Unresolved Immunogenicity Concerns: ADA Incidence Difference
Severity: criticalThe observed difference in anti-drug antibody (ADA) incidence rates between CHS-1701 (9.8%) and US-licensed Neulasta (5.8%) creates residual uncertainty regarding biosimilarity. The FDA's independent analysis yielded a 1-sided upper exact limit of 10.97%, exceeding the 10% threshold for clinically meaningful differences. Additional information is required to clarify whether anti-PEG or anti-G-CSF antibodies are driving this difference, and further clinical studies may be needed.
Recommended response: Conduct further clinical studies or provide comprehensive data to clarify the observed difference in anti-drug antibody (ADA) rates, specifically investigating the drivers (anti-PEG or anti-G-CSF antibodies) and their clinical significance to establish biosimilarity.
Inadequate Analytical Similarity Assessment: Degradation Profiles
Severity: majorThe application lacked adequate physicochemical and functional assessment of degradation profiles. Specifically, potency of CHS-1701 and US-licensed Neulasta was not evaluated in the forced degradation study, failing to demonstrate similar degradation extents. Potency data for samples subjected to forced degradation conditions are required.
Recommended response: Perform and submit potency data for CHS-1701 and US-licensed Neulasta samples subjected to forced degradation conditions to demonstrate similar degradation profiles and support analytical similarity.
Missing Potency Data for US-licensed Neulasta Clinical Lot
Severity: majorPotency data for US-licensed Neulasta lot 1054829, used in the CHS-1701-04 clinical study, was not included in the Tier 1 analyses due to material limitations. This data is requested to complete the analytical similarity assessment.
Recommended response: Provide the requested potency data for US-licensed Neulasta lot 1054829, which was used in the clinical study, to complete the analytical similarity assessment.
Comprehensive Safety Update Required
Severity: majorA comprehensive safety update is required upon resubmission. This update must include data from all nonclinical and clinical studies, detailing significant changes in the safety profile, incorporating new safety data into adverse event tabulations, retabulating reasons for premature study discontinuation, providing case report forms and narrative summaries for deaths and serious adverse events, describing changes in common adverse events, updating exposure information, summarizing worldwide safety experience, and providing English translations of foreign labeling.
Recommended response: Submit a comprehensive safety update incorporating all new nonclinical and clinical data, including detailed analysis of safety profile changes, adverse event tabulations, discontinuation reasons, case report forms for serious events, updated exposure information, worldwide safety experience, and translations of foreign labeling.
Poor Quality and Organization of Module 3 Submission
Severity: majorModule 3 of the BLA was not well prepared, frequently referring to numerous reports without providing informative summaries, interpretations, or conclusions. This hindered efficient review, particularly for process characterization and in-process controls. The submission also contained inconsistencies, missing information, and typographical errors, which must be addressed in any resubmission.
Recommended response: Thoroughly revise and reorganize Module 3 to provide clear, concise summaries with interpretations and conclusions for all data, ensuring consistency, completeness, and accuracy, and addressing all identified inconsistencies and errors.
Proprietary Name Resubmission Required
Severity: minorThe proposed proprietary name, Udenyca, was found acceptable pending approval of the application. It must be resubmitted when responding to the application deficiencies.
Recommended response: Resubmit the proposed proprietary name, Udenyca, as part of the complete response to the application deficiencies.
