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The Lorbrena Resubmission Journey: From FDA CRL to Approval 

Categories: Clinical Studies
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Hello Regulatory Scientists, 

Today, let’s explore the journey of Lorbrena (lorlatinib) 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: Lorbrena (lorlatinib) 
Mechanism of Action: ALK (anaplastic lymphoma kinase) inhibitor, which targets and inhibits ALK and ROS1, proteins involved in the growth of cancer cells 
Indication: Treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC) 
Initial Submission Date: February 2018 

The Complete Response Letter (CRL) 

CRL Date: July 2018 
CRL Concerns: 

  1. Clinical Data Requirements: The FDA requested additional data to confirm the efficacy and safety of Lorbrena, particularly in previously treated patients. 
  1. Safety Profile: Concerns were raised about the long-term safety profile, including potential adverse effects such as cognitive and mood changes. 
  1. Risk Management Plan: Need for a detailed risk management plan to monitor and mitigate potential adverse effects. 

Resubmission Strategy 

Pfizer, the company behind Lorbrena, implemented a comprehensive strategy to address the FDA’s concerns: 

  1. Additional Clinical Data: Conducted further studies to gather more robust data on the drug’s efficacy and safety, particularly focusing on previously treated patients. 
  1. Enhanced Safety Monitoring: Provided additional data and analyses on the long-term safety profile, focusing on cognitive and mood changes. 
  1. Detailed Risk Management Plan: Developed a robust risk management plan, including monitoring guidelines and patient education materials. 
  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: September 2018 

Outcome 

Approval Date: November 2018 
Lorbrena was approved for the treatment of ALK-positive metastatic non-small cell lung cancer, providing a new option for patients with this specific genetic profile. 

Lessons Learned 

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

  1. Comprehensive Data Collection: Providing extensive clinical data, particularly addressing specific concerns such as efficacy in previously treated patients, is crucial to addressing FDA concerns. 
  1. Enhanced Safety Monitoring: Ensuring thorough understanding and management of the drug’s long-term safety profile can help mitigate regulatory concerns. 
  1. Effective Risk Management: Developing and implementing a detailed risk management plan can help mitigate potential adverse effects and ensure patient safety. 
  1. Continuous FDA Engagement: Maintaining open and ongoing communication with the FDA helps align development efforts with regulatory expectations. 
  1. Proactive Quality Control: Implementing stringent quality control measures ensures the consistency and reliability of the drug’s production. 

Relevance for Current Drug Developers 

For companies developing drugs today, the Lorbrena case underscores the importance of strategic planning and meticulous attention to detail 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 risk management plans, meet FDA standards. 
  1. Proactive Risk Management: Identify and address potential risks 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. Invest in Quality Data: Prioritize the collection of high-quality, detailed safety and efficacy data to support the submission. 
  1. Utilize Advisory Committees: Seek feedback from advisory committees to validate data and address potential concerns, even if formal hearings are not required. 

By learning from the Lorbrena 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