Assyro AI
US FDA•United StatesCRL•Complete Response Letter

Complete Response Letter NDA 505b1 216586 (May 16, 2024)

Issued May 16, 2024

Issued

May 16, 2024

Application

NDA 505b1 • 216586

Review center

CDER

Stage

Final Decision

Letter type

Complete Response Letter

Response due May 16, 2025Requires resubmission addressing deficiencies.

Summary

This document outlines requirements for New Drug Application (NDA) submissions, specifically regarding the resubmission of a proprietary name and the provision of a comprehensive safety update when responding to application deficiencies. The safety update must include detailed data from all nonclinical and clinical studies, incorporating new findings, retabulated adverse event frequencies, and narrative summaries for serious events or deaths.

Key points

  • Resubmit the proposed proprietary name when responding to all identified application deficiencies.
  • 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.
  • 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.
  • Include tables that compare frequencies of adverse events in the original application with the retabulated frequencies.

Cited reasons

  • Proprietary Name Resubmission Required
  • Inadequate Comprehensive Safety Update Submission
  • Deficiencies in Adverse Event Data Presentation
  • Insufficient Analysis of Premature Trial Discontinuations
  • Missing Case Report Forms and Narrative Summaries for Safety Events
  • Lack of Description for Changes in Common Adverse Event Incidence
  • The application received a Complete Response Letter primarily due to significant deficiencies in the safety update submission. The agency requires a comprehensive safety update, detailed presentation of adverse event data, analysis of premature trial discontinuations, and submission of missing case report forms and narrative summaries. Additionally, the proprietary name requires resubmission after all other deficiencies are addressed.

Recommended actions

  • Resubmit the proposed proprietary name when responding to all identified application deficiencies.
  • 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.
  • 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.
  • Include tables that compare frequencies of adverse events in the original application with the retabulated frequencies.

Deficiency summary

The application received a Complete Response Letter primarily due to significant deficiencies in the safety update submission. The agency requires a comprehensive safety update, detailed presentation of adverse event data, analysis of premature trial discontinuations, and submission of missing case report forms and narrative summaries. Additionally, the proprietary name requires resubmission after all other deficiencies are addressed.

Findings

Proprietary Name Resubmission Required

Severity: minor

The proposed proprietary name was found conditionally acceptable but requires resubmission after all other application deficiencies are addressed.

Recommended response: Address all clinical and safety deficiencies before resubmitting the proprietary name.

Inadequate Comprehensive Safety Update Submission

Severity: major

A comprehensive safety update is required as described at 21 CFR 314.50(d)(5)(vi)(b), including data from all nonclinical and clinical studies/trials regardless of indication, dosage form, or dose level, and detailing significant changes in the safety profile.

Recommended response: Compile a complete safety update incorporating all available nonclinical and clinical data, highlighting any significant changes in the safety profile as per regulatory requirements.

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

Deficiencies in Adverse Event Data Presentation

Severity: major

New safety data from studies for the proposed indication must be presented in the same format as the original submission. Tabulations of new safety data combined with original application data are required, along with tables comparing frequencies of adverse events. Separate tables for frequencies of adverse events in clinical trials for indications other than the proposed indication must also be provided.

Recommended response: Reformat and retabulate all adverse event data, ensuring consistency with original submission formats, providing combined data, comparative tables, and separate tables for off-label indications.

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

Insufficient Analysis of Premature Trial Discontinuations

Severity: major

A retabulation of reasons for premature trial discontinuation is required, incorporating drop-outs from newly completed trials, and any new trends or patterns identified must be described.

Recommended response: Update and analyze all premature trial discontinuation data, including new trials, and clearly describe any emerging trends.

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

Missing Case Report Forms and Narrative Summaries for Safety Events

Severity: critical

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

Recommended response: Expeditiously compile and submit all missing case report forms and narrative summaries for deaths, trial discontinuations due to AEs, and all serious adverse events.

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

Lack of Description for Changes in Common Adverse Event Incidence

Severity: major

Information suggesting a substantial change in the incidence of common, but less serious, adverse events between new data and original application data must be described.

Recommended response: Conduct a thorough comparison of common adverse event incidences between new and original data, and provide a detailed description of any substantial changes.

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

Regulatory context

Submission stage
final decision
Regulatory pathway
NDA

Impact

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

Strategic insights

The primary theme of the Complete Response Letter is the inadequacy of the safety data submission, requiring a comprehensive update, detailed adverse event reporting, and specific analyses of clinical trial outcomes. The proprietary name issue is secondary and contingent on resolving the safety deficiencies.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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