Failure to establish validated test method for elemental impurities
Severity: majorEstablish a validated test method for elemental impurities as part of the drug product specification consistent with ICH Q3D and USP <232/233>. Update the drug product specifications accordingly with controls for elemental impurities, if necessary.
Recommended response: Develop and validate a test method for elemental impurities, update drug product specifications, and provide supporting data demonstrating compliance with ICH Q3D and USP <232/233>.
Cited: ICH Q3D, USP <232/233>
Inadequate prescribing information content and format
Severity: majorThe proposed labeling is not adequate. Review the labeling review resources on the PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) − a checklist of important format items from labeling regulations and guidances. If 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.
Recommended response: Revise prescribing information to comply with PLR requirements, Pregnancy and Lactation Labeling Final Rule, and SRPI checklist. Submit updated content in SPL format.
Cited: 21 CFR 314.50(l)(1)(i)
Inadequate carton and container labeling
Severity: majorSubmit draft carton and container labeling that are identical to the carton and immediate container labels submitted on December 22, 2017 (or October 18, 2017, as referenced in a prior letter).
Recommended response: Ensure carton and container labeling are consistent with the final approved prescribing information and resubmit updated drafts.
Incomplete and inadequate safety update
Severity: criticalInclude 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. Specific requirements include: describing significant changes in safety profile, presenting new safety data (tabulations, comparisons), retabulating premature discontinuations, providing case report forms/narrative summaries for deaths/serious adverse events, describing changes in common adverse events, providing updated exposure information, and summarizing worldwide experience.
Recommended response: Provide a comprehensive safety update incorporating all new nonclinical and clinical data, detailed analyses of adverse events, patient narratives, exposure data, and worldwide experience, adhering to 21 CFR 314.50(d)(5)(vi)(b).
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Missing English translations of foreign labeling
Severity: minorProvide 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.
Unresolved manufacturing facility inspection deficiencies
Severity: criticalDuring a recent inspection of the manufacturing facility for this NDA, our field investigator conveyed deficiencies to the representative of the facility. Satisfactory resolution of these deficiencies is required before this NDA may be approved.
Recommended response: Address and resolve all deficiencies identified during the manufacturing facility inspection and provide documentation of satisfactory resolution to the agency.
