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Background: This study was aimed at estimating the appropriate price of tucatinib plus trastuzumab and capecitabine (TXC), as third-line treatment, in HER2+ breast cancer (BC) patients from the Italian National Health System (NHS) perspective. Methods: A partitioned survival model with three mutually exclusive health states (i.e., progression-free survival (PFS), progressive disease (PD), and death) was used to estimate the price of tucatinib vs trastuzumab emtansine (TDM-1), considering a willingness to pay (WTP) of 60,000 EUR. Data from the HER2CLIMB trial, the Italian population, and the literature were used as input. The model also estimated the total costs and the life-years (LY) of TXC and TDM1. Deterministic and probabilistic (PSA) sensitivity analyses were conducted to evaluate the robustness of the model. Results: In the base case scenario, the appropriate price of tucatinib was 4828.44 EUR per cycle. The TXC resulted in +0.28 LYs and +16,628 EUR compared with TDM-1. Results were mainly sensitive to therapy intensity variation. In PSA analysis, TXC resulted cost-effective in 53% of the simulations. Assuming a WTP ranging 20,000–80,000 EUR, the tucatinib price ranged from 4090.60 to 5197.41 EUR. Conclusions: This study estimated the appropriate price for tucatinib according to different WTP in order to help healthcare decision makers to better understand the treatment value.

Background/Aims: There is growing interest in the use of adaptive designs to improve the efficiency of clinical trials. We apply a Bayesian decision-theoretic model of a sequential experiment using cost and outcome data from the ProFHER pragmatic trial. We assess the model’s potential for delivering value-based research. Methods: Using parameter values estimated from the ProFHER pragmatic trial, including the costs of carrying out the trial, we establish when the trial could have stopped, had the model’s value-based stopping rule been used. We use a bootstrap analysis and simulation study to assess a range of operating characteristics, which we compare with a fixed sample size design which does not allow for early stopping. Results: We estimate that application of the model could have stopped the ProFHER trial early, reducing the sample size by about 14%, saving about 5% of the research budget and resulting in a technology recommendation which was the same as that of the trial. The bootstrap analysis suggests that the expected sample size would have been 38% lower, saving around 13% of the research budget, with a probability of 0.92 of making the same technology recommendation decision. It also shows a large degree of variability in the trial’s sample size. Conclusions: Benefits to trial cost stewardship may be achieved by monitoring trial data as they accumulate and using a stopping rule which balances the benefit of obtaining more information through continued recruitment with the cost of obtaining that information. We present recommendations for further research investigating the application of value-based sequential designs.

Purpose The aim of this study was to evaluate the cost-effectiveness and net monetary benefit of olaparib maintenance therapy compared with no maintenance therapy after first-line platinum-based chemotherapy in newly diagnosed advanced BRCA1/2-mutated ovarian cancer from the Italian National Health Service (NHS) perspective. Methods We developed a lifetime Markov model in which a cohort of patients with newly diagnosed advanced BRCA1/2-mutated ovarian cancer was assigned to receive either olaparib maintenance therapy or active surveillance (Italian standard of care) after first-line platinum-based chemotherapy to compare cost-effectiveness and net monetary benefit of the 2 strategies. Data on clinical outcomes were obtained from related clinical trial literature and extrapolated using parametric survival analyses. Data on costs were derived from Italian official sources and relevant real-world studies. The incremental cost-effectiveness ratio (ICER), incremental cost-utility ratio (ICUR), and incremental net monetary benefit (INMB) were computed and compared against an incremental cost per quality-adjusted life-year (QALY) gained of €16,372 willingness-to-pay (WTP) threshold. We used deterministic sensitivity analysis (DSA) and probabilistic sensitivity analysis (PSA) to assess how uncertainty affects results; we also performed scenario analyses to compare results under different pricing settings. Findings In the base-case scenario, during a 50-year time horizon, the total costs for patients treated with olaparib therapy and active surveillance were €124,359 and €97,043, respectively, and QALYs gained were 7.29 and 4.88, respectively, with an ICER of €9,515 per life-year gained, an ICUR of €11,345 per QALY gained, and an INMB of €12,104. In scenario analyses, considering maximum selling prices for all other drugs, ICUR decreased to €11,311 per QALY and €7,498 per QALY when a 10% and 20% discount, respectively, was applied to the olaparib official price, and the INMB increased to €12,186 and €21,366, respectively. DSA found that the model results were most sensitive to the proportion of patients with relapsing disease in response to platinum-based chemotherapy, time receiving olaparib first-line maintenance treatment, and subsequent treatments price. According to PSAresults, olaparib was associated with a probability of being cost-effective at a €16,372 per QALY WTP threshold ranging from 70% to 100% in the scenarios examined. Implications Our analysis indicates that olaparib maintenance therapy may deliver a significant health benefit with a contained upfront cost during a 50-year time horizon, from the Italian NHS perspective, providing value in a setting with curative intent.

Umberto Restelli,1,2 Davide Croce,1,2 Valeria Pacelli,1 Fabio Ciceri,3,4 Corrado Girmenia51Center for Health Economics, Social and Health Care Management, LIUC - Università Cattaneo, Castellanza, VA, Italy; 2School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; 3Hematology and BMT Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; 4University Vita-Salute San Raffaele, Milan, Italy; 5Department of Haematology, Oncology and Dermatology, Azienda Policlinico Umberto I, Sapienza University, Rome, ItalyBackground: The aim of the analysis is to assess the efficiency of the allocation of economic resources related to the use of letermovir cytomegalovirus (CMV) prophylaxis in adult seropositive recipients (R+) patients receiving an allogenic hematopoietic stem cell transplantation (HSCT), compared with a no-prophylaxis strategy, assuming preemptive antiviral administration in both groups from the perspective of the Italian National Health Service (NHS), through a cost-effectiveness analysis.Methods: The model used is based on a decision tree which simulates on a lifetime horizon the progression of CMV infection, considering two alternatives: the use of letermovir CMV prophylaxis, followed by preemptive therapy in case of clinically significant CMV infection, or the avoided use of letermovir CMV prophylaxis, considering direct medical costs (referred to 2018) and quality-adjusted life years (QALYs), both discounted considering a 3% annual rate. Two scenarios were considered, representing the differences related to regional contexts and clinical practice of different typologies of hospitals (public or private accredited with Regional Health Services).Results: The use of letermovir prophylaxis compared with no prophylaxis strategy would lead to an increase of QALYs and direct medical costs in the two scenarios considered, with a mean increase of 0.45 QALYs, and an increase of direct medical costs of 10,222.4 € and of 10,809.9 € in the two scenarios. The incremental cost-effectiveness ratios are equal to 22,564 €/QALY and 23,861 €/QALY. The probabilistic sensitivity analysis conducted showed a percentage of results below the threshold of 40,000 €/QALY of 67.4% and 71.3%; and below a threshold of 25,000 €/QALY equal to 50.4% and to 53.0%.Conclusions: The use of letermovir CMV prophylaxis in adult R+ patients receiving allogenic HSCT, compared with a no-prophylaxis strategy, would be cost-effective for the Italian NHS considering the incremental cost-effectiveness thresholds of 40,000 €/QALY and of 25,000 €/QALY.Keywords: cytomegalovirus, letermovir, allogenic hematopoietic stem cell transplantation, cost-effectiveness analysis

Purpose: Health state utility values are derived from preference-based measurements and are useful in calculating quality-adjusted life years (QALYs), which is a metric commonly used in cost-effectiveness studies. The purpose of this study was to convert the Achilles Tendon Rupture Score (ATRS) to the preference-based European Quality of Life-5 Dimension Questionnaire (EQ-5D) by estimating the relationship between the two scores using mapping. Methods: Data were collected from a randomised controlled trial, where 100 patients were treated either surgically or non-surgically for Achilles tendon rupture. Forty-three and forty-four patients in surgical group and non-surgical group completed the ATRS and the EQ-5D alongside each other during follow-up at three time points. Different models of the relationship between the ATRS and the EQ-5D were developed and analysed based on direct mapping and cross-validation. The model with the lowest mean absolute error was observed as the one with the best fit. Results: Among the competing models, mapping based on using a combination of the ATRS items four, five, and six associated with limitation due to pain, during activities of daily living and when walking on uneven ground, produced the best predictor of the EQ-5D score. Conclusions: The present study provides a mapping algorithm to enable the derivation of utility values directly from the ATRS. This approach makes it feasible for researchers, as well as medical practitioners, to obtain preference-based values in clinical studies or settings where only the ATRS is being administered. The algorithm allows for the calculation of QALYs for use in cost-effectiveness analyses, making it valuable in the study of acute Achilles tendon ruptures. Level of evidence: II.

Security management of critical infrastructures is a complex task as a great variety of technical and socio-political information is needed to realistically predict the risk of intentional malevolent acts. In the present study, a methodology based on Limited Memory Influence Diagram (LIMID) has been developed for the protection of critical infrastructures via cost-effective allocation of security measures. LIMID is an extension of Bayesian network (BN) intended for decision-making, allowing for efficient modelling of complex systems while accounting for interdependencies and interaction of system components. The probability updating feature of BN has been used to investigate the effect of vulnerabilities on adversaries’ preferences when planning attacks. Moreover, the proposed methodology has been shown to be able to identify an optimal defensive strategy given an attack through maximizing defenders’ expected utility. Despite being demonstrated via a chemical facility, the methodology can easily be tailored to a wide variety of critical infrastructures.

Introduction Long-term regular administrations of factor VIII (FVIII) concentrate (prophylaxis) initiated at an early age prevents bleeding in patients with severe haemophilia A (HA). The 5-year prospective Italian POTTER study provided evidence of benefits in adolescents and adults of late prophylaxis (LP) vs. on-demand therapy (OD) in reducing bleeding episodes and joint morbidity and improving quality of life; however, costs were increased. Aim The aim of this study was to determine the cost-effectiveness of LP vs. OD with sucrose-formulated recombinant FVIII in adolescents and adults with severe HA in Italy. Methods A Markov model evaluated lifetime cost-effectiveness of LP vs. OD in patients with severe HA in Italy, from both the healthcare and societal perspectives. Clinical input parameters were taken from the POTTER study and published literature. Health utility values were assigned to each health state as measured by the joint disease severity Pettersson score. Costs were expressed in Euro (€) 2014, including drug and other medical costs. Sensitivity analyses were performed considering societal perspective (including productivity lost) and varying relative risk of bleeding episodes between regimens. Clinical outcomes and costs were discounted at 6% according to previous studies. Results Lifetime incremental discounted quality-adjusted life-years (QALYs) were +4.26, whereas incremental discounted costs were +€229,694 from a healthcare perspective, with estimated incremental cost-effectiveness ratios (ICERs) equal to €53,978/QALY. Sensitivity analyses confirmed the base-case results showing lower ICERs with the societal perspective. Conclusion Late prophylaxis vs. on-demand therapy results in a cost-effective approach with ICERs falling below the threshold considered acceptable in Italy.

In recent years several European air pollution policies have been based on a cost-effectiveness approach. In the European Union, the European Commission starts using the multi-pollutant, multi-effect GAINS (Greenhouse Gas Air Pollution Interactions and Synergies) model to identify cost-effective National Emission Ceilings and specific emission control measures for each Member State to reach these targets. In this paper, we apply the GAINS methodology to the case of Italy with 20 subnational regions. We present regional results for different approaches to environmental target setting for PM2.5 pollution in the year 2030. We have obtained these results using optimization techniques consistent with those of GAINS-Europe, but at a higher resolution. Our results show that an overall health-impact oriented approach is more cost-effective than setting a nation-wide limit value on ambient air quality, such as the one set for the year 2030 by the European Directive on ambient air quality and cleaner air for Europe. The health-impact oriented approach implies additional emission control costs of 153 million €/yr on top of the baseline costs, compared to 322 million €/yr for attaining the nation-wide air quality limit. We provide insights into the distribution of costs and benefits for regions within Italy and identify the main beneficiaries of a health-impact approach over a limit-value approach. © 2016 Elsevier Ltd.

Objective:Across Italy up to 7.3% of the population is infected with hepatitis C virus (HCV), with long-term complications resulting in high medical costs and significant morbidity and mortality. Current treatment options have limitations due to side effects, interferon intolerability and ineligibility, long treatment durations and low sustained virological response (SVR) rates, especially for the most severe patients). Sofosbuvir is the first nucleotide polymerase inhibitor with pan-genotypic activity. Sofosbuvir, administered with ribavirin (RBV) and with or without pegylated interferon (PEG-INF), resulted in >90% SVR across treatment-naïve (TN) genotype (GT) 1-6 patients. It is also the first treatment option for patients that are unsuitable for interferon (UI). This analysis evaluates the cost-effectiveness of sofosbuvir for GTs 1-6 in Italy.Research design and methods:A Markov model followed a cohort of 10,000 patients until they reached 80 years old. Approximately 20% of naïve and 30% of experienced patients initiated treatment at the cirrhosis stage. Comparators included PEG-INF + RBV for all GTs and plus telaprevir or boceprevir for GT1, or no treatment. Costs and outcomes were discounted at 3% and the cost perspective was that of the National Health Service in Italy.Results:Sofosbuvir was cost-effective with incremental cost-effectiveness ratios (ICERs) below 40,000/QALY in all patient populations, particularly in cirrhotic patients. The exception was for a mixed cohort of GT2 TN patients where the ICER was 68,500/QALY and for a cirrhotic cohort of GT4/5/6 where the ICER was 68,434/QALY. Nevertheless, the prevalence of HCV in this patient population is expected to be low. Results were robust to sensitivity analysis.Conclusions:Sofosbuvir-based regimens are cost-effective in Italy, particular for the most severe patients. The interferon-free regimens are a real treatment option for UI patients. The high cure rates of this breakthrough treatment are expected to substantially reduce the burden of HCV in Italy.

Background and Aims: A relevant proportion of patients affected by Chronic Hepatitis C (CHC) is older than 65 years. In the interferon era, comorbidities and a higher susceptibility to interferon/ribavirin adverse events have historically limited treatment in these patients. Recent approval of interferon-free regimens, characterized by high efficacy and limited toxicity, provide unprecedented chances for these patients to receive curative treatments. However, the costeffectiveness of all-oral Direct-Acting Antivirals (DAAs) has not been addressed in the elderly population. We have performed a cost-effectiveness analysis taking into account the severity of liver disease, the age of the patient and the geriatric (frailty) status. Methods: A semi-Markov model of CHC natural history was built. The study focuses on CHC patients older than 65 years, stratified according to liver fibrosis (METAVIR F3 and F4), age (65 to 85 years old) and frailty phenotype defined by Fried’s (not frail, pre-frail and frail) for a total of 30 cohorts simulated. Treatment with sofosbuvir plus simeprevir (SOF/SMV) combination versus no treatment was assessed for each cohort population. The model estimated costs, Life Years and Quality Adjusted Life Years (QALY) using a lifetime time horizon and the Health System perspective. Results are presented as incremental cost-effectiveness ratios (ICERs) per QALY gained. Cost-effectiveness was defined as an ICER under the willingness-to-pay threshold of €37,000 per QALY gained. Results: At each fibrosis score, ICER increased with age and frailty index. Among patients with F3 fibrosis, ICER ranged from €13,934/QALY in not-frail 65 years old and €79,354 in frail 85 years old patients. Among F4 patients ICER ranged from €13,873/QALY in not frail 65 years old and €115,965 in frail 85 years old patients. In both F3 and F4 cohorts ICER was below €37,000/QALY up to age 80 in non-frail pts, up to age 75 in pre-frail patients, up to age 70 in frail patients. Adopting an alternative scenario with a 20% discount of SOF/SMV treatment, the number of cohort population simulated with an ICER below € 37,000/QALY increased. Conclusions: SOF/SMV treatment is cost-effective in most CHC patients older than 65 years, however a careful assessment of the patient geriatric status is mandatory. This cost-effectiveness analysis should promote a prospective clinical study to verify efficacy and side effects in elderly HCV patients.

Summary There are reports of pretransplant sofosbuvir (SOF) plus ribavirin being effective in preventing recurrent hepatitis C virus (HCV) infection after liver transplantation (LT). The aim of this study was to assess the cost-effectiveness of this strategy in the area served by the North Italy Transplant program. We retrospectively assessed the impact of HCV infection on post-LT survival in 2376 consecutive adult patients (MELD ≤ 25, unknown genotype, period 2004–2009) and the prevalence costs of conventional standard of care (SOC) antiviral therapy (pegylated interferon plus ribavirin) after LT. A Markov model was developed to compare two strategies: 12–24 weeks of SOF+ ribavirin for pre-LT anti-HCV treatment versus on-demand post-LT SOC antiviral therapy. Among the 1794 patients undergoing LT, 860 (48%) were HCV+ and 50% of them were given SOC therapy after LT (mean cost of drugs and adverse effect management = 14 421€ per patient). HCV etiology had a strong impact on post-LT survival (hazard ratio = 1.59, 95% CI = 1.22–2.09, P = 0.0007). After Monte Carlo simulation, pre-LT SOF therapy showed a median survival benefit of 1.5 quality-adjusted life years and an Incremental cost-effectiveness ratio (ICER) of 30 663€/QALY, proving cost-effective in our particular Italian scenario. The costs of SOF therapy, sustained viral response rate 12 weeks after LT, and recipient's age were the main ICER predictors at multivariate analysis. This study proposes a dynamic model based on real-life data from northern Italy for adjusting the costs of pre-LT direct-acting antiviral therapies to the actual sustained virological response reached after LT.

Background and aims: To allocate treatment resources for chronic hepatitis C (CHC) genotype 1 naive patients, we performed a cost-effectiveness analysis of Boceprevir (BOC) and Telaprevir (TVR) based triple therapy according to different patient selection strategies. Methods: A semi-Markov model of CHC natural history and progression toward end stage liver diseases (decompensated cirrhosis, HCC and liver transplantation) was built. Model health states were defined by METAVIR fibrosis stages (F0–F4), and complications of cirrhosis. We considered 3 selection strategies based on fibrosis stage: (1) treat all patients with F1–F4 fibrosis, (2) only F2–F4 and (3) only F3–F4. For each strategy, TVR IL28B-guided and BOC RVRguided therapy was applied. The model assessed the costs and outcomes, including QALYs, Life Years and the number of End Stage Liver Diseases developed or Death (ESLD-D), using lifetime as time horizon and adopting the NHS perspective. An alternative simulation was performed using 5 year as time horizon, as coherent with upcoming main changes in standard of care (all-oral protocols). Results: The F3–F4 selection strategy proved the least expensive and the least effective. Adopting the lifetime horizon, F1–F4 strategy was cost-effective with an ICER of D 5132.13 for QALY, in TVR IL28B-guided, and D 7042.49 for QALY, in BOC RVR-guided therapy. In the 5 year scenario, only F3–F4 strategy showed costeffectiveness, while the F1–F4 strategy was not cost-effective, with an ICER of D 1,818,679 (TVR IL28B guided) and D 1866.437 (BOC RVR-guided) for each ESLD-D avoided. Conclusions: The present simulation study demonstrated that treating all CHC patients regardless of fibrosis stage is cost-effective in a lifetime horizon scenario. In a more realistic 5-year time horizon scenario, to treat patients with advanced fibrosis and cirrhosis was the only strategy to show cost-effectiveness.

Post-liver transplant recurrent hepatitis C virus (HCV) infection severely limits the prognosis of HCV-infected patients. Sofosbuvir in combination with ribavirin (SOF/RBV) is a novel interferon-free treatment able to suppress HCV viremia when applied to HCV patients listed for transplant, thereby preventing HCV recurrence. Aim of this study was to assess the cost-effectiveness of this regimens in patients listed for transplant for cirrhosis (HCV-cirrhosis) or for hepatocellular carcinoma in cirrhosis (HCV-HCC). A semi-Markov model was developed to assess the cost-effectiveness of pre-transplant SOF/RBV treatment in patients listed for HCV-cirrhosis and HCV-related HCC. The model simulates the progression of HCV-cirrhosis or HCV-HCC patients from the time of listing until death considering the risk of HCV recurrence post-transplant. The model compared 2 different strategies: 1) SOF/RBV up to a maximum of 24 weeks or until OLT if performed before the 24th week from the initiation of treatment, 2) No antiviral treatment. The model estimated the costs related to the treatment with SOF/RBV, the costs associated to each health state, the life-years (LYSs), the quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) expressed as € per QALY gained. The analysis was performed from the Italian National Health System perspective with a lifetime time horizon and one-month Markov cycles. Future costs and clinical benefits, expressed as QALYs, were discounted at 3% per year. Results: in the base-case analysis the ICER for 24 weeks of SOF/RBVR was €30,518 per QALY gained in HCV-cirrhosis patients and €41,610 in HCV-HCC patients. The reliability of our results was confirmed by the one way sensitivity-analysis and by the cost-effectiveness acceptability curve that reported 97.5% probability of SOF/RBV to be cost-effective at a willingness to pay threshold of €60,000 in the HCV–cirrhosis scenario, and 88.1% in the HCV-HCC scenario. Further, SOF/RBV cost-effectiveness was clearly sensitive to the duration of treatment; assuming 12 weeks SOF/RBV treatment duration, the ICER decreased to €19,317 in HCV-Cirrhosis and €29,540 in HCV-HCC. In conclusion, our study shows that treating patients with HCV-cirrhosis or HCV-HCC in the transplant waiting list with SOF/RBV is cost-effective and may become the new standard of care for these patients. However a well-defined prospective study is needed to confirm the value of the parameters assumed in the model and the results. Furthermore, associations of direct acting antivirals will soon appear into the horizon also in the transplant setting and bring new challenges and opportunities.

Objectives: Sofosbuvir in combination with ribavirin (SOF/RBV) is a novel treatment able to suppress HCV viremia when applied to HCV patients listed for transplant, preventing HCV recurrence. Aim of this study was to assess the costeffectiveness of this regimen in HCV patients listed for transplant for cirrhosis (HCVcirrhosis) or for hepatocellular carcinoma (HCV-HCC). Methods: a semi-Markov model was developed. The model simulates the progression of HCV-cirrhosis or HCV-HCC patients from the time of listing until death considering the risk of HCV recurrence post-transplant. The model compared 2 different strategies: 1) SOF/RBV up to a maximum of 24 weeks or until OLT if performed before the 24th week, 2) No antiviral treatment. The model estimated the costs related to the treatment with SOF/RBV, the costs associated to each health state, the life-years (LYSs), the quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) expressed as € per QALY gained. The analysis was performed from the Italian National Health System perspective with a lifetime time horizon and one-month Markov cycles. Future costs and clinical benefits, expressed as QALYs, were discounted at 3% per year. Results: in the base-case analysis the ICER for 24 weeks of SOF/RBVR was € 30,518 per QALY gained in HCV-cirrhosis patients and € 41,610 in HCV-HCC patients. The reliability of our results was confirmed by the one way sensitivity-analysis and by the cost-effectiveness acceptability curve. Further, SOF/RBV cost-effectiveness was clearly sensitive to the duration of treatment; assuming 12 weeks SOF/RBV treatment duration, the ICER decreased to € 19,317 in HCVCirrhosis and € 29,540 in HCV-HCC. Conclusions: our study shows that treating patients with HCV-cirrhosis or HCV-HCC listed for transplant with SOF/RBV is costeffective and may become the new standard of care for these patients. However a well-defined prospective study is needed to confirm the value of the parameters assumed in the model and the results

PEG-electrolyte solution has been considered the method of choice for preparation to colonoscopy, but no data about cost-effectiveness have been available so far. A controlled study enrolling 722 patients has been carried out in order to compare the cost-effectiveness of PEG-electrolyte solution and a traditional method consisting of low-residue diet, sennosides, magnesium sulphate and sodium phosphate enemas for preparation to colonoscopy. As primary measure, the proportion of patients submitted to repeated colonoscopy due to insufficient bowel cleansing PEG-electrolyte solution has been used. This was significantly lower after PEG-electrolyte solution (2%) than after traditional method (9%). Direct costs, reported per 100 cases, were lower with PEG-electrolyte solution (L. 20.655.000) than with traditional preparation (L. 21.746.000) with a saving of 5%. As far as total costs (direct plus indirect) are concerned the economical savings associated with use of PEG-electrolyte solution were L. 9.684.000 (21.5%). PEG-electrolyte solution appears more cost-effective than a traditional method for preparation to colonoscopy; therefore its use is also motivated by substantial economical benefits for the National Health System.