Part 2 FDA Expedited Programs Series: Breakthrough Therapy


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). Preliminary clinical evidence should show a clear advantage over available therapy. When no other therapies are available, it must show meaningful clinical benefit.


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 diseases.
  • A significantly improved safety profile compared to available therapy (e.g., less dose-limiting toxicity for an oncology agent), with evidence of similar efficacy

Potential Benefits

  • All Fast Track designation features (more face to face and written communications with/from FDA, elegibility for accelerated approval and priority review, rolling review of NDA/BLA)
  • Intensive guidance on an efficient drug development program, beginning as early as Phase 1.
  • Organizational commitment involving senior managers

Breakthrough Designation Process

  • Sponsors may request a Breakthrough Therapy designation when the IND is first submitted and no later than the end-of-phase-2 meetings. Decisions are made within 60 days of submission. A sponsor can contact the regulatory project manager (RPM) in the division to which the active IND is assigned and request the “Preliminary Breakthrough Therapy Designation Request Advice” template. This template should then be submitted as a formal amendment to the IND and a subsequent teleconference between the sponsor and the review division will be set-up by the RPM. The review division will make a recommendation as to whether a request for a BTD is appropriate, may be too preliminary, or does not currently meet the criteria for a BTD. The Agency’s recommendation is advisory and is not to be interpreted to predict the Agency’s decision on the BTD request.
  • Particulars are found in Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics (2014)