US FDA•United StatesAL•Approval Letter

Approval Letter Other 216482 (Jan 1, 2024)

Issued January 1, 2024

Issued

January 1, 2024

Application

Other • 216482

Review center

Other

Stage

Final Decision

Letter type

Approval Letter

Response due December 31, 2024Product may be marketed.

Summary

This is a Complete Response letter from the FDA to Liqmeds Worldwide Limited regarding New Drug Application (NDA) 216482 for mycophenolate mofetil oral suspension. The application cannot be approved in its present form primarily due to the lack of a required Risk Evaluation and Mitigation Strategy (REMS). The letter outlines specific deficiencies and provides recommendations for addressing them, including detailed requirements for a safety update and submission procedures.

Key points

Submit a proposed Risk Evaluation and Mitigation Strategy (REMS) to address the deficiency, ensuring it includes elements previously communicated by the FDA.
Designate all submissions related to the proposed REMS as 'PROPOSED REMS for NDA 216482-AMENDMENT'.
Submit proposed REMS and other REMS-related materials in Microsoft Word format (preferred, with exceptions for PDF).
Submit the REMS document in Structured Product Labeling (SPL) format.
Review labeling review resources and revise labeling if necessary, ensuring conformity with format items in regulations and guidances.
Include updated content of labeling in structured product labeling (SPL) format if labeling is revised.
Resubmit the proposed proprietary name.
Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies.

Cited reasons

Missing Risk Evaluation and Mitigation Strategy (REMS)
REMS Document Format Requirements
Proprietary Name Resubmission
Comprehensive Safety Update Required
The application cannot be approved in its present form primarily due to the lack of a proposed Risk Evaluation and Mitigation Strategy (REMS) to address significant safety risks. Additional deficiencies include requirements for REMS document formatting, resubmission of the proprietary name, and a comprehensive safety update.

Recommended actions

Submit a proposed Risk Evaluation and Mitigation Strategy (REMS) to address the deficiency, ensuring it includes elements previously communicated by the FDA.
Designate all submissions related to the proposed REMS as 'PROPOSED REMS for NDA 216482-AMENDMENT'.
Submit proposed REMS and other REMS-related materials in Microsoft Word format (preferred, with exceptions for PDF).
Submit the REMS document in Structured Product Labeling (SPL) format.
Review labeling review resources and revise labeling if necessary, ensuring conformity with format items in regulations and guidances.
Include updated content of labeling in structured product labeling (SPL) format if labeling is revised.
Resubmit the proposed proprietary name.
Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies.

Deficiency summary

The application cannot be approved in its present form primarily due to the lack of a proposed Risk Evaluation and Mitigation Strategy (REMS) to address significant safety risks. Additional deficiencies include requirements for REMS document formatting, resubmission of the proprietary name, and a comprehensive safety update.

Findings

Missing Risk Evaluation and Mitigation Strategy (REMS)

Severity: critical

The application cannot be approved without a proposed REMS. A REMS is necessary for mycophenolate mofetil to ensure that the benefits of the drug outweigh the risks of first-trimester pregnancy loss and congenital malformations. The agency had previously communicated the required elements for the REMS.

Recommended response: Develop and submit a comprehensive REMS document addressing the risks of pregnancy loss and congenital malformations, incorporating elements previously communicated by the agency. Ensure submission in both Microsoft Word and Structured Product Labeling (SPL) formats.

Cited: section 505-1 of the FDCA

REMS Document Format Requirements

Severity: major

The proposed REMS and related materials should be submitted in Microsoft Word format. Additionally, the REMS document must be submitted in Structured Product Labeling (SPL) format as described in the relevant FDA guidance.

Recommended response: Ensure all REMS-related submissions are provided in Microsoft Word format where possible, and the final REMS document is also submitted in Structured Product Labeling (SPL) format, following the specified guidance.

Cited: Guidance for Industry, Providing Regulatory Submission in Electronic Format – Content of the Risk Evaluation and Mitigation Strategies Document Using Structured Product Labeling

Proprietary Name Resubmission

Severity: minor

The previously found acceptable proprietary name must be resubmitted when responding to the application deficiencies, as its acceptance was pending approval in the current review cycle.

Recommended response: Resubmit the proposed proprietary name along with the response to other deficiencies.

Comprehensive Safety Update Required

Severity: major

A comprehensive safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), is required when responding to the deficiencies. This includes detailed changes in safety profile, updated data presentation, retabulation of adverse events, case reports for deaths/serious adverse events, updated exposure information, worldwide experience summary, and English translations of foreign labeling.

Recommended response: Prepare a complete safety update according to 21 CFR 314.50(d)(5)(vi)(b), incorporating all new safety data, updated analyses, and worldwide experience, ensuring proper formatting and translations.

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

Regulatory context

Submission stage: final decision
Regulatory pathway: 505(b)(2) of the Federal Food, Drug, and Cosmetic Act

Impact

Impact score: 0.95
Estimated delay: 545 days
Estimated rework cost: $0
Subsequent action: resubmission

Strategic insights

The primary theme of this Complete Response Letter is the critical need for a robust Risk Evaluation and Mitigation Strategy (REMS) to manage significant safety risks (pregnancy loss, congenital malformations) associated with mycophenolate mofetil. Procedural and data update requirements are also noted.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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