Breakthrough Therapy Designation represents the most intensive FDA expedited program, created by the FDA Safety and Innovation Act of 2012 to accelerate development of drugs that show early evidence of transformative clinical benefit. While Fast Track focuses on drugs that may address unmet need, Breakthrough Therapy requires preliminary clinical evidence of substantial improvement over existing treatments, reflecting a higher bar that identifies drugs with exceptional therapeutic potential deserving the most intensive agency engagement.

The evidentiary standard for Breakthrough Therapy Designation requires preliminary clinical evidence, typically from early-phase trials, demonstrating substantial improvement over available therapy on clinically significant endpoints. The comparison is made to existing treatments, not to placebo, meaning that the drug must show potential to meaningfully advance the therapeutic landscape. The substantial improvement may be based on efficacy, safety, or other clinically meaningful advantages. This evidence requirement distinguishes Breakthrough Therapy from Fast Track, which can be granted based on potential rather than demonstrated benefit.

Drugs with Breakthrough Therapy Designation receive all benefits of Fast Track plus intensive FDA guidance on efficient drug development, organizational commitment involving senior managers, and eligibility for Rolling Review. The intensive guidance includes advice on clinical trial design, use of biomarkers, development strategies that might shorten development time, and FDA involvement in scientific discussions throughout development. This collaborative approach aims to enable efficient development programs that bring transformative therapies to patients as quickly as possible while maintaining appropriate standards for safety and efficacy demonstration.