What Is Breakthrough Therapy Designation?
Explore the FDA's Breakthrough Therapy Designation, a pathway defined by a high bar for clinical evidence and intensive collaboration on drug development.
The U.S. Food and Drug Administration (FDA) utilizes several pathways to accelerate the availability of new medicines, with Breakthrough Therapy Designation representing a specific and intensive option. This designation is a formal status granted to a drug intended for a serious or life-threatening condition. Its purpose is to expedite the development and review of therapies that have shown early, promising signs of being substantially better than what is currently available.
This program was established through the Food and Drug Administration Safety and Innovation Act (FDASIA) in 2012. It provides a mechanism for the FDA to work more closely with drug developers, or sponsors, to help bring impactful treatments to patients sooner.
Criteria for Breakthrough Therapy Designation
For a drug to be considered for Breakthrough Therapy Designation, it must meet two primary criteria. The first is that the therapy is intended to treat a serious or life-threatening disease or condition. The FDA interprets a “serious condition” as a disease associated with morbidity that has a substantial impact on a person’s day-to-day functioning.
The second requirement is the presence of preliminary clinical evidence indicating the drug may offer a substantial improvement over existing therapies. This evidence must be based on one or more clinically significant endpoints, which are outcomes that measure a meaningful aspect of patient well-being. The data must suggest a clear and significant advantage over the current standard of care, and this standard relies on human clinical data, not just nonclinical models.
Obtaining Breakthrough Therapy Status
The process of securing Breakthrough Therapy Designation is initiated by the drug sponsor, typically a pharmaceutical or biotechnology company. The company submits a formal request to the FDA, which can be done at various points during the drug development process. Ideally, the request is submitted no later than the end-of-phase-2 meeting, allowing the benefits to be applied to late-stage clinical trials.
The application package must contain a summary of the drug, the specific condition it targets, and a review of the therapies that are currently available. It must include the preliminary clinical data that supports the claim of substantial improvement over those existing treatments.
Upon receiving the request, the FDA has a 60-day window to make a decision. Agency reviewers, including senior managers, evaluate the submitted data to determine if the drug meets the defined criteria. If denied, the sponsor can continue with the standard development process and may reapply later if more compelling data becomes available.
Impact on Drug Development and Review
Receiving Breakthrough Therapy Designation significantly alters the trajectory of a drug’s development. The FDA provides intensive guidance on creating an efficient clinical trial program, often starting as early as Phase 1. This involves an organizational commitment from the agency, ensuring that experienced review staff and senior managers are actively involved in the drug’s journey toward approval.
One of the features is the collaborative effort to optimize the design of clinical trials, making them as efficient as possible without compromising scientific rigor. The designation also grants the drug all the features of the Fast Track program, including more frequent meetings with the FDA and the possibility of a rolling review.
A rolling review allows a company to submit completed sections of its marketing application for FDA review as they become available, rather than waiting for every section to be finished. This concurrent submission and review process can shorten the time between the completion of clinical trials and a potential approval.
Distinctions from Other FDA Expedited Pathways
The FDA has several programs to speed up drug review, and it is useful to understand how Breakthrough Therapy Designation differs from them. The Fast Track designation, for example, is also for serious conditions with an unmet medical need, but its evidence threshold is lower. It can be granted based on nonclinical data or a mechanistic rationale, whereas Breakthrough requires preliminary clinical evidence of a substantial improvement.
Accelerated Approval is another pathway, but it is distinct because it allows for approval based on a surrogate endpoint—a marker thought to predict a clinical benefit—rather than a direct measure of clinical benefit. While a drug with Breakthrough status might use the Accelerated Approval pathway, the designation itself is based on early clinical evidence of substantial improvement on a clinically significant endpoint, not just a surrogate.
Finally, Priority Review is a designation that shortens the FDA’s review timeline for a submitted application, setting a goal of six months instead of the standard ten. Many drugs with Breakthrough Therapy Designation are also granted Priority Review, but the two are separate. A drug can receive Priority Review without having Breakthrough status if it is deemed to offer a significant improvement in safety or effectiveness at the time of its final application submission.