Issued November 14, 2024
Issued
November 14, 2024
Application
BLA • 761212
Review center
CBER
Stage
Final Decision
Letter type
Complete Response Letter
This letter from the FDA outlines deficiencies in a Biologics License Application (BLA) for a biosimilar product, providing specific instructions for a safety update, proprietary name resubmission, and general resubmission procedures to achieve approval.
The application received a Complete Response Letter primarily due to significant deficiencies in the safety update, including inadequate presentation of clinical safety data, missing case report forms and narratives for serious adverse events, and insufficient worldwide safety experience. Additionally, English translations of foreign labeling are required, and the proprietary name cannot be approved until all other deficiencies are resolved.
The proposed proprietary name was found conditionally acceptable but requires resubmission once all other application deficiencies identified in this letter have been addressed.
Recommended response: Address all clinical and safety deficiencies before resubmitting the proprietary name for final approval.
Provide a comprehensive safety update including data from all nonclinical and clinical studies, describing in detail any significant changes or findings in the safety profile and their relevance to potential clinically meaningful differences between the proposed biosimilar product and the U.S.-licensed reference product.
Recommended response: Conduct a thorough review of all safety data, both nonclinical and clinical, and provide a detailed update that clearly addresses any significant changes or differences compared to the reference product.
Present new safety data from clinical studies for the proposed indication using the same format as the original BLA submission. Include tabulations of new safety data combined with original BLA data, and tables comparing frequencies of adverse events between the original BLA and retabulated frequencies.
Recommended response: Reformat and retabulate all safety data to ensure consistency with the original BLA submission, providing clear comparative analyses of adverse event frequencies.
Present a retabulation of the reasons for premature study discontinuation by incorporating drop-outs from newly completed studies. Describe any new trends or patterns identified.
Recommended response: Update and analyze all discontinuation data from clinical studies, identifying and explaining any new trends or patterns.
Provide case report forms and narrative summaries for each subject who died during a clinical study or who did not complete a study because of an adverse event. Additionally, provide narrative summaries for all serious adverse events.
Recommended response: Compile and submit all requested case report forms and detailed narrative summaries for all deaths and serious adverse events to ensure complete safety documentation.
Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original BLA data.
Recommended response: Perform a comparative analysis of common adverse event incidences between new and original data, providing explanations for any significant changes observed.
Provide updated exposure information for the clinical studies, including details such as the number of subjects and person time.
Recommended response: Update and submit all clinical exposure data to reflect the most current and complete information.
Provide a summary of worldwide experience on the safety of this product, including adverse events known to be associated with its use and immunogenicity. Include an updated estimate of use for this product marketed in other countries.
Recommended response: Compile and submit a comprehensive summary of global safety data, including immunogenicity and market usage, for the product.
Provide English translations of current approved foreign labeling that have not been previously submitted.
Recommended response: Obtain and submit certified English translations of all current approved foreign labeling documents.
The primary theme of the Complete Response Letter is the inadequacy of the safety data package, requiring comprehensive updates, detailed analyses, and complete documentation of adverse events and worldwide experience. Labeling compliance, specifically foreign labeling translations, also needs to be addressed.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
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