US FDA•United StatesAL•Approval Letter

Approval Letter Other 214012 (Jan 1, 2022)

Issued January 1, 2022

Issued

January 1, 2022

Application

Other • 214012

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due January 1, 2023Product may be marketed.

Summary

This is a Complete Response Letter from the FDA to Novartis Pharmaceuticals Corporation regarding New Drug Application (NDA) 214012 for inclisiran injection. The FDA has determined that the application cannot be approved in its present form due to objectionable conditions noted during a review of records at a manufacturing facility and other outstanding issues.

Key points

Satisfactory resolution of objectionable conditions at the manufacturing facility is required before the application may be approved.
Resubmit the proposed proprietary name (Leqvio) when responding to the application deficiencies.
Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies.
Describe in detail any significant changes or findings in the safety profile in the safety update.
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.
For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.

Cited reasons

Unsatisfactory Manufacturing Facility Conditions
Incomplete Safety Update
Proprietary Name Resubmission Required
The application cannot be approved in its present form primarily due to objectionable conditions at a manufacturing facility and the need for a comprehensive safety update. The proposed proprietary name is acceptable pending resolution of other issues.

Recommended actions

Satisfactory resolution of objectionable conditions at the manufacturing facility is required before the application may be approved.
Resubmit the proposed proprietary name (Leqvio) when responding to the application deficiencies.
Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies.
Describe in detail any significant changes or findings in the safety profile in the safety update.
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.
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 in its present form primarily due to objectionable conditions at a manufacturing facility and the need for a comprehensive safety update. The proposed proprietary name is acceptable pending resolution of other issues.

Findings

Unsatisfactory Manufacturing Facility Conditions

Severity: critical

During a review of records requested under Federal Food, Drug, and Cosmetic Act section 704(a)(4) provided by a manufacturing facility, the FDA noted objectionable conditions. Satisfactory resolution of these objectionable conditions (e.g., preapproval inspection and/or adequate facility responses) is required before this application may be approved.

Recommended response: Address all objectionable conditions at the manufacturing facility, provide adequate facility responses, and prepare for a potential preapproval inspection. Ensure all quality systems are compliant with FDA regulations.

Cited: Federal Food, Drug, and Cosmetic Act section 704(a)(4)

Incomplete Safety Update

Severity: major

A comprehensive safety update is required as described at 21 CFR 314.50(d)(5)(vi)(b). This includes data from all nonclinical and clinical studies/trials, describing significant changes, incorporating new safety data into tabulations, comparing frequencies of adverse events, providing separate tables for other indications, presenting retabulation of premature discontinuations, providing case report forms and narrative summaries for deaths/adverse event discontinuations/serious adverse events, describing changes in common adverse events, providing updated exposure information, and summarizing worldwide safety experience with English translations of foreign labeling.

Recommended response: Compile a comprehensive safety update including all new nonclinical and clinical data. Ensure all specified elements are addressed, such as detailed adverse event reporting, updated exposure data, and worldwide safety experience. Provide all requested case report forms and narrative summaries.

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

Proprietary Name Resubmission Required

Severity: minor

The proposed proprietary name, Leqvio, was found acceptable pending approval of the application. It must be resubmitted when responding to the application deficiencies.

Recommended response: Include the proprietary name resubmission with the complete response to other deficiencies.

Regulatory context

Submission stage: final decision
Regulatory pathway: 505(b) NDA

Impact

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

Strategic insights

Approval is withheld due to critical manufacturing facility issues and the need for a comprehensive update to the clinical safety data package.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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