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US FDA•United StatesCRL•Complete Response Letter

Complete Response Letter NDA 505b1 216195 (Jul 25, 2024)

Issued July 25, 2024

Issued

July 25, 2024

Application

NDA 505b1 • 216195

Review center

CDER

Stage

Final Decision

Letter type

Complete Response Letter

Response due July 25, 2025Requires resubmission addressing deficiencies.

Summary

This document is a Complete Response Letter (CRL) from the FDA for New Drug Application (NDA) 216195, outlining deficiencies that prevent approval and detailing the requirements for a complete response resubmission, including specific instructions for a safety update and addressing facility issues.

Key points

  • The facility must provide satisfactory responses to deficiencies indicated on the FDA 483 to the FDA office prior to complete response resubmission.
  • The complete response should include the date(s) of the facility's response(s) to the FDA Form 483.
  • Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) in the complete response.
  • The safety update should include data from all nonclinical and clinical studies/trials of the drug under consideration, regardless of indication, dosage form, or dose level.
  • Describe in detail any significant changes or findings in the safety profile.
  • Incorporate new safety data into sections describing discontinuations due to adverse events, serious adverse events, and common adverse events.
  • Present new safety data from 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.

Cited reasons

  • Unresolved Facility Inspection Findings (FDA 483)
  • Comprehensive Safety Update Required
  • Significant Changes in Safety Profile Description
  • Incomplete/Inadequate Incorporation of New Safety Data
  • Premature Trial Discontinuation Data Update
  • Missing/Incomplete Case Report Forms and Narrative Summaries
  • Missing Updated Clinical Exposure Information
  • Incomplete Worldwide Safety Experience Summary

Recommended actions

  • The facility must provide satisfactory responses to deficiencies indicated on the FDA 483 to the FDA office prior to complete response resubmission.
  • The complete response should include the date(s) of the facility's response(s) to the FDA Form 483.
  • Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) in the complete response.
  • The safety update should include data from all nonclinical and clinical studies/trials of the drug under consideration, regardless of indication, dosage form, or dose level.
  • Describe in detail any significant changes or findings in the safety profile.
  • Incorporate new safety data into sections describing discontinuations due to adverse events, serious adverse events, and common adverse events.
  • Present new safety data from 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.

Deficiency summary

The FDA issued a Complete Response Letter for NDA 216195, citing unresolved facility inspection findings (FDA 483) and numerous deficiencies related to the clinical safety data. Key issues include the need for a comprehensive safety update, detailed presentation of new and combined safety data, updated exposure information, worldwide safety experience, and English translations of foreign labeling. Missing case report forms and narrative summaries for deaths and serious adverse events were also highlighted.

Findings

Unresolved Facility Inspection Findings (FDA 483)

Severity: critical

The facility must provide satisfactory responses to deficiencies identified during the FDA 483 inspection prior to resubmission. Resolution of these findings is critical for application approvability and may involve re-inspection.

Recommended response: Address all FDA 483 observations with comprehensive responses and corrective actions. Coordinate with the facility to ensure all deficiencies are resolved and documented before resubmission.

Comprehensive Safety Update Required

Severity: major

A complete safety update is required, encompassing data from all nonclinical and clinical studies/trials of the drug, regardless of indication, dosage form, or dose level, as described in 21 CFR 314.50(d)(5)(vi)(b).

Recommended response: Prepare a detailed safety update covering all requested aspects, ensuring consistency and completeness across all studies.

Cited: 21 CFR 314.50(d)(5)(vi)(b)

Significant Changes in Safety Profile Description

Severity: major

Provide a detailed description of any significant changes or new findings in the safety profile of the drug.

Recommended response: Conduct a thorough re-analysis of all safety data to identify and clearly describe any new or significant changes in the safety profile.

Incomplete/Inadequate Incorporation of New Safety Data

Severity: major

New safety data from studies/clinical trials for the proposed indication must be presented in the same format as the original submission, combined with original application data, and compared with original frequencies. Separate tables for adverse events in other indications are also required.

Recommended response: Re-tabulate and present all new safety data, ensuring proper integration with original data, comparative analyses, and appropriate formatting for all indications.

Premature Trial Discontinuation Data Update

Severity: major

Retabulate reasons for premature trial discontinuation, incorporating drop-outs from newly completed trials, and describe any new trends or patterns identified.

Recommended response: Update and analyze premature discontinuation data, focusing on identifying and explaining any new trends.

Missing/Incomplete Case Report Forms and Narrative Summaries

Severity: critical

Submit case report forms and narrative summaries for each subject who died during a clinical trial or who did not complete a trial due to an adverse event. Additionally, provide narrative summaries for all serious adverse events.

Recommended response: Compile and submit all required case report forms and narrative summaries for deaths, discontinuations due to AEs, and all serious adverse events.

Missing Updated Clinical Exposure Information

Severity: major

Provide updated exposure information for all clinical studies/trials, including details such as the number of subjects and person-time.

Recommended response: Update and provide comprehensive clinical exposure data for all relevant studies.

Incomplete Worldwide Safety Experience Summary

Severity: major

Submit a summary of worldwide safety experience for the drug, including updated estimates of use in countries where it is marketed.

Recommended response: Gather and summarize all available worldwide safety data and usage estimates for the drug.

Missing English Translations of Foreign Labeling

Severity: major

Provide English translations of all current approved foreign labeling that has not been previously submitted.

Recommended response: Obtain and translate all current approved foreign labeling for submission.

Regulatory context

Submission stage
final decision
Regulatory pathway
NDA

Impact

Impact score
0.95
Estimated delay
365 days
Estimated rework cost
$0
Subsequent action
resubmission

Strategic insights

The primary themes of this Complete Response Letter are significant deficiencies in manufacturing/quality systems, as evidenced by unresolved FDA 483 findings, and extensive gaps and inadequacies in the clinical safety data presentation and completeness, requiring a comprehensive safety update and detailed re-analysis of clinical trial data.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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