Insufficient Bioanalytical Method Selectivity for PK Data
Severity: criticalSelectivity data from experiments conducted in normal human serum during the validation of the bioanalytical method to quantitate concentrations of BAT1706 and EU-Avastin did not meet acceptance criteria, suggesting interference. This impacts the ability to accurately measure concentrations and thus the PK data from Study BAT1706-001-CR cannot support biosimilarity or the scientific bridge to EU-Avastin. Consequently, there is insufficient PK data to conclude no clinically meaningful differences from US-Avastin.
Recommended response: Repeat experiments at the lower limit of quantitation (LLOQ) and high quality control (HQC) to establish the selectivity of the bioanalytical method for BAT1706 and EU-Avastin.
Labeling Comments Reserved
Severity: infoComments on the proposed prescribing information are reserved until the application is otherwise adequate. Review of labeling review resources, regulations, and related guidance documents is encouraged.
Recommended response: Review labeling review resources on the Prescription Drug Labeling Resources and Pregnancy and Lactation Labeling Final Rule websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI). Review the FDA guidance for industry Labeling for Biosimilar Products.
Carton and Container Labeling Comments Reserved
Severity: infoComments on the proposed carton and container labeling are reserved until the application is otherwise adequate.
Recommended response: No specific action required at this stage, but will need to be addressed once other deficiencies are resolved.
Proprietary Name Review Halted
Severity: minorThe review of your proposed proprietary name has been stopped due to the deficiencies with the application as described in this letter.
Recommended response: Resubmit the proposed proprietary name when you respond to the application deficiencies.
Inadequate Safety Update
Severity: majorA comprehensive safety update is required, including data from all nonclinical and clinical studies, detailed significant changes in safety profile, new safety data from clinical studies (presented in original format, combined with original BLA data, and compared), retabulation of premature study discontinuations, case report forms and narrative summaries for deaths/adverse event discontinuations/serious adverse events, information on common but less serious adverse events, updated exposure information, worldwide safety experience summary (including immunogenicity and updated use estimates), and English translations of current approved foreign labeling.
Recommended response: Provide a comprehensive safety update addressing all specified points, including new safety data, updated exposure information, worldwide experience, and foreign labeling translations.
Outstanding Facility Inspection
Severity: majorAn inspection of the Bio-Thera Solutions, Ltd. facility at Guangzhou, China, FEI: 3017231337 is required before approval.
Recommended response: Acknowledge the comment in your response and facilitate the required facility inspection.
Glycosylation Method Robustness Issues
Severity: majorSystem suitability failures were reported in the robustness study for the glycosylation by HILIC method, specifically for results generated using a particular labeling reagent due to interfering peaks. This indicates the method is not robust with respect to the use of these specific sources of labeling reagents.
Recommended response: Provide additional data (e.g., robustness data) to support the performance of the HILIC method with respect to different sources of the labeling reagent. Alternatively, revise the analytical method description to specify the source of the labeling reagent used as part of the analytical method validation. Update appropriate BLA sections.
Suboptimal Bioanalytical Cross-Validation Comparability
Severity: majorDuring the validation of the bioanalytical method to quantitate concentrations of BAT1706, US-Avastin, and EU-Avastin from Studies BAT1706-001-CR and BAT1706-003-CR, the bioanalytical cross-validation comparability between the three products was not considered optimal.
Recommended response: Conduct precision and accuracy experiments to assess bias using QC samples and calibration curves prepared from the three products (BAT1706, EU-Avastin, and US-Avastin).
