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The Imfinzi Resubmission Journey: From FDA CRL to Approval 

Categories: Clinical Studies / Cell Therapy
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Hello Regulatory Scientists, 

Today, let’s delve into the journey of Imfinzi (durvalumab) 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: Imfinzi (durvalumab) 
Mechanism of Action: PD-L1 inhibitor, which helps the immune system recognize and attack cancer cells 
Indication: Treatment of locally advanced or metastatic urothelial carcinoma 
Initial Submission Date: April 2017 

The Complete Response Letter (CRL) 

CRL Date: October 2017 
CRL Concerns: 

  1. Overall Survival Data: The FDA requested more mature overall survival data from the ongoing clinical trials to confirm the benefit-risk profile. 
  1. Safety Profile: Concerns about the long-term safety profile and the need for additional data on immune-related adverse events. 
  1. Post-Marketing Commitments: Requests for a detailed post-marketing commitment plan to monitor long-term safety and efficacy. 

Resubmission Strategy 

AstraZeneca, the company behind Imfinzi, implemented a comprehensive strategy to address the FDA’s concerns: 

  1. Extended Data Collection: Collected and submitted more mature overall survival data from the pivotal clinical trials. 
  1. Enhanced Safety Monitoring: Provided additional data and analyses on the safety profile, focusing on immune-related adverse events. 
  1. Post-Marketing Commitment Plan: Developed a detailed post-marketing commitment plan to monitor long-term safety and efficacy. 
  1. Continuous FDA Engagement: Maintained open lines of communication with the FDA to ensure alignment on the resubmission strategy and clarify any outstanding questions. 

Resubmission Date: December 2017 

Outcome 

Approval Date: May 2018 
Imfinzi was approved for the treatment of locally advanced or metastatic urothelial carcinoma, marking a significant milestone in immuno-oncology. 

Lessons Learned 

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

  1. Mature Data Submission: Providing mature overall survival data is crucial for demonstrating the efficacy of oncology drugs. 
  1. Robust Safety Data: Ensuring comprehensive long-term safety data, particularly for immune-related adverse events, is essential to address FDA concerns. 
  1. Detailed Post-Marketing Plans: Developing detailed post-marketing plans can help assure the FDA of ongoing monitoring and risk management. 
  1. Effective Use of Advisory Committees: Leveraging advisory committees can provide valuable feedback and support the resubmission process. 
  1. 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 Imfinzi case underscores the importance of strategic planning and meticulous data collection 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 maturity and post-marketing plans, meet FDA standards. 
  1. Proactive Data Collection: Identify and address potential gaps in clinical data early in the development process to prevent issues from arising during FDA review. 
  1. Engage with the FDA Early and Often: Regular interactions with the FDA can provide valuable guidance and help steer the development process. 
  1. Utilize Advisory Committees: Seek feedback from advisory committees to validate data and address potential concerns. 
  1. Invest in Quality Data: Prioritize the collection of high-quality, detailed safety and efficacy data to support the submission. 

By learning from the Imfinzi 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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Asad Khan