The US Food and Drug Administration (FDA) has issued new draft guidance that defines a new authorisation pathway for individualised drugs and biologics that target specific genetic conditions with identified biological causes. Comments are invited until 27 April 2026.
The draft guidance, ‘Considerations for the use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause’, introduces flexibility for developers of individualised medicines designed for patients with rare diseases where a randomised controlled trial typically is not feasible due to small patient numbers. The guidance states: ‘The Agency anticipates that substantial evidence of effectiveness for individualized therapies could be established based on a single adequate and well-controlled clinical investigation with confirmatory evidence’. Detailed sections on nonclinical and clinical data, and chemistry, manufacturing and controls data necessary to support product quality are included.
For an application to use this pathway, specific criteria must be met, as follows:
- Identification of the specific disease-causing abnormality
- Demonstration that their therapy targets the underlying cause or proximate biological pathway
- Provision of well-characterised natural history data in untreated patients
- Confirmation that the target was successfully drugged/edited
- Demonstration of improvement on clinical outcomes or course
The door has also been potentially opened for developers to use master protocols for the evaluation of therapies that target different genetic changes for the same disease. When announcing the issue of this draft guidance, the FDA stated: ‘… a product targeting different mutations in a single gene could be included in a single product application and potentially evaluated through the use of master protocols that evaluate these product variations in a single trial’.
It continues: ‘A highly supported “plausible” mechanism of action may then be used to support the addition of other such genome editing product variants, intended to treat patients with mutations that were not included in the clinical trial used to support the original approval’.
The release of this new pathway is aligned with the FDA’s aim of facilitating faster approvals of therapies for rare and ultra-rare diseases.
Comments can be submitted here.
