Prescribing Information Not Yet Adequate
Severity: majorThe agency reserves comment on the proposed labeling until the application is otherwise adequate. The sponsor is encouraged to review labeling resources, regulations, and guidance documents, including the SRPI checklist. A response must include updated content of labeling [21 CFR 601.14(b)] in structured product labeling (SPL) format.
Recommended response: Revise and resubmit the Prescribing Information, ensuring compliance with all relevant regulations and guidances, and provide it in SPL format.
Cited: 21 CFR 601.14(b)
Proprietary Name Resubmission Required
Severity: majorThe proposed proprietary name, Yuflyma, was addressed in prior correspondence (August 11, 2022, and February 22, 2021) and found conditionally acceptable pending approval. The sponsor must resubmit the proposed proprietary name when responding to application deficiencies.
Recommended response: Resubmit the proprietary name, Yuflyma, as part of the complete response to the application deficiencies.
Comprehensive Safety Update Required
Severity: criticalA safety update is required, including data from all nonclinical and clinical studies regardless of indication, dosage form, or dose level. This update must detail significant changes in the safety profile and their relevance to clinically meaningful differences between the biosimilar and reference product.
Recommended response: Provide a detailed and comprehensive safety update, analyzing and describing any significant changes in the safety profile and their implications for biosimilarity.
Inadequate Safety Data Presentation and Tabulation
Severity: criticalNew safety data from clinical studies for the proposed indication must be incorporated into sections describing discontinuations due to adverse events, serious adverse events, and common adverse events. This includes presenting new safety data in the same format as the original BLA, tabulations of new data combined with original BLA data, and tables comparing frequencies of adverse events.
Recommended response: Re-tabulate and present all safety data, including new clinical study data, combined with original BLA data, and provide comparative analyses of adverse event frequencies.
Analysis of Premature Study Discontinuation Needed
Severity: majorA retabulation of the reasons for premature study discontinuation is required, incorporating drop-outs from newly completed studies. Any new trends or patterns identified must be described.
Recommended response: Update and analyze data on premature study discontinuations, identifying and describing any new trends.
Missing Case Report Forms and Narrative Summaries for Safety 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. Additionally, narrative summaries for all serious adverse events are required.
Recommended response: Submit all requested case report forms and narrative summaries for deaths, study discontinuations due to AEs, and serious adverse events.
Analysis of Changes in Common Adverse Event Incidence
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: Conduct an analysis to identify and describe any substantial changes in the incidence of common adverse events.
Updated Clinical Exposure Information Required
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.
Worldwide Safety Experience and Foreign Labeling Translations Needed
Severity: criticalProvide 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. Additionally, English translations of current approved foreign labeling not previously submitted are required.
Recommended response: Compile and submit a comprehensive summary of worldwide safety data, including immunogenicity and usage estimates, along with English translations of all relevant foreign labeling.
