The U.S. Food and Drug Administration on Monday published draft guidance intended to streamline approval for individualized therapies when conventional randomized controlled trials are not feasible because patient populations are extremely small. The guidance was issued by the agency's Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER).
The document centers on therapies that directly address a specific genetic, cellular or molecular abnormality and are designed to correct or modify the underlying cause of disease. It calls out genome editing platforms and RNA-based treatments, including antisense oligonucleotides, as examples of modalities that could fall under the framework. The agency notes the framework also may be relevant to other tailored therapeutics provided they act on the defined biological cause of a condition.
Health and Human Services Secretary Robert F. Kennedy, Jr. was quoted characterizing the initiative as a reduction in regulatory barriers, saying it will help accelerate access to therapies for patients with ultra-rare diseases. The statement, as presented in the draft guidance context, framed the effort as an alignment of regulation with contemporary biological tools to move potential breakthrough treatments toward patients in need more quickly.
The guidance sets out core criteria for application of what the FDA calls the Plausible Mechanism Framework. Key elements include identifying the disease-causing abnormality, demonstrating that the therapeutic targets the root cause or a proximate biological pathway, relying on well characterized natural history data in untreated patients, and confirming successful target drugging or editing.
For therapies seeking traditional approval, the draft guidance reiterates that sponsors should show improvement in clinical outcomes or disease course. It also allows for the use of biomarkers in support of approval when those biomarkers are established to predict clinical benefit.
CBER's chief medical and scientific officer and director, Vinay Prasad, MD, MPH, is cited in the guidance describing the framework as a long-awaited step toward enabling personalized treatments. He framed the Plausible Mechanism Framework as an advance in regulatory science that could help translate the longstanding promise of patient-specific therapies into a practicable approval pathway.
The guidance explains how genome editing technologies - because of their high specificity to unique DNA sequences - could permit multiple product variants that target different mutations within a single gene to be included under one product application. The agency suggests that such related variants might be evaluated within master protocols that assess product variations in a single clinical trial. Where a mechanism of action is strongly supported, that rationale could be used to justify adding additional genome editing product variants intended for patients with mutations that were not enrolled in the initial clinical trial supporting approval.
The FDA acknowledges the inherent constraints of clinical investigations in this space. It recognizes that adequate and well controlled studies for individualized therapies will often involve small sample sizes, and therefore emphasizes that the results must be robust enough to exclude chance findings. In assessing effectiveness, the agency will weigh the specific disease under study, the strength of the available evidence, and the practical challenges of conducting clinical trials for individualized therapies.
The draft guidance, titled Considerations for the Use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause, is open for public comment. Interested parties must submit comments within 60 days of the guidance being published in the Federal Register via Regulations.gov.
Summary of procedural next steps: sponsors and stakeholders have a 60-day window from publication in the Federal Register to file comments through Regulations.gov. Following that comment period, the agency may revise the draft guidance before issuing a final policy.