Content of Labeling (Prescribing Information) Deficiencies
Severity: majorFailure to submit updated content of labeling in structured product labeling (SPL) format and non-conformance to 21 CFR 201.56(a), (d) and 201.57 regarding content and format of Prescribing Information. A highlighted/marked-up copy and a clean Word version are required.
Recommended response: Revise Prescribing Information to comply with 21 CFR 201.56 and 201.57, and submit in SPL format as per 21 CFR 601.14(b). Provide 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 Deficiencies
Severity: majorSubmit draft carton and container labeling based on the agency's proposed revisions.
Recommended response: Submit revised draft carton and container labeling incorporating agency feedback.
Medication Guide Statement Deficiency
Severity: majorThe required bolded statement or appropriate alternative per 21 CFR 208.24(d) must appear on the carton and container labeling.
Recommended response: Ensure the required Medication Guide statement per 21 CFR 208.24(d) is correctly placed on carton and container labeling.
Cited: 21 CFR 208.24(d)
Risk Evaluation and Mitigation Strategy (REMS) Discussion Pending
Severity: infoFurther discussion of the proposed REMS is pending the complete response to this action letter. The agency agrees a REMS will be necessary if approved, to ensure benefits outweigh risks of severe hypocalcemia.
Recommended response: Prepare for further discussion and potential revisions to the REMS proposal upon submission of the complete response.
Cited: Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FDCA)
Proprietary Name Resubmission Required
Severity: minorThe proposed proprietary name was found conditionally acceptable. Resubmit the proposed proprietary name when all application deficiencies identified in this letter have been addressed.
Recommended response: Resubmit the proprietary name proposal once all other deficiencies in the CRL have been addressed.
Comprehensive Safety Update Required
Severity: criticalProvide a comprehensive safety update including detailed descriptions of significant changes or findings in the safety profile, new safety data from clinical studies, tabulations combining new and original BLA data, and retabulation of reasons for premature study discontinuation.
Recommended response: Compile and present a detailed safety update, integrating all new nonclinical and clinical data, and provide comparative analyses as requested.
Missing Case Report Forms and Narrative Summaries
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, provide narrative summaries for all serious adverse events.
Recommended response: Submit all requested case report forms and narrative summaries for deaths, discontinuations due to AEs, and all SAEs.
Updated Clinical Exposure Information Required
Severity: majorProvide updated exposure information for the clinical studies, including details such as the number of subjects and person time.
Recommended response: Update and submit comprehensive exposure information for all clinical studies.
Worldwide Safety Experience Summary Required
Severity: majorProvide 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 the product marketed in other countries.
Recommended response: Prepare and submit a summary of worldwide safety experience, including immunogenicity data and updated usage estimates from other markets.
English Translations of Foreign Labeling Required
Severity: minorProvide English translations of current approved foreign labeling not previously submitted.
Recommended response: Submit English translations for all approved foreign labeling not yet provided.
