Issued October 10, 2024
Issued
October 10, 2024
Application
NDA 505b1 • 218923
Review center
CDER
Stage
Final Decision
Letter type
Complete Response Letter
This FDA letter communicates deficiencies in NDA 218923, deferring clinical inspections and reserving comments on labeling and proprietary name until the application is otherwise adequate. It outlines specific requirements for a safety update, including detailed data presentation and analysis, and provides instructions for resubmission within one year, emphasizing that all deficiencies must be addressed.
The FDA issued a Complete Response Letter for NDA 218923 primarily due to significant deficiencies in the clinical safety data package. Key issues include the need for a comprehensive safety update as per 21 CFR 314.50(d)(5)(vi)(b), inadequate presentation and analysis of new and existing clinical safety data, missing case report forms and narrative summaries for adverse events, and a lack of worldwide safety experience summary. Additionally, updated clinical exposure information and English translations of foreign labeling are required. The proprietary name, though conditionally acceptable, needs resubmission. Clinical inspections were deferred due to travel restrictions.
The proposed proprietary name was found conditionally acceptable but requires resubmission concurrently with the response to other application deficiencies.
Recommended response: Resubmit the proprietary name application along with the complete response to address all identified deficiencies.
A comprehensive safety update is required, including data from all nonclinical and clinical studies/trials of the drug under consideration, regardless of indication, dosage form, or dose level, as described in 21 CFR 314.50(d)(5)(vi)(b).
Recommended response: Compile and submit a complete safety update covering all relevant nonclinical and clinical data, ensuring full compliance with 21 CFR 314.50(d)(5)(vi)(b).
Cited: 21 CFR 314.50(d)(5)(vi)(b)
The submission lacks detailed descriptions of significant safety profile changes, proper presentation of new safety data (including combined tabulations and comparisons with original data), separate tables for adverse events in non-proposed indications, and retabulation of premature trial discontinuations with trend analysis. Additionally, changes in the incidence of common, less serious adverse events between new and original data must be described.
Recommended response: Conduct a thorough re-analysis and re-presentation of all clinical safety data, ensuring new data is integrated, compared, and presented clearly, addressing all specific requests for tabulations and trend analyses.
Case report forms and narrative summaries are required for all subjects who died during a clinical trial or who did not complete a trial due to an adverse event. Narrative summaries for all serious adverse events are also required.
Recommended response: Collect and submit all requested case report forms and narrative summaries for deaths, discontinuations due to adverse events, and all serious adverse events.
Updated exposure information for the clinical studies/trials, including the number of subjects and person-time, is required.
Recommended response: Provide comprehensive and updated exposure information for all clinical trials.
A summary of worldwide experience on the safety of the drug, including an updated estimate of use for the drug marketed in other countries, is required.
Recommended response: Compile and submit a detailed summary of worldwide safety experience, including usage estimates from all countries where the drug is marketed.
English translations of all current approved foreign labeling not previously submitted are required.
Recommended response: Obtain and submit English translations for all current approved foreign labeling that has not yet been provided.
OSIS inspections were deferred during this review cycle due to travel restrictions and will be conducted upon resubmission. This is an informational note from the agency, not a deficiency requiring direct action by the sponsor, but it indicates a pending regulatory activity.
Recommended response: Prepare for potential OSIS inspections upon resubmission by ensuring all clinical site documentation and data are readily available and auditable.
The primary themes of this Complete Response Letter are the critical need for a robust and comprehensively presented clinical safety data package, including detailed adverse event reporting and global safety experience. There are also significant data integrity and documentation gaps related to clinical trials and administrative requirements for labeling. The deferral of inspections indicates that even if data issues are resolved, further regulatory scrutiny is pending.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 25%
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