Hello Regulatory Scientists,

Today, let’s delve into the journey of Brilinta (ticagrelor) from receiving an FDA Complete Response Letter (CRL) to achieving approval. Understanding this case provides valuable insights and lessons that can guide companies developing new drugs today.

Regulatory History and Initial Submission

Drug: Brilinta (ticagrelor) Mechanism of Action: P2Y12 receptor antagonist, which inhibits platelet aggregation Indication: Acute coronary syndrome (ACS) Initial Submission Date: November 2010

The Complete Response Letter (CRL)

CRL Date: June 2011 CRL Concerns:

1. Clinical Data Consistency: The FDA requested more detailed analyses of the clinical data, specifically the PLATO trial, to better understand the variations in outcomes based on geographic regions.

2. Efficacy and Safety: Clarifications on the efficacy and safety profile, particularly concerning differences in outcomes observed in North America versus the rest of the world.

Resubmission Strategy

AstraZeneca, the company behind Brilinta, implemented a thorough strategy to address the FDA’s concerns:

1. Detailed Data Reanalysis: Conducted an in-depth reanalysis of the PLATO trial data, focusing on the variations in clinical outcomes by geographic regions.

2. Additional Data Submission: Submitted additional clinical data and analyses to provide a clearer picture of the drug’s efficacy and safety across different populations.

3. Engagement with FDA: Maintained continuous communication with the FDA to ensure alignment on the resubmission strategy and to clarify any outstanding questions.

Resubmission Date: October 2011

Outcome

Approval Date: July 2011 Brilinta was approved for the reduction of thrombotic cardiovascular events in patients with acute coronary syndrome, marking a significant achievement for AstraZeneca.

Lessons Learned

The journey of Brilinta from CRL to approval highlights several key lessons for drug developers:

1. Thorough Data Analysis: AstraZeneca’s success was largely due to their comprehensive reanalysis of clinical data, addressing the FDA’s specific concerns.

2. Clear Communication of Data: Providing clear and detailed clinical data, particularly when addressing regional variations, is crucial to demonstrating a drug’s efficacy and safety.

3. Effective Use of Advisory Committees: Leveraging advisory committees can provide critical feedback and help validate the approach to addressing FDA concerns.

4. Continuous FDA Engagement: Maintaining open and ongoing communication with the FDA helps align development efforts with regulatory expectations.

Relevance for Current Drug Developers

For companies developing drugs today, the Brilinta case underscores the importance of strategic planning and meticulous data analysis in the regulatory process. Here are some takeaways to help avoid a CRL and achieve first-cycle approval:

1. Thorough Pre-Submission Preparation: Ensure that all aspects of your submission, including clinical data and regional analyses, meet FDA standards.

2. Proactive Data Analysis: Identify and address potential inconsistencies in clinical data early in the development process to prevent issues from arising during FDA review.

3. Engage with the FDA Early and Often: Regular interactions with the FDA can provide valuable guidance and help steer the development process.

4. Utilize Advisory Committees: Seek feedback from advisory committees to validate data and address potential concerns.

5. Invest in Quality Data: Prioritize the collection of high-quality, detailed clinical data to support the submission.

By learning from the Brilinta resubmission experience, current drug developers can better navigate the regulatory landscape, avoid common pitfalls, and increase the likelihood of a successful first review cycle approval.

Stay diligent and strategic,

CERES Regulatory Services

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