Issued March 7, 2024
Issued
March 7, 2024
Application
NDA 505b1 • 215749
Review center
CDER
Stage
Final Decision
Letter type
Complete Response Letter
This letter from the FDA outlines deficiencies in NDA 215749, primarily focusing on the requirement for a comprehensive safety update and instructions for resubmission. It details specific data and documentation needed for the safety update, including new and combined safety data, adverse event comparisons, and worldwide safety experience. The letter also sets a one-year deadline for resubmission or other actions and provides guidance on the format and content of a resubmission.
The FDA issued a Complete Response Letter for NDA 215749, primarily due to significant deficiencies in the safety data update and reporting. The agency requires a comprehensive safety update, detailed analysis of adverse events, updated clinical exposure information, worldwide safety experience, and English translations of foreign labeling.
A comprehensive safety update is required, as described at 21 CFR 314.50(d)(5)(vi)(b), including data from all nonclinical and clinical studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.
Recommended response: Prepare a comprehensive safety update report integrating all nonclinical and clinical data as per regulatory requirements.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Describe in detail any significant changes or findings in the safety profile.
Recommended response: Analyze and document any significant changes or new findings in the safety profile since the original submission.
When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data. This includes presenting new safety data from studies for the proposed indication in the same format, tabulating new safety data combined with original application data, including tables comparing frequencies of adverse events, and providing separate tables for frequencies of adverse events for indications other than the proposed indication.
Recommended response: Re-analyze and re-present all adverse event data, including discontinuations and serious adverse events, integrating new data and comparing frequencies as requested.
Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials. Describe any new trends or patterns identified.
Recommended response: Update the analysis of premature trial discontinuations, incorporating new trial data and identifying any emerging trends.
Provide case report forms and narrative summaries for each subject who died during a clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.
Recommended response: Compile and submit all requested case report forms and narrative summaries for deaths and serious adverse events.
Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original application data.
Recommended response: Conduct a comparative analysis of common adverse event incidence between new and original data, and report any substantial changes.
Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).
Recommended response: Update and submit all clinical exposure information, including subject numbers and person-time data.
Provide a summary of worldwide experience on the safety of this drug. Include an updated estimate of use for drug marketed in other countries.
Recommended response: Compile and submit a comprehensive summary of worldwide safety experience and updated usage estimates for the drug.
Provide English translations of current approved foreign labeling not previously submitted.
Recommended response: Obtain and submit English translations of all current approved foreign labeling not yet provided.
The primary theme is the inadequacy and incompleteness of the safety data presented, requiring a thorough re-evaluation and comprehensive submission of all relevant clinical and nonclinical safety information, including global data and proper documentation.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 25%
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