The U.S. Food and Drug Administration (FDA) periodically releases guidance documents to describe FDA’s interpretation of, or policy on a regulatory issue. These documents are non-binding recommendations, that are designed to provide additional context to Sponsors of drugs, biologics, or devices. 

The process of producing a new guidance document begins with an FDA subject matter expert, who drafts the document and issues a Notice of Availability in the Federal Register. Then the Draft guidance document is released, with 60 days for the public to read the guidance and provide feedback. Public comments are important because FDA staff review all submitted feedback and incorporate comments into a final version of the guidance. 

The Plausible Mechanism Framework guidance describes the FDA’s current thinking on how developers can bring highly individualized therapies to patients with ultra-rare genetic diseases when traditional randomized clinical trials are not feasible. The guidance does not create a new approval pathway or lower FDA standards. All drugs need to prove substantial evidence of effectiveness in order to support licensure. This guidance lays out some possible study designs and regulatory flexibility that can be used as “substantial evidence” in certain defined conditions. 

The SCGE commented on the vague phrasing of a “well-characterized” natural history of disease. Many of the diseases that SCGE consortium members are developing treatments for are rare or ultra-rare, and establishing natural history is challenging. The Agency should support flexibility in the standards for characterizing natural history for individualized therapies and provide additional clarity in the standards they plan to use when evaluating whether a retrospective natural history study is fit for purpose. You can read other comments written by individual consortium members here and here. 

In addition to submitting public comments on FDA draft guidance documents, the SCGE Consortium has actively engaged with the FDA and the broader regulatory community to help advance the translation of genome-editing therapies. SCGE investigators have contributed to regulatory discourse through published perspective and opinion articles (see related publications below). The SCGE also publishes regulatory documents, including briefing materials and Agency responses. Taken together, the SCGE is committed to providing valuable resources for the genome-editing community and demonstrating commitment to constructive engagement with regulatory processes. 

Related publications: