US FDA•United StatesCRL•Complete Response Letter

Complete Response Letter NDA 505b1 218698 (Jun 12, 2024)

Issued June 12, 2024

Issued

June 12, 2024

Application

NDA 505b1 • 218698

Review center

CDER

Stage

Final Decision

Letter type

Complete Response Letter

Response due June 12, 2025Requires resubmission addressing deficiencies.

Summary

This FDA letter communicates deficiencies in New Drug Application (NDA) 218698, reserving comment on proposed labeling until the application is otherwise adequate. It outlines specific requirements for a safety update, details for resubmission, and options for meeting requests.

Key points

Review 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).
Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies.
The safety update must 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 within the safety update.
Incorporate new safety data into sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, presenting new data from studies/clinical trials for the proposed indication in the same format as the original submission.
Present tabulations of new safety data combined with the original application data.
Include tables comparing 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.

Cited reasons

Inadequate Safety Update Submission
Insufficient Adverse Event Data for Non-Proposed Indications
Incomplete Case Report Forms and Narrative Summaries
Outdated Exposure Information
Missing Worldwide Safety Experience Summary
Untranslated Foreign Labeling Documents
The application received a Complete Response Letter primarily due to insufficient and inadequately presented safety data from clinical trials, including a lack of comprehensive safety updates, detailed adverse event reporting for non-proposed indications, complete case report forms for serious events, updated exposure information, and a summary of worldwide safety experience. Additionally, English translations of foreign labeling were requested.

Recommended actions

Review 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).
Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies.
The safety update must 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 within the safety update.
Incorporate new safety data into sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, presenting new data from studies/clinical trials for the proposed indication in the same format as the original submission.
Present tabulations of new safety data combined with the original application data.
Include tables comparing 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.

Deficiency summary

The application received a Complete Response Letter primarily due to insufficient and inadequately presented safety data from clinical trials, including a lack of comprehensive safety updates, detailed adverse event reporting for non-proposed indications, complete case report forms for serious events, updated exposure information, and a summary of worldwide safety experience. Additionally, English translations of foreign labeling were requested.

Findings

Inadequate Safety Update Submission

Severity: major

The response must include a comprehensive safety update as described in 21 CFR 314.50(d)(5)(vi)(b), incorporating new safety data from all nonclinical and clinical studies/trials, describing significant changes, presenting new and combined safety data, and comparing adverse event frequencies.

Recommended response: Conduct a thorough review of all safety data, including nonclinical and clinical studies, to identify and report any significant changes in the safety profile. Ensure all new data is integrated and presented in the required format, comparing frequencies of adverse events.

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

Insufficient Adverse Event Data for Non-Proposed Indications

Severity: major

Provide separate tables for the frequencies of adverse events occurring in clinical trials for indications other than the proposed indication.

Recommended response: Generate and submit separate, detailed tables of adverse event frequencies for all clinical trials conducted for indications not covered by the current proposed indication.

Incomplete Case Report Forms and Narrative Summaries

Severity: critical

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 missing case report forms and narrative summaries for subjects who died or withdrew due to adverse events, and for all serious adverse events, to ensure a complete safety profile.

Outdated Exposure Information

Severity: major

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, ensuring accurate reporting of subject numbers and person-time to reflect the most current data.

Missing Worldwide Safety Experience Summary

Severity: major

Provide a summary of worldwide experience on the safety of this drug, including an updated estimate of use for drug marketed in other countries.

Recommended response: Prepare and submit a detailed summary of the drug's worldwide safety experience, including usage estimates from all countries where it is marketed, to provide a global safety context.

Untranslated Foreign Labeling Documents

Severity: major

Provide English translations of current approved foreign labeling not previously submitted.

Recommended response: Obtain and submit certified English translations for all currently approved foreign labeling documents that have not yet been provided to the agency.

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 theme of the Complete Response Letter is the inadequacy and incompleteness of safety data and documentation, particularly concerning clinical trial reporting, global safety experience, and foreign labeling translations, which are critical for a comprehensive safety assessment.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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