Unresolved Facility Inspection Deficiencies
Severity: criticalThe assessment of application approvability is pending resolution of inspection deficiencies. A re-inspection of the facility may be required upon receipt of the complete response. The sponsor must work with the facility to resolve all related deficiencies.
Recommended response: Address all outstanding FDA Form 483 observations and ensure corrective and preventive actions (CAPA) are fully implemented and verified for effectiveness. Coordinate with the facility for potential re-inspection readiness and provide documentation of resolution.
Inadequate Safety Update Submission
Severity: majorA comprehensive safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), is required. This update must include data from all nonclinical and clinical studies/trials of the drug, regardless of indication, dosage form, or dose level, and describe any significant changes or findings in the safety profile.
Recommended response: Prepare a comprehensive safety update covering all nonclinical and clinical studies/trials as per 21 CFR 314.50(d)(5)(vi)(b), detailing any significant changes or findings in the safety profile and incorporating new safety data as specified.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Incomplete AE Frequency Tables for Other Indications
Severity: majorSeparate tables for the frequencies of adverse events occurring in clinical trials for indications other than the proposed indication must be provided.
Recommended response: Generate and submit separate tables detailing adverse event frequencies for all clinical trials conducted for indications other than the primary proposed indication, ensuring consistency in format with the original submission.
Missing Case Report Forms and Narratives for Deaths/Discontinuations due to AEs
Severity: majorCase report forms and narrative summaries are required for each subject who died during a clinical trial or who did not complete a trial because of an adverse event.
Recommended response: Compile and submit all case report forms and detailed narrative summaries for subjects who died or discontinued clinical trials due to adverse events.
Missing Narrative Summaries for Serious Adverse Events
Severity: majorNarrative summaries for all serious adverse events observed in clinical trials must be provided.
Recommended response: Prepare and submit comprehensive narrative summaries for all serious adverse events observed in clinical trials.
Outdated Clinical Exposure Information
Severity: majorUpdated exposure information for the clinical studies/trials, including metrics such as the number of subjects and person-time, is required.
Recommended response: Update and submit all clinical exposure information, ensuring accurate reporting of subject numbers and person-time for all studies.
