Background:In a single-payer setting,the payer aims to maximize the net-monetary-benefit(NMB)given a cost-effectiveness(CE) threshold,whilst the manufacturer aims to maximize the expected discounted-cash-flow(DCF)resulting from the sales of that technology.Managed entry agreements(MEAs) are tools that are used to improve access to expensive technologies that would otherwise not be deemed to be cost-effective to payers.While simple discount on the list-price is the most commonly applied MEA type,there are different forms,each having different impact on the cost-effectiveness of the technology,on the lifetime DCF-per-patient and on the decision uncertainty.We aim to analyze the sequential decision-making of different MEAs (i.e. simple discount,free treatment initiation,lifetime/cycle treatment acquisition cost-capping[LTTACC/CTACC],performance-based risk sharing[PBRSA],etc.)at the manufacturer and at the payer level,respectively.Methods:A UK-based cost-utility analysis using three-state,partitioned-survival-model was constructed to determine the cost-effectiveness of regorafenib versus best-supportive-care for the second-line treatment of hepatocellular carcinoma.The optimal agreement terms that would maximise the lifetime DCF-per-patient for each MEA,whilst remaining below the CE-threshold(£50,000/QALY gained)were obtained in the deterministic base-case.Robustness for each optimized MEA was then assessed using probabilistic sensitivity and scenario analyses,value of information(VoI),and HTA-risk analyses.Results:As expected,the introduction of all MEAs improved the probabilistic ICER and NMB values to (almost)acceptable levels,compared to “no-MEA”case(ICER~£78,000/QALY-gained).The expected DCFs across the explored MEAs were all similar,whilst the payer strategy&uncertainty burden(PSUB) for regorafenib decreased in all MEAs explored.VoI analyses revealed that regorafenib mean-dose-intensity and time-on-treatment(ToT) parameters attributed most to the decision uncertainty.LTTACC provided the smallest PSUB and the most robust NMB estimates under parametric uncertainty.For scenarios on increased regorafenib ToT or mean-dose-intensity,LTACC again provided acceptable cost-effectiveness outcomes,whereas for scenarios on decreased regorafenib PFS&OS, only PBRSA resulted in plausible ICER values. In some scenarios(e.g.exploring uncertainty on the progressed disease resource utilization),none of the MEAs resulted in acceptable cost-effectiveness outcomes.Conclusion:While simple discount might be practical,other MEAs can provide additional benefits to the payer in terms of increased NMB,reduced decision risk and parametric/structural uncertainty.