Issued January 30, 2024
Issued
January 30, 2024
Application
NDA 505b1 • 218470
Review center
CDER
Stage
Final Decision
Letter type
Complete Response Letter
This FDA letter acknowledges receipt of a draft labeling for NDA 218470 and reserves further comment until the application is otherwise adequate. It provides detailed instructions for a required safety update, outlines specific data presentation requirements for adverse events and clinical trial information, and sets a one-year deadline for resubmission or other actions under 21 CFR 314.110. The letter also specifies formatting for resubmissions and states that the product cannot be marketed until approved.
The application received a Complete Response Letter primarily due to insufficient and inadequately presented clinical safety data, requiring comprehensive updates and detailed analyses. Additionally, English translations of current approved foreign labeling are missing.
Describe in detail any significant changes or findings in the safety profile.
Recommended response: Provide a comprehensive analysis and detailed description of any new or changed safety findings, ensuring all relevant data are included and clearly presented.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows: Present new safety data from the studies/clinical trials for the proposed indication using the same format as in the original submission. Present tabulations of the new safety data combined with the original application data. Include tables that compare frequencies of adverse events in the original application with the retabulated frequencies described in the bullet above. For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.
Recommended response: Revise the safety sections to properly integrate and present all new safety data, ensuring consistent formatting, combined tabulations, comparative tables, and separate tables for other indications as requested.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
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 trial discontinuations to include all new data, providing a retabulation and a description of any emerging 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: Submit all requested case report forms and narrative summaries for subjects experiencing death or discontinuation due to adverse events, and for all serious adverse events.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
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 substantial changes in the incidence of common adverse events when comparing new and original application 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: Submit updated and complete exposure information for all clinical studies, including metrics like number of subjects and person-time.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
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 the drug's worldwide safety experience, including updated usage estimates from other markets.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Provide English translations of current approved foreign labeling not previously submitted.
Recommended response: Submit complete English translations for all current approved foreign labeling that has not yet been provided to the agency.
The primary theme of the Complete Response Letter is the inadequacy and incomplete nature of the clinical safety data presentation, requiring extensive updates, detailed analyses, and proper documentation. Additionally, there is a deficiency regarding the submission of English translations for foreign labeling.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 25%
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