Inadequate Clinical Safety Data Presentation
Severity: majorThe submission lacks adequate presentation of clinical safety data. This includes the need to provide separate tables for adverse event frequencies for indications other than the proposed one, present tabulations of new safety data combined with original application data, compare frequencies of adverse events between original and retabulated data, retabulate reasons for premature trial discontinuation incorporating new data, and describe any substantial changes in common, less serious adverse events between new and original data.
Recommended response: Re-analyze and re-present all clinical safety data, including adverse event frequencies and premature discontinuations, comparing new and original data, and providing separate tables for other indications as requested.
Missing Case Report Forms and Serious Adverse Event Narratives
Severity: criticalCase 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. Additionally, narrative summaries for all serious adverse events must be provided.
Recommended response: Compile and submit all requested case report forms and narrative summaries for deaths, discontinuations due to adverse events, and all serious adverse events.
Insufficient Updated Clinical Exposure Data
Severity: majorUpdated exposure information for the clinical studies/trials (e.g., number of subjects, person time) needs to be provided.
Recommended response: Update and submit comprehensive exposure data for all clinical trials, including number of subjects and person-time.
Incomplete Worldwide Safety Experience Summary
Severity: majorA comprehensive summary of worldwide experience on the safety of cefepime for injection and taniborbactam for injection, co-packaged for intravenous use, is required. This must include an updated estimate of use for the product marketed in other countries.
Recommended response: Collect and summarize global post-marketing safety data and usage estimates for the product from all countries where it is marketed.
Missing English Translations of Foreign Labeling
Severity: minorEnglish translations of current approved foreign labeling not previously submitted must be provided.
Recommended response: Obtain and submit English translations of all relevant current approved foreign labeling.
Inadequate Dosing Regimen for Hemodialysis Patients
Severity: criticalThe proposed dosage for patients on intermittent hemodialysis (1 g cefepime and 0.25 taniborbactam every 24 hours) is expected to result in higher taniborbactam exposures. Additional dosing regimens must be evaluated, and a probability of target attainment analysis using the latest updated population pharmacokinetic model is required to identify a dosage that provides comparable exposures and results in a probability of target attainment of ≥90%.
Recommended response: Conduct further clinical pharmacology studies, modeling, and analyses to determine an appropriate and safe dosing regimen for hemodialysis patients that achieves comparable exposures and target attainment.
