Inadequate Labeling Format and Content
Severity: majorIf you revise labeling, use the SRPI checklist to ensure that the Prescribing Information conforms with format items in regulations and guidances. Your response must include updated content of labeling [21 CFR 314.50(l)(1)(i)]in structured product labeling (SPL) format as described at FDA.gov.
Recommended response: Revise the Prescribing Information to conform with regulatory format requirements using the SRPI checklist and submit updated content of labeling in Structured Product Labeling (SPL) format.
Cited: 21 CFR 314.50(l)(1)(i)
Comprehensive Safety Update Required
Severity: criticalWhen you respond to the above deficiencies, include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical studies/trials of the drug under consideration regardless of indication, dosage form, or dose level. Describe in detail any significant changes or findings in the safety profile. 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. 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. 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: Prepare a comprehensive safety update incorporating all new nonclinical and clinical safety data. Detail any significant changes in the safety profile, re-tabulate adverse events and discontinuations, and compare new data with original application data, identifying any new trends.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Adverse Event Tables for Other Indications
Severity: majorFor indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.
Recommended response: Generate and submit separate tables detailing adverse event frequencies for clinical trials conducted for indications other than the proposed one.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Missing Case Report Forms and Narrative Summaries
Severity: criticalProvide 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 subjects who died or discontinued due to adverse events, and for all serious adverse events.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Incomplete Clinical Exposure Information
Severity: majorProvide 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 and trials, including metrics such as number of subjects and person-time.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Missing Worldwide Safety Experience Summary
Severity: majorProvide 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: Prepare and submit a comprehensive summary of the drug's worldwide safety experience, including updated estimates of use in all countries where it is marketed.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Missing English Translations of Foreign Labeling
Severity: majorProvide English translations of current approved foreign labeling not previously submitted.
Recommended response: Submit English translations for all current approved foreign labeling that has not yet been provided to the agency.
Carton and Container Labeling Comments Reserved
Severity: infoWe reserve comment on the proposed labeling until the application is otherwise adequate.
Recommended response: Address all other deficiencies first; be prepared for potential future comments on carton and container labeling once the application is otherwise adequate.
