Unresolved Objectionable Conditions at Manufacturing Facility
Severity: criticalDuring a review of records requested under section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act, and provided by Alkermes, Inc./FEI: 1000142940, Wilmington, OH, USA manufacturing facility, the FDA noted objectionable conditions. Satisfactory resolution of these objectionable conditions is required (e.g., preapproval inspection and adequate facility responses addressing these conditions) before this application may be approved.
Recommended response: Address all objectionable conditions identified during the facility inspection and provide an adequate response, potentially requiring a re-inspection and demonstrating compliance with cGMP.
Cited: section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act
Labeling Review Reserved Pending Other Issues
Severity: minorThe agency reserves comment on the proposed labeling until the application is otherwise adequate. The sponsor is encouraged to review PLR Requirements for Prescribing Information, Pregnancy and Lactation Labeling Final Rule, and the Selected Requirements for Prescribing Information (SRPI). Any revised labeling must conform to format items in regulations and guidances, and the response must include updated content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format.
Recommended response: Revise labeling according to PLR requirements, Pregnancy and Lactation Labeling Final Rule, and SRPI checklist, and submit updated content in SPL format once other deficiencies are resolved.
Cited: 21 CFR 314.50(l)(1)(i)
Inadequate Clinical Trial Discontinuation Data
Severity: majorPresent a re-tabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials. Describe any new trends or patterns identified.
Recommended response: Re-tabulate and analyze reasons for premature trial discontinuation, including new trial data, and identify any new trends or patterns.
Missing Case Report Forms and Narrative Summaries for Deaths/SAEs
Severity: majorProvide case report forms and narrative summaries for each patient who died during a clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.
Recommended response: Submit all requested case report forms and narrative summaries for patient deaths and serious adverse events to allow for a complete safety evaluation.
Inadequate Updated Clinical Exposure Information
Severity: majorProvide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).
Recommended response: Provide comprehensive updated exposure information for all clinical studies, including subject numbers and person-time data, to support safety and efficacy assessments.
Missing Summary of Worldwide Safety Experience
Severity: majorProvide a summary of worldwide experience on the safety of this drug. Include an updated estimate of use for drug marketed in other countries.
Recommended response: Compile and submit a summary of worldwide safety experience, including usage estimates from other countries where the drug is marketed, to provide a global safety profile.
Missing English Translations of Foreign Labeling
Severity: minorProvide English translations of current approved foreign labeling not previously submitted.
Recommended response: Submit English translations of all current approved foreign labeling that has not yet been provided for review.
