Product Quality Deficiencies Impacting Bioavailability Studies
Severity: majorOutstanding product quality deficiencies need to be addressed, as they impact the acceptability of drug product lots used in relative bioavailability (Study 14323/21-22) and food effect (Study 14324/21-22) studies. The acceptability of these lots will be assessed upon NDA resubmission.
Recommended response: Address all outstanding product quality deficiencies and provide data demonstrating the acceptability of the drug product lots used in the specified bioavailability studies upon resubmission.
Resubmission of Proprietary Name
Severity: minorThe proposed proprietary name, Arbli, was found conditionally acceptable pending approval of the application. It must be resubmitted when all other application deficiencies identified in this letter have been addressed.
Recommended response: Resubmit the proprietary name application once all other deficiencies in the Complete Response Letter have been fully addressed.
Comprehensive Safety Update Required
Severity: majorA comprehensive safety update, including data from all nonclinical and clinical studies/trials of the drug under consideration (regardless of indication, dosage form, or dose level), is required as described at 21 CFR 314.50(d)(5)(vi)(b).
Recommended response: Prepare a detailed safety update covering all nonclinical and clinical data, ensuring compliance with 21 CFR 314.50(d)(5)(vi)(b).
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Detailed Adverse Event Data Presentation
Severity: majorNew safety data from clinical trials for the proposed indication must be presented using the same format as the original submission. Tabulations of new safety data combined with original application data, and comparative tables of adverse event frequencies, are required. Separate tables for adverse event frequencies are needed for indications other than the proposed indication.
Recommended response: Ensure all new adverse event data are integrated and presented according to FDA's specified format, including comparative tables and separate tables for other indications.
Retabulation of Premature Trial Discontinuations
Severity: majorA retabulation of the reasons for premature trial discontinuation, incorporating drop-outs from newly completed trials, is required. Any new trends or patterns identified must be described.
Recommended response: Update and retabulate all premature trial discontinuation data, analyzing and reporting any new trends or patterns.
Submission of Case Report Forms and Narratives for Deaths/Serious AEs
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 are required.
Recommended response: Compile and submit all requested case report forms and narrative summaries for deaths and serious adverse events, ensuring completeness and accuracy.
Analysis of Changes in Common Adverse Event Incidence
Severity: majorInformation suggesting a substantial change in the incidence of common, but less serious, adverse events between the new data and the original application data must be described.
Recommended response: Conduct a comparative analysis of common adverse event incidence between new and original data, highlighting any significant changes.
Updated Clinical Exposure Information
Severity: majorUpdated exposure information for the clinical studies/trials, including details such as the number of subjects and person-time, is required.
Recommended response: Provide a comprehensive update on clinical exposure data, including subject numbers and person-time, for all relevant studies.
Summary of Worldwide Safety Experience
Severity: majorA summary of worldwide experience on the safety of this drug is required, including an updated estimate of use for the drug marketed in other countries.
Recommended response: Compile and submit a summary of global safety data and usage estimates for the drug.
English Translations of Foreign Labeling
Severity: minorEnglish translations of current approved foreign labeling not previously submitted must be provided.
Recommended response: Provide English translations for all relevant foreign approved labeling that has not yet been submitted.
