Inadequate Product Quality Data for Impurities
Severity: majorThe application lacks updated release and stability specifications for identified and unidentified impurities. Analytical methods and their validations are required, along with release and stability data from at least three batches to demonstrate that impurity levels do not exceed allowable daily intakes as per FDA Guidance. A commitment to continuous monitoring of impurities throughout the product's shelf-life is also needed.
Recommended response: Revise release and stability specifications to include all identified and unidentified impurities. Develop and validate analytical methods for impurity testing. Provide stability data from at least three batches demonstrating compliance with allowable daily intake limits. Implement a plan for continuous impurity monitoring throughout shelf-life.
Cited: FDA Guidance
Missing Required Medication Guide Statement on Labeling
Severity: minorThe carton and container labeling must include the bolded statement "ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide." or an appropriate alternative, as mandated by 21 CFR 208.24(d).
Recommended response: Update carton and container labeling to include the required Medication Guide statement as per 21 CFR 208.24(d).
Cited: 21 CFR 208.24(d)
Incomplete and Inadequate Clinical Safety Update
Severity: majorA comprehensive safety update, as described in 21 CFR 314.50(d)(5)(vi)(b), is required. This update must include: detailed description of significant changes or findings in the safety profile; incorporation of new safety data from studies/clinical trials for the proposed indication, presented in the same format as the original submission, with tabulations of new data combined with original application data, and comparative tables of adverse event frequencies; separate tables for adverse event frequencies for indications other than the proposed one; retabulation of reasons for premature trial discontinuation, including new drop-outs, and description of new trends; case report forms and narrative summaries for all subjects who died or discontinued due to an adverse event, and for all serious adverse events; information suggesting substantial changes in the incidence of common, less serious adverse events between new and original data; updated exposure information for clinical studies/trials (e.g., number of subjects, person time); a summary of worldwide safety experience, including updated estimates of use for drugs marketed in other countries; and English translations of current approved foreign labeling not previously submitted.
Recommended response: Conduct a thorough and systematic review of all nonclinical and clinical safety data. Prepare a detailed safety update addressing each specific point raised, ensuring all new data are integrated, analyzed, and presented according to regulatory requirements, including worldwide experience and foreign labeling translations.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Prescribing Information and Carton/Container Labeling Review Deferred
Severity: infoThe agency reserves comment on the proposed Prescribing Information and Carton and Container Labeling until other deficiencies are resolved. The applicant is encouraged to review FDA's Prescription Drug Labeling Resources and Pregnancy and Lactation Labeling Final Rule websites, and use the Selected Requirements for Prescribing Information (SRPI) checklist to ensure compliance with format items in regulations and guidances. Any response must include updated content of labeling in structured product labeling (SPL) format as described at 21 CFR 314.50(l)(1)(i).
Recommended response: Proactively review and revise Prescribing Information and Carton and Container Labeling using FDA's Prescription Drug Labeling Resources and the SRPI checklist to ensure compliance with format and content requirements, preparing for future review. Ensure updated content is provided in SPL format.
Cited: 21 CFR 314.50(l)(1)(i)
