Issued January 17, 2025
Issued
January 17, 2025
Application
NDA 505b1 • 219112
Review center
CDER
Stage
Final Decision
Letter type
Complete Response Letter
This document from the U.S. Food and Drug Administration (FDA) addresses deficiencies in New Drug Application (NDA) 219112, specifically regarding proposed labeling and the requirement for a comprehensive safety update.
The FDA issued a Complete Response Letter for NDA 219112, primarily citing deficiencies related to the comprehensive safety update, clinical data presentation, and labeling. Key issues include the need for detailed safety profile changes, re-tabulation of adverse event frequencies, provision of case report forms for serious events, updated exposure information, and a summary of worldwide safety experience. Revisions to carton and container labeling are also required, incorporating the safety update as per 21 CFR 314.50(d)(5)(vi)(b).
Submit draft carton and container labeling revised as follows: SAFETY UPDATE When you respond to the above deficiencies, include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b).
Recommended response: Revise carton and container labeling to incorporate updated safety information and ensure compliance with 21 CFR 314.50(d)(5)(vi)(b).
Cited: 21 CFR 314.50(d)(5)(vi)(b)
For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials. Present new safety data from the studies/clinical trials for the proposed indication using the same format as in the original submission. Present tabulations of the new safety data combined with the original application data. Include tables that compare frequencies of adverse events in the original application with the retabulated frequencies described in the bullet above.
Recommended response: Re-analyze and present adverse event data, ensuring separate tables for different indications and combined/comparative tabulations of new and original safety data.
Provide case report forms and narrative summaries for each subject 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: Compile and submit all requested case report forms and narrative summaries for deaths and serious adverse events from clinical trials.
Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).
Recommended response: Update and submit comprehensive exposure information for all clinical studies, including subject numbers and person-time data.
Provide 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: Prepare and submit a comprehensive summary of worldwide safety experience, including usage estimates from other countries.
Provide English translations of current approved foreign labeling not previously submitted.
Recommended response: Obtain and submit English translations for all current approved foreign labeling that has not yet been provided.
Describe in detail any significant changes or findings in the safety profile.
Recommended response: Conduct a thorough analysis to identify and describe any significant changes or new findings in the drug's safety profile.
Present 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 discontinuations, integrating data from newly completed trials and identifying new trends.
Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original application data.
Recommended response: Compare new and original application data to identify and describe any substantial changes in the incidence of common adverse events.
The primary theme of the deficiencies revolves around the inadequacy of the safety data presentation and the need for a comprehensive, integrated safety update across all clinical and nonclinical studies, impacting both the clinical modules and labeling. There is a strong emphasis on detailed adverse event reporting, exposure data, and global safety experience.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
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