[Administrative delays of temporary recommendation for use: Impact on access to innovation in melanoma]. / Délais administratifs des RTU, effet sur l'accès à l'innovation dans le mélanome.

INTRODUCTION: Melanoma has benefited in recent years from therapeutic innovations, which have improved overall survival of patients. France has developed a regulatory arsenal allowing faster access to innovative drugs before marketing authorization: temporary authorization for use (ATU) and temporary recommendation for use (RTU). METHOD: We describe here the decision-making processes that led to the non-publication of the decree on the funding of three RTU in adjuvant melanoma therapy: nivolumab, pembrolizumab and the combination of dabrafenib and trametinib, and we analyse the fate of these drugs in order to quantify the potential loss of chance. RESULTS: On 03AUG2018, the French National Agency for Medicines and Health Product Safety (ANSM) published 3 RTU in order to give rapid access to major innovations in adjuvant melanoma therapy: nivolumab, pembrolizumab and the combination of dabrafenib and trametinib. These drugs have respectively demonstrated reductions in the risk of recurrence by 35 %, 43% and 55% for target populations of 2200, 1900 and 650 patients per year. Despite a favourable opinion on reimbursement from the French National Authority for Health (HAS), the decrees on reimbursement will never be published, prohibiting the use of these products before the marketing authorisation, and depriving many patients of a potential cure. CONCLUSION: Despite a favourable opinion from scientists and health agencies for the rapid availability of a drug, the French public health code does not systematically imply access to a therapeutic innovation. The reform of access to innovation implemented on 01JUL2021 may help tackle this issue.

Patterns of care and economic consequences of using bone-targeted agents for castration-sensitive prostate cancer patients with bone metastases to prevent skeletal-related events in Switzerland - the SAKK 95/16 prostate study.

BACKGROUND: International guidelines state that bone-targeted agents such as denosumab or zoledronic acid at doses used for bone metastasis are not indicated for patients with metastatic castration-sensitive prostate cancer (mCSPC) with bone metastases. Whereas denosumab has never been studied in this patient population, zoledronic acid has been shown to be ineffective in decreasing the risk for skeletal-related events. This study estimates the prevalence and economic consequences of real-world use of bone-targeted agents for mCSPC patients in Switzerland. METHODS: To estimate the frequency of bone-targeted agent administration and skeletal-related events, data from a non-interventional, cross-sectional survey involving oncologists across Switzerland (SAKK 95/16) was combined with data from the Swiss National Institute for Cancer Epidemiology and Registration (NICER). Economic parameters were calculated from the perspective of the healthcare system over the median time to prostate-specific antigen (PSA) progression for the extrapolated patient group, using data from NICER. The cost calculation covered costs for bone-targeted agents, their administration and skeletal-related events. The time to PSA progression (33.2 months), as well as the probability and cost of skeletal-related events were derived from the literature. RESULTS: The survey was answered by 86 physicians treating 417 patients, of whom 106 (25.4%) had prostate cancer, with 36 (34.0%) of these mCSPC. The majority of mCSPC patients (52.8%, n = 19) received bone-targeted agents monthly. Denosumab was the treatment of choice in 84.2% of patients (n = 16). Extrapolation using data from NICER indicated that 568 mCSPC patients may be treated with bone-targeted agents at doses used for bone metastasis  every year in Switzerland, leading to estimated total costs of more than CHF 8.3 million over 33.2 months. Because of its more frequent prescription and higher price, it appears that almost 93% of the total costs can be attributed to denosumab. For both denosumab and zoledronic acid, the most expensive components were the cost of administration and the drug cost, making up more than 90% of the total costs, with the rest being costs of skeletal-related events. CONCLUSIONS: This study found that the administration of bone-targeted agents in doses used for bone-metastatic diseases to prevent skeletal-related events is frequent in the setting of mCSPC and results in significant costs for the healthcare system.

Highly Efficient Reusable Carboxy Group Functionalized Imidazolium Salts for a Simple and Cost-effective Preparation of pyrano[2,3-d]pyrimidinone Derivatives.

AIMS AND OBJECTIVE: In the current study, environmentally benign and cost-effective procedures were suggested for the preparation of carboxy group functionalized imidazolium salts, including [Cmmim]BF4 - or [Cmmim]Br- as a new, reusable Brønsted acidic ionic liquid (BAIL) catalyst. Then, the catalytic performance of [Cmmim]BF4 - or [Cmmim]Br- were successfully inspected towards the three---components one---pot preparation of pyrano[2,3-d]pyrimidinone derivatives 4a-4q. The mentioned procedures show short reaction times, easy work-up procedure, green conditions, high yields of the products, high potent of recovering, and reusing capability. The current study is useful and adequate for the application and development of imidazolium salts on the basis of green chemistry principles. MATERIALS AND METHODS: An aromatic aldehyde (1 mmol), barbituric acid (1 mmol), and malononitrile (1 mmol) were placed in a round---bottomed flask containing ethanol (5 mL). BAILs A and B (0.1 mmol, 10 mol%) were added to the mixture. The suspension was magnetically stirred at room temperature for an appropriate time (Table 2). After completion of the reaction, which was monitored by TLC (n---hexane:ethyl acetate = 3:1), the pure product was filtered off to separate the catalyst, washed with water, and recrystallized from ethanol to afford the pure compound. After separation of the product, the catalyst was recovered by evaporation of water, washed with Et2O, dried under vacuum for 2 h, and reused for the same reaction. RESULTS: The mentioned procedure shows short reaction times, easy work-up procedure, green conditions, high yields of the products, and high potent of recovering and reusing capability. CONCLUSION: In this study, we unveiled the synthesis of a new acetic acid functionalized ionic liquids [Cmmim]BF4 - BAIL A or [Cmmim]Br- BAIL B and their application for the preparation of pyrano[2,3-d]pyrimidinone derivatives via a three-component reaction among various aromatic aldehydes, barbituric acid, and malononitrile under mild and metal-free conditions. A wide range of pyrano[2,3-d]pyrimidinone derivatives bearing diverse functional groups was obtained in short reaction and excellent yields. Operational simplicity, recoverability, and reusability of catalysts, cheap and chemically stable reagents, high catalytic activity, easy work-up, and the eco-friendly procedure, make this method environmentally benign and cost-effective.

[Impact of stopping reimbursement of olmesartan for hypertensive patients in primary care]. / Impact du déremboursement de l'olmésartan chez les patients hypertendus en soins premiers.

AIMS OF STUDY: Since January 2017, olmesartan-based treatment are no longer reimbursed by French national health insurance. Indeed, enteropathy cases, potentially lethal, were described in relation to this medication. Objectives were to study the impact of stopping the reimbursement of olmesartan for hypertensive patients. PATIENTS AND METHOD: A descriptive retrospective study was performed with data from two primary care facilities in French occidental Normandy. To evaluate the blood pressure control, different blood pressure measurements were considered during the year before (period 1) and the year after (period 2) potential stopping olmesartan. A medico-economic analysis was also realized. RESULTS: From June 2015 to July 2017, 107 hypertensive patients treated by olmesartan were included. Among them, 47 patients (44%) had an antihypertensive monotherapy. olmesartan had been mainly switched by another sartan (75%, 80/107) including valsartan (59%, 47/80). Mean blood pressures during period 1 and period 2 were not statistically different. Moreover, 83% of patients were initially controlled with olmesartan and 81% after switching medication (P=0,86). The use of olmesartan generated an additional cost of 58% compared to the other drugs that replaced it during period 2. CONCLUSIONS: Stopping olmesartan reimbursement didn't seem to have a significant impact on blood pressure control of hypertensive patients while its cost is significant. In addition to potential serious side effects, olmesartan has not shown any improvement in cardiovascular morbi-mortality.

Economic evaluation of olmesartan/amlodipine fixed-dose combination for hypertension treatment in China.

Objectives: To evaluate the cost-effectiveness of olmesartan/amlodipine fixed-dose combination vs olmesartan and amlodipine free combination, amlodipine single drug, and valsartan/amlodipine fixed-dose combination in the treatment of hypertensive patients from payer perspective in China.Methods: A Markov model was constructed, which included five health states of hypertensive patients who are aged 35-84 years at baseline and free of cardiovascular disease. Clinical data were obtained from a network meta-analysis. Epidemiology data, adverse events (AEs), cost, and utility data were obtained from the literature. The cost associated with AEs was estimated based on the cost of same symptoms of hypertensive patients in an electric medical record database. The model projected quality-adjusted life years (QALYs) gained, total costs per patient in a 20-year time horizon, and incremental cost-effectiveness ratios. Probability sensitivity analyses (PSA) and one-way sensitivity analyses were conducted for the main parameters to test the robustness of the model.Results: Compared to olmesartan and amlodipine free combination, amlodipine, and valsartan/amlodipine fixed-dose combination, treatment with olmesartan/amlodipine fixed-dose combination led to fewer CVD events and deaths; resulted in an incremental cost of ¥-5,439 ($-791.36), ¥6,530 ($950.09), and ¥-1,019 ($-148.26) and gained additional QALYs of 0.052, 0.094, and 0.037 per patient, respectively. Compared with olmesartan and amlodipine free combination and valsartan/amlodipine fixed-dose combination, olmesartan/amlodipine fixed-dose combination was dominant. Compared with amlodipine alone, the incremental cost-effectiveness ratios were below the WHO recommended cost-effectiveness threshold, indicating the olmesartan/amlodipine fixed-dose combination was a cost-effective option for hypertensive patients in China. The 10-years' time horizon scenario analysis showed similar results to the 20-years' time horizon. Probabilistic sensitivity analysis and one-way sensitivity analyses showed the robustness of the model results.Conclusions: Olmesartan/amlodipine fixed-dose combination confers better health outcomes and costs less compared with olmesartan and amlodipine free combination and valsartan/amlodipine fixed-dose combination, and is cost-effective compared to amlodipine for hypertension treatment in China.

Budget Impact of Dabrafenib and Trametinib in Combination as Adjuvant Treatment of BRAF V600E/K Mutation-Positive Melanoma from a U.S. Commercial Payer Perspective.

BACKGROUND: Before the approval of dabrafenib and trametinib in combination, there were no approved therapies in the adjuvant setting that target the RAS/RAF/MEK/ERK pathway. OBJECTIVE: To evaluate the budget impact of dabrafenib and trametinib in combination for adjuvant treatment of patients with BRAF V600 mutation-positive resected Stage IIIA, IIIB, or IIIC melanoma from a U.S. commercial payer perspective using data from the COMBI-AD trial, as well as other sources. METHODS: The budget impact of dabrafenib and trametinib in combination for patients with BRAF V600E/K mutation-positive, resected Stage IIIA, IIIB, or IIIC melanoma was evaluated from the perspective of a hypothetical population of 1 million members with demographic characteristics consistent with those of a commercially insured U.S. insurance plan (i.e., adults aged less than 65 years) using an economic model developed in Microsoft Excel. The model compared melanoma-related health care costs over a 3-year projection period under 2 scenarios: (1) a reference scenario in which dabrafenib and trametinib are assumed to be unavailable for adjuvant therapy and (2) a new scenario in which the combination is assumed to be available. Treatments potentially displaced by dabrafenib and trametinib were assumed to include observation, high-dose interferon alpha-2b, ipilimumab, and nivolumab. Costs considered in the model include those of adjuvant therapies and treatment of locoregional and distant recurrences. The numbers of patients eligible for treatment with dabrafenib and trametinib were based on data from cancer registries, published sources, and assumptions. Treatment mixes under the reference and new scenarios were based on market research data, clinical expert opinion, and assumptions. Probabilities of recurrence and death were based on data from the COMBI-AD trial and an indirect treatment comparison. Medication costs were based on wholesale acquisition cost prices. Costs of distant recurrence were from a health insurance claims study. RESULTS: In a hypothetical population of 1 million commercially insured members, 48 patients were estimated to become eligible for treatment with dabrafenib and trametinib in combination over the 3-year projection period; in the new scenario, 10 patients were projected to receive such treatment. Cumulative costs of melanoma-related care were estimated to be $6.3 million in the reference scenario and $6.9 million in the new scenario. The budget impact of dabrafenib and trametinib in combination was an increase of $549 thousand overall and 1.5 cents per member per month. CONCLUSIONS: For a hypothetical U.S. commercial health plan of 1 million members, the budget impact of dabrafenib and trametinib in combination as adjuvant treatment for melanoma is likely to be relatively modest and within the range of published estimates for oncology therapies. These results may assist payers in making coverage decisions regarding the use of adjuvant dabrafenib and trametinib in melanoma. DISCLOSURES: Funding for this research was provided to Policy Analysis Inc. (PAI) by Novartis Pharmaceuticals. Stellato, Moynahan, and Delea are employed by PAI. Ndife, Koruth, Mishra, and Gunda are employed by Novartis. Ghate was employed by Novartis at the time of this study and is shareholder in Novartis, Provectus Biopharmaceuticals, and Mannkind Corporation. Gerbasi was employed by PAI at the time of this study and is currently an employee, and stockholder, of Sage Therapeutics. Delea reports grant funding from Merck and research funding from Amgen, Novartis, Sanofi, Seattle Genetics, Takeda, Jazz, EMD Serono, and 21st Century Oncology, unrelated to this work.

Cost-effectiveness of dabrafenib and trametinib in combination as adjuvant treatment of BRAF V600E/K mutation-positive melanoma from a US healthcare payer perspective.

Objective: The COMBI-AD trial demonstrated the efficacy and safety of dabrafenib and trametinib in combination vs placebo as adjuvant treatment of patients with BRAF V600E/K mutation-positive resected Stage IIIA (lymph node metastasis >1 mm), IIIB, or IIIC melanoma. This analysis evaluated the cost-effectiveness of dabrafenib and trametinib vs observation from a US healthcare payer perspective.Methods: This evaluation employed a non-homogeneous, semi-Markov, cohort model with health states for relapse-free survival (RFS), post-locoregional recurrence (LR), post-distant recurrence (DR) receiving first-line treatment, and post-DR receiving second-line treatment. A 50-year modeling time horizon was used. Transition probabilities were estimated based on individual patient data (IPD) from the COMBI-AD trial. Health-state utilities were estimated using EuroQol (EQ-5D) index values from COMBI-AD and published sources. Direct medical costs associated with treatment of melanoma were considered, including costs of BRAF mutation testing, medication and administration costs for adjuvant and metastatic treatments, costs of treating recurrence, and costs of adverse events. Costs and quality-adjusted life-years (QALYs) were discounted at 3.0% annually.Results: Compared with observation, adjuvant dabrafenib and trametinib was estimated to result in a gain of 2.15 QALYs at an incremental cost of $74,518. The incremental cost-effectiveness ratio (ICER) was estimated to be $34,689 per QALY. In deterministic sensitivity analyses, the ICER was sensitive to the cost of dabrafenib and trametinib and the distribution used for projecting RFS beyond the end of follow-up in the COMBI-AD trial. At a cost-effectiveness threshold of $100,000 per QALY, the probability that dabrafenib and trametinib is cost-effective was estimated to be 92%.Conclusions: Given generally-accepted cost-effectiveness threshold values in the US, dabrafenib plus trametinib is likely to be a cost-effective adjuvant therapy for patients with BRAF mutation positive melanoma. These results may be useful for policy-makers in their deliberations regarding reimbursement and access to this treatment.

Cost Effectiveness of the Third-Generation Tyrosine Kinase Inhibitor (TKI) Ponatinib, vs. Second-Generation TKIs or Stem Cell Transplant, as Third-Line Treatment for Chronic-Phase Chronic Myeloid Leukemia.

BACKGROUND AND OBJECTIVES: Third-line treatment options for patients with chronic-phase chronic myeloid leukemia include tyrosine kinase inhibitors and allogeneic hematopoietic stem cell transplantation (alloHSCT). The objective of this study was to develop a Markov model with a lifetime time horizon to assess the cost effectiveness of ponatinib for third-line chronic-phase chronic myeloid leukemia vs. second-generation tyrosine kinase inhibitors (dasatinib, nilotinib, bosutinib) or alloHSCT from the public healthcare system perspective in Germany, Sweden, and Canada. METHODS: Clinical outcomes were derived from the literature, and from patient-level data (phase II PACE trial) for ponatinib. Resource use included drugs, alloHSCT, monitoring and follow-up, adverse events, and end-of-life care; costs were based on national tariffs. Quality-adjusted life-years (QALYs) were calculated using chronic myeloid leukemia health-state utilities from an international time-trade-off study. Costs and benefits were discounted at 3% per annum for Germany and Sweden, and 5% for Canada. RESULTS: Ponatinib yielded more discounted QALYs than any second-generation tyrosine kinase inhibitor/alloHSCT in all three countries, mainly owing to better response rates and longer durations of response. Incremental cost-effectiveness ratios for ponatinib vs. second-generation tyrosine kinase inhibitors were US$21,543-37,755/QALY in Germany, $24,018-38,227/QALY in Sweden, and $43,001-58,515/QALY in Canada. Ponatinib was dominant over alloHSCT in Germany, while incremental cost-effectiveness ratios for ponatinib vs. alloHSCT in Sweden and Canada were $715/QALY and $31,534/QALY, respectively. CONCLUSIONS: Ponatinib may improve outcomes (mainly because of higher response rates and longer response durations) at an acceptable cost level compared with other third-line treatment options for chronic-phase chronic myeloid leukemia in Germany, Sweden, and Canada; however, the lack of an indirect comparison is a limitation of our study.

Custo-utilidade de terapias-alvo comparadas à dacarbazina para o tratamento de primeira linha do melanoma avançado não-cirúrgico e metastático no Sistema Único de Saúde do Brazil.

OBJECTIVE: To estimate the incremental cost-utility ratio (ICUR) of isolated and combined targeted therapy regimens compared to dacarbazine for first-line treatment of advanced and metastatic melanoma with BRAF V600 mutation. METHODS: A Markov model with three health states (no progression, progression and death), monthly duration cycle and 10-year time horizon was constructed to compare targeted therapy regimens (vemurafenib, dabrafenib, vemurafenib/cobimetinib and dabrafenib/trametinib) with dacarbazine chemotherapy under the Brazilian public health perspective. One-way and probabilistic sensitivity analyses were performed. RESULTS: Mean cost was R$5662.50 ($1490.13) for dacarbazine, R$175 937.18 (46 299.26) for vemurafenib, R$167 461.70 ($44 068.87) for dabrafenib, R$425 901 ($112 079.21) for vemurafenib/cobimetinib and R$411 799.81 ($108 368.37) for dabrafenib/trametinib, whereas QALY was 0.91 for dacarbazine, 1.08 for vemurafenib, 1.12 for dabrafenib, 1.64 for vemurafenib/cobimetinib and 1.56 for dabrafenib/trametinib. The ICUR was estimated from R$572 165.76 ($150 569.94) to R$1 012 524.56 ($266 453.83) per patient, and the most impactful parameters were risk of progression and death, and treatment cost. CONCLUSION: The incorporation of targeted therapies in the Brazilian public health system would produce an additional expenditure of at least 19 times the national GDP per capita to increase in one year the quality-adjusted survival of each patient with advanced/metastatic BRAF-mutant melanoma.

Was It Worth Introducing Health Economic Evaluation of Innovative Drugs in the French Regulatory Setting? The Case of New Hepatitis C Drugs.

OBJECTIVE: This paper constitutes the first attempt to draw lessons from the recent uptake of health economic evaluation of innovative drugs in the French regulatory framework. STUDY DESIGN: Taking the example of new direct-acting antivirals against hepatitis C virus, the paper asks whether and how the cost-effectiveness (CE) opinions issued by the French National Health Authority improve the information available to support the pricing decisions. METHODS: The analysis compares the assessment of these drugs based on three different sources: CE opinions, clinical opinions, and the published cost-utility analyses (CUA) available in the literature and identified through a systematic review. RESULTS: The results show that CE opinions bring to the fore three issues prone to impact the incremental cost utility ratio and those were not available to the decision maker through clinical opinions or published CUA: the stage of treatment initiation, the modeling of the disease progression, and the uncertainty around the efficacy rates. CONCLUSIONS: France has introduced the criterion of the cost per QALY gained in the pricing and regulation of innovative pharmaceuticals since 2013. Our analysis shows that the use of CUA does enhance the information available to the decision makers on the value of the treatments.

Cost-effectiveness analysis of Daclatasvir/Sofosbuvir for the treatment of the HCV patients failed after the first line with second generation of DAAs in Italy.

BACKGROUND: Daclatasvir (DCV) combinated with Sofosbuvir (SOF) has shown good efficacy and safety profile for HCV patients. The aim was to evaluate the cost-effectiveness of DCV/SOF regimen versus HCV alternative treatments for patients who failed to achieve the SVR12 after a first DAA treatment from Italian perspective (PITER cohort). METHODS: A Markov model of HCV chronically infected patients was used to develop two scenarios: 1) DCV+ SOF versus Ledipasvir (LDV)+ SOF in Genotype (Gt)1 and Gt4; 2) DCV+ SOF versus no retreatment option in Gt1, Gt3, and Gt4. The percentage of patients who failed the first line with SOF/Simeprevir/Ribavirin (RBV) or SOF/RBV and were retreated or not according to evidences from PITER cohort, were used to populate the model. HCV resources consumption and SVR rates were quantified using PITER data. Transition probabilities and utility rates were derived from the literature. The outcomes were expressed in terms of Quality adjusted life years (QALYs). Probabilistic sensitivity analysis (PSA) was performed considering a cost-effectiveness threshold of € 30,000/QALY. RESULTS: In the base-case analysis, DCV+ SOF represents a cost-effectiveness therapy with ICERs lower than the threshold. The PSA showed robust results, ICERs remain below the threshold in 94% and 99% simulations in Scenario 1 and 2, respectively.

Cost-Effectiveness of Elbasvir/Grazoprevir Versus Daclatasvir Plus Asunaprevir in Patients with Chronic Hepatitis C Virus Genotype 1b Infection in China.

BACKGROUND AND OBJECTIVE: New direct-acting antivirals (DAAs) have high efficacy and tolerability in the treatment of hepatitis C virus (HCV) infection. The objective of this study was to assess the cost-effectiveness of elbasvir/grazoprevir (EBR/GZR) versus daclatasvir plus asunaprevir (DCV + ASV) in Chinese patients with chronic HCV genotype (GT) 1b infection stratified by cirrhosis status and treatment history. METHODS: A cohort state-transition model was constructed to simulate the course of chronic HCV infection in patients stratified by cirrhosis status and treatment history. The model projected lifetime outcomes and costs in terms of HCV treatment, laboratory tests, clinical procedures, and hospitalizations. Mean age of the study cohort at baseline was 45 years, based on published sources. Sustained virologic response (SVR) rates were derived from clinical trials. Healthcare resource utilization and health utilities were extracted or estimated from published studies in Chinese populations. The stability of the base-case analysis was validated by deterministic and probabilistic sensitivity analyses. RESULTS: In each subpopulation of Chinese patients, treatment with EBR/GZR dominated treatment with DCV + ASV, with lower costs and higher quality-adjusted life-years (QALYs). Sensitivity analysis demonstrated that EBR/GZR was the cost-effective option compared to DCV + ASV in 77.4-97.4% or 94.1-100% of model simulations in Chinese treatment-naïve or treatment-experienced patients, respectively, as the cost-effectiveness threshold changed from zero to US$24,150/QALY (three times GDP per capita in China). CONCLUSIONS: Treatment with EBR/GZR was the cost-effective option for patients with chronic HCV GT1b infection in China, regardless of cirrhosis status or treatment history.

Daclatasvir combined with asunaprevir is a cost-effective and cost-saving treatment for hepatitis C infection in China.

Aim: To evaluate the cost-effectiveness of the novel all-oral direct-acting antiviral regimen daclatasvir + asunaprevir (DUAL), versus interferon-based regimens for the treatment of chronic hepatitis C virus genotype 1b infection. Methods: Inputs for a lifetime Markov model were sourced from clinical trials and published literature. Outputs include disease management costs, life expectancy, quality-adjusted life-years and cost-effectiveness. Sensitivity analyses assessed the drivers of cost-effectiveness and sustained virologic response thresholds at which DUAL is cost-saving. Results: DUAL was associated with discounted incremental quality-adjusted life-years of 1.29-3.85 and incremental life-years of 0.85-2.59 per patient, with discounted lifetime cost savings of USD$1415-8525. Associated sustained virologic response rates could fall to 45.1-84.8%, while remaining dominant. Conclusion: Treatment with DUAL provides significant clinical benefit, while accruing lower lifetime costs.

The repercussion of stopping reimbursement of olmésartan on antihypertensive drugs prescription and blood pressure control of treated hypertensive patients in France.

OBJECTIVE: Since January 2017, olmesartan-based treatments are no longer reimbursed by French health insurance. Health authorities have recommended switch to one of the "many effective, better tolerated and reimbursed alternatives". The objective of this study was to evaluate the consequences on the prescription of antihypertensive drugs in France and to evaluate the blood pressure control of treated hypertensive patients after the switch from olmesartan to another Angiotensin receptor blocker (ARB). METHODS: To evaluate antihypertensive prescriptions, the French League Against Hypertension Survey (FLAHS) was conducted in 2007, 2012 and 2017 by self-questionnaire sent by mail to a representative panel of the population living in metropolitan France aged 35 years and over. Antihypertensive treatments were grouped by pharmacological class. To evaluate blood pressure control in hypertensive patients treated with olmesartan alone or in combination, 3 home blood pressure monitoring (HBPM) were performed. The first and the second were performed without modification of the dose of olmesartan. The third was performed 1 month after the switch to another ARB. RESULTS: Antihypertensive prescriptions changed between 2007 and 2017. Beta-blockers decreased between 2007 and 2012 and then increased slightly. Between 2012 and 2017, ARB and diuretics decreased and ACE inhibitors (ACE-I) and calcium antagonist (CA) drugs increased. Blood pressure control was assessed in 82 hypertensive patients aged 63±11 years treated with olmesartan. The difference in SBP/DBP between the first 2 self-measurements was -0.96/-0.83mmHg. After therapy switch, the 3rd self-measurement showed an increase in SBP/DBP of 3.4/1.2mmHg. In the subgroup of olmesartan-treated controlled hypertensive patients, the switch to another ARB lead to uncontrolled hypertension for 20% of patients with a 12.1mmHg increase in SBP. CONCLUSION: With the halt of reimbursement of olmesartan, there was a decrease in the prescription of ARB in France. When olmersartan was replaced by another ARB, a worse blood pressure control was observed in treated hypertensive patients. The cessation of the reimbursement of olmesartan has had consequences on the treatment of hypertension in France.

Economic evaluation of Zepatier for the management of HCV in the Italian scenario.

BACKGROUND: Hepatitis C virus (HCV) is a major health issue worldwide. New generation of direct-active antiviral medications is an epoch-making turning point in the management of HCV infections. OBJECTIVE: Conducing a cost-effectiveness analysis comparing the combination of elbasvir/grazoprevir and sofosbuvir + pegylated interferon/ribavirin for the management of all HCV patients (even those in the initial stages of fibrosis). METHODS: A Markov model was built on the natural history of the disease to assess the efficacy of the alternatives. The outcomes are expressed in terms of quality adjusted life-years (QALYs) and result in terms of incremental cost-effectiveness ratio). RESULTS: Elbasvir/grazoprevir implies an expenditure of €21,104,253.74 with a gain of 19,287.90 QALYs and sofosbuvir + pegylated interferon/ribavirin implies an expenditure of €31,904,410.11 with a gain of 18,855.96 QALYs. Elbasvir/grazoprevir is thus a dominant strategy. CONCLUSION: Consideration should be given to the opportunity cost of not treating patients with a lower degree of fibrosis (F0-F2).

Cost-effectiveness of daclatasvir plus asunaprevir for chronic hepatitis C genotype 1b treatment-naïve patients in China.

BACKGROUND: Hepatitis C is the second fastest growing infectious disease in China. The standard-of-care for chronic hepatitis C in China is Pegylated interferon plus ribavirin (PR), which is associated with tolerability and efficacy issues. An interferon- and ribavirin-free, all-oral regimen comprising daclatasvir (DCV) and asunaprevir (ASV), which displays higher efficacy and tolerability, has recently been approved in China. OBJECTIVES: This study is to estimate the cost-effectiveness of DCV+ASV (24 weeks) for chronic hepatitis C genotype 1b treatment-naïve patients compared with PR regimen (48 weeks) in China. METHODS: A cohort-based Markov model was developed from Chinese payer perspective to project the lifetime outcomes of treating 10,000 patients with an average age of 44.5 with two hypothetical regimens, DCV+ASV and PR. Chinese-specific health state costs and efficacy data were used. The annual discount rate was 5%. Base-case analysis and sensitivity analysis were conducted. RESULTS: For HCV Genotype 1b treatment-naïve patients, DCV+ASV proved to be dominant over PR, with a cost saving of ¥33,480(5,096 USD) and gains in QALYs and life years of 1.29 and 0.85, respectively. The lifetime risk of compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and liver-related death was greatly reduced with DCV+ASV. Univariate sensitivity analysis demonstrated that key influencers were the discount rate, time horizon, initial disease severity and sustained virological response rate of DCV+ASV, with all scenarios resulting in additional benefit. Probabilistic sensitivity analysis demonstrated that DCV+ASV has a high likelihood (100%) of being cost-effective. CONCLUSION: DCV+ASV is not only an effective and well-tolerated regimen to treat chronic HCV genotype 1b infection treatment-naïve patients, but also is more cost-effective than PR regimen. DCV+ASV can benefit both the public health and reimbursement system in China.

The Additional Costs per Month of Progression-Free Survival and Overall Survival: An Economic Model Comparing Everolimus with Cabozantinib, Nivolumab, and Axitinib for Second-Line Treatment of Metastatic Renal Cell Carcinoma.

BACKGROUND: When considering optimal second-line treatments for metastatic renal cell carcinoma (mRCC), clinicians and payers seek to understand the relative clinical benefits and costs of treatment. OBJECTIVE: To use an economic model to compare the additional cost per month of overall survival (OS) and of progression-free survival (PFS) for cabozantinib, nivolumab, and axitinib with everolimus for the second-line treatment of mRCC from a third-party U.S. payer perspective. METHODS: The model evaluated mean OS and PFS and costs associated with drug acquisition/administration; adverse event (AE) treatment; monitoring; and postprogression (third-line treatment, monitoring, and end-of-life costs) over 1- and 2-year horizons. Efficacy, safety, and treatment duration inputs were estimated from regimens' pivotal clinical trials; for everolimus, results were weighted across trials. Mean 1- and 2-year OS and mean 1-year PFS were estimated using regimens' reported OS and PFS Kaplan-Meier curves. Dosing and administration inputs were consistent with approved prescribing information and the clinical trials used to estimate efficacy and safety inputs. Cost inputs came from published literature and public data. Additional cost per additional month of OS or PFS was calculated using the ratio of the cost difference per treated patient and the corresponding difference in mean OS or PFS between everolimus and each comparator. One-way sensitivity analyses were conducted by varying efficacy and cost inputs. RESULTS: Compared with everolimus, cabozantinib, nivolumab, and axitinib were associated with 1.6, 0.3, and 0.5 additional months of PFS, respectively, over 1 year. Cabozantinib and nivolumab were associated with additional months of OS compared with everolimus (1 year: 0.7 and 0.8 months; 2 years: 1.6 and 2.3 months; respectively); axitinib was associated with fewer months (1 year: -0.2 months; 2 years: -0.7 months). The additional costs of treatment with cabozantinib, nivolumab, or axitinib versus everolimus over 1 year were $34,141, $19,371, and $17,506 higher, respectively. Everolimus had similar OS and lower costs compared with axitinib. The additional cost per month of OS was $48,773 for cabozantinib and $24,214 for nivolumab versus everolimus. The additional treatment cost with cabozantinib, nivolumab, or axitinib versus everolimus for each additional month of PFS was estimated at $21,338, $64,570, and $35,012, respectively. Over 2 years, the additional costs per additional month of OS for nivolumab and axitinib versus everolimus were similar to the 1-year analysis; for cabozantinib, the cost was lower. Results were sensitive to changes in mean OS, mean PFS, therapy duration, and drug costs estimates. CONCLUSIONS: Everolimus for second-line mRCC was associated with similar OS and lower costs compared with axitinib over 1- and 2-year horizons. The additional cost per additional month of OS and PFS associated with cabozantinib or nivolumab versus everolimus creates a metric for evaluating the cost of second-line therapies in relation to their respective treatment effects. DISCLOSURES: Funding for this research was provided by Novartis, which was involved in all stages of study research and manuscript preparation. Ghate and Perez are employees of Novartis and own stock/stock options. Swallow, Messali, McDonald, and Duchesneau are employees of Analysis Group, which has received consultancy fees from Novartis. Study concept and design were contributed by Swallow, Messali, Ghate, and Perez, along with McDonald and Duchesneau. Swallow, Messali, McDonald, and Duchesneau collected the data, and all authors participated in data interpretation. The manuscript was written by Swallow, Messali, and Ghate, along with the other authors, and revised by Swallow, Messali, Ghate, and Perez. A synopsis of the current research was presented in poster format at the 15th International Kidney Cancer Symposium on November 4-5, 2016, in Miami, Florida.

Cost-effectiveness analysis of elbasvir-grazoprevir regimen for treating hepatitis C virus genotype 1 infection in stage 4-5 chronic kidney disease patients in France.

OBJECTIVE: To assess the cost-effectiveness of the elbasvir/grazoprevir (EBR/GZR) regimen in patients with genotype 1 chronic hepatitis C virus (HCV) infection with severe and end-stage renal disease compared to no treatment. DESIGN: This study uses a health economic model to estimate the cost-effectiveness of treating previously untreated and treatment experienced chronic hepatitis C patients who have severe and end stage renal disease with the elbasvir-grazoprevir regimen versus no treatment in the French context. The lifetime homogeneous markovian model comprises of forty combined health states including hepatitis C virus and chronic kidney disease. The model parameters were from a multicentre randomized controlled trial, ANRS CO22 HEPATHER French cohort and literature. 1000 Monte Carlo simulations of patient health states for each treatment strategy are used for probabilistic sensitivity analysis and 95% confidence intervals calculations. The results were expressed in cost per quality-adjusted life year (QALY) gained. PATIENTS: The mean age of patients in the HEPATHER French cohort was 59.6 years and 56% of them were men. 22.3% of patients had a F0 fibrosis stage (no fibrosis), 24.1% a F1 stage (portal fibrosis without septa), 7.1% a F2 stage (portal fibrosis with few septa), 21.4% a F3 stage (numerous septa without fibrosis) and 25% a F4 fibrosis stage (compensated cirrhosis). Among these HCV genotype 1 patients, 30% had severe renal impairment stage 4, 33% had a severe renal insufficiency stage 5 and 37% had terminal severe renal impairment stage 5 treated by dialysis. INTERVENTION: Fixed-dose combination of direct-acting antiviral agents elbasvir and grazoprevir compared to no-treatment. RESULTS: EBR/GZR increased the number of life years (6.3 years) compared to no treatment (5.1 years) on a lifetime horizon. The total number of QALYs was higher for the new treatment because of better utility on health conditions (6.2 versus 3.7 QALYs). The incremental cost-utility ratio (ICUR) was of €15,212 per QALY gained for the base case analysis. CONCLUSIONS: This cost-utility model is an innovative approach that simultaneously looks at the disease evolution of chronic hepatitis C and chronic kidney disease. EBR/GZR without interferon and ribavirin, produced the greatest benefit in terms of life expectancy and quality-adjusted life years (QALY) in treatment-naïve or experienced patients with chronic hepatitis C genotype 1 and stage 4-5 chronic kidney disease including dialysis patients. Based on shape of the acceptability curve, EBR/GZR can be considered cost-effective at a willingness to pay of €20,000 /QALY for patients with renal insufficiency with severe and end-stage renal disease compared to no treatment.

The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England.

BACKGROUND: Nivolumab was the first programmed death receptor 1 (PD-1) immune checkpoint inhibitor to demonstrate long-term survival benefit in a clinical trial setting for advanced melanoma patients. OBJECTIVE: To evaluate the cost effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England. METHODS: A Markov state-transition model was developed to estimate the lifetime costs and benefits of nivolumab versus ipilimumab and dacarbazine for BRAF mutation-negative patients and versus ipilimumab, dabrafenib, and vemurafenib for BRAF mutation-positive patients. Covariate-adjusted parametric curves for time to progression, pre-progression survival, and post-progression survival were fitted based on patient-level data from two trials and long-term ipilimumab survival data. Indirect treatment comparisons between nivolumab, ipilimumab, and dacarbazine were informed by these covariate-adjusted parametric curves, controlling for differences in patient characteristics. Kaplan-Meier data from the literature were digitised and used to fit progression-free and overall survival curves for dabrafenib and vemurafenib. Patient utilities and resource use data were based on trial data or the literature. Patients are assumed to receive nivolumab until there is no further clinical benefit, assumed to be the first of progressive disease, unacceptable toxicity, or 2 years of treatment. RESULTS: Nivolumab is the most cost-effective treatment option in BRAF mutation-negative and mutation-positive patients, with incremental cost-effectiveness ratios of £24,483 and £17,362 per quality-adjusted life year, respectively. The model results are most sensitive to assumptions regarding treatment duration for nivolumab and the parameters of the fitted parametric survival curves. CONCLUSIONS: Nivolumab is a cost-effective treatment for advanced melanoma patients in England.