Prescribing Information (PI) Formatting and Content
Severity: majorSubmit draft labeling responsive to FDA's electronic communication, correct formatting errors using the SRPI checklist, and submit updated content of labeling in Structured Product Labeling (SPL) format as described at FDA.gov, in accordance with 21 CFR 601.14(b). Provide a highlighted/marked-up copy showing all changes, as well as a clean Word version. The proposed PI must conform to the content and format regulations found at 21 CFR 201.56(a), (d), and 201.57.
Recommended response: Revise PI according to FDA's electronic communication, SRPI checklist, and relevant CFR sections. Ensure SPL format and provide both marked-up and clean versions.
Cited: 21 CFR 601.14(b), 21 CFR 201.56(a), 21 CFR 201.56(d), 21 CFR 201.57
Carton and Container Labeling Revisions
Severity: majorSubmit draft carton and container labeling based on FDA's proposed revisions dated February 6, 2025.
Recommended response: Update carton and container labeling per FDA's February 6, 2025 revisions.
Proprietary Name Resubmission
Severity: minorResubmit the proposed proprietary name when all other application deficiencies identified in this letter have been addressed, as the name was found conditionally acceptable pending approval of the application.
Recommended response: Do not resubmit proprietary name until all other deficiencies are resolved.
Comprehensive Safety Update Required
Severity: majorInclude a safety update with data from all nonclinical and clinical studies of the product under consideration, regardless of indication, dosage form, or dose level, when responding to the deficiencies.
Recommended response: Prepare a comprehensive safety update covering all studies, nonclinical and clinical, for the resubmission.
Detailed 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: Analyze and document all significant safety profile changes, comparing them to the reference product.
Presentation of New Safety Data
Severity: majorPresent new safety data from the clinical studies for the proposed indication using the same format as the original BLA submission. Provide tabulations of the new safety data combined with the original BLA data, and include tables that compare frequencies of adverse events in the original BLA with the retabulated frequencies.
Recommended response: Format and present new safety data consistently with the original BLA, including combined and comparative tabulations.
Retabulation of Premature Study Discontinuation Reasons
Severity: majorPresent a retabulation of the reasons for premature study discontinuation by incorporating the drop-outs from the newly completed studies. Describe any new trends or patterns identified.
Recommended response: Update and analyze data on premature study discontinuations, identifying new trends.
Case Report Forms and Narrative Summaries for Deaths/SAEs
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: Compile and submit all requested case report forms and narrative summaries for deaths and serious adverse events.
Information on 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: Analyze and report on any substantial changes in the incidence of common adverse events.
Updated Clinical Study Exposure Information
Severity: majorProvide updated exposure information for the clinical studies (e.g., number of subjects, person time).
Recommended response: Update and submit all clinical study exposure data.
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 summarize worldwide safety data, including immunogenicity and usage estimates.
English Translations of Foreign Labeling
Severity: minorProvide English translations of current approved foreign labeling not previously submitted.
Recommended response: Submit English translations for all new or updated foreign labeling.
