Issued January 1, 2023
Issued
January 1, 2023
Application
Other • 761192
Review center
Other
Stage
Final Decision
Letter type
Approval Letter
This is a Complete Response Letter from the FDA to MediWound, Ltd. regarding their Biologics License Application (BLA) 761192 for 'concentrate of proteolytic enzymes enriched in bromelain' gel. The FDA has determined that the application cannot be approved in its present form due to various deficiencies related to product quality, clinical study data integrity, and safety information.
The application cannot be approved due to significant product quality issues related to botanical raw material authentication and microbial control, critical clinical data integrity concerns stemming from GCP violations and unblinding events, and outstanding requirements for a comprehensive safety update and an adequate maximal use study to support proposed labeling.
BRM authentication is solely based on morphology. Genetic, chemical, or biological methods with appropriate acceptance criteria are required. While biological and chemical assays were proposed, this remains a deficiency.
Recommended response: Implement robust genetic, chemical, or biological authentication methods for BRM with defined acceptance criteria to ensure product quality and consistency.
The overall microbial control strategy does not mitigate the risk of potential adventitious agents introduced during manufacturing. The current Bromelain Special Production (BSP) and Drug Substance (DS) manufacturing processes lack adequate microbial control for in-process intermediates.
Recommended response: Develop and implement a comprehensive microbial control strategy for BSP and DS manufacturing processes, including in-process intermediates, to ensure product safety.
Based on inspection observations, Study MW2010-03-02 was not conducted in accordance with the protocol and current GCP standards, resulting in poor data quality. Significant unblinding events occurred, making the data interpretable only as an open-label study.
Recommended response: Provide a comprehensive evaluation of how inspection observations and unblinding events impact the interpretability of efficacy findings in Study MW2010-03-02. Consider re-evaluating or re-conducting critical studies if necessary.
The proposed proprietary name, NexoBrid, was found acceptable pending approval. It needs to be resubmitted when responding to the application deficiencies.
Recommended response: Resubmit the proprietary name as part of the complete response package.
A complete safety update is required, including data from all nonclinical and clinical studies/trials, significant changes/findings in the safety profile, updated adverse event data (new and combined with original), retabulation of premature discontinuations, case report forms/narratives for deaths/serious adverse events, changes in common adverse events, updated exposure information, worldwide safety experience, and English translations of foreign labeling.
Recommended response: Compile and submit a comprehensive safety update addressing all requested data points, including detailed analyses, narratives, and translations.
The completed maximal use study does not support the proposed labeling. To seek the current proposed labeling, a new maximal use study is needed to address systemic safety with adequate patient numbers, TBSA, and dosing to support the proposed regimens. Alternatively, labeling will be restrictive based on the currently completed study.
Recommended response: Either conduct a new maximal use study to support the desired labeling or revise the proposed labeling to align with the existing study data and its limitations.
Recommendations to follow USP <561> for aflatoxins and pesticides, USP <61>/<62> for microbial limits, and USP <232>/<233> for elemental impurities for future manufacturing, despite current justifications for exclusion.
Recommended response: Consider implementing recommended USP tests for BRM in future manufacturing processes to enhance quality control.
Cited: USP <561>, USP <61>, USP <62>, USP <232>, USP <233>
Recommend conducting orthogonal analysis of chemical and biological data for BSP/DS and final product used in Phase 3 trials, correlating batch analysis to clinical outcomes to ensure batch-to-batch consistency.
Recommended response: Perform orthogonal analysis and correlation studies to demonstrate batch-to-batch consistency and its impact on clinical outcomes.
Key themes include the need for robust manufacturing and quality control for botanical raw materials, ensuring clinical trial data integrity and adherence to GCP, and providing a complete and updated safety profile, potentially requiring new clinical studies to support the desired labeling.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
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