Unfavorable Benefit-Risk Assessment (Overall)
Severity: criticalThe submitted data do not support a favorable benefit-risk assessment of vadadustat for the proposed indication in both NDD and DD CKD populations. While efficacy endpoint for hemoglobin (Hb) response was met, there was higher use of rescue therapy (ESA, RBC transfusion) with vadadustat. The identified major safety concerns outweigh these benefits.
Recommended response: Re-evaluate the overall clinical development program and consider a revised indication or patient population with a more favorable benefit-risk profile, potentially requiring new clinical trials.
Major Adverse Cardiac Events (MACE) Safety Signal
Severity: majorIn the NDD-CKD population, non-inferiority for MACE was not established (HR 1.17, 95% CI 1.01, 1.36); the upper bound excluded the prespecified non-inferiority margin of 1.25. Furthermore, there was an increased hazard ratio for the non-fatal MI component of MACE in the U.S. subgroup (HR, 1.49, 95% CI, 0.97, 2.30).
Recommended response: Conduct new clinical trials to establish MACE non-inferiority or superiority in a defined patient population or with a different dosing regimen, addressing the observed safety signal.
Thromboembolic (TE) Events Safety Signal
Severity: majorA concerning signal for adjudicated thromboembolic (TE) events was observed in the DD-CKD population (HR 1.20, 95% CI 0.96, 1.50 overall; HR 1.46, 95% CI 1.13, 1.89 in U.S. subgroup). Over 80% of adjudicated TE events were vascular access thromboses (HR 1.28, 95% CI 1.00, 1.63), which is particularly concerning for this patient population.
Recommended response: Design new clinical trials to address the increased risk of TE events, particularly vascular access thrombosis, potentially exploring different dosing strategies or patient selection criteria.
Drug-Induced Liver Injury (DILI) Risk
Severity: criticalConcerns for a clinically significant risk for drug-induced liver injury (DILI) were raised, based on one Hy’s Law case, at least seven probable DILI cases with significant ALT elevation, and an imbalance in ALT elevations compared to darbepoetin alfa. There are also concerns that real-world monitoring may be inadequate, potentially underestimating risks.
Recommended response: Propose and assess a strategy to successfully mitigate the risk of hepatotoxicity, acknowledging the idiosyncratic nature of DILI and the challenges with real-world monitoring. This may involve further clinical studies or a risk evaluation and mitigation strategy (REMS).
Need for Safety Update
Severity: minorA comprehensive safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), must be included when responding to deficiencies. This update should incorporate new safety data from all nonclinical and clinical studies/trials, describe significant changes, and present combined and comparative tabulations of adverse events.
Recommended response: Prepare a comprehensive safety update following the specified regulatory guidelines, ensuring all new safety data are integrated and presented clearly for resubmission.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Proprietary Name Resubmission Required
Severity: infoThe proposed proprietary name, Vafseo, was found acceptable pending approval of the application. It must be resubmitted when responding to the application deficiencies.
Recommended response: Include the proprietary name resubmission as part of the complete response package.
Labeling and Carton/Container Labeling Comments Reserved
Severity: infoComments on proposed labeling and carton/container labeling are reserved until the application is otherwise adequate. The sponsor is encouraged to review labeling resources and use the Selected Requirements for Prescribing Information (SRPI) checklist.
Recommended response: Proactively review and update all labeling (Prescribing Information, carton, container) in anticipation of future submission, ensuring compliance with current regulations and guidances, and utilizing the SRPI checklist.
