Interchangeability Exclusivity Period Not Expired
Severity: criticalThe application relies on a reference product for which a prior biological product received a determination of interchangeability on July 28, 2021. As a second or subsequent biological product, a determination of interchangeability cannot be made until the exclusivity period described in section 351(k)(6)(A)-(C) of the Public Health Service Act has expired.
Recommended response: Monitor the exclusivity period of the first interchangeable biosimilar and resubmit the application once the exclusivity period has expired, as per section 351(k)(6) of the PHS Act.
Cited: section 351(k) of the Public Health Service Act, section 351(k)(6), section 351(k)(4)
Comprehensive Safety Update Required
Severity: majorA comprehensive safety update must be included with the response, encompassing data from all nonclinical and clinical studies of the product, regardless of indication, dosage form, or dose level.
Recommended response: Prepare a comprehensive safety update incorporating all nonclinical and clinical study data, ensuring it covers all indications, dosage forms, and dose levels.
Significant Safety Profile Changes and Clinical Meaningfulness
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: Analyze and describe any significant changes in the safety profile, specifically addressing their clinical meaningfulness in comparison to the reference product.
Incorporation of New Safety Data
Severity: majorIncorporate new safety data 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: Integrate new safety data into existing sections for discontinuations, SAEs, and common AEs, ensuring consistent formatting and comparative tabulations with original BLA data.
Retabulation of Premature Study Discontinuations
Severity: majorPresent a retabulation of the reasons for premature study discontinuation by incorporating drop-outs from newly completed studies and describe any new trends or patterns identified.
Recommended response: Update the tabulation of premature study discontinuations with data from newly completed studies and identify any emerging trends.
Case Report Forms and Narrative Summaries for Deaths/SAEs
Severity: majorProvide case report forms and narrative summaries for each patient who died during a clinical study or who did not complete a study because of an adverse event. Additionally, provide narrative summaries for serious adverse events.
Recommended response: Compile and submit all required case report forms and narrative summaries for patient deaths and serious adverse events from clinical studies.
Changes in Incidence of 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 report any substantial changes in the incidence of common, less serious adverse events when comparing new and original BLA data.
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 exposure information for all clinical studies, including metrics like number of subjects and person-time.
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 a comprehensive summary of worldwide safety experience, including adverse events, immunogenicity, and updated usage estimates from other countries.
English Translations of Foreign Labeling
Severity: minorProvide 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.
