Unresolved Facility Inspection Deficiencies
Severity: majorFollowing pre-license inspection of the facility listed in this application, FDA conveyed deficiencies to the representative of the facility. The BLA resubmission should include the date of the facility’s response to the FDA Form 483. Assessment of application approvability and the resolution of inspection deficiencies would be evaluated upon receipt of your BLA resubmission and may include reinspection of the facility.
Recommended response: Address all FDA Form 483 observations, provide the facility's response date, and collaborate with the facility to resolve deficiencies. Prepare for potential reinspection.
Inadequate Description of Safety Profile Changes
Severity: majorDescribe in detail any significant changes or findings 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: Provide a comprehensive analysis of any new safety findings, detailing their impact and relevance to the biosimilarity assessment against the reference product.
Incomplete Tabulation of New and Combined Safety Data
Severity: majorWhen assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data. Present new safety data from the clinical studies for the proposed indication, tabulations of the new safety data combined with the original BLA data, and tables that compare frequencies of adverse events.
Recommended response: Retabulate all safety data, including new clinical study data, and combine it with original BLA data. Provide comparative tables for adverse event frequencies.
Insufficient Analysis of Premature Study Discontinuation
Severity: majorPresent a re-tabulation of the reasons for premature study discontinuation by incorporating the dropouts from the newly completed studies. Describe any new trends or patterns identified.
Recommended response: Update the analysis of premature study discontinuations with new data, identifying and describing any emerging trends.
Missing Case Report Forms and Narrative Summaries for Deaths and Serious Adverse Events
Severity: criticalProvide 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. In addition, provide narrative summaries for serious adverse events.
Recommended response: Submit all requested case report forms and narrative summaries for deaths, study discontinuations due to AEs, and all serious adverse events.
Insufficient Description of Changes in Common Adverse Events
Severity: majorDescribe 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: Analyze and describe any substantial changes in the incidence of common adverse events when comparing new and original BLA data.
Missing Updated Clinical Study Exposure Information
Severity: majorProvide updated exposure information for the clinical studies (e.g., number of subjects, person time).
Recommended response: Submit updated clinical exposure data, including subject numbers and person-time, for all relevant studies.
Incomplete Summary of Worldwide Safety Experience
Severity: majorProvide a summary of worldwide experience on the safety of this product, including adverse events known to be associated with the use of the product and immunogenicity. Include an updated estimate of use for this product marketed in other countries.
Recommended response: Compile and submit a comprehensive summary of worldwide safety data, including adverse events, immunogenicity, and updated usage estimates from other countries.
Missing English Translations of Foreign Labeling
Severity: majorProvide English translations of current approved foreign labeling not previously submitted.
Recommended response: Submit English translations for all current approved foreign labeling that has not yet been provided.
