Snapshot

The FDA Breakthrough Therapy pathway has been developed by the US Food and Drug Administration of United States.

This pathway can be used where Section 506(a) of the FD&C Act provides for 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.” It is important to recognize that the standard for breakthrough therapy designation is not the same as the standard for drug approval. The clinical evidence needed to support breakthrough designation is preliminary. In contrast, as is the case for all drugs, FDA will review the full data submitted to support approval of drugs designated as breakthrough therapies to determine whether the drugs are safe and effective for their intended use before they are approved for marketing. A. Qualifying Criteria for Breakthrough Therapy Designation: Breakthrough therapy designation applies to the drug (either alone or in combination with other drugs) and the specific use for which it is being studied. The term drug refers to the combination of two or more drugs if the combination is the subject of the breakthrough therapy designation or request. Where appropriate, FDA may grant designation to the development of a new use of an approved drug. 1. Serious Condition. 2. Existing (or Available) Therapies. 3. Preliminary Clinical Evidence: Unlike the information that could support fast track designation, which could include theoretical rationale, mechanistic rationale (based on nonclinical data), or evidence of nonclinical activity, breakthrough therapy designation requires preliminary clinical evidence of a treatment effect that may represent substantial improvement over available therapies for the treatment of a serious condition. For purposes of breakthrough therapy designation, preliminary clinical evidence means evidence that is sufficient to indicate that the drug may demonstrate substantial improvement in effectiveness or safety over available therapies, but in most cases is not sufficient to establish safety and effectiveness for purposes of approval. FDA expects that such evidence generally would be derived from phase 1 or 2 trials. Nonclinical information could support the clinical evidence of drug activity. In all cases, preliminary clinical evidence demonstrating that the drug may represent a substantial improvement over available therapy should involve a sufficient number of patients to be considered credible. However, FDA recognizes that the data cannot be expected to be definitive at the time of designation. Ideally, preliminary clinical evidence indicating a substantial improvement over available therapies would be derived from a study that compares the investigational drug to an available therapy (or placebo, if there is no available therapy) in clinical testing or from a study that compares the new treatment plus SOC to the SOC alone. FDA encourages sponsors to obtain some preliminary comparative data of this type early in development. Other types of clinical data that also could be persuasive include single-arm studies comparing the new treatment with well-documented historical experience. Generally, FDA expects that such historically controlled data would be persuasive only if there is a large difference between the new treatment and historical experience. For example, where lung function decline is a major manifestation of a disease, single-arm study data showing that a new drug significantly increases lung function could be persuasive if there is no available therapy that increases lung function. Data demonstrating that a cancer drug substantially increases overall response rate compared with historical controls (e.g., historical response rate with available therapy), with consideration of duration of the response, also could be persuasive. Sponsors contemplating the use of historical controls should consult FDA’s ICH guidance for industry E10 Choice of Control Group and Related Issues in Clinical Trials for more-detailed discussions. 4. May Demonstrate Substantial Improvement on Clinically Significant Endpoint(s): To support a breakthrough therapy designation, the preliminary clinical evidence must show that the drug may demonstrate substantial improvement over available therapy on one or more clinically significant endpoints. Substantial Improvement: The determination of whether the improvement over available therapy is substantial is a matter of judgment and depends on both the magnitude of the drug’s effect on a clinically significant endpoint (which could include duration of the effect) and the importance of the observed effect to the treatment of the serious condition or serious aspect of the condition. In general, the preliminary clinical evidence should show a clear advantage over available therapy. Approaches to demonstrating substantial improvement include the following: (i) Direct comparison of the new drug to available therapy shows a much greater or more important response (e.g., complete responses where the control treatment generally results only in partial responses). Such a trial could be conducted in treatment-naïve patients or in those whose disease failed to respond to available therapies, either as a comparison with the failed therapy (if ethically acceptable) or as a no-treatment controlled study; (ii) If there is no available therapy, the new drug shows a substantial and clinically meaningful effect on an important outcome when compared with a placebo or a welldocumented historical control; (iii) The new drug added to available therapy results in a much greater or more important response compared to available therapy in a controlled study or to a well-documented historical control. This trial also could be conducted in treatment-naïve patients or in those whose disease failed to respond to available therapies; (iv) The new drug has a substantial and clinically meaningful effect on the underlying cause of the disease, in contrast to available therapies that treat only symptoms of the disease, and preliminary clinical evidence indicates that the drug is likely to have a disease; (v) modifying effect in the long term (e.g., a sustained clinical benefit compared with a temporary clinical benefit provided by available therapies); (vi) The new drug reverses or inhibits disease progression, in contrast to available therapies that only provide symptomatic improvement; and (vii) The new drug has an important safety advantage that relates to serious adverse reactions (e.g., those that may result in treatment interruption) compared with available therapies and has similar efficacy. Clinically Significant Endpoint: For purposes of breakthrough therapy designation, FDA considers clinically significant endpoint generally to refer to an endpoint that measures an effect on irreversible morbidity or mortality (IMM) or on symptoms that represent serious consequences of the disease. It can also refer to findings that suggest an effect on IMM or serious symptoms, including: (i) An effect on an established surrogate endpoint that typically would be used to support traditional approval; (ii) An effect on a surrogate endpoint or intermediate clinical endpoint considered reasonably likely to predict a clinical benefit (i.e., the accelerated approval standard); and (iii) A significantly improved safety profile compared with available therapy (e.g., less dose-limiting toxicity for an oncology agent), with evidence of similar efficacy. In a breakthrough therapy designation request, a sponsor should provide justification for why the endpoint or other findings should be considered clinically significant. In rare cases, a pharmacodynamic (PD) biomarker may be considered a clinically significant endpoint if it strongly suggests the potential for a clinically meaningful effect on the underlying disease. In such cases, a sponsor should provide evidence supporting the use of the PD biomarker. Such evidence should include, for example, (1) the extent of understanding of the disease pathophysiology, (2) whether the biomarker is on a causal pathway of the disease process, and (3) the time course of the drug’s effect on the biomarker (e.g., the biomarker can be measured earlier than a surrogate endpoint used for accelerated approval). In addition, strong evidence of the drug’s effect on the PD biomarker generally is expected. FDA is more likely to rely on a PD biomarker for breakthrough therapy designation in a disease setting in which there is no available therapy, if the evidence supports such use. If the FDA grants a company’s request for designation, companies can benefit from the designation in several ways. Breakthrough designation allows manufacturers to receive all the benefits of Fast Track Designation , which includes more frequent meetings with the Agency, “rolling reviews” intended to help minimize administrative delays, hands-on interaction by FDA staff to help minimize issues as they arise. Designation also conveys eligibility for Priority Review by the FDA, which accelerates the review of the sponsor’s New Drug Application or Biologics License Application by 4 months. Another key benefit is FDA assistance on the efficient design of clinical trials, which can help facilitate eventual approval of the product..

This pathway accelerates the regulatory review process.

It is an abridged review (a reliance pathway).

FDA has determined that it is appropriate for a drug designated as a breakthrough therapy to be able to obtain rolling review. Therefore, if FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that a breakthrough therapy product may be effective, the Agency may consider reviewing portions of a marketing application before the sponsor submits the complete application. For the most part, sponsors must request the designation to the FDA in order for it to be available. However, the FDA can also suggest that a sponsor submit a request for a breakthrough designation if the Agency determines that the product meets the criteria, or if the development program could benefit from designation. FDA recommends companies “submit a request for Breakthrough Therapy Designation with the submission of a new [Investigational New Drug Application] IND, or as an amendment to an active IND” and expect response back “within 60 days of receipt of the request.” Generally, the total target (Agency) time for assessment is variable.