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The Klisyri Resubmission Journey: From FDA CRL to Approval 

Categories: Regulatory Strategy
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Hello Regulatory Scientists, 

Today, let’s explore the journey of Klisyri (tirbanibulin) 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: Klisyri (tirbanibulin) 
Mechanism of Action: Microtubule inhibitor, which disrupts cellular processes essential for the growth and spread of actinic keratosis cells 
Indication: Treatment of actinic keratosis on the face or scalp 
Initial Submission Date: December 2019 

The Complete Response Letter (CRL) 

CRL Date: August 2020 
CRL Concerns: 

  1. Manufacturing Process: The FDA raised concerns about the quality and consistency of the drug’s manufacturing process. 
  1. Efficacy Data: Request for more comprehensive data to support the drug’s clinical efficacy. 
  1. Safety Data: Concerns about the safety profile, particularly regarding local skin reactions. 
  1. Risk Management Plan: Need for a robust risk management plan to monitor and mitigate potential adverse effects. 

Resubmission Strategy 

Almirall, the company behind Klisyri, implemented a comprehensive strategy to address the FDA’s concerns: 

  1. Manufacturing Process Improvements: Enhanced the manufacturing process to ensure consistency and quality, including more rigorous quality control measures. 
  1. Additional Clinical Data: Conducted further studies to gather more robust data on the efficacy of Klisyri, focusing on its effectiveness and safety profile in treating actinic keratosis. 
  1. Safety Data Enhancement: Provided detailed safety data, with a focus on local skin reactions, to demonstrate that the benefits of Klisyri outweighed the risks. 
  1. Risk Management Plan: Developed a detailed risk management plan, including patient monitoring guidelines and educational materials for healthcare providers. 
  1. Continuous FDA Engagement: Maintained open communication with the FDA to ensure alignment on the resubmission strategy and clarify any outstanding questions. 

Resubmission Date: November 2020 

Outcome 

Approval Date: December 2020 
Klisyri was approved for the treatment of actinic keratosis on the face or scalp, providing a new, effective option for patients with this common precancerous skin condition. 

Lessons Learned 

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

  1. Manufacturing Process Improvements: Ensuring the quality and consistency of the manufacturing process is crucial. Proactive improvements and rigorous quality control measures can prevent setbacks. 
  1. Comprehensive Data Collection: Providing extensive clinical data to support the drug’s efficacy and safety profile is essential to addressing FDA concerns. 
  1. Enhanced Safety Monitoring: Ensuring thorough understanding and management of potential adverse effects, particularly local skin reactions, is crucial. 
  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. 

Relevance for Current Drug Developers 

For companies developing drugs today, the Klisyri 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 manufacturing processes and clinical data, 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 Klisyri 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