Insufficient Clinical Data for 420 mg Every Two Weeks Dosing Regimen
Severity: majorInsufficient clinical data were provided to describe the effect of the 420 mg every two week dosage in labeling for the treatment of homozygous familial hypercholesterolemia in patients on other lipid-lowering therapies who require additional lowering of LDL-C. Specifically, the submitted data were inadequate to describe for providers what incremental benefit, if any, is achieved by doubling the dosing frequency of 420 mg once monthly to 420 mg every two weeks. Additional information from adequate and well-controlled study(ies) will be required to better characterize this dosing regimen.
Recommended response: Conduct additional adequate and well-controlled clinical studies to characterize the incremental benefit of the 420 mg every two weeks dosing regimen for HoFH.
Comprehensive Safety Update Required
Severity: majorA comprehensive safety update is required, including data from all non-clinical and clinical studies regardless of indication, dosage form, or dose level. This includes describing significant changes in the safety profile, presenting new safety data from studies for the proposed indication, tabulating new safety data combined with initial data, comparing frequencies of adverse events, providing separate tables for adverse events for other indications, retabulating reasons for premature study discontinuation, providing case report forms and narrative summaries for deaths and serious adverse events, describing changes in incidence of common adverse events, providing updated exposure information, and summarizing worldwide safety experience with English translations of foreign labeling.
Recommended response: Compile and submit a comprehensive safety update incorporating all new non-clinical and clinical data, including detailed adverse event reporting, narrative summaries for serious events and deaths, updated exposure information, and worldwide safety experience.
Labeling Comments Reserved Pending Clinical Resolution
Severity: infoComments on the proposed labeling are reserved until the application is otherwise adequate. The sponsor is encouraged to review PLR Requirements for Prescribing Information resources, including regulations and related guidance documents, and the Selected Requirements for Prescribing Information (SRPI) checklist. Any revised labeling must conform to format items in regulations and guidances and be submitted as updated content of labeling in structured product labeling (SPL) format.
Recommended response: Review and revise labeling according to PLR requirements and SRPI checklist once clinical deficiencies are addressed, ensuring submission in SPL format.
Cited: 21 CFR 601.14(b)
