Issued January 1, 2024
Issued
January 1, 2024
Application
Other • 215179
Review center
Other
Stage
Final Decision
Letter type
Approval Letter
The FDA issued a Complete Response letter for Shilpa Medicare Limited's New Drug Application (NDA 215179) for Pemetrexed Injection, indicating that the application cannot be approved in its current form due to unresolved product quality issues, facility inspection deficiencies, and outstanding safety update requirements. The letter outlines specific actions and data submissions required for potential approval.
The application is not approvable due to significant product quality issues, including insufficient long-term stability data, an inadequate leachables study, and unsubmitted deliverable volume data. These issues also prevent establishing the scientific bridge to the listed drug. Furthermore, unresolved deficiencies from a manufacturing facility inspection and the need for a comprehensive safety update contribute to the complete response. Labeling comments are reserved.
Per ICH Q1A(R2), provide at least 12 months of long-term stability data on the NDA exhibit batches manufactured at the Cadila Healthcare Limited/Zydus Lifesciences Limited site.
Recommended response: Conduct and submit 12 months of long-term stability data for the specified batches to demonstrate product stability.
Provide an acceptable leachables study performed on 12-month samples taken from the long-term stability study for the NDA exhibit batches manufactured at the Cadila Healthcare Limited/Zydus Lifesciences Limited site.
Recommended response: Perform and submit an acceptable leachables study on 12-month stability samples to assess potential extractables/leachables from the container closure system.
The product quality deficiencies need to be resolved before the adequacy of the scientific bridge between the proposed drug product and the relied upon Listed Drug product can be established, in accordance with 21 CFR 320.24(b)(6).
Recommended response: Address all product quality deficiencies to establish the scientific bridge required for a 505(b)(2) application.
Cited: 21 CFR 320.24(b)(6)
When responding to the deficiencies, include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b). This includes data from all nonclinical and clinical studies, significant changes in safety profile, specific presentation of new and combined adverse event data, retabulation of premature trial discontinuations, case report forms/narrative summaries for deaths/SAEs, updated exposure information, worldwide experience summary, and English translations of foreign labeling.
Recommended response: Prepare and submit a comprehensive safety update, ensuring all specified data elements and presentation formats are met as per 21 CFR 314.50(d)(5)(vi)(b).
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Comments on the proposed prescribing information, carton, and container labeling are reserved until the application is otherwise adequate. Review labeling review resources on FDA websites.
Recommended response: Proactively review FDA labeling resources and guidance documents to prepare for potential labeling revisions once other deficiencies are resolved.
The response to the May 30, 2021, information request related to deliverable volume (dose) data was not submitted. Satisfactory resolution is required.
Recommended response: Submit the requested deliverable volume (dose) data from the May 30, 2021, information request.
During a recent inspection of the manufacturing facility, field investigator conveyed deficiencies to the facility representative. Satisfactory resolution of these deficiencies is required.
Recommended response: Address and resolve all deficiencies identified during the manufacturing facility inspection.
The Complete Response highlights critical deficiencies across product quality (stability, leachables, deliverable volume), manufacturing quality systems (facility inspection findings), and clinical data presentation (safety update requirements). These issues collectively prevent approval and necessitate substantial data generation and remediation efforts.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
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