Under the Breakthrough Therapy designation, the FDA will closely collaborate with the developing company in a dynamic, multi-disciplinary process to expedite the development program to ensure an early access of innovative medicine to patients with underlying serious disease condition with unmet medical needs.
In the US, there are several approaches allowing shorter review times to speed up the availability of new therapies to patients with serious conditions. The Breakthrough Therapy designation includes expedited development and review along with intensive FDA guidance during drug development. In 2022, 35% of the novel drugs approved was designated as Breakthrough.
Created by the US Food and Drug Administration (FDA) Safety and Innovation Act of 2012, breakthrough therapy designation is one of the programs aiming to accelerate the development and review of drugs and biologics that address unmet medical needs. The Breakthrough Therapy Designation is distinct from other expedited development programs in that greater evidence of efficacy is required.
What does Breakthrough Therapy mean?
Breakthrough Therapy designation requires preliminary clinical evidence of a treatment effect indicating substantial improvement in effectiveness or safety over the available therapies in a given, serious condition. Ideally, the preliminary clinical evidence is derived from a comparative study early in the development, from phase I or phase II trials and non-clinical evidence supporting the drug activity. Whether the improvement over an existing therapy is substantial depends on the extent of the treatment effect and the importance of the observed clinical outcome. As FDA commits significant resources to Breakthrough Therapy designation, the preliminary clinical evidence should show a clear advantage over existing treatments.
The main advantage of receiving Breakthrough Therapy designation is the commitment the Agency demonstrates when the applicant has got very promising early clinical data.
The breakthrough designation process provides, besides shorter timelines and rolling review, an opportunity to engage with senior managers at the Agency on the overall development of the program, including getting feedback on design, endpoints and manufacturing.
How to get Breakthrough Therapy Designation
The company needs to submit a request for breakthrough therapy designation in order to be considered for the designation. The application can be submitted together with IND or after, but ideally no later than the end-of-phase II meeting. The key point with this designation is, however, that requests should not be submitted until preliminary clinical evidence is available indicating that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.
In some cases, after reviewing submitted information, the FDA may suggest the company to send in a request for breakthrough therapy designation. This could be the case if the Agency consider the development program meeting the designation criteria and if the remaining program can benefit from going in this direction.
The agency will then review the application and reply within 60 calendar days of receipt of the request.
What to expect
If the developer is granted breakthrough therapy designation, the next step would be to submit a request for a comprehensive multidisciplinary meeting – a Type B meeting - to discuss the high-level plan for the drug development program. What is discussed during this meeting depends on which therapeutic area, development phase, and specific issues of the proposed drug and indication. Within the scope of this meeting is also to establish a communication plan, allowing efficient interactions between the company and the CDER.
Some examples of topics to discuss could be:
- planned clinical trials and endpoints
- manufacturing development strategy
- post-approval studies
- expectations, timing, format of interactions and information exchange
Given the resource-intensive nature of the Breakthrough Therapy it’s in the Agency’s interest to grant the designation only to drugs that meet the criteria over time. Therefore, the FDA every so often assesses whether designated products continue to meet these standards. If not, FDA may rescind the designation.
Examples of reasons for a Breakthrough Therapy designation to be rescinded could be that the emerging data for the drug no longer support that preliminary clinical evidence indicates the demonstration of substantial improvement over existing therapies, or a different drug is approved for treating the same unmet need – as a result, this drug no longer meet the criteria of substantial improvement over existing therapies.
A breakthrough therapy designation is not the same as a drug approval, the program must generate evidence of effectiveness and safety to meet the legislative standard for approval.
Conclusion
A drug can be granted expediated designation programmes if the FDA determines that the drug treats a serious condition, and it would provide a significant improvement in safety or effectiveness of the treatment. For Breakthrough Therapy designation, clinical data must be available to demonstrate the benefit of the product over available therapies. Having this extended opportunity to interact with the regulators, clear and transparent communication could help facilitate the need of the product, and ultimately the unmet need of patients.
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