Issued April 2, 2025
Issued
April 2, 2025
Application
NDA 505b1 • 218345
Review center
CDER
Stage
Final Decision
Letter type
Complete Response Letter
This FDA letter provides feedback on NDA 218345, acknowledging revised labeling and carton/container labeling submissions, but reserving further comment until the application is otherwise adequate. It outlines detailed requirements for a safety update, including specific data presentation and analysis, and provides instructions for resubmission or other actions within one year.
The FDA issued a Complete Response Letter primarily due to significant deficiencies in the safety data presentation, analysis, and reporting from clinical trials, including the need for updated exposure information, case report forms for serious events, and a comprehensive summary of worldwide safety experience. Additionally, English translations of foreign labeling are required. The agency reserves further comments on labeling until other deficiencies are addressed.
Describe in detail any significant changes or findings in the safety profile.
Recommended response: Conduct a thorough re-analysis of all safety data to identify and describe any significant changes or new findings in the safety profile.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Incorporate new safety data into sections describing discontinuations, serious adverse events, and common adverse events, including presenting new data in the same format, combining with original data, comparing frequencies, and providing separate tables for other indications.
Recommended response: Reformat and present all new safety data according to FDA guidelines, ensuring proper integration and comparison with original submission data, and providing separate tables for different indications.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Present a retabulation of reasons for premature trial discontinuation, incorporating drop-outs from newly completed trials, and describe any new trends or patterns identified.
Recommended response: Update and retabulate all premature trial discontinuation data, including new trial data, and analyze for new trends or patterns.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
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 from clinical trials.
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: Analyze and describe any significant changes in the incidence of common adverse events between the original and new safety data.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).
Recommended response: Update and submit comprehensive exposure information for all clinical studies/trials.
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 drug usage estimates from all countries where the drug is marketed.
Provide English translations of current approved foreign labeling not previously submitted.
Recommended response: Obtain and submit English translations for all relevant foreign approved labeling that has not yet been provided.
Further comment on the proposed prescribing information and carton/container labeling is reserved until the application is otherwise adequate.
Recommended response: Review and update all proposed labeling (prescribing information, carton, container) in anticipation of future comments, ensuring compliance with FDA guidelines.
The primary theme of the deficiencies revolves around the completeness, accuracy, and appropriate presentation of safety data from clinical trials, including the need for detailed adverse event reporting, updated exposure information, and global safety surveillance. Labeling issues, specifically foreign labeling translations, also contribute to the deficiencies.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
Document viewer
Read the FDA letter and send context to the co-pilot at any time.