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  6. Frequently Asked Questions: Breakthrough Therapies
  1. Food and Drug Administration Safety and Innovation Act (FDASIA)

Frequently Asked Questions: Breakthrough Therapies

  1. How many requests for breakthrough therapy (BT) designation has the FDA's Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) received since the Food and Drug Administration Safety and Innovation Act was signed into law on July 9, 2012?

    CDER and CBER Breakthrough Therapy Requests Received

    CDER and CBER Breakthrough Therapy Approvals

    CDER and CBER Breakthrough Therapy Withdrawn After Granting (WAG) and Rescinded

    Related Information

  2. What are the benefits of a breakthrough therapy designation?

    Breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for breakthrough therapy designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.

    A breakthrough therapy designation conveys all of the fast track program features (see below for more details on fast track designation), more intensive FDA guidance on an efficient drug development program, an organizational commitment involving senior managers, and eligibility for rolling review and priority review. Section 902 of FDASIA requires the following actions, as appropriate:

    • holding meetings with the sponsor and the review team throughout the development of the drug
    • providing timely advice to, and interactive communication with, the sponsor regarding the development of the drug to ensure that the development program to gather the nonclinical and clinical data necessary for approval is as efficient as practicable
    • taking steps to ensure that the design of the clinical trials is as efficient as practicable, when scientifically appropriate, such as by minimizing the number of patients exposed to a potentially less efficacious treatment
    • assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the cross-discipline members of the review team (i.e., clinical, pharmacology-toxicology, chemistry, manufacturing and control, compliance) for coordinated internal interactions and communications with the sponsor through the review division’s Regulatory Health Project Manager
    • involving senior managers and experienced review staff, as appropriate, in a collaborative, cross-disciplinary review

  3. What other programs does FDA have to expedite drug development for serious conditions?

    FDA has various programs that are intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of serious or life-threatening conditions. These expedited programs help ensure that therapies for serious conditions are available as soon as it can be concluded that the therapies’ benefits justify their risks, taking into account the seriousness of the condition and the availability of alternative treatment. These programs include breakthrough therapy designation as noted above, fast track designation, accelerated approval, and priority review.

    Fast Track Designation: Fast track designation is intended to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Designation may be granted on the basis of preclinical data. A sponsor of a drug that receives fast track designation will typically have more frequent interactions with FDA during drug development. In addition, products that have been designated as fast track can obtain rolling review.

    Accelerated Approval: This program can be used for speeding the development and approval of promising therapies that treat a serious or life-threatening condition and provide meaningful therapeutic benefit over available therapies. Accelerated approval allows approval of a drug that demonstrates an effect on a “surrogate endpoint” that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit.

    Thus, the accelerated approval pathway is most often useful in settings in which the disease course is long and an extended period of time is required to measure the intended clinical benefit of a drug, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly. Nevertheless, even after the drug enters the market, the sponsor may be required to conduct post-marketing trials to verify and describe the drug’s clinical benefit. If further trials fail to verify the predicted clinical benefit, FDA may withdraw approval.

    Note that a drug that has received a breakthrough therapy designation or a fast track designation can be eligible for the accelerated approval pathway, if the relevant criteria are met.

    Priority Review: As part of its commitments in PDUFA V, FDA has established a review model, the Program. The Program applies to all new molecular entity NDAs and original BLAs, including applications that are resubmitted following a Refuse-to-File action, received from October 1, 2012, through September 30, 2017. For applications filed by FDA under the Program, the PDUFA review clock will begin at the conclusion of the 60 calendar day filing review period that begins on the date of FDA receipt of the original submission.

    This review designation is determined at the time of a BLA, NDA, or efficacy supplement submission. Any drug, including those that have received a fast track designation, breakthrough therapy designation, or those being evaluated for accelerated approval, can be granted priority review, if the relevant criteria are met.

  4. What are the differences between the criteria for breakthrough therapy designation and fast track designation?

    Breakthrough therapy and fast track designation programs both are intended to expedite the development and review of drugs for serious or life-threatening conditions, but there are differences in what needs to be demonstrated to qualify for the programs. A breakthrough therapy designation is for a drug that treats a serious or life-threatening condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies.  In contrast, a fast track designation is for a drug that treats a serious or life-threatening condition, and nonclinical or clinical data demonstrate the potential to address unmet medical needs for the serious condition.

  5. Is there a deadline for a sponsor to submit a request for breakthrough therapy designation?

    The Food Drug and Cosmetic Act (21 USC 356) states that a request for a breakthrough therapy designation may be made concurrently with, or at any time after, the submission of an application for [the IND]. To maximize the benefits of the program, FDA encourages sponsors to submit breakthrough therapy designation requests by the time of the end-of-phase-2 meeting, and also before initiation of the clinical trial(s) intended to serve as the primary basis for demonstration of efficacy (see “Expedited Programs for serious Conditions – Drugs and Biologics”). Given that the primary intent of breakthrough therapy designation is to provide timely advice and interactive communications to help the sponsor design and conduct a drug development program as efficiently as possible, including the potential use of alternative trial designs, the full benefits of breakthrough therapy designation can only be realized during the development program, well in advance of the submission of the original BLA or NDA, or a supplement.

  6. Does a sponsor have to request breakthrough therapy designation in order to be considered for the designation?

    A sponsor needs to submit a request for breakthrough therapy designation in order to be considered for the designation.  In some cases, FDA may suggest that the sponsor consider submitting a request for breakthrough therapy designation if: (1) after reviewing submitted data and information (including preliminary clinical evidence), FDA 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.

  7. Where can I find the “Guidance for Industry” on breakthrough therapies?

    The final Guidance for Industry: “Expedited Programs for Serious Conditions––Drugs and Biologics” published on May 30, 2014.

  8. Where can I find the CDER Manual of Policies and Procedures (MAPP) on the management of breakthrough therapy-designated drugs?

    MAPP 6025.6 “Good Review Practice: Management of Breakthrough Therapy-Designated Drugs and Biologics” was published on July 29, 2014.

  9. Where can I find the CDER Manual of Policies and Procedures (MAPP) on the review of a marketing application for a breakthrough therapy-designated drug that is receiving an expedited review?

    MAPP 6025.7 “Good Review Practice: Review of Marketing Applications for Breakthrough Therapy-Designated Drugs and Biologics That Are Receiving an Expedited Review” was published on March 9, 2015.

  10. Where can I find the CBER Standard Operating Policy and Procedure (SOPP) on the management of breakthrough therapy-designated products?

    SOPP 8212 “Management of Breakthrough Therapy-Designated Products:  Sponsor Interactions and Status Assessment Including Rescinding” was published on June 13, 2016.

  11. Where can I find the webcast and presentations from the FDA Public Meeting: Breakthrough Therapy Designation: Exploring the Qualifying Criteria held on April 24, 2015 in Washington, DC?

    The webcast and presentations from the FDA Public Meeting: Breakthrough Therapy Designation: Exploring the Qualifying Criteria can be found at: Breakthrough therapy designation: Exploring the qualifying criteria.

  12. Can a sponsor submit a request for breakthrough therapy/fast track designation for multiple indications of the same drug? A breakthrough therapy/fast track designation applies to a combination of a drug (either alone or in combination with other drugs) and the specific use for which it is being studied. A separate breakthrough designation/fast track request must be submitted for each proposed development program (i.e., each indication for a drug (or drug combination)).

  13. Can a request for a breakthrough therapy designation be submitted for a combination product?

    A breakthrough therapy designation can apply for a combination product (drug-device, biologic-device) as long as the primary mode of action in the combination product is a drug or biologic.

  14. Can a product be granted a breakthrough therapy designation if another product has already been granted breakthrough therapy designation for the same indication?

    One of the criteria for breakthrough therapy designation is the drug may demonstrate substantial improvement over existing (or available) therapies. A product that has been granted breakthrough therapy designation and is not approved or licensed in the U.S. is not considered available therapy.

  15. Whom should sponsors contact if they wish to discuss the potential for their product meeting the breakthrough therapy criteria?

    The review division managing the investigational new drug application (IND) for the drug in question is the sponsor’s first resource for questions related to the development program of the specific drug, and its potential for breakthrough therapy qualification. If an IND is not yet open, then the contact would be the review division that manages the particular therapeutic area of the proposed indication.

  16. Would a clinical trial for a drug that has been designated as a breakthrough therapy generally have to enroll fewer patients prior to approval?

    After a development program is designated as a breakthrough therapy, FDA will work closely with the sponsor to ensure that the design of the clinical trials is as efficient as practicable, when scientifically appropriate. An efficient trial design typically would help minimize the number of patients exposed to a potentially less efficacious treatment, which could translate to fewer patients enrolled in clinical trials that support marketing approval. Regulatory standards to demonstrate safety and efficacy must still be met.

  17. May a sponsor submit a request for Special Protocol Assessment (SPA) for a drug that has breakthrough therapy designation?

    Breakthrough therapy designation and SPA are two independent regulatory pathways. Therefore, a drug designated as a breakthrough therapy is eligible for SPA if the protocol meets the criteria for SPA. Conversely, a drug for which an SPA is under review may be considered for breakthrough therapy designation, if the breakthrough therapy designation criteria are met.

  18. Will FDA announce when a drug has been granted breakthrough therapy designation?

    FDA will not disclose information regarding sponsors who submitted requests for or who have been granted or denied breakthrough therapy designation. Breakthrough therapy designation requests are typically submitted to an IND, and the FDA cannot disclose the existence of an IND, or any submissions that have been submitted to the IND, unless it has previously been publicly disclosed or acknowledged per 21 CFR 312.130(a).

  19. If a drug is denied breakthrough therapy designation, is it automatically reviewed for fast track designation?

    Fast track and breakthrough therapy designation programs are separate programs and require separate requests for FDA consideration.

  20. To what section of the electronic Common Technical Document should a sponsor submit a request for breakthrough therapy designation?

    A sponsor should submit a request for breakthrough therapy designation to Module I, Section 1.12.4 "Request for Comments and Advice” of the electronic Common Technical Document.

  21. Can a sponsor submit a request for breakthrough therapy designation to a pre-IND?

    A sponsor should submit a request for breakthrough therapy designation with the submission of a new IND, or as an amendment to an active IND. Requests for breakthrough therapy designation should not be submitted to inactive INDs or INDs that are on partial or complete clinical hold. In general, breakthrough therapy designation requests should not be submitted to a PIND. However, there are some limited circumstances where this may be acceptable, if done at the request of the FDA.

  22. What are the timelines for FDA to respond to a breakthrough therapy designation request? 

    FDA will respond to breakthrough therapy designation requests within 60 days of receipt of the request. 

  23. Can a sponsor get preliminary breakthrough therapy designation (BTD) advice from the review division prior to the submission of a formal BTD request?

    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 (BTD) Advice Request” 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. NOTE: A Preliminary BTD Advice Request may be submitted to an active PIND, although a formal BTD request may not be submitted until the IND is opened.

  24. The European Medicines Agency (EMA) PRIME program, similar to the Food and Drug Administration (FDA) breakthrough therapy designation program, was launched in March 2016 to enhance support for the development of medicines that target an unmet medical need. To what extent do the two agencies work together to harmonize Breakthrough Therapy designation/PRIME request evaluations and processes, application reviews for products receiving both Breakthrough Therapy designations and eligibility to PRIME (dually designated), and advice to sponsors for dually designated product development programs?

    • PRIME and the US breakthrough therapy designation share the same objective (timely patient access to innovative medicines) but have a different legal basis, hence comparison and harmonization is difficult.
    • In late 2016, as part of the confidentiality arrangements, FDA and EMA began regular exchange of information and meetings regarding breakthrough therapy designation and PRIME eligibility requests, focusing on high level topics and comparing general experience and program implementation challenges.
    • In this context, FDA and EMA track submitted requests for PRIME and breakthrough therapy designations and compare final review outcomes, including specific reasons for a designation request denial.
    • These meetings facilitate increased awareness of FDA/EMA dually designated products and stimulate early dialogue by therapeutic area experts in both regions on an ad hoc basis within the existing clusters, or in the context of Parallel Scientific Advice (PSA) program via a formal meeting.
    • The agencies do not routinely share scientific and regulatory reviews regarding dually designated product development programs or marketing applications, unless a topic of specific interest has been defined by the agencies’ subject matter expert teams or sponsors.
    • When requesting breakthrough therapy designation or eligibility to PRIME, sponsors are encouraged to inform the agency whether they have submitted a request for designation or eligibility to the other agency and the outcome of this request. 
    • For successful planning of global development and clinical studies, both agencies encourage sponsors to contact FDA and EMA on a dually designated product’s development program and seek joint advice under the PSA program.  Sponsors wishing to nominate a product for a PSA procedure should address one single “Request for PSA” letter to both emainternational@ema.europa.eu at EMA.

Note: For purposes of this webpage, all references to “drugs” include both human drugs and biological drug products regulated by CDER and CBER.

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