Unacceptable Risk-Benefit Profile and Need for Additional Clinical Study
Severity: criticalDespite meeting the primary efficacy endpoint in the CONFIRM study, safety findings, particularly a higher incidence of serious adverse events of respiratory failure in the terlipressin arm (14%) as compared to the placebo arm (5%), raise concerns that the risks of terlipressin may outweigh its benefits. An additional adequate and well-controlled study is required to demonstrate an acceptable risk-benefit profile, potentially utilizing the proposed risk mitigation strategy. The primary endpoint and analytic plan should be discussed with and agreed upon by the FDA prior to initiation.
Recommended response: Design and conduct a new adequate and well-controlled clinical study to demonstrate an acceptable risk-benefit profile, discussing the primary endpoint and analytic plan with FDA prior to initiation. Consider prospectively testing the proposed risk mitigation strategy.
Incomplete Safety Update Submission
Severity: majorA comprehensive safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), is required. This includes detailing significant changes in the safety profile, incorporating new safety data into adverse event tables (including for other indications), retabulating reasons for premature trial discontinuation, providing case report forms and narrative summaries for deaths and serious adverse events, describing changes in common adverse events, providing updated exposure information, summarizing worldwide safety experience, and submitting English translations of current approved foreign labeling.
Recommended response: Compile and submit a complete safety update addressing all specified requirements, including new and updated clinical safety data, narratives for serious adverse events and deaths, and worldwide experience, ensuring compliance with 21 CFR 314.50(d)(5)(vi)(b).
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Proprietary Name Resubmission Required
Severity: minorThe proposed proprietary name, TERLIVAZ, was found acceptable pending approval of the application in the current review cycle. However, it must be resubmitted when responding to the application deficiencies.
Recommended response: Resubmit the proposed proprietary name along with the complete response to all deficiencies.
Prescribing Information Review Reserved
Severity: minorThe FDA reserves further comment on the proposed labeling until the application is otherwise adequate. This indicates that the current labeling is not yet acceptable for approval and will be reviewed once the clinical and safety deficiencies are resolved.
Recommended response: Review and update prescribing information in accordance with PLR requirements and other relevant guidances once clinical and safety deficiencies are addressed.
