On 25 Jun 2013, FDA released the long-awaited guidance on breakthrough therapies: “Expedited Programs for Serious Conditions-Drugs and Biologics”. Since the breakthrough therapy program was mandated in FDASIA in 2012, CDER has issued 24 breakthrough therapy designations, but until June 25, had not provided much in the way of definitions and information on what the Breakthrough Therapy program is, how to apply, how to gain designation, and what the benefits are. This guidance document provides that information, along with updated information on other expedited programs including fast track, accelerated approval, and priority review.
First, a bit of semantics.
- A breakthrough therapy is defined as a drug that treats“a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant endpoints” (italics theirs).
- The definition for serious condition remains the same as that used in the past for accelerated approval: “a disease or condition associated with morbidity that has substantial impact on day-to-day functioning.”
- Available therapies are those that are approved and licensed in the US for the same indication being considered for the new drug AND are relevant to current US standard of care (SOC) for that indication.
Preliminary Clinical Evidence
The breakthrough therapy program is unique in that it requires preliminary clinical evidence for designation. FDA suggests that this clinical evidence should be from studies that demonstrate superiority to either an active or placebo comparator or to SOC. Comparisons against historical controls can also be accepted, but this data will likely only be considered persuasive if there is a “large difference between the new treatment and historical experience.” The evidence should be from clinical experience that involves “a sufficient number of patients to be considered credible”. If you’re early in development, be sure to consult your biostatistician before embarking on a trial to demonstrate “preliminary clinical evidence” for a breakthrough designation.
FDA admits in the guidance that the determination of sufficient preliminary clinical evidence to show “substantial improvement” is a matter of judgment, but will depend on the magnitude of the treatment effect and the importance of the observed clinical outcome.
FDA provides the following specific examples:
- Direct comparison of the new drug to an available therapy showing a much greater or more important response
- Direct comparison of the new drug added to available therapy in comparison to available therapy alone or to historical controls
- Display of efficacy for new drug that treats the underlying cause of the disease, in contrast to available therapies that treat only symptoms of disease
- Reversal of disease progression by the new drug, whereas available therapies only provide symptomatic improvement, or
- The new drug has similar efficacy but important safety advantages relative to available therapies
Clinically Significant Endpoint
The preliminary clinical evidence should have an endpoint that measures an effect on irreversible morbidity or mortality (IMM) or on symptoms that represent serious consequences of the diseases. However, FDA will consider evidence based on other endpoints including the following:
- Established surrogate endpoints
- Surrogate endpoint or intermediate clinical endpoint that is reasonably likely to predict clinical benefit
- Pharmacodynamic biomarker that does not meet surrogate endpoint criteria but does strongly suggest potential for a clinically meaningful effect on the underlying disease, or
- Similar efficacy but significantly improved safety profile relative to available therapy
Benefits of Breakthrough Therapy Designation
- All benefits of fast track designation, including opportunities for frequent interactions with the review team, and rolling review of the marketing application (NDA or BLA)
- “Intensive Guidance” on efficient drug development, including timely and interactive advice and communications, especially regarding alternative trial designs (such as adaptive designs or enrichment strategies) that could result in more efficient trials
- Assignment of a cross-disciplinary project lead to act as a scientific liaison and to facilitate efficient review by the different members of the review team
This is a draft guidance, and all comments should be submitted to FDA by 25 Aug 2013.