FDA Provides Insight Into Breakthrough Therapy Designation, Consolidates Guidance for Expedited Programs

July 1, 2013

By Alexander J. Varond

On June 25, FDA released a draft guidance entitled “Expedited Programs for Serious Conditions—Drugs and Biologics” and a related Manual of Policies and Procedures entitled “Review Designation Policy: Priority (P) and Standard (S).”   The draft guidance provides important insight into FDA’s breakthrough therapy designation program and serves as a de facto desktop reference for FDA’s four expedited programs:  fast track designation, breakthrough therapy designation, accelerated approval, and priority review designation. 

Breakthrough Therapy Designation

FDA’s draft guidance offers the agency’s interpretation of the breakthrough therapy designation program.  This program was created by the Food and Drug Administration Safety and Innovation Act (“FDASIA”) that was signed into law nearly a year ago, on July 9, 2012 (see our summary here).  The draft guidance was highly anticipated, as FDA has already received 62 requests for breakthrough therapy designation.  Despite the fact that FDA has granted breakthrough designation to 20 potential innovative new drugs that have shown encouraging early clinical results, guidance has been wanting, especially because FDA does not publicly announce its rationales for granting or denying individual breakthrough therapy designations due to confidentiality concerns.  The draft guidance also describes the conditions under which a breakthrough therapy can lose its designation.

Section 506(a) of the FD&C Act, as amended by FDASIA, provides for the designation of a drug as a breakthrough therapy “if the drug is intended, alone or in combination with 1 or more other drugs, to treat 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, such as substantial treatment effects observed early in clinical development.”

Serious condition.  The draft guidance states that FDA intends to interpret the term “serious” consistent with how it has done so in the past.  A serious disease or condition is defined in 21 CFR 312.300(b)(1) as:

a disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible if it is persistent or recurrent. Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.

Available therapy.  While FDA’s Available Therapy Guidance issued in 2004 provided a definition of “existing therapy,” the draft guidance updates the definition in response to FDASIA.  FDA maintains that an “existing therapy” or “available therapy” is a therapy that “[i]s approved or licensed . . . for the same indication being considered for the new drug” but adds a second limitation.  Thus, to be considered an available therapy, it must also be “relevant to current U.S. standard of care (SOC) for the indication.”  As a result, if a therapy is approved but is either no longer used or rarely used, the therapy may not be considered an available therapy.  “In evaluating the current SOC, FDA considers recommendations by authoritative scientific bodies (e.g., National Comprehensive Cancer Network, American Academy of Neurology) based on clinical evidence and other reliable information that reflects current clinical practice.  In the absence of a well established and documented SOC, FDA may consult with special government employees or other experts . . . .”  The draft guidance also provides that the SOC for a given condition may evolve.

Consistent with the Available Therapy Guidance, a drug granted accelerated approval on surrogate or clinical endpoints that have not been verified is not considered an available therapy.  However, a drug approved with a risk evaluation and mitigation strategy (“REMS”) that includes elements to assure safe use (ETASU) would be considered an available therapy if the study population for the new drug is eligible to receive the approved drug under the REMS.

Substantial improvement.  To determine whether the improvement over available therapy is “substantial,” FDA weights the magnitude of the treatment effect and the importance of the observed clinical outcome.  Preliminary clinical evidence should show a clear advantage over available therapy.  The draft guidance lists a number of ways to demonstrate preliminary clinical evidence of substantial improvement, including:  direct comparison of a new drug to the available therapy showing a much greater or more important response, or a drug that treats the underlying cause of a disease where the available therapy only treats the symptoms of the disease.

Clinically significant endpoint.  For purposes of breakthrough therapy designation, FDA considers “clinical significant endpoint” generally to refer to an endpoint that measures an effect on irreversible morbidity or mortality or on symptoms that represent serious consequences of the disease.  The term can also refer to an effect on an established clinical surrogate endpoint; a surrogate endpoint or intermediate clinical endpoint considered reasonably likely to predict a clinical benefit; 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; or a significantly improved safety profile compared to available therapy.

Benefits of breakthrough therapy designation.  The benefits of breakthrough therapy designation include the features of fast track designation, “intensive” guidance on developing an efficient drug development program, beginning as early as Phase 1, and organizational commitment from FDA involving senior managers.  Breakthrough therapy designation may also be useful in distinguishing which drugs FDA believes truly have the ability to change a given disease space.

Conditions that may lead to the loss of the designation.  FDA’s draft guidance makes it clear that certain products that are granted breakthrough therapy designation can lose their designation.  For example, a drug’s development program may show that the response rate is substantially smaller than the response seen in early clinical testing.  Also, if “breakthrough therapy designation is granted to two drugs that are being developed for the same use [and i]f one of the two drugs gains traditional approval, the other would not retain its designation unless its sponsor provided evidence that the drug may demonstrate substantial improvement over the recently approved drug.”  FDA has discretion in revoking breakthrough therapy designation.

A Consolidated Desktop Reference

The guidance provides a consolidated resource for information on FDA’s policies and procedures for the four expedited programs, threshold criteria applicable to concluding that a drug qualifies for one or more programs, and certain features of each program.  In Fiscal Year 2012, 56 percent of the New Chemical Entities approved by CDER used a combination of these programs.  The programs are intended “to help ensure that therapies for serious conditions are approved and available to patients as soon as it can be concluded that the therapies’ benefits justify the risks.”  The draft guidance provides a helpful table that summarizes the four programs:


Importantly, the draft guidance’s definition of “available therapies,” mentioned above, applies to accelerated approval, fast track designation, and priority review, thus providing additional flexibility as compared to FDA’s current regulations.

When the guidance is finalized, it will replace the current guidances entitled “Fast Track Drug Development Programs—Designation, Development, and Application Review” (issued January 2006) and “Available Therapy” (issued July 2004).  Comments on the draft guidance are due on August 25, 2013.