The Breakthrough Therapy Designation is a program of the US Food and Drug Administration for the expedited development and review of certain drugs. The prerequisite is that a drug is intended for a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint. The designation is neither a marketing authorization nor a lowered standard of evidence for the approval decision.
Requirements and regulatory effect
The sponsor requests the designation from the FDA. Preliminary clinical evidence is decisive, not merely a theoretical superiority, preclinical results, or an unmet medical need. The FDA evaluates whether the observed improvement over available therapy may be substantial. In doing so, it considers the magnitude and, if applicable, the duration of the effect as well as the importance of the clinical outcome. In general, endpoints related to irreversible morbidity or mortality or symptoms with serious consequences of the disease are considered clinically significant.
If granted, the Breakthrough Therapy Designation combines the features of Fast Track with more intensive guidance on efficient development and an organizational commitment by the FDA involving senior managers. It can be requested early in development when the required clinical evidence is available. The classification can change the interaction with the agency and development planning, but does not relieve the obligation to submit sufficient data on quality, safety, and efficacy for the requested use. The standard of the designation is expressly not to be equated with the standard of an approval.
Differentiation from Fast Track, Priority Review and Accelerated Approval
Fast Track is also a designation for drugs for serious conditions that address an unmet medical need. It can be based on non-clinical or clinical data and opens up, among other things, more frequent interactions and, if applicable, rolling review. The Breakthrough Therapy Designation, in contrast, requires preliminary clinical evidence that indicates a substantial improvement over available therapy on a clinically significant endpoint. It includes the Fast Track features but demands a more specific and higher reference to evidence.
Priority Review does not concern the development pathway, but the review of a submitted marketing application. With this classification, the FDA aims for a decision within six instead of ten months. The classification changes neither the duration of the clinical trials nor the scientific standard for approval. Accelerated Approval is not a designation, but an approval pathway: under the legal prerequisites, the FDA can approve drugs for serious conditions based on a surrogate endpoint or an intermediate clinical endpoint that is reasonably likely to predict clinical benefit. Confirmatory trials are central in this process.
Differentiation from the European PRIME scheme
PRIME, Priority Medicines, is a support scheme by the EMA for medicines in development that target an unmet medical need and are expected to offer a major therapeutic advantage. It provides early and proactive scientific support so that the evidence for a later marketing authorization application is generated appropriately. PRIME can additionally support access to an accelerated assessment in the centralized procedure if the requirements are met at the time of submission.
PRIME and Breakthrough Therapy Designation thus pursue similar goals, but are independent programs of different legal jurisdictions. The FDA designation is expressly based on preliminary clinical evidence of a potential substantial improvement. Acceptance into PRIME is not a US designation and establishes neither Priority Review nor Accelerated Approval. Likewise, a Breakthrough Therapy Designation replaces neither European scientific advice, nor an assessment by the Committee for Medicinal Products for Human Use, nor an approval by the European Commission.
Relevance for clinical trials
A potential Breakthrough Therapy Designation requires an early, robust clinical development strategy. Studies must make the comparison to available therapy and the clinical significance of the observed effect traceable. The expedited communication with the FDA increases the need for promptly available, consistent data on safety, efficacy, and manufacturability. A justified choice of endpoint, clear decision rules, and a planning for the evidence that may be needed after a later approval remain essential.
Full-service CROs such as Mediconomics support the analysis of the existing body of evidence, the planning and conduct of suitable studies, data management, biostatistics, safety monitoring, and medical writing for regulatory documents. They can additionally coordinate the preparation of agency meetings and the follow-up of decisions, so that the development plan, protocols, and data packages consistently map the requirements of an expedited program.
Frequently Asked Questions (FAQ)
Is the Breakthrough Therapy Designation a marketing authorization?
No. It expedites development and review, but does not replace the regulatory assessment of the later marketing authorization application.
Can a drug receive Fast Track and Breakthrough Therapy?
A Breakthrough Therapy Designation includes the features of the Fast Track program. However, the prerequisites for Breakthrough are more specific.
Does the designation automatically lead to Accelerated Approval?
No. Accelerated Approval is a distinct approval pathway with its own requirements for endpoints and the confirmation of clinical benefit.
Regulatory references
- Federal Food, Drug, and Cosmetic Act, Section 506(a) — basis for the Breakthrough Therapy Designation.
- FDA Guidance “Expedited Programs for Serious Conditions” — classifies the four expedited programs.
- FDA, Accelerated Approval — describes approval based on surrogate or intermediate endpoints.
- EMA, PRIME: priority medicines — explains the European support scheme.