Incomplete Cardiovascular Safety Assessment
Severity: criticalPreliminary findings from Study 20110142 show a higher incidence of cardiovascular serious adverse events with romosozumab compared to alendronate in women with postmenopausal osteoporosis. A similar signal was seen in Study 20110174, a smaller study comparing romosozumab to placebo in men with osteoporosis. These findings raise concerns that romosozumab may increase cardiovascular risk. Although Study 20070337 did not appear to have a cardiovascular safety signal, these disparate findings across studies require detailed review once the completed final analyses have been submitted. These additional data, including the efficacy data from the head-to-head comparison of romosozumab to alendronate, are needed before the benefit/risk assessment can be completed and whether the benefits of romosozumab outweigh its risks can be determined.
Recommended response: Complete analyses of Studies 20110142 and 20110174. Submit individual clinical study reports together with an integrated assessment of cardiovascular risk that takes into account the totality of the data, including the basis for your conclusion that the benefits of romosozumab outweigh the identified cardiovascular risks. Provide all pertinent narratives and datasets. Request a meeting to discuss the details of your proposal for responding to the deficiency before resubmitting the application.
Proprietary Name Resubmission Requirement
Severity: minorThe proposed proprietary name, Evenity, was found acceptable pending approval of the application in the current review cycle. It must be resubmitted when responding to the application deficiency.
Recommended response: Resubmit the proposed proprietary name when responding to the application deficiency.
Required Comprehensive Safety Update for Resubmission
Severity: majorWhen responding to the primary deficiency, a comprehensive safety update must be included. This update should incorporate data from all nonclinical and clinical studies/trials of the product under consideration regardless of indication, dosage form, or dose level. It requires detailing significant changes in the safety profile, presenting new safety data from studies/clinical trials for the proposed indication (using the same format as the original submission), presenting tabulations of new safety data combined with original application data, including tables comparing frequencies of adverse events, providing separate tables for adverse events in clinical trials for other indications, retabulating reasons for premature trial discontinuation, providing case report forms and narrative summaries for deaths or discontinuations due to adverse events, describing information suggesting substantial changes in common adverse events, providing updated exposure information, summarizing worldwide safety experience, and providing English translations of current approved foreign labeling not previously submitted. The updated content of labeling must be in structured product labeling (SPL) format.
Recommended response: Include a comprehensive safety update with the resubmission, covering all nonclinical and clinical data, significant safety changes, new data presentation, combined tabulations, comparative tables, separate tables for other indications, retabulated discontinuations, case reports/narratives for deaths/SAEs, changes in common AEs, updated exposure, worldwide experience, and English translations of foreign labeling. Ensure updated content of labeling is in SPL format.
Cited: 21 CFR 601.14(b)
