Issued August 5, 2025
Issued
August 5, 2025
Application
BLA • 761147
Review center
CBER
Stage
Final Decision
Letter type
Complete Response Letter
This document is a letter from the U.S. Food and Drug Administration (FDA) to an applicant regarding Biologics License Application (BLA) 761147. It outlines deficiencies in the application, provides guidance on labeling resources, addresses the proprietary name, and details extensive requirements for a safety update that must be included in the resubmission.
The application received a Complete Response Letter primarily due to significant deficiencies in the clinical safety data update, including inadequate integration and presentation of new safety information, missing case report forms and narrative summaries for serious adverse events and deaths, and a lack of comprehensive worldwide safety experience. Additionally, updated exposure information and English translations of foreign labeling are required. The proprietary name resubmission is contingent upon addressing all other deficiencies.
The proposed proprietary name was found conditionally acceptable but requires resubmission after all application deficiencies are addressed.
Recommended response: Resubmit the proprietary name application once all other deficiencies are fully resolved and the application is ready for re-submission.
A comprehensive safety update is required, including data from all nonclinical and clinical studies, regardless of indication, dosage, or dose level. This update must describe significant changes in the safety profile and their relevance, if any, to whether there may be clinically meaningful differences between the proposed biosimilar product and the U.S.-licensed reference product.
Recommended response: Compile and submit a complete safety update, ensuring all relevant nonclinical and clinical data are included and analyzed for significant changes and biosimilarity relevance.
New safety data from clinical studies must be incorporated into sections describing discontinuations due to adverse events, serious adverse events, and common adverse events. This includes presenting new data in the same format as the original BLA, tabulating new data combined with original BLA data, and comparing frequencies of adverse events.
Recommended response: Re-analyze and re-present all safety data, ensuring new clinical study data is fully integrated, tabulated, and compared with original BLA data according to specified formats.
A retabulation of reasons for premature study discontinuation, incorporating drop-outs from newly completed studies, is required. Any new trends or patterns identified must be described.
Recommended response: Update the analysis of premature study discontinuations, including all new data, and provide a detailed description of any emerging trends.
Case report forms and narrative summaries are required for each subject who died during a clinical study or discontinued due to an adverse event. Narrative summaries for all serious adverse events are also needed.
Recommended response: Immediately compile and submit all missing case report forms and narrative summaries for deaths and serious adverse events, ensuring completeness and accuracy.
Information suggesting a substantial change in the incidence of common, but less serious, adverse events between new data and original BLA data must be described.
Recommended response: Conduct a thorough comparative analysis of common adverse event incidence between new and original data, highlighting and explaining any substantial changes.
Updated exposure information for the clinical studies (e.g., number of subjects, person time) is required.
Recommended response: Provide a complete and updated summary of clinical study exposure data, including all relevant metrics.
A summary of worldwide experience on the safety of this product, including known adverse events and immunogenicity, is required. An updated estimate of use for the product marketed in other countries must also be included.
Recommended response: Compile and submit a comprehensive summary of worldwide safety data, including adverse events, immunogenicity, and updated usage estimates from all countries where the product is marketed.
English translations of current approved foreign labeling not previously submitted are required.
Recommended response: Provide certified English translations for all approved foreign labeling that has not yet been submitted to the agency.
The application's primary hurdle is the inadequacy and incompleteness of clinical safety data, particularly regarding updates, detailed adverse event reporting, and global safety experience. Labeling compliance with foreign translations is also a key issue.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
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