Dear Regulatory Scientists,

Receiving an FDA Complete Response Letter (CRL) after submitting a New Drug Application (NDA) or Biologics License Application (BLA) can feel like a major setback. However, with the right approach, this feedback can be a springboard to ultimate approval. Let’s dive into the immediate actions to take, how to convert a CRL into a full approval, and learn from companies who have navigated this path successfully and unsuccessfully.

Immediate Actions After Receiving a CRL

1. Thoroughly Analyze the CRL: Carefully review the CRL to understand the FDA’s concerns and deficiencies cited. This includes clinical, manufacturing, and labeling issues.

2. Assemble a Response Team: Form a multidisciplinary team including regulatory affairs, clinical, manufacturing, and legal experts to address the issues raised.

3. Request a Meeting with the FDA: Schedule a Type A meeting to clarify the deficiencies and seek advice on the necessary steps to resolve them.

4. Develop a Detailed Plan: Create a comprehensive plan addressing each deficiency. This might involve conducting additional studies, reanalyzing data, or improving manufacturing processes.

5. Communicate Transparently: Keep stakeholders informed about the CRL, the plan to address it, and the expected timeline for resubmission.

Converting a CRL into Full Approval

Turning a CRL into an approval involves strategic planning, diligent execution, and often, innovation. Here are strategies that have proven successful:

1. Strengthen Clinical Data: If clinical data was a concern, consider additional trials or reanalysis to demonstrate efficacy and safety convincingly.
2.  Enhance Manufacturing Processes: Address any CMC (Chemistry, Manufacturing, and Controls) issues by improving processes, ensuring consistency, and meeting regulatory standards.
3.  Optimize Labeling: Ensure that the product labeling clearly reflects the intended use, benefits, and risks, complying with FDA requirements.
4.  Engage in Continuous Dialogue with the FDA: Maintain open communication to ensure that the FDA’s feedback is continuously incorporated.

Companies Who Succeeded After a CRL

1. Amgen: After receiving a CRL for Repatha, Amgen conducted additional cardiovascular outcomes trials, which eventually led to approval.
2.  Pfizer: Pfizer’s Xeljanz received a CRL, but additional data on long-term efficacy and safety led to approval.
3.  Johnson & Johnson: The initial CRL for Invokana was overcome by conducting additional studies to address cardiovascular risks.
4.  AstraZeneca: After a CRL for Brilinta, AstraZeneca conducted further analysis on the PLATO study, resulting in approval.
5.  Sanofi: Lemtrada received a CRL, but after additional trials and addressing FDA’s concerns, it was approved.
6. Roche: Tecentriq’s initial CRL was resolved by providing further evidence on overall survival benefits.
7.  Merck: Bridion overcame its CRL by addressing manufacturing concerns and demonstrating consistent quality.
8.  Gilead: Vemlidy received a CRL, but additional data on its efficacy in HBV patients led to approval.
9.  Bristol-Myers Squibb: Opdivo’s CRL was addressed by providing additional clinical data showing survival benefits.
10. AbbVie: Venclexta initially received a CRL, but after addressing dosing concerns and providing more clinical data, it was approved.

Companies Who Were Unsuccessful After Resubmission

1. MannKind: Afrezza received multiple CRLs due to concerns about its clinical data and manufacturing process, leading to significant delays.
2.  Dendreon: Provenge’s initial CRL highlighted issues in clinical benefit evidence and manufacturing, causing lengthy resubmissions.
3.  Eli Lilly: Solanezumab received a CRL due to insufficient efficacy data, and resubmissions did not lead to approval.
4. Sanofi: Zimulti’s CRL was due to safety concerns, and subsequent efforts to address these did not result in approval.
5. Novo Nordisk: Tresiba faced a CRL over cardiovascular safety concerns, and resolving these took extensive time.
6. Vivus: Qnexa’s CRL cited safety issues, and despite efforts, approval was delayed significantly.
7. Amarin: Vascepa’s initial CRL highlighted concerns about data robustness, delaying approval until further trials were completed.
8. Celgene: Ozanimod received a CRL due to manufacturing and clinical trial data issues, causing resubmission delays.
9. BioMarin: Kyndrisa faced a CRL due to efficacy concerns, and subsequent efforts did not achieve approval.
10. Intercept Pharmaceuticals: Ocaliva received a CRL related to safety concerns, leading to protracted discussions and delays.

Role of Strategic Regulatory Consultancies

Engaging a strategic regulatory consultancy can significantly enhance the likelihood of a successful resubmission.

Consultancies provide:

• Expertise: Deep understanding of regulatory requirements and strategies to meet them.
• Experience: Proven track records with similar products and situations.
• Resources: Access to a network of experts and additional resources for comprehensive plan execution.
• Objectivity: An external perspective to identify and address potential blind spots.
• Glossary of Terms
• CRL (Complete Response Letter): A communication from the FDA indicating that the review cycle is complete and the application is not ready for approval.
• NDA (New Drug Application): Application for the approval of a new pharmaceutical for sale and marketing in the U.S.
• BLA (Biologics License Application): Application for the approval of biologic products for sale and marketing in the U.S.
• CMC (Chemistry, Manufacturing, and Controls): Information on the drug’s manufacturing process and quality controls.
• Type A Meeting: A meeting with the FDA to discuss critical path issues and get advice on addressing deficiencies.

Examples of Companies and Drugs

Successful Resubmissions:

• Amgen (Repatha)
• Pfizer (Xeljanz)
• Johnson & Johnson (Invokana)
• AstraZeneca (Brilinta)
• Sanofi (Lemtrada)
• Roche (Tecentriq)
• Merck (Bridion)
• Gilead (Vemlidy)
• Bristol-Myers Squibb (Opdivo)
• AbbVie (Venclexta)

Unsuccessful Resubmissions:

• MannKind (Afrezza)
• Dendreon (Provenge)
• Eli Lilly (Solanezumab)
• Sanofi (Zimulti)
• Novo Nordisk (Tresiba)
• Vivus (Qnexa)
• Amarin (Vascepa)
• Celgene (Ozanimod)
• BioMarin (Kyndrisa)
• Intercept Pharmaceuticals (Ocaliva)

Lessons Learned Success Factors:

• Comprehensive understanding and addressing of FDA’s concerns.
•  Strong and robust clinical data.
• Improved manufacturing processes and controls.
•  Continuous engagement and communication with the FDA.
• Challenges Faced:
• Inadequate data to address efficacy or safety concerns.
• Persistent manufacturing issues.
• Delays in additional data collection and analysis.
• Inability to meet FDA’s expectations despite efforts.

In conclusion, receiving a CRL is not the end but a crucial part of the journey towards drug approval. With strategic planning, robust data, and continuous dialogue with the FDA, companies can turn a CRL into a successful approval. Engaging a regulatory consultancy can provide the expertise and resources needed to navigate this complex process and increase the chances of success.

Stay resilient and strategic,