Extrapyramidal adverse events and anticholinergics use after the long-term treatment of patients with schizophrenia with the new long-acting antipsychotic Risperidone ISM®: results from matching-adjusted indirect comparisons versus once-monthly formulations of Paliperidone palmitate and Aripiprazole monohydrate in 52-week studies.

BACKGROUND: Risperidone ISM® is a newly developed long-acting injectable (LAI) treatment for schizophrenia in adults. In the absence of head-to-head comparisons with other similar antipsychotics, the objective of this study was to generate indirect evidence of some aspects of the safety and tolerability of Risperidone ISM compared to other LAI antipsychotics for treatment of patients with schizophrenia in the maintenance treatment setting. METHODS: A literature review was conducted systematically to identify maintenance treatment studies reporting safety and tolerability outcomes for LAI antipsychotic therapies. Following an assessment of between-trial heterogeneity, a matching-adjusted indirect comparison (MAIC) was performed to account for between-trial imbalances in patient characteristics and to generate comparative evidence for safety and tolerability endpoints. RESULTS: The analysis showed that incidence of extrapyramidal symptoms (EPS) was found to be numerically, but not statistically significantly, lower in patients receiving Risperidone ISM than in those receiving Paliperidone palmitate (PP) (OR [95% CI] 0.63 [0.29, 1.38], p = 0.253) and statistically significantly lower than with Aripiprazole monohydrate once-monthly (AOM) (OR [95% CI] 0.25 [0.12, 0.53], p < 0.001). Use of anticholinergic agents for the alleviation of EPS was also shown to be significantly lower in Risperidone ISM patients than in those receiving PP (OR [95% CI] 0.29 [0.10, 0.83], p = 0.021) or AOM (OR [95% CI] 0.01 [0.003, 0.06], p < 0.001), suggesting a superior tolerability profile for clinically relevant EPS. Results from the sensitivity analyses comparing stabilized and stable patients receiving Risperidone ISM to those receiving AOM yielded similarly favorable conclusions in line with the base case analyses. CONCLUSIONS: This MAIC is consistent with the safety and tolerability results obtained during the PRISMA-3 clinical trial in the long-term treatment of schizophrenia and suggests a favorable safety and tolerability profile in terms of EPS incidence and anticholinergic agent use, relative to other antipsychotic therapies used for treatment of patients with schizophrenia in the maintenance setting.

Cost-effectiveness of encorafenib with binimetinib in unresectable or metastatic BRAF-mutant melanoma.

OBJECTIVE: The objective of this study was to determine the cost-effectiveness of encorafenib with binimetinib (EncoBini) as compared to other targeted double combination therapies, namely dabrafenib with trametinib (DabraTrame) and vemurafenib with cobimetinib (VemuCobi), for the treatment of BRAF V600-mutant unresectable or metastatic melanoma (MM) from the French payer perspective. METHODS: A partitioned survival model was developed considering a lifetime horizon. The model structure simulated the clinical pathway of patients with BRAF V600-mutant MM. Clinical effectiveness and safety inputs were sourced from the COLUMBUS trial, a network meta-analysis and published literature. Costs, resource use, and the quality of life inputs were obtained from the literature and appropriate French sources. RESULTS: Over a lifetime horizon, EncoBini was associated, on average, with reduced costs and increased quality adjusted life years (QALYs), dominating both targeted double combination therapies. For a willingness-to-pay threshold of €90,000 per QALY, the probability of EncoBini being cost-effective against either comparator remained above 80%. The most influential model parameters were the hazard ratios for the overall survival of EncoBini vs DabraTrame and VemuCobi, the pre- and post-progression utility values, as well as treatment dosages and the relative dose intensity of all interventions. CONCLUSION: EncoBini is associated with reduced costs and increased QALYs, dominating other targeted double combination therapies (DabraTrame, VemuCobi) for patients with BRAF V600-mutant MM in France. EncoBini is a highly cost-effective intervention in MM.

Validity of event-free survival as a surrogate endpoint in haematological malignancy: Review of the literature and health technology assessments.

OBJECTIVE: Event-free survival (EFS) is increasingly used as a primary endpoint in trials of haematological malignancies (HMs). A key consideration is whether EFS can reliably predict survival. METHODS: We conducted a review of the scientific literature and health technology assessments to evaluate evidence for EFS-OS surrogacy in HMs and acceptability of EFS by payers. RESULTS: Evidence of surrogacy varies by indication and line of therapy. In first-line AML, EFS is highly correlated with OS at the trial-level supporting its use as an early endpoint for traditional approval of treatments with curative intent. Surrogacy was also demonstrated in first-line DLBCL but remains unexplored in relapsed/refractory setting where post-transplant EFS24 was not prognostic of survival. In first-line FL, PTCL, T-LBL, and MCL, EFS24 is prognostic of survival but trial-level surrogacy has not yet been evaluated. CONCLUSION: Strong EFS-OS correlation required for surrogacy may only be achievable in HMs with treatments characterised by high rates of durable remissions. Nevertheless, EFS24 is associated with favourable outcomes and remains a clinically meaningful endpoint in HMs.

The cost of cancer - A comparative analysis of the direct medical costs of cancer and other major chronic diseases in Europe.

BACKGROUND: Cancer poses a significant mortality, morbidity, economic and humanistic burden to patients and health systems. This study aims to better understand healthcare expenditure on cancer relative to other major chronic diseases across France, Germany, Italy, Spain and the United Kingdom, whilst also considering the burden of illness posed by these conditions. METHODS: A targeted literature review was performed to identify and extract relevant demographic, epidemiological and economic data. A health care payer perspective was adopted for the analysis, with a focus on direct healthcare costs. RESULTS: Between 2006-2015, the cancer-related disability-adjusted life year (DALY) disease burden decreased by 9.3% despite a 6.5% increase in prevalence. Whilst the per patient drug costs increased by a compound annual growth rate (CAGR) of 5.1%, the overall per patient cancer costs decreased over the 10-year study period (CAGR of -1.4%). Compared to cardiovascular disease, neurological/mental disorders and diabetes, cancer was associated with the highest disease burden (20.8% of DALYs across all diseases) but the second-lowest healthcare expenditure levels (4.8% of total healthcare expenditure) among the studied major chronic diseases. CONCLUSIONS: Our study suggests that the costs associated with treating cancer account for a low proportion of total healthcare expenditure relative to the burden of the disease and compared to other major chronic diseases across the countries included in the analysis.

Evidence synthesis in pulmonary arterial hypertension: a systematic review and critical appraisal.

BACKGROUND: The clinical landscape of pulmonary arterial hypertension (PAH) has evolved in terms of disease definition and classification, trial designs, available therapies and treatment strategies as well as clinical guidelines. This study critically appraises published evidence synthesis studies, i.e. meta-analyses (MA) and network-meta-analyses (NMA), to better understand their quality, validity and discuss the impact of the findings from these studies on current decision-making in PAH. METHODS: A systematic literature review to identify MA/NMA studies considering approved and available therapies for treatment of PAH was conducted. Embase, Medline and the Cochrane's Database of Systematic Reviews were searched from database inception to April 22, 2020, supplemented by searches in health technology assessment websites. The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) checklist covering six domains (relevance, credibility, analysis, reporting quality and transparency, interpretation and conflict of interest) was selected for appraisal of the included MA/NMA studies. RESULTS: Fifty-two full publications (36 MAs, 15 NMAs, and 1 MA/NMA) in PAH met the inclusion criteria. The majority of studies were of low quality, with none of the studies being scored as 'strong' across all checklist domains. Key limitations included the lack of a clearly defined, relevant decision problem, shortcomings in assessing and addressing between-study heterogeneity, and an incomplete or misleading interpretation of results. CONCLUSIONS: This is the first critical appraisal of published MA/NMA studies in PAH, suggesting low quality and validity of published evidence synthesis studies in this therapeutic area. Besides the need for direct treatment comparisons assessed in long-term randomized controlled trials, future efforts in evidence synthesis in PAH should improve analysis quality and scrutiny in order to meaningfully address challenges arising from an evolving therapeutic landscape.

A modeling framework for the economic evaluation of baricitinib in moderate-to-severe rheumatoid arthritis.

Objectives: The approval in more than 50 countries of baricitinib, an oral Janus Kinase inhibitor for the treatment of Rheumatoid Arthritis (RA), warrants a framework for corresponding economic evaluations. To develop a comprehensive economic model assessing the cost-effectiveness of baricitinib for the treatment of moderately-to-severely active RA patients in comparison to other relevant treatments, considering the natural history of the disease, real world treatment patterns, and clinical evidence from the baricitinib trials.Methods: A systematic literature review of previously developed models in RA was conducted to inform the model structure, key modeling assumptions and data inputs. Consultations with rheumatologists were undertaken to validate the modeling approach and underlying assumptions.Results: A discrete event simulation model was developed to international best practices with flexibility to assess the cost-effectiveness of baricitinib over a lifetime in a variety of markets. The model incorporates treatment sequencing to adequately reflect treatment pathways in clinical practice. Outcomes assessed include cost and quality-adjusted life years, allowing for a full incremental analysis of cost-effectiveness of competing treatments and treatment sequences.Conclusion: The economic model developed provides a robust framework for future analyses assessing the cost-effectiveness of baricitinib for the treatment of RA in specific country settings.

Cost-effectiveness analysis of baricitinib versus adalimumab for the treatment of moderate-to-severe rheumatoid arthritis in Spain.

Background: Baricitinib is an oral janus kinase inhibitor for the treatment of rheumatoid arthritis (RA) and is approved in Europe for use in adults with moderately-to-severely active RA and an inadequate response or intolerance to conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy. To date, no economic evaluations have assessed the cost-effectiveness of baricitinib in the Spanish setting. Objectives: To evaluate the cost-effectiveness of baricitinib versus adalimumab for the treatment of moderately-to-severely active RA in the Spanish setting. Methods: A discrete event simulation model was developed in Microsoft Excel. Costs and outcomes were estimated over a lifetime horizon using the Spanish national payer perspective. The model compared baricitinib 4 mg once daily in combination with methotrexate with adalimumab 40 mg every other week in combination with methotrexate. Effectiveness and physical function were captured using the American College of Rheumatology criteria and the Health Assessment Questionnaire-Disability Index, input values of which were derived from a phase 3, double-blind, placebo- and active-controlled trial (RA-BEAM; funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01710358). Costs are presented in Euros, 2018 values. Results: In the base case analysis, baricitinib was associated with a quality-adjusted life year gain of 0.09 years over a lifetime horizon, at an incremental cost of -€558 versus adalimumab. Results of various scenario analyses and probabilistic sensitivity analysis generally were consistent with the base case analysis. Conclusion: This analysis suggests that baricitinib is a cost-effective treatment option compared to adalimumab for Spanish patients with moderately-to-severely active RA and a previous inadequate response or intolerance to csDMARD therapy.

Lurasidone compared to other atypical antipsychotic monotherapies for bipolar depression: A systematic review and network meta-analysis.

OBJECTIVES: To assess the efficacy and tolerability of lurasidone versus other atypical antipsychotic monotherapy agents in patients with bipolar depression, using a Bayesian network meta-analysis. METHODS: Fourteen randomised clinical trials (6221 patients) of lurasidone, quetiapine (extended release and immediate release), aripiprazole, olanzapine, and ziprasidone for bipolar depression were included. Efficacy assessments included change in the Montgomery-Åsberg Depression Rating Scale (MADRS), rates of response (≥50% improvement in MADRS) and remission (MADRS ≤12 at study endpoint), and change in the Clinical Global Impressions-Bipolar Disorder-Severity (CGI-BP-S) scale. Tolerability outcomes included weight, somnolence, extrapyramidal symptoms (EPS), and all-cause discontinuation. Changes from baseline or odds ratios (OR) with 95% credible intervals (CrI) were evaluated. RESULTS: Improvement in the MADRS associated with lurasidone treatment was significantly greater than placebo (-4.70, 95%CrI: -7.20, -2.21), aripiprazole (-3.62, 95%CrI: -7.04, -0.20), and ziprasidone (-3.38, 95%CrI: -6.68, -0.11), but not olanzapine (-0.15, 95%CrI: -3.12, 2.74) or quetiapine (0.10, 95%CrI: -2.68, 2.84). Results for improvement in the CGI-BP-S, and for response and remission were similar. Lurasidone was associated with less weight gain than olanzapine (-2.54 kg, 95%CrI: -3.42, -1.67) and quetiapine (-0.83kg, 95%CrI: -1.59, -0.08); and with lower rates of somnolence than quetiapine (OR: 0.33, 95%CrI: 0.11, 0.82) and ziprasidone (OR: 0.34, 95%CrI: 0.09, 0.93). No significant differences among atypical antipsychotic agents were observed in rates of discontinuation or in rates of EPS. CONCLUSIONS: In this network meta-analysis, lurasidone was found to be more efficacious than aripiprazole and ziprasidone, and was associated with less weight gain than quetiapine and olanzapine and less somnolence than quetiapine and ziprasidone.

Cost-utility analysis of life-long prophylaxis with recombinant factor VIIIFc vs recombinant factor VIII for the management of severe hemophilia A in Sweden.

AIMS: Prophylaxis with recombinant factor VIII (rFVIII) is the standard of care for severe hemophilia A in Sweden. The need for frequent injections with existing rFVIII products may, however, result in poor adherence to prophylaxis, leading to increased bleeding and long-term joint damage. Recombinant FVIIIFc (rFVIIIFc) is an extended half-life fusion protein which can offer prolonged protection and reduced dosing frequency. The objective of this study was to evaluate the cost-utility of prophylaxis with rFVIIIFc in severe hemophilia A from the perspective of the Swedish health system. METHODS: A Markov model was built to estimate lifetime costs and benefits of prophylaxis with rFVIIIFc vs rFVIII products. Clinical outcomes were represented by annualized bleeding rate (ABR) and quality of life via disutility applied to bleeding events and injection frequency. Costs included the cost of FVIII for routine prophylaxis and bleed resolution. The pooled comparator was costed by weighting the cost of individual products by their market share. RESULTS: In the base case, rFVIIIFc was dominant vs the pooled comparator. Savings of SEK 9.0 million per patient resulted from lower factor consumption for prophylaxis and bleed resolution. Fewer bleeds and reduced injection frequency yielded an estimated 0.59 quality-adjusted life years (QALYs). Results were sensitive to drug dosage and robust to variation in other parameters. Probabilistic sensitivity analysis suggested a greater than 85% probability of rFVIIIFc being cost-effective at a willingness-to-pay threshold of 500,000 SEK/QALY. LIMITATIONS: Due to unavailibilty of patient-level data, treatment benefit was based on a non-adjusted indirect comparison. Dosing and treatment outcomes were assumed to persist over the model duration in the absence of long-term outcome data. CONCLUSION: The results suggest that rFVIIIFc may be a cost-effective option for hemophilia A prophylaxis, generating greater quality of life and reduced costs for the Swedish payer compared to more frequently administered rFVIII alternatives.

Cost-Effectiveness of Liraglutide Versus Dapagliflozin for the Treatment of Patients with Type 2 Diabetes Mellitus in the UK.

INTRODUCTION: To date there is a lack of economic analysis comparing glucagon-like peptide-1 receptor agonists (GLP-1RAs) to sodium-glucose co-transporter 2 inhibitors (SGLT-2i) for the treatment of type 2 diabetes mellitus (T2DM). Liraglutide and dapagliflozin are the most commonly prescribed GLP-1RA and SGLT-2i in the UK. This analysis investigated the cost-effectiveness of liraglutide 1.2 and 1.8 mg/day compared to dapagliflozin 10 mg/day for the treatment of T2DM in the UK in patients on dual and triple antidiabetic therapy. METHODS: Cost-effectiveness analysis was conducted in the QuintilesIMS CORE Diabetes Model (CDM). The model estimated expected costs and outcomes over a lifetime horizon using the UK national payer perspective. Liraglutide efficacy estimates and patient characteristics were sourced from a trial in patients on prior metformin monotherapy, and from a trial in patients on prior combination therapy. Comparative efficacy data for the other interventions were derived from a network meta-analysis. Utility inputs were extracted from a systematic literature review. Costs are presented in Great British Pound (GBP), 2016 values. RESULTS: In dual and triple therapy, liraglutide 1.2 mg was less costly and more effective compared with dapagliflozin 10 mg, providing a QALY gain of 0.04 and cost savings of GBP 11 per patient in dual therapy, and a QALY gain of 0.06 and cost savings of GBP 71 per patient in triple therapy. For liraglutide 1.8 mg, increased efficacy and costs compared with dapagliflozin 10 mg were observed in both dual and triple therapy. In dual therapy, a QALY gain of 0.07 and additional costs of GBP 888 per patient yielded an ICER of GBP 13,227, whereas in triple therapy a QALY gain of 0.07 and additional cost of GBP 791 per patient gave an ICER of 11,857. CONCLUSION: This long-term modelling analysis found that both dosages of liraglutide may be cost-effective treatment alternatives as part of a dual or a triple antidiabetic therapy in patients for whom an SGLT-2i therapy is considered. FUNDING: Novo Nordisk.

Comparative efficacy of fixed-dose combinations of long-acting muscarinic antagonists and long-acting ß2-agonists: a systematic review and network meta-analysis.

BACKGROUND: A number of long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) fixed-dose combinations (FDCs) for treatment of moderate-to-very severe chronic obstructive pulmonary disease (COPD) have recently become available, but none have been directly compared in head-to-head randomized controlled trials (RCTs). The purpose of this study was to assess the relative clinical benefit of all currently available LAMA/LABA FDCs using a Bayesian network meta-analysis (NMA). METHODS: A systematic literature review identified RCTs investigating the efficacy, safety and quality of life associated with licensed LAMA/LABA FDCs for the treatment of moderate-to-very severe COPD. RCTs were screened for inclusion in the NMA using prespecified eligibility criteria. Data were extracted for outcomes of interest, including change in trough forced expiratory volume in 1 second (tFEV1) from baseline, St. George Respiratory Questionnaire (SGRQ) percentage of responders, Transition Dyspnea Index (TDI) percentage of responders, change in SGRQ score from baseline, change in TDI focal score from baseline, moderate-to-severe exacerbations, all-cause discontinuation, and discontinuation due to adverse events. RESULTS: Following screening, a total of 27 trials from 26 publications with 30,361 subjects were eligible for inclusion in the NMA. Nonsignificant results were seen in most analyses comparing efficacy, exacerbations and discontinuation rates of included LAMA/LABA FDCs (i.e. aclidinium/formoterol 400/12 µg, glycopyrronium/indacaterol 110/50 µg, tiotropium + olodaterol 5/5 µg, umeclidinium/vilanterol 62.5/25 µg). Meta-regression controlling for post-bronchodilator percentage of tFEV1 predicted at baseline as well as meta-regression adjusting for concomitant use of inhaled corticosteroids at baseline was performed to assess the magnitude of effect modification and produced similar results as observed in the base case analysis. CONCLUSION: All LAMA/LABA FDCs were found to have similar efficacy and safety. Definitive assessment of the relative efficacy of different treatments can only be performed through direct comparison in head-to-head RCTs. In the absence of such data, this indirect comparison may be of value in clinical and health economic decision-making.

Cost of unintended pregnancy in Norway: a role for long-acting reversible contraception.

OBJECTIVES: The objective of this study was to quantify the cost burden of unintended pregnancies (UPs) in Norway, and to estimate the proportion of costs due to imperfect contraceptive adherence. Potential cost savings that could arise from increased uptake of long-acting reversible contraception (LARC) were also investigated. METHODS: An economic model was constructed to estimate the total number of UPs and associated costs in women aged 15-24 years. Adherence-related UP was estimated using 'perfect use' and 'typical use' contraceptive failure rates. Potential savings from increased use of LARC were projected by comparing current costs to projected costs following a 5% increase in LARC uptake. RESULTS: Total costs from UP in women aged 15-24 years were estimated to be 164 million Norwegian Kroner (NOK), of which 81.7% were projected to be due to imperfect contraceptive adherence. A 5% increase in LARC uptake was estimated to generate cost savings of NOK 7.2 million in this group. CONCLUSIONS: The cost of UP in Norway is substantial, with a large proportion of this cost arising from imperfect contraceptive adherence. Increased LARC uptake may reduce the UP incidence and generate cost savings for both the health care payer and contraceptive user.

Crime victims and criminal offenders among adults with serious mental illness.

OBJECTIVE: This study compared crime victimization rates with rates of criminal offending among adults with serious mental illness. METHODS: Statistical estimation determined caseload overlap between anonymous extracts from public mental health and criminal justice databases for 13 rural Vermont counties. Participants included 2,610 adults who received community-based services during the study year (July 2005 through June 2006). RESULTS: Among the 2,610 adults 6.6% were identified by police as criminal offenders and 7.1% were identified as crime victims. Compared with the general population, however, their elevated risk of being identified as a victim (2.4) was lower than their elevated risk of being identified as an offender (2.6). These categories are not mutually exclusive. CONCLUSIONS: To better understand involvement in the criminal justice system among adults with serious mental illness, research should consider rates of criminal offending and victimization and compare these with rates for the general population.