Breakthrough Therapy designation is a process designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).
To determine whether the improvement over available therapy is substantial is a matter of judgment and depends on both the magnitude of the treatment effect, which could include duration of the effect, and the importance of the observed clinical outcome. In general, the preliminary clinical evidence should show a clear advantage over available therapy.
For purposes of Breakthrough Therapy designation, clinically significant endpoint generally refers to an endpoint that measures an effect on irreversible morbidity or mortality (IMM) or on symptoms that represent serious consequences of the disease. A clinically significant endpoint can also refer to findings that suggest an effect on IMM or serious symptoms, including:
- An effect on an established surrogate endpoint
- An effect on a surrogate endpoint or intermediate clinical endpoint considered reasonably likely to predict a clinical benefit (i.e., the accelerated approval standard)
- An effect on a pharmacodynamic biomarker(s) that does not meet criteria for an acceptable surrogate endpoint, but strongly suggests the potential for a clinically meaningful effect on the underlying disease
- A significantly improved safety profile compared to available therapy (e.g., less dose-limiting toxicity for an oncology agent), with evidence of similar efficacy
A drug that receives Breakthrough Therapy designation is eligible for the following:
- All Fast Track designation features
- Intensive guidance on an efficient drug development program, beginning as early as Phase 1
- Organizational commitment involving senior managers
Breakthrough Therapy designation is requested by the drug company. If a sponsor has not requested breakthrough therapy designation, FDA may suggest that the sponsor consider submitting a request if: (1) after reviewing submitted data and information (including preliminary clinical evidence), the Agency thinks the drug development program may meet the criteria for Breakthrough Therapy designation and (2) the remaining drug development program can benefit from the designation.
Ideally, a Breakthrough Therapy designation request should be received by FDA no later than the end-of-phase-2 meetings if any of the features of the designation are to be obtained. Because the primary intent of Breakthrough Therapy designation is to develop evidence needed to support approval as efficiently as possible, FDA does not anticipate that Breakthrough Therapy designation requests will be made after the submission of an original BLA or NDA or a supplement. FDA will respond to Breakthrough Therapy designation requests within sixty days of receipt of the request.