Approval Letter Other 214628 (Jan 1, 2022)

Summary

This is a Complete Response letter from the FDA to Nevakar, Inc. for their New Drug Application (NDA) 214628 for Norepinephrine Bitartrate in Sodium Chloride Injection. The FDA has determined that the application cannot be approved in its present form due to unresolved facility inspection deficiencies, additional CMC deficiencies, and requirements for a comprehensive safety update.

Key points

• Satisfactorily resolve deficiencies identified during the manufacturing facility inspection.
• Address additional CMC deficiencies pertinent for NDA resubmission.
• Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b).
• Describe in detail any significant changes or findings in the safety profile.
• Present new safety data from studies/clinical trials for the proposed indication using the same format as in the original submission.
• Present tabulations of new safety data combined with 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.

Cited reasons

• Unresolved Manufacturing Facility Inspection Deficiencies
• Additional CMC Deficiencies
• Inadequate Safety Update and Data Presentation
• Missing English Translations of Foreign Labeling
• The application cannot be approved due to unresolved manufacturing facility inspection deficiencies, additional undisclosed CMC issues, and significant outstanding requirements for a comprehensive safety update, including detailed adverse event reporting, updated exposure information, and worldwide safety experience. Labeling comments are reserved pending resolution of these core issues.

Recommended actions

• Satisfactorily resolve deficiencies identified during the manufacturing facility inspection.
• Address additional CMC deficiencies pertinent for NDA resubmission.
• Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b).
• Describe in detail any significant changes or findings in the safety profile.
• Present new safety data from studies/clinical trials for the proposed indication using the same format as in the original submission.
• Present tabulations of new safety data combined with 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.

Deficiency summary

The application cannot be approved due to unresolved manufacturing facility inspection deficiencies, additional undisclosed CMC issues, and significant outstanding requirements for a comprehensive safety update, including detailed adverse event reporting, updated exposure information, and worldwide safety experience. Labeling comments are reserved pending resolution of these core issues.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

505(b)(2)

Impact

Impact score

0.95

Estimated delay

365 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The application was not approved due to critical manufacturing compliance issues, undisclosed CMC deficiencies, and a lack of comprehensive and adequately presented safety data, including global experience and detailed adverse event reporting. Labeling review is contingent on resolving these fundamental issues.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%