Combined Safety Data Tabulations
Severity: majorPresent tabulations of the new safety data combined with the original application data.
Recommended response: Integrate and present new safety data tabulations with the original application data.
US FDA•United StatesCRL•Complete Response Letter
Complete Response Letter NDA 505b1 218571 (Mar 27, 2025)
Issued March 27, 2025
Issued
March 27, 2025
Application
NDA 505b1 • 218571
Review center
CDER
Stage
Final Decision
Letter type
Complete Response Letter
Response due March 27, 2026Requires resubmission addressing deficiencies.
Summary
This FDA letter for NDA 218571 outlines deficiencies in the application, particularly concerning labeling and safety data, and provides instructions for resubmission and further actions required for approval.
Key points
- Review the labeling review resources on the Prescription Drug Labeling Resources and Pregnancy and Lactation Labeling Final Rule websites, including regulations, guidance documents, and the Selected Requirements for Prescribing Information (SRPI).
- Use the SRPI checklist to ensure that the Prescribing Information conforms with format items in regulations and guidances if revising labeling.
- Include the SRPI checklist in the response if revising labeling.
- Present tabulations of 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.
- For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.
- Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials.
- Describe any new trends or patterns identified in trial discontinuation.
Cited reasons
- Combined Safety Data Tabulations
- Comparative Adverse Event Frequencies
- Clinical Trial Adverse Event Tables (Other Indications)
- Premature Trial Discontinuation Retabulation
- Clinical Safety Data Narratives and CRFs
- Changes in Common Adverse Event Incidence
- Updated Clinical Exposure Information
- Worldwide Safety Experience Summary
Recommended actions
- Review the labeling review resources on the Prescription Drug Labeling Resources and Pregnancy and Lactation Labeling Final Rule websites, including regulations, guidance documents, and the Selected Requirements for Prescribing Information (SRPI).
- Use the SRPI checklist to ensure that the Prescribing Information conforms with format items in regulations and guidances if revising labeling.
- Include the SRPI checklist in the response if revising labeling.
- Present tabulations of 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.
- For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.
- Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials.
- Describe any new trends or patterns identified in trial discontinuation.
Deficiency summary
The FDA issued a Complete Response Letter for NDA 218571, primarily due to insufficient and inadequately presented clinical safety data, including adverse event tabulations, case report forms, narrative summaries, updated exposure information, and a summary of worldwide safety experience. Additionally, English translations of foreign labeling are required.
Findings
Comparative Adverse Event Frequencies
Severity: majorInclude tables that compare frequencies of adverse events in the original application with the retabulated frequencies described in the bullet above.
Recommended response: Provide comparative tables showing adverse event frequencies between original and updated data.
Clinical Trial Adverse Event Tables (Other Indications)
Severity: majorFor indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.
Recommended response: Compile and present separate adverse event tables for all indications, clearly differentiating by proposed and other indications.
Premature Trial Discontinuation Retabulation
Severity: majorPresent a retabulation 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: Retabulate and analyze reasons for premature trial discontinuation, including new trial data, and identify any emerging trends.
Clinical Safety Data Narratives and CRFs
Severity: majorProvide 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: Submit all requested case report forms and comprehensive narrative summaries for all deaths, trial discontinuations due to adverse events, and serious adverse events.
Changes in Common Adverse Event Incidence
Severity: majorDescribe 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: Analyze and describe any substantial changes in the incidence of common, less serious adverse events between new and original clinical data.
Updated Clinical Exposure Information
Severity: majorProvide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).
Recommended response: Update and submit complete clinical exposure information, including subject numbers and person-time data, for all studies.
Worldwide Safety Experience Summary
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 comprehensive summary of the drug's worldwide safety experience, including updated use estimates from other countries.
Foreign Labeling Translations
Severity: majorProvide 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.
Regulatory context
- Submission stage
- final decision
- Regulatory pathway
- NDA
Impact
- Impact score
- 0.75
- Estimated delay
- 545 days
- Estimated rework cost
- $0
- Subsequent action
- resubmission
Strategic insights
The application lacks comprehensive and well-organized clinical safety data, requiring significant updates to adverse event reporting, exposure information, and global safety summaries. Additionally, administrative deficiencies related to foreign labeling translations need to be addressed.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 25%
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