Draft Guidance Shows How FDA's Plausible Mechanism Framework Would Work

The Food and Drug Administration released a draft guidance on February 23 describing how developers of individualized therapies for rare genetic diseases could generate the evidence needed for approval under what it calls a plausible mechanism framework. At an event announcing the draft, Health and Human Services Secretary Robert F. Kennedy Jr. said "Randomized control trials are mostly just not feasible" for such conditions, Spectrum News reported. A Federal Register notice of availability, scheduled for publication on February 25, opens a 60-day comment period.

The draft guidance, from the Center for Biologics Evaluation and Research and the Center for Drug Evaluation and Research, is nonbinding and would represent FDA's current thinking once finalized.

Who the framework is for

The draft defines individualized therapies as those that target a specific abnormality that is the root cause of a disease, such as pathogenic genetic variants causing a severely debilitating or life-threatening condition in a small number of patients where a randomized controlled trial typically is not feasible. It discusses genome editing and RNA-based therapies such as antisense oligonucleotides, and says the concepts may apply to other individualized products.

Applying the framework involves five steps the draft lists: identifying a specific genetic, cellular or molecular abnormality clearly connected to the disease; developing a therapy that targets it; relying on a well-characterized natural history of the untreated disease; confirming that the target was successfully drugged or edited; and demonstrating improvement in clinical outcomes or course.

The same evidence standard, applied to tiny trials

The draft does not create a new legal standard. It says approval of an individualized therapy would, as with other drugs, require substantial evidence of effectiveness and enough information to conclude the drug is safe under its proposed labeling, and that it discusses when such data may be adequate to support approval under existing regulatory approval pathways.

The document says FDA anticipates that substantial evidence of effectiveness for individualized therapies could be established by a single adequate and well-controlled clinical investigation with confirmatory evidence. Where a disease's untreated course can be reasonably characterized, an externally controlled study comparing a patient's change after treatment with baseline could serve as that investigation. A substantial improvement inconsistent with the natural history may count, but the sponsor must show the result cannot reasonably be attributed to other treatments or natural variability. Because samples will be small, the draft says results should be robust enough to exclude chance findings. Confirmatory evidence could include mechanistic or pharmacodynamic data, confirmation of target engagement and exposure-response data.

Approval could be traditional or accelerated, depending on the endpoints. For accelerated approval, FDA generally intends to require the confirmatory study to be underway before approval. Because safety data will be limited at submission, the draft says FDA may require continued safety data collection after approval and will watch for delayed adverse events.

The draft also addresses how one product could cover many mutations. For CRISPR-based products, variants that use different guide RNAs to target different mutations in one gene may be included in a single investigational and licence application if the method of correction is the same. A highly supported plausible mechanism could then support adding other such gene-editing variants for mutations not included in the trial behind the original approval, the draft says. Kennedy said a disease with 100 mutations of the same gene would no longer require 100 clinical trials, Spectrum News reported.

The draft encourages early nonclinical planning, including new approach methodologies such as cell-based, organoid and in silico methods, and says it does not address specific development programs, endpoints or approval pathways, which sponsors should discuss with the relevant review division.