Comprehensive Safety Update Required
Severity: majorA comprehensive safety update is required as described at 21 CFR 314.50(d)(5)(vi)(b). This includes data from all nonclinical and clinical studies/trials, detailed descriptions of significant safety profile changes, incorporation of new safety data into existing sections, and comparison of adverse event frequencies.
Recommended response: Compile and submit a comprehensive safety update as per 21 CFR 314.50(d)(5)(vi)(b), integrating all new nonclinical and clinical safety data, and providing detailed comparisons of adverse event frequencies.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Adverse Event Frequencies for Other Indications
Severity: majorProvide separate tables for the frequencies of adverse events occurring in clinical trials for indications other than the proposed indication.
Recommended response: Generate and submit separate tables detailing adverse event frequencies for all clinical trials related to indications other than the primary proposed indication.
Missing Case Report Forms and Narratives for Deaths/SAEs
Severity: majorProvide 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 missing case report forms and narrative summaries for deaths, discontinuations due to AEs, and all serious adverse events.
Updated Clinical Exposure Information
Severity: majorProvide updated exposure information for the clinical studies/trials, including details such as the number of subjects and person-time.
Recommended response: Update and submit comprehensive exposure information for all clinical studies, including subject counts and person-time data.
Worldwide Safety Experience Summary
Severity: majorProvide a summary of worldwide experience on the safety of this drug, including an updated estimate of use for the drug marketed in other countries.
Recommended response: Prepare and submit a detailed summary of the drug's worldwide safety experience, incorporating updated usage estimates from all countries where it is marketed.
English Translations of Foreign Labeling
Severity: majorProvide English translations of current approved foreign labeling not previously submitted.
Recommended response: Obtain and submit English translations for all current approved foreign labeling documents not yet provided to the agency.
Labeling Comments Reserved
Severity: infoThe agency reserves comment on the proposed prescribing information, carton, and container labeling until the application is otherwise adequate, implying that the underlying clinical and safety deficiencies must be resolved first.
Recommended response: Address all underlying clinical and safety deficiencies to allow the agency to proceed with the labeling review. Review FDA's Prescription Drug Labeling Resources and Pregnancy and Lactation Labeling Final Rule websites for guidance.
