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Hello Regulatory Scientists,

Today, let’s explore the journey of Eliquis (apixaban) from receiving an FDA Complete Response Letter (CRL) to achieving approval. This case study provides valuable insights and lessons that can guide companies developing new drugs today.

Regulatory History and Initial Submission

Drug: Eliquis (apixaban) Mechanism of Action: Factor Xa inhibitor, which helps to prevent blood clots Indication: Prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation Initial Submission Date: September 2011

The Complete Response Letter (CRL)

CRL Date: June 2012 CRL Concerns:

1. Data Management and Verification: The FDA requested more information on data management and site monitoring for the ARISTOTLE trial.

2. Data Consistency: Concerns about the consistency and accuracy of data reporting.

3. Additional Analyses: Requested further analyses to ensure the robustness of the trial results.

Resubmission Strategy

Bristol-Myers Squibb and Pfizer, the companies behind Eliquis, implemented a comprehensive strategy to address the FDA’s concerns:

1. Enhanced Data Verification: Conducted extensive reanalyses of the ARISTOTLE trial data, focusing on data integrity and verification.

2. Detailed Data Submission: Submitted additional analyses and detailed responses to the FDA’s queries regarding data management and site monitoring practices.

3. Improved Monitoring Processes: Enhanced site monitoring processes to ensure data consistency and accuracy.

4. Continuous FDA Engagement: Maintained open lines of communication with the FDA to clarify requirements and align the resubmission strategy with regulatory expectations.

Resubmission Date: August 2012

Outcome

Approval Date: December 2012 Eliquis was approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, marking a significant milestone in anticoagulation therapy.

Lessons Learned

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

1. Thorough Data Verification: Ensuring the integrity and consistency of clinical trial data is paramount. Addressing any issues related to data management early can prevent delays.

2. Robust Data Submission: Providing detailed responses and additional analyses to the FDA’s queries is crucial to demonstrate the robustness of the trial results.

3. Enhanced Monitoring Practices: Improving site monitoring processes can help ensure data accuracy and consistency, addressing potential regulatory concerns.

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

5. Effective Use of Advisory Committees: Leveraging advisory committees can provide valuable feedback and support the resubmission process.

Relevance for Current Drug Developers

For companies developing drugs today, the Eliquis case underscores the importance of strategic planning and meticulous data management 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 data management and site monitoring practices, meet FDA standards.

2. Proactive Data Verification: Identify and address potential data management issues 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 Eliquis 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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