issue a second draft instead of a final version.

There are two shortcuts. FDA may skip prior comment on a Level 1 guidance when it decides that public participation beforehand is not feasible or appropriate; it then implements the document immediately and takes comments afterward. Level 2 guidances are posted and generally implemented at once, with comments invited after the fact. Under the regulation, anyone can comment on any guidance at any time.

Where the new draft fits

FDA said the genome editing draft builds on a January 2024 guidance on human gene therapy products that incorporate genome editing, adding recommendations specific to sequencing-based safety assessment. The agency also linked it to a framework it launched in February for individualized therapies for ultra-rare diseases.

Until a final version is issued, the draft states FDA's proposed approach rather than its settled recommendations. The agency encouraged sponsors to discuss their plans early, before submitting an IND, through its INTERACT program or pre-IND meetings.