The Acceptance of Indirect Treatment Comparison Methods in Oncology by Health Technology Assessment Agencies in England, France, Germany, Italy, and Spain.

INTRODUCTION: Randomized controlled trials (RCTs) are the gold standard when comparing treatment effectiveness, and Health Technology Assessment (HTA) agencies state a clear preference for such direct comparisons. When these are not available, an indirect treatment comparison (ITC) is an alternative option. The objective of this study was to assess the acceptance of ITC methods by HTA agencies across England, France, Germany, Italy, and Spain, using oncology cases for a homogeneous sample of HTA evaluations. METHODS: The study was conducted on the PrismAccess database in May 2021 to retrieve HTA evaluation reports for oncology treatments for solid tumors, in which an ITC was presented. The analysis was restricted to HTA evaluation reports published between April 2018 and April 2021 in England, France, Germany, Italy, and Spain. Identified HTA evaluation reports were screened and reviewed by two independent reviewers. For each ITC presented, the methodology and its acceptance by the HTA agency were analyzed. RESULTS: Five hundred and forty-three HTA evaluation reports were identified, of which 120 (22%) presented an ITC. This proportion was the highest in England (51%) and lowest in France (6%). The overall acceptance rate of ITC methods was 30%, with the highest in England (47%) and lowest in France (0%). Network meta-analysis (NMA; 23%) was the most commonly used ITC technique, with a 39% acceptance rate overall, followed by Bucher ITC (19%; 43% acceptance rate) and matching-adjusted indirect comparison (13%; 33% acceptance rate). The most common criticisms of the ITC methods from HTA agencies related to data limitations (heterogeneity and lack of data; 48% and 43%, respectively) and the statistical methods used (41%). CONCLUSIONS: The generally low acceptance rate of ITC methods by HTA agencies in oncology suggests that, whilst in the absence of a direct comparison ITCs may provide relevant evidence, this evidence is not widely considered sufficient for the purpose of HTA evaluations. The perception of ITC methods for the purpose of HTA evaluations varies substantially between countries. There is a need for further clarity on the properties of ITC techniques and the assessment of their results as ITC methods continue to evolve quickly and further techniques may become available in the future.

Validation of the FINE-CKD model for future health technology assessments for finerenone in patients with chronic kidney disease and type 2 diabetes.

BACKGROUND: The FINE-CKD model was developed to estimate the cost-effectiveness of finerenone in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). OBJECTIVE: To perform internal and external validation by comparing the model estimates with trial results and outcomes from other models. METHODS: Incidence rates from trials were compared with the model predictions. Statistical tests were then performed to assess whether modeled event rates aligned with trial observations. A cross-validation was also performed using the online version of the SHARP CKD-Cardiovascular Disease (SHARP CKD-CVD) model, with population characteristics from the finerenone trials analyzed. Where no finerenone data were available, the default SHARP CKD-CVD values were used. Comparison of the results considered the ranges from both models. RESULTS: The outcomes of the FINE-CKD model reflect the event rates observed in the trials. Based on the results of the statistical tests, the hypothesis of no difference between observed and modeled events cannot be rejected for any of the outcomes. The results of the FINE-CKD model are within the ranges from the SHARP CKD-CVD model. Disease progressions align across the models; however, incident kidney failure events in the SHARP CKD-CVD model were higher. This can be explained by simulation of more severely affected patients in the SHARP CKD-CVD model. CONCLUSIONS: This study demonstrates that the FINE-CKD model adequately reflects the clinical data and provides reliable extrapolation relative to the existing predictive tools while also being conservative in its approach.

Real-world cost-effectiveness analysis of NOACs versus VKA for stroke prevention in Spain.

AIMS: A Markov model was adapted to assess the real-world cost-effectiveness of rivaroxaban, dabigatran and apixaban. Each of these non-vitamin K antagonist oral anticoagulants was compared with vitamin K antagonist for stroke prevention in patients with non-valvular atrial fibrillation in Spain. METHODS: All inputs were derived from real-world studies: baseline patient characteristics, clinical event rates, as well as persistence rates for the vitamin K antagonist treatment option. A meta-analysis of real-world studies provided treatment effect and persistence data for rivaroxaban, dabigatran and apixaban, each compared with vitamin K antagonist therapy. The model considered 3-month cycles over a lifetime horizon. The model outcomes included different costs, quality-adjusted life years and life-years gained. Sensitivity analyses were performed to test the robustness of the model. RESULTS: When compared with vitamin K antagonist, rivaroxaban incurred incremental costs of €77 and resulted in incremental quality-adjusted life years of 0.08. The incremental cost per quality-adjusted life year was €952. For the same comparison, the incremental cost per quality-adjusted life year for dabigatran was €4,612. Finally, compared with vitamin K antagonist, the incremental cost per quality-adjusted life year for apixaban was €32,015. The sensitivity analyses confirmed the robustness of the base case results. The probabilities to be cost-effective versus vitamin K antagonist were 94%, 86% and 35%, respectively, for rivaroxaban, dabigatran and apixaban, considering a willingness-to-pay threshold of €22,000 per quality-adjusted life year gained, based on a cost-effectiveness study of the Spanish National Health System. CONCLUSION: These results suggest that rivaroxaban and dabigatran are cost-effective versus vitamin K antagonist for stroke prevention in non-valvular atrial fibrillation, from the Spanish National Health System perspective.

FINE-CKD model to evaluate economic value of finerenone in patients with chronic kidney disease and type 2 diabetes.

BACKGROUND: Chronic kidney disease (CKD) is a progressive and irreversible disease often associated with type 2 diabetes (T2D). CKD is associated with an elevated risk of cardiovascular (CV) events, increased mortality, and diminished quality of life. Finerenone is a new treatment for patients with CKD and T2D that delays CKD progression and reduces CV complications. OBJECTIVE: To describe the approach and structure of a costeffectiveness model for finerenone for patients with CKD and T2D and compare it with existing economic models in CKD. METHODS: A de novo cost-effectiveness model (FINE-CKD model), reflective of FIDELIO-DKD results, was developed for finerenone. The FINE-CKD model was designed and implemented in accordance with published guidance on modeling and was developed with input from economic and clinical experts. The final model approach was evaluated against existing modeling structures in CKD identified through a systematic literature review. RESULTS AND CONCLUSIONS: The FINE-CKD model structure follows recommended modeling guidelines and has been designed in accordance with the best practices of modeling in CKD, while also incorporating important features of the FIDELIO-DKD design and results. The approach is consistent with the published literature, ensuring transparency and minimizing uncertainty that can arise from unnecessary complexity. The FINE-CKD model allows for reliable assessment of benefits and costs related to the use of finerenone in patients with CKD and T2D, and it is a reliable assessment of cost-effectiveness.

Targeted literature review of the burden of illness in patients with chronic kidney disease and type 2 diabetes.

OBJECTIVES: Chronic kidney disease (CKD) is increasingly prevalent among patients with type 2 diabetes (T2D). CKD is associated with increased mortality rates, clinical and humanistic burden, and substantial health care costs in the T2D population. The objective of this review was to summarize the burden of illness among patients with CKD and T2D, including the profile of patients, incidence, prevalence, mortality, progression, diagnosis and screening rates, and cardiovascular (CV) events. METHODS: A targeted literature review of published studies was conducted using Embase; Medline; Medline In-Process Citations, Daily Update, and Epub Ahead of Print; Igaku Chuo Zasshi databases; and 7 websites. Methods recommended by the Cochrane collaboration handbook, the Centre for Reviews and Dissemination, and the Joanna Briggs Institute critical appraisal checklist were employed. RESULTS: A total of 1290 full-text articles were reviewed for eligibility and 73 were included in this analysis. Patient profiles indicated older age was associated with more severe disease and number of comorbidities. The definition of kidney disease varied between studies reporting incidence and prevalence, with reported values up to 37.0% and 43.5% for incidence and prevalence, respectively. CKD among patients with T2D contributed to higher mortality rates. Higher disease progression rates were associated with higher albuminuria and lower estimated glomerular filtration rate levels. The available literature suggested annual screening rates for CKD declined over time. CV events were reported to have a substantial effect on morbidity and resource use. CONCLUSIONS: This review highlights the burden of CKD among patients with T2D and underscores a need for new treatment alternatives to reduce the burden of disease.

Health economic evaluation of gene replacement therapies: methodological issues and recommendations.

Objective: To provide recommendations for addressing previously identified key challenges in health economic evaluations of Gene Replacement Therapies (GRTs), including: 1) the assessment of clinical effectiveness; 2) the valuation of health outcomes; 3) the time horizon and extrapolation of effects beyond trial duration; 4) the estimation of costs; 5) the selection of appropriate discount rates; 6) the incorporation of broader elements of value; and 7) affordability. Methods: A literature review on economic evaluations of GRT was performed. Interviews were conducted with 8 European and US health economic experts with experience in evaluations of GRT. Targeted literature reviews were conducted to investigate further potential solutions to specific challenges. Recommendations: Experts agreed on factors to be considered to ensure the acceptability of historical cohorts by HTA bodies. Existing prospective registries or, if not available, retrospective registries, may be used to analyse different disease trajectories and inform extrapolations. The importance of expert opinion due to limited data was acknowledged. Expert opinion should be obtained using structured elicitation techniques. Broader elements of value, beyond health gains directly related to treatment, can be considered through the application of a factor to inflate the quality-adjusted life years (QALYs) or a higher cost-effectiveness threshold. Additionally, the use of cost-benefit analysis and saved young life equivalents (SAVE) were proposed as alternatives to QALYs for the valuations of outcomes of GRT as they can incorporate broader elements of value and avoid problems of eliciting utilities for paediatric diseases. Conclusions: While some of the limitations of economic evaluations of GRT are inherent to limited clinical data and lack of experience with these treatments, others may be addressed by methodological research to be conducted by health economists.

Real-world cost-effectiveness of rivaroxaban and apixaban vs VKA in stroke prevention in non-valvular atrial fibrillation in the UK.

BACKGROUND: Morbidity and mortality associated with non-valvular atrial fibrillation (NVAF) imposes a substantial economic burden on the UK healthcare system. OBJECTIVES: An existing Markov model was adapted to assess the real-world cost-effectiveness of rivaroxaban and apixaban, each compared with a vitamin K antagonist (VKA), for stroke prevention in patients with NVAF from the National Health Service (NHS) and personal and social services (PSS) perspective. METHODS: The model considered a cycle length of 3 months over a lifetime horizon. All inputs were drawn from real-world evidence (RWE): baseline patient characteristics, clinical event and persistence rates, treatment effect (meta-analysis of RWE studies), utility values and resource use. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: The incremental cost per quality-adjusted life year was £14,437 for rivaroxaban, and £20,101 for apixaban, compared with VKA. The probabilities to be cost-effective compared with VKA were 90% and 81%, respectively for rivaroxaban and apixaban, considering a £20,000 threshold. In both comparisons, the results were most sensitive to clinical event rates. CONCLUSIONS: These results suggest that rivaroxaban and apixaban are cost-effective vs VKA, based on RWE, considering a £20,000 threshold, from the NHS and PSS perspective in the UK for stroke prevention in patients with NVAF. This economic evaluation may provide valuable information for decision-makers, in a context where RWE is more accessible and its value more acknowledged.

Use of real-world evidence in meta-analyses and cost-effectiveness models.

Real-world evidence (RWE) provides external validity, supplementing and enhancing the randomized controlled trial data with valuable information on patient behaviors and outcomes, turning efficacy and safety results into real-world effectiveness and risks, but the use of RWE is associated with challenges. The objectives of this communication were to (1) summarize all guidance on how to conduct an RWE meta-analysis (MA) and how to develop an RWE cost-effectiveness model, (2) to describe our experience, challenges faced and solutions identified, (3) to provide recommendations on how to conduct such analyses. No formal guidelines on how to conduct an RWE MA or to develop an RWE cost-effectiveness model were identified. Using the context of non-vitamin K antagonist oral anticoagulants in stroke prevention in atrial fibrillation, we conducted an RWE MA, after having identified sources of uncertainty. We then implemented the results in an RWE cost-effectiveness model, defined as a model where all inputs come from RWE, including all parameters related to treatment effect. Based on challenges faced, our first recommendation relates to the necessity of conducting sensitivity analyses, either based on clinical or methodological considerations. Our second recommendation is the need for extensive collaboration with a wide range of experts, during the development of the analyses protocols, the implementation of the analyses and the interpretation of the results. RWE may address a number of gaps related to the treatment effect, and RWE economic evaluations for the treatment effect can provide extremely valuable insights into real-world economic value of interventions. As the increased recognition of the value of RWE could influence health technology assessment decision, and current practices, this communication supports the urgent need of more formal guidelines.

Cost-Effectiveness of Coronary and Peripheral Artery Disease Antithrombotic Treatments in Finland.

INTRODUCTION: Currently, 15-20% of individuals with coronary artery disease (chronic coronary syndrome [CCS]) or peripheral artery disease (PAD) receiving routine treatment experience cardiovascular events (CVEs) within 3-4 years. Using PICOSTEPS (Patients-Intervention-Comparators-Outcomes-Setting-Time-Effects-Perspective-Sensitivity analysis) reporting, we evaluated the cost-effectiveness of recently approved rivaroxaban 2.5 mg twice daily in combination with acetylsalicylic acid 100 mg daily (RIV + ASA) for the prevention of CVEs among Finns with CCS or symptomatic PAD. METHODS: Myocardial infarction, ischemic stroke, intracranial hemorrhage, acute limb ischemia, amputations, major extracranial bleeding, venous thromboembolism, and cardiovascular deaths were modeled in a Markov model examining a cohort of patients with CCS or symptomatic PAD. Relative effects of the intervention (RIV + ASA) and comparator (ASA) were based on the COMPASS trial. The primary outcome was 3%/year discounted incremental cost-effectiveness ratio (ICER), defined as cost (2019 euros) per quality-adjusted life year (QALY) gained in the Finnish setting over a lifetime horizon. In addition to nonfatal and fatal CVEs, the effects factored Finnish non-CVE mortality, quality of life, and direct costs from a public payer perspective. Disaggregated costs and QALYs, costs per life year gained (LYG), and ischemic strokes avoided, net monetary benefit (NMB), expected value of perfect information (EVPI), economic value-added (EVA), cost-effectiveness table, and acceptability frontier were examined. Probabilistic and deterministic sensitivity analyses were conducted. RESULTS: In the deterministic comparison with ASA over a lifetime horizon, RIV + ASA resulted in a benefit of 0.404 QALYs and 0.474 LYGs for an additional cost of €3241, resulting in an ICER of €8031/QALY. The probabilistic ICER was €4313/QALY (EVPI €1829/patient). RIV + ASA had positive NMB (€8791/patient), low EVPI (€88/patient), high EVA (€8703/patient), and 91% probability of cost-effectiveness using the willingness-to-pay of €25,254/QALY. The primary result was conservative and robust for RIV + ASA. CONCLUSION: RIV + ASA was a cost-effective treatment alternative compared with ASA in patients with CCS or symptomatic PAD in Finland.

Finland lacks published evidence on the cost-effectiveness of approved interventions for the prevention of cardiovascular events among individuals with chronic coronary syndrome (stable coronary artery disease) or symptomatic peripheral artery disease at risk of cardiovascular complications. Rivaroxaban 2.5 mg twice daily plus acetylsalicylic acid 100 mg once daily is indicated and reimbursed in Finland for the prevention of cardiovascular events for patients with stable coronary artery disease or symptomatic peripheral artery disease. We assessed the effectiveness and costs of treatment with rivaroxaban plus acetylsalicylic acid in comparison with treatment with acetylsalicylic acid. That is, we examined whether rivaroxaban is cost-effective when prescribed in combination with acetylsalicylic acid.Cardiovascular events with their associated costs and impact on quality of life were modeled over the lifetime of patients. The main effectiveness outcome was quality-adjusted life years (modeled survival multiplied by the expected quality of life), and costs included those relevant to the Finnish public payer in 2019. Extensive sensitivity analyses were carried out to evaluate the impacts of different model inputs and rationale.Rivaroxaban plus acetylsalicylic acid had high probability of being cost-effective, compared with acetylsalicylic acid. By valuing quality-of-life benefit with a plausible willingness-to-pay, net cost savings of €8791 per patient could be gained or economic value added by €8703 per patient if rivaroxaban was used.

Real-world cost-effectiveness of rivaroxaban compared with vitamin K antagonists in the context of stroke prevention in atrial fibrillation in France.

OBJECTIVE: The objective was to assess the real-world cost-effectiveness of rivaroxaban, versus vitamin K antagonists (VKAs), for stroke prevention in patients with atrial fibrillation (AF) from a French national health insurance perspective. METHODS: A Markov model was developed with a lifetime horizon and cycle length of 3 months. All inputs were drawn from real-world evidence (RWE) studies: data on baseline patient characteristics at model entry were obtained from a French RWE study, clinical event rates as well as persistence rates for the VKA treatment arm were estimated from a variety of RWE studies, and a meta-analysis provided comparative effectiveness for rivaroxaban compared to VKA. Model outcomes included costs (drug costs, clinical event costs, and VKA monitoring costs), quality-adjusted life-years (QALY) and life-years (LY) gained, incremental cost per QALY, and incremental cost per LY. Sensitivity analyses were performed to test the robustness of the model and to better understand the results drivers. RESULTS: In the base-case analysis, the incremental total cost was €714 and the total incremental QALYs and LYs were 0.12 and 0.16, respectively. The resulting incremental cost/QALY and incremental cost/LY were €6,006 and €4,586, respectively. The results were more sensitive to the inclusion of treatment-specific utility decrements and clinical event rates. CONCLUSIONS: Although there is no official willingness-to-pay threshold in France, these results suggest that rivaroxaban is likely to be cost-effective compared to VKA in French patients with AF from a national insurance perspective.

Health economic evaluation of rivaroxaban in the treatment of patients with chronic coronary artery disease or peripheral artery disease.

AIMS: In the COMPASS trial, rivaroxaban 2.5 mg twice daily (bid) plus acetylsalicylic acid (ASA) 100 mg once daily (od) performed better than ASA 100 mg od alone in reducing the rate of cardiovascular disease, stroke, or myocardial infarction (MI) in patients with coronary artery disease (CAD) and peripheral artery disease (PAD). A Markov model was developed to assess the cost-effectiveness of rivaroxaban plus ASA vs. ASA alone over a lifetime horizon, from the UK National Health System perspective. METHODS AND RESULTS: The base case analysis assumed that patients entered the model in the event-free health state, with the possibility to experience ≤2 events, transitioning every three-month cycle, through acute and post-acute health states of MI, ischaemic stroke (IS), or intracranial haemorrhage (ICH), and death. Costs, quality-adjusted life-years (QALYs), life years-all discounted at 3.5%-and incremental cost-effectiveness ratios (ICERs) were calculated. Deterministic and probabilistic sensitivity analyses were conducted, as well as scenario analyses. In the model, patients on rivaroxaban plus ASA lived for an average of 14.0 years with no IS/MI/ICH, and gained 9.7 QALYs at a cost of £13 947, while those receiving ASA alone lived for an average of 12.7 years and gained 9.3 QALYs at a cost of £8126. The ICER was £16 360 per QALY. This treatment was cost-effective in 98% of 5000 iterations at a willingness-to-pay threshold of £30 000 per QALY. CONCLUSION: This Markov model suggests that rivaroxaban 2.5 mg bid plus ASA is a cost-effective alternative to ASA alone in patients with chronic CAD or PAD.

Systematic review of utility values used in the pharmacoeconomic evaluations for schizophrenia: implications on cost-effectiveness results.

Background and Objectives: Utility elicitation studies for schizophrenia generate different utility values for the same health states. We reviewed utility values used in schizophrenia pharmacoeconomic evaluations and evaluated the impact of their selection on the incremental cost-effectiveness ratio (ICER). Methods: A systematic search was performed in Medline and Embase. Health state definitions, associated utility values, elicitation studies, and value selection processes were extracted. Sets of utility values for all schizophrenia health states were used in a cost-effectiveness model to evaluate the ICER. Results: Thirty-five cost-utility analyses (CUAs) referring to 11 utility elicitation studies were included. The most frequent health states were 'stable' (28 CUAs, 7 utility elicitation studies, 10 values, value range 0.650-0.919), 'relapse requiring hospitalisation' (18, 5, 7, 0.270-0.604), 'relapse not requiring hospitalisation' (18, 5, 10, 0.460-0.762), and 'relapse only' (10, 5, 6, 0.498-0.700). Seventeen sets of utility values were identified with difference in utility values between relapse and stable ranging from -0.358 to -0.050, resulting in ICERs ranging from -56.2% to +222.6% from average. Conclusion: The use of utility values for schizophrenia health states differs among CUAs and impacts on the ICER. More rigorous and transparent use of utility values and sensitivity analysis with different sets of utility values are suggested for future CUAs.

Cost-effectiveness analyses using real-world data: an overview of the literature.

Objectives: Real-world evidence (RWE) may provide good estimates of absolute event probabilities and costs in patients in actual clinical practice, but their use in decision-analytic models poses many challenges. A literature review based on a systematic search was conducted to summarize the limitations of using RWE in decision-analytic modeling reported in the literature, but also to identify existing recommendations about real-world modeling. Methods: A literature search was performed on Medline and Embase databases, as well as relevant websites. No restrictions in language or geographical scope were imposed. Results: A total of 14 references were included. RWE is recognized as a valuable source of data for market access and reimbursement, and as a complement to clinical trial evidence for treatment pathways, resource use, long-term natural history, and effectiveness. The main limitations identified in the literature were: confounding bias, missing data, lack of accurate data related to drug exposure and outcomes, errors during the record-keeping process, protection of private data, and insufficient numbers of patients. Although most submission guidelines recognized the potential biases associated with RWE, guidance on the appropriate methods to deal with these biases, and approaches to review different relevant evidence to inform model development, were scarce. Several initiatives have attempted to provide guidance on the use of RWE in decision-modeling. Conclusions: RWE is likely to be particularly valuable for informing healthcare policy-makers when formulating appropriate treatment pathways, encouraging the optimal allocation of scarce resources, and improving aggregate patient outcomes. However, little guidance is available on the relative merits of using efficacy and/or effectiveness evidence in Health Technology Appraisal submissions. Further research is needed to better understand these methods and their potential applications in a broader range of scenarios and simulation studies, and their impact on economic modeling.

Cost-effectiveness analysis of pembrolizumab versus standard-of-care chemotherapy for first-line treatment of PD-L1 positive (>50%) metastatic squamous and non-squamous non-small cell lung cancer in France.

INTRODUCTION: In the KEYNOTE-024 trial, pembrolizumab demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS) versus Standard-of-Care (SoC) platinum-based doublets for first-line treatment of PD-L1 -positive (≥50%) metastatic Non-Small-Cell Lung Cancer (NSCLC) patients with no EGFR mutations or ALK translocations. This study aims to assess the cost-effectiveness of pembrolizumab versus SoC platinum-based chemotherapy from the French healthcare system perspective. METHODS: A three-state partitioned-survival model was adapted to project outcomes and costs of squamous and non-squamous NSCLC patients respectively, over a 10-year time horizon. Clinical and utility data were collected from the trial. A network meta-analysis was performed to consider platinum-based triplets also used for non-squamous NSCLC. Direct medical costs were considered based on ressources identified from the trial and literature. Costs and outcomes were discounted at 4% per year. Incremental cost-effectiveness ratios (ICERs) were calculated as cost per Life Year (LY) and cost per Quality-Adjusted Life Year (QALY). Sensitivity and scenario analyses were performed to assess the robustness of results. RESULTS: For squamous NSCLC, pembrolizumab was projected to increase life expectancy of patients by 0.93 LY (11 months), and 0.74 QALY (9 months) for an incremental cost of €62,032 compared with platinum-based doublets. The ICER of pembrolizumab versus platinum-based doublets was €66,825/LY and €84,097/QALY. For non-squamous NSCLC, pembrolizumab was projected to increase life expectancy of patients by 0.85-1.32 LYs (10.2-15.8 months) and 0.64-1.02 QALYs (7.7-12.2 months) for an incremental cost varying from €-14,947-+47,064 depending on the specific comparator. The ICER of pembrolizumab versus platinum-based chemotherapy with paclitaxel plus bevacizumab was €62,846/LY and €78,729/QALY; regimens including pemetrexed were dominated. Results were most sensitive to extrapolations of survival outcomes and assumptions for continued effectiveness and treatment duration of pembrolizumab. CONCLUSIONS: Pembrolizumab appears cost-effective versus SoC chemotherapy for first-line treatment of PD-L1-positive (50%) metastatic NSCLC patients in France, assuming willingness-to-pay under 100,000€/QALY (OECD threshold in the discussion section).

Meta-analyses using real-world data to generate clinical and epidemiological evidence: a systematic literature review of existing recommendations.

OBJECTIVES: To identify existing guidelines, key recommendations, and existing limitations regarding the evaluation and use of real-world evidence (RWE) in meta-analyses (MAs) to generate clinical and epidemiological evidence: a systematic review of existing recommendations. METHODS: A literature search was performed in April 2017 in MEDLINE and Embase using the Ovid platform, the Cochrane Library, and other sources. No specific inclusion and exclusion criteria were applied, and no restrictions in timeframe, language, or geographical scope were imposed. RESULTS: The search strategy identified 1681 citations; 12 references were included in this review. Recommendations within the literature regarding the use of RWE in MAs are: (1) it may be useful to extract and analyze adjusted results because confounding is expected; (2) testing heterogeneity in the MA of RWE is important as it may minimize the potential for bias and generate hypotheses for future research; (3) limiting a search ≤2 bibliographic databases when conducting MAs of RWE will not provide a thorough summary of existing literature; and (4) the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) checklist is a 35-item checklist developed to allow for more standardized reporting of MAs of RWE and address their limitations. LIMITATIONS: (1) No formal guidelines were found regarding the use of RWE in MAs; (2) no consensus was found on a preferred instrument for the assessment of RWE; and (3) critical appraisal of RWE is often omitted from Health Technology Assessment submissions. CONCLUSIONS: The inclusion of RWE in MAs may facilitate the confirmation of conclusions drawn from randomized controlled trials and, thus, reassure decision-makers that findings can be extrapolated to real-world populations. However, qualitative and quantitative bias may co-exist in MAs of RWE. Reviewers should select the most appropriate tools that match the study designs identified in a particular systematic review.

Systematic review of pharmacoeconomic models for schizophrenia.

Background: Economic models are broadly used in the economic evaluation of antipsychotics in schizophrenia. Our objective was to summarize the structure of these models. Methods: Model-based economic evaluations of antipsychotics in schizophrenia were identified through Medline and Embase. General information was extracted including analysis type, model type, perspective, population, comparator, outcome, and timeframe. Model-specific structures for decision tree (DT), cohort- and patient-level Markov model (CLMM, PLMM), and discrete-event simulation (DES) models were extracted. Results: A screen of 1870 records identified 79 studies. These were mostly cost-utility analyses (n = 48) with CLMM (n = 32) or DT models (n = 29). They mostly applied payer perspective (n = 68), focused on general schizophrenia for relapse prevention (n = 73), compared pharmacotherapies as first-line (n = 71), and evaluated incremental cost per quality-adjusted life year (QALY) gained (n = 40) with a 1-year (n = 32) or 5-year (n = 26) projection. DT models progressed with the branching points of response, relapse, discontinuation, and adherence. CLMM models transitioned between disease states, whereas PLMM models transitioned between adverse event states with/without disease state. DES models moved forward with times to remission, relapse, psychiatrist visit, and death. Conclusions: A pattern of pharmacoeconomic models for schizophrenia was identified. More subtle structures and patient-level models are suggested for a future modelling exercise.

Cost-Effectiveness of Nalmefene Added to Psychosocial Support for the Reduction of Alcohol Consumption in Alcohol-Dependent Patients With High/Very High Drinking Risk Levels: A Microsimulation Model.

OBJECTIVE: A microsimulation model was adapted to evaluate the cost-effectiveness of nalmefene combined with psychosocial support (NMF + PS) versus psychosocial support alone (PS). The economic impact of alcohol reduction using nalmefene treatment was not evaluated. METHOD: The model simulates patient-level alcohol consumption over a 5-year time horizon across different treatment cohorts. Study outcomes included probabilities of alcohol-attributable diseases and injuries as well as deaths from these events. The approach used nalmefene clinical trial data, a time horizon of 1 and 5 years, and a U.K. societal perspective. Extensive deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Compared with the PS strategy, NMF + PS was associated at Year 5 with a gain of 0.047 quality-adjusted life years (QALYs) and an additional £503, leading to an incremental cost-effectiveness ratio (ICER) of £10,613 per QALY gained. When compared with the strategy without treatment, NMF + PS was associated with a gain of 0.228 QALYs and an additional £1,795, leading to an ICER of £1,758 per QALY gained. The NMF + PS strategy dominated both treatment strategies when considering the U.K. societal perspective. Sensitivity analyses confirmed the robustness of the results. CONCLUSIONS: A combination of NMF and PS was better than PS alone, considering a 5-year time horizon and a societal perspective.

Cost analysis of adverse events associated with non-small cell lung cancer management in France.

BACKGROUND: Adverse events (AEs) related to medical treatments in non-small cell lung cancer (NSCLC) are frequent and need an appropriate costing in health economic models. Nevertheless, data on costs associated with AEs in NSCLC are scarce, particularly since the development of immunotherapy with specific immune-related AEs. OBJECTIVE: To estimate the costs of grades 3 and 4 AEs related to NSCLC treatments including immunotherapy in France. METHODS: Grades 3 and 4 AEs related to treatment and reported in at least 1% of patients in Phase III clinical trials for erlotinib, ramucirumab plus docetaxel, docetaxel, pemetrexed plus carboplatin plus bevacizumab, platinum-based chemotherapies, nivolumab and pembrolizumab were identified. When no cost evaluation was reported in literature, estimates on standard treatments and medical resource use for each AE were obtained thanks to an expert panel. Total cost per AE was calculated from a French national health insurance perspective and updated in 2017 Euros. Hospital stay costs were estimated based on public and private weighted tariffs and data from the French Medical Information System (Programme de Médicalisation des Systèmes d'Information). Costs of tests, consultations and treatments were calculated based on national reimbursement tariffs. RESULTS: Overall, costs of grades 3 and 4 AEs related to treatment ranged from €46 per event to €7,742 per year. Fourteen out of 24 AEs identified had a mean estimated cost over €2,000. The highest mean costs were related to type 1 diabetes (€7,742 per year) followed by pneumonitis (€5,786 per event), anemia (€5,752 per event), dehydration (€5,207 per event) and anorexia (€4,349 per event). Costs were mostly driven by hospitalization costs. CONCLUSION: Among the AEs identified, a majority appeared to have an important economic impact, with a management cost of at least €2,000 per event mainly driven by hospitalization costs. This study may be of interest for economic evaluations of new interventions in NSCLC.

Analysis of health economics assessment reports for pharmaceuticals in France - understanding the underlying philosophy of CEESP assessment.

Background: Despite the guidelines for Economic and Public Health Assessment Committee (CEESP) submission having been available for nearly six years, the dossiers submitted continue to deviate from them, potentially impacting product prices. Objective: to review the reports published by CEESP, analyse deviations from the guidelines, and discuss their implications for the pricing and reimbursement process. Study design: CEESP reports published until January 2017 were reviewed, and deviations from the guidelines were extracted. The frequency of deviations was described by type of methodological concern (minor, important or major). Results: In 19 reports, we identified 243 methodological concerns, most often concerning modelling, measurement and valuation of health states and results presentation and sensitivity analyses; nearly 63% were minor, 33% were important and 4.5% were major. All reports included minor methodological concerns, and 17 (89%) included at least one important and/or major methodological concern. Global major methodological concerns completely invalidated the analysis in seven dossiers (37%). Conclusion: The CEESP submission dossiers fail to adhere to the guidelines, potentially invalidating the health economics analysis and resulting in pricing negotiations. As these negotiations tend to be unfavourable for the manufacturer, the industry should strive to improve the quality of the analyses submitted to CEESP.

Determinants of orphan drugs prices in France: a regression analysis.

BACKGROUND: The introduction of the orphan drug legislation led to the increase in the number of available orphan drugs, but the access to them is often limited due to the high price. Social preferences regarding funding orphan drugs as well as the criteria taken into consideration while setting the price remain unclear. The study aimed at identifying the determinant of orphan drug prices in France using a regression analysis. METHODS: All drugs with a valid orphan designation at the moment of launch for which the price was available in France were included in the analysis. The selection of covariates was based on a literature review and included drug characteristics (Anatomical Therapeutic Chemical (ATC) class, treatment line, age of target population), diseases characteristics (severity, prevalence, availability of alternative therapeutic options), health technology assessment (HTA) details (actual benefit (AB) and improvement in actual benefit (IAB) scores, delay between the HTA and commercialisation), and study characteristics (type of study, comparator, type of endpoint). The main data sources were European public assessment reports, HTA reports, summaries of opinion on orphan designation of the European Medicines Agency, and the French insurance database of drugs and tariffs. A generalized regression model was developed to test the association between the annual treatment cost and selected covariates. RESULTS: A total of 68 drugs were included. The mean annual treatment cost was €96,518. In the univariate analysis, the ATC class (p = 0.01), availability of alternative treatment options (p = 0.02) and the prevalence (p = 0.02) showed a significant correlation with the annual cost. The multivariate analysis demonstrated significant association between the annual cost and availability of alternative treatment options, ATC class, IAB score, type of comparator in the pivotal clinical trial, as well as commercialisation date and delay between the HTA and commercialisation. CONCLUSION: The orphan drug pricing is a multivariate phenomenon. The complex association between drug prices and the studied attributes and shows that payers integrate multiple variables in decision making when setting orphan drug prices. The interpretation of the study results is limited by the small sample size and the complex data structure.