What Is an FDA Breakthrough Therapy Designation?

The breakthrough therapy designation is one of the FDA's expedited programs aimed at accelerating the development and review of drugs and biologics for serious conditions.  

For treatments targeting serious or life-threatening conditions, time is of the essence. The FDA's breakthrough therapy designation offers a pathway to expedite the development and review of such therapies, potentially bringing critical treatments to patients sooner. But what exactly does this designation entail, and how can biotech companies leverage it effectively? 

Overview of FDA Breakthrough Therapy designation 

Established under the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, the breakthrough therapy designation is designed to expedite the development of therapies that show preliminary clinical evidence of substantial improvement over existing treatments based on preliminary clinical evidence. 

Key objectives of the designation: 

• Accelerate Development: Streamline clinical trials and reduce development timelines. 
• Enhance Communication: Foster close collaboration between the FDA and sponsors. 
• Ensure Efficiency: Optimize the review process without compromising safety and efficacy standards. 

What is the approval rate for an FDA breakthrough therapy designation? 

As of June 30, 2024, the FDA has received 1516 requests for breakthrough therapy designation, of which 587 have been granted (38.7%). Out of these, 317 breakthrough-designated products have received FDA approval.¹ This represents a significant increase in both designations and approvals since the program's inception, highlighting its growing impact on accelerating medical advancements. 

Requirements for breakthrough therapy designation 

To qualify for this designation, a therapy must meet two primary criteria: 

• The therapy must target a disease or condition with significant morbidity or mortality rates. 
• Early clinical data should indicate that the therapy offers substantial improvement over available therapies on one or more clinically significant endpoints. 

Substantial improvement in treatments is characters by three key factors: 

• Efficacy, where the new treatment demonstrates better effectiveness than existing options.
• Enhanced safety, with fewer or less severe side effects. 
• A novel mechanism of action, particularly in addressing unmet medical needs. 

What are the benefits of breakthrough therapy designation? 

Obtaining this designation offers several advantages that can significantly impact a therapy's development trajectory. 

Intensive FDA Guidance 

• Sponsors receive proactive support from the FDA, facilitating faster resolution of issues. 
• Joint strategizing on clinical trial designs to optimize data collection. 

Organizational Commitment 

• High-level FDA officials engage in the review process, ensuring alignment and resource allocation. 

Rolling Review and Priority Review 

• Sponsors can submit portions of their New Drug Application (NDA) or Biologics License Application (BLA) as they become available. 
• Eligibility for priority review reduces the FDA's review time from the standard 10 months to six months. 

Impact on development time 

Studies have shown that breakthrough status can significantly reduce development and review times. According to an FDA analysis, drugs with Breakthrough Therapy Designation had an estimated 30% reduction in clinical development time compared to non-designated drugs.² This acceleration is critical for bringing life-saving treatments to patients sooner.  

Application process for breakthrough therapy designation  

Timing of Submission 

• Sponsors should submit a request no later than the end-of-Phase-II meetings. The designation can be requested concurrently with, or at any time after, the submission of an Investigational New Drug (IND) application. 
• Sponsors may request a template from the regulatory project manager (RPM) for their IND via a templated form.³
  • A subsequent teleconference between the sponsor and the review division will be scheduled. The division will make a recommendation as to whether a request for BTD is appropriate, may be too preliminary, or does not currently meet the criteria for a BTD.  

Required Documentation 

• Include robust clinical data demonstrating substantial improvement over existing therapies. 
• Provide context on how the investigational drug outperforms current treatment options. 
• Outline proposed plans for future studies, emphasizing how they will meet regulatory requirements. 

FDA Review Process 

• The FDA commits to responding to breakthrough therapy designation requests within 60 days of receipt. 
• Approval of the designation, denial, or a request for additional information. 

Potential challenges associated with breakthrough status

Success Rate and Common Challenges 

• Historically, the FDA grants approximately one-third of breakthrough requests.⁴ This underscores the importance of a well-prepared application with compelling clinical evidence. 
• Applications may be denied if the preliminary clinical data doesn't convincingly demonstrate substantial improvement. 
• Accelerated timelines may lead to heightened scrutiny and expectations from the FDA. 

Strategies for Success 

• Data Robustness: Focus on generating strong clinical data early in development and choose endpoints that are meaningful to patients and regulators. 
• Regulatory Expertise: Utilize regulatory specialists who understand the nuances of the breakthrough therapy designation process and consider requesting a Type B meeting with the FDA to discuss the potential application. 
• Proactive Communication: Engage with the FDA early to align on expectations and requirements and be open about challenges and data limitations while demonstrating a plan to address them. 

Recent FDA Trends 

In September 2023, the FDA issued updates to the final guidance on the Breakthrough Devices Program, which, while specific to medical devices, reflects the FDA's ongoing efforts to refine and expand expedited programs. Other trends include: 

• Emphasis on Health Equity: The FDA encourages applications that target underserved populations or address health disparities and urges sponsors to design clinical trials that reflect the diversity of the patient population. 
• Impact of COVID-19: The pandemic has accelerated the adoption of innovative trial designs, which can be advantageous in the context of the breakthrough designation, and the FDA has shown increased willingness to work with sponsors on flexible approaches to data collection and trial execution. 

Strategic considerations for companies perusing breakthrough therapy designation 

To navigate the FDA expedited programs successfully, it’s crucial to follow a strategic approach. Start with early planning to lay a solid foundation. Assess your therapy’s eligibility for breakthrough therapy designation early on and develop a comprehensive data strategy to gather robust preliminary clinical evidence. 

1. Engage with the FDA proactively. Request pre-submission meetings to gain valuable insights and align on expectations. Keeping open lines of communication with the FDA is essential to inform them of significant developments and foster a collaborative relationship. 
2. Optimize your clinical trial designs by incorporating flexibility and ensuring diversity to enhance the trial’s adaptability and generalizability. When preparing your application, highlight unmet needs and emphasize clinical significance to make a compelling case. 
3. Plan for accelerated development by effectively managing resources to meet expedited timelines. Ensure manufacturing readiness early to prepare for scale-up and commercialization. These steps will streamline your development process, ultimately bringing innovative therapies to patients more efficiently. 

How Precision supports breakthrough therapy designation efforts

The FDA's Breakthrough Therapy Designation presents a significant opportunity for biotech companies to expedite the development of therapies that can profoundly impact patients' lives. By understanding the criteria, benefits, and strategic considerations, companies can position themselves to take full advantage of this expedited pathway. 

Precision for Medicine specializes in guiding biotech firms through the journey to approval. Our expertise in FDA’s expedited programs, coupled with our comprehensive clinical and translational research services, makes us an ideal partner for companies aiming to bring breakthrough therapies to market swiftly and efficiently. 

Have a potential candidate? See how Precision can support your journey toward FDA Breakthrough Therapy Designation and beyond. 

 References

1. Friends of Cancer Research. About Breakthrough Therapies. https://friendsofcancerresearch.org/about-breakthrough-therapies/ 
2. ASPE. FDA Breakthrough Therapy Designation Reduced Late-Stage Drug Development Time. https://aspe.hhs.gov/reports/fda-breakthrough-therapy-designation-reduced-late-stage-drug-development-time 
3. FDA. Frequently Asked Questions: Breakthrough Therapies. https://www.fda.gov/regulatory-information/food-and-drug-administration-safety-and-innovation-act-fdasia/frequently-asked-questions-breakthrough-therapies

4. Mooghali M, Wallach JD, Ross JS, Ramachandran R. Premarket Pivotal Trial End Points and Postmarketing Requirements for FDA Breakthrough Therapies. JAMA Netw Open. 2024;7(8):e2430486. doi:10.1001/jamanetworkopen.2024.30486