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The Inrebic Resubmission Journey: From FDA CRL to Approval 

Categories: Clinical Studies
The FDA Srug Approval Process from nonclinical to clinical development and Phase 1 to Phase 3 Studies leading to approval.
Navigating Accelerated Approval Pathways: A Story of Speeding to Success

Hello Regulatory Scientists, 

Today, let’s explore the journey of Inrebic (fedratinib) 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: Inrebic (fedratinib) 
Mechanism of Action: Janus kinase 2 (JAK2) inhibitor, which targets and inhibits JAK2 to reduce abnormal blood cell production and alleviate symptoms of myelofibrosis 
Indication: Treatment of intermediate-2 or high-risk primary or secondary myelofibrosis 
Initial Submission Date: June 2013 

The Complete Response Letter (CRL) 

CRL Date: November 2013 
CRL Concerns: 

  1. Safety Profile: The FDA raised significant concerns about the risk of Wernicke’s encephalopathy observed in clinical trials. 
  1. Additional Data Requirements: Request for more detailed safety data and evidence to support the efficacy of the drug. 
  1. Risk Management Plan: Need for a robust risk management plan to monitor and mitigate potential adverse effects. 

Resubmission Strategy 

Bristol-Myers Squibb, the company behind Inrebic, implemented a comprehensive strategy to address the FDA’s concerns: 

  1. Enhanced Safety Monitoring: Conducted further studies to gather more detailed safety data, specifically focusing on the risk of Wernicke’s encephalopathy. 
  1. Risk Management Plan: Developed a comprehensive risk management plan, including patient monitoring guidelines, educational materials for healthcare providers, and protocols for early detection and management of Wernicke’s encephalopathy. 
  1. Additional Clinical Data: Provided additional data and analyses to support the drug’s efficacy and demonstrate a favorable benefit-risk profile. 
  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 2018 

Outcome 

Approval Date: August 2019 
Inrebic was approved for the treatment of intermediate-2 or high-risk primary or secondary myelofibrosis, providing a new therapeutic option for patients with this challenging condition. 

Lessons Learned 

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

  1. Enhanced Safety Monitoring: Ensuring thorough understanding and management of potential safety risks, such as Wernicke’s encephalopathy, is crucial to addressing FDA concerns. 
  1. Comprehensive Data Collection: Providing extensive clinical data to support the safety and efficacy profile of the drug is essential for regulatory approval. 
  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 Inrebic 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 safety 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 Inrebic 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 

Picture of Asad Khan
Asad Khan