Does the Structure Matter? An External Validation and Health Economic Results Comparison of Event Simulation Approaches in Severe Obesity.

OBJECTIVES: As obesity-associated events impact long-term survival, health economic (HE) modelling is commonly applied, but modelling approaches are diverse. This research aimed to compare the events simulation and the HE outcomes produced by different obesity modelling approaches. METHODS: An external validation, using the Swedish obesity subjects (SOS) study, of three main structural event modelling approaches was performed: (1) continuous body mass index (BMI) approach; (2) risk equation approach; and (3) categorical BMI-related approach. Outcomes evaluated were mortality, cardiovascular events, and type 2 diabetes (T2D) for both the surgery and the control arms. Concordance between modelling results and the SOS study were investigated by different state-of-the-art measurements, and categorized by the grade of deviation observed (grades 1-4 expressing mild, moderate, severe, and very severe deviations). Furthermore, the costs per quality-adjusted life-year (QALY) gained of surgery versus controls were compared. RESULTS: Overall and by study arm, the risk equation approach presented the lowest average grade of deviation (overall grade 2.50; control arm 2.25; surgery arm 2.75), followed by the continuous BMI approach (overall 3.25; control 3.50; surgery 3.00) and by the categorial BMI approach (overall 3.63; control 3.50; surgery 3.75). Considering different confidence interval limits, the costs per QALY gained were fairly comparable between all structural approaches (ranging from £2,055 to £6,206 simulating a lifetime horizon). CONCLUSION: None of the structural approaches provided perfect external event validation, although the risk equation approach showed the lowest overall deviations. The economic outcomes resulting from the three approaches were fairly comparable.

Replication of Published Health Economic Obesity Models: Assessment of Facilitators, Hurdles and Reproduction Success.

OBJECTIVES: This research aims to (1) replicate published health economic models, (2) compare reproduced results with original results, (3) identify facilitators and hurdles to model replicability and determine reproduction success, and (4) suggest model replication reporting standards to enhance model reproducibility, in the context of health economic obesity models. METHODS: Four health economic obesity models simulating an adult UK population were identified, selected for replication, and evaluated using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Reproduction results were compared to original results, focusing on cost-effectiveness outcomes, and the resulting reproduction success was assessed by published criteria. Replication facilitators and hurdles were identified and transferred into related reporting standards. RESULTS: All four case studies were state-transition models simulating costs and quality-adjusted life-years (QALYs). Comparing original versus reproduction outcomes, the following deviation ranges were observed: costs - 3.9 to 16.1% (mean over all model simulations 3.78%), QALYs - 3.7 to 2.1% (mean - 0.11%), and average cost-utility ratios - 3.0 to 17.9% (mean 4.28%). Applying different published criteria, an overall reproduction success was observed for three of four models. Key replication facilitators were input data tables and model diagrams, while missing standard deviations and missing formulas for equations were considered as key hurdles. CONCLUSIONS: This study confirms the feasibility of rebuilding health economic obesity models, but minor to major assumptions were needed to fill reporting gaps. Model replications can help to assess the quality of health economic model documentation and can be used to validate current model reporting practices. Simple changes to actual CHEERS reporting criteria may solve identified replication hurdles.

Incidence of acquired thrombotic thrombocytopenic purpura in Germany: a hospital level study.

BACKGROUND: Acquired thrombotic thrombocytopenic Purpura (aTTP) is a life-threatening ultra-orphan disease with a reported annual incidence between 1.5 and 6.0 cases per million in Europe and mainly affecting otherwise young and healthy adults aged 40 years on average. The goal of this study was to assess the incidence of aTTP in Germany. METHODS: A systematic review was performed to determine the published evidence on the aTTP epidemiology in Germany. To obtain additional evidence on the proportion of aTTP cases within the national Thrombotic Microangiopathy (TMA) population a hospital-level study was performed, using a retrospective data collection approach. Diagnosis of aTTP was confirmed if ADAMTS13 level were < 10% and/or the medical records explicitly mentioned aTTP diagnosis. The aggregated hospital data were then projected to the national level using logistic regression techniques. RESULTS: The systematic literature search did not provide incidence estimates of aTTP in Germany. Eight centers (≈27% of the top 30 TMA hospitals) delivered data according to a predefined data collection form. On average (year 2014-2016) a total number of 172 aTTP episodes per year was projected (95% confidence interval [95%CI]: 132-212). The majority were newly diagnosed aTTP cases (n = 121; 95%CI: 105-129), and 51 were recurrent aTTP cases (95%CI: 27-84). The average annual projected incidence (year 2014-2016) of aTTP episodes was 2.10 per million inhabitants in Germany (95%CI: 1.60-2.58). CONCLUSIONS: The determined annual incidence of newly diagnosed aTTP cases and the overall annual incidence of aTTP episodes in Germany confirm the ultra-orphan character of aTTP. An external validation against international registries (France, UK and USA) shows that our findings are quite comparable with those international incidence rates.

Evaluation of a possible predictor for Federal Joint Committee decisions on early benefit assessments according to the German act on the reform of the market for medicinal products.

OBJECTIVES: As of 1st January 2011 the German drug market is regulated by the act on the reform of the market for medicinal products (AMNOG). Since then the normal procedure for reimbursement of a new pharmaceutical is a benefit assessment by the joint federal committee (G-BA) which determines one of six additional benefit levels. METHODS: In order to evaluate a possible predictor of G-BA decisions, the 'evaluation of pharmaceutical innovations (EVITA)' score was calculated for 40 out of 63 dossiers and compared with published G-BA appraisals. RESULTS: Univariate ordinary least squares (p<0.001) and ordered logit regression (p=0.008) analyses show statistically significant correlations between EVITA scores and the G-BA additional benefit levels. Moreover, for the prediction of an additional benefit level of at least 'minor', an EVITA score cutpoint of ≥3 is associated with a sensitivity of 100% and a specificity of 80%. For the prediction of an additional benefit level of at least 'considerable', an EVITA score cutpoint of ≥7.5 is associated with a sensitivity of 100% and a specificity of 93.1%. CONCLUSION: The present investigation indicates that the EVITA score may have some potential to act as a possible predictor of G-BA decisions related to AMNOG early benefit assessments.

Indirect treatment comparison of bevacizumab + interferon-α-2a vs tyrosine kinase inhibitors in first-line metastatic renal cell carcinoma therapy.

BACKGROUND: The vascular endothelial growth factor inhibitor bevacizumab (BEV) given in combination with interferon-α-2a (IFN), and the tyrosine kinase inhibitors (TKIs) sunitinib (SUN) and pazopanib (PAZ), have all shown significant increase in progression-free survival (PFS) in first-line metastatic renal-cell carcinoma (mRCC) therapy. These targeted therapies are currently competing to be primary choice; hence, in the absence of direct head-to-head comparison, there is a need for valid indirect comparison assessment. METHODS: Standard indirect comparison methods were applied to independent review PFS data of the pivotal Phase III trials, to determine indirect treatment comparison hazard-ratios (HR) with 95% confidence intervals (95% CI). As BEV+IFN and SUN have been compared to IFN, indirect comparison was enabled by the common IFN comparator arms. As PAZ was compared to placebo (PLA), a connector trial (IFN vs PLA) was required for the indirect comparison to BEV+IFN. Sensitivity analyses taking into account real-life influence of patient compliance on clinical outcomes were performed. RESULTS: The indirect efficacy comparison resulted in a statistically nonsignificant PFS difference of BEV+IFN vs SUN (HR: 1.06; 95% CI: 0.78-1.45; P = 0.73) and of BEV+IFN vs PAZ (range based on different connector trials; HR: 0.74-1.03; P = 0.34-0.92). Simulating real-life patient compliance and its effectiveness impact showed an increased tendency towards BEV+IFN without reaching statistical significance. CONCLUSIONS: There is no statistically significant PFS difference between BEV+IFN and TKIs in first-line mRCC. These findings imply that additional treatment decision criteria such as tolerability and therapy sequencing need to be considered to guide treatment decisions.

Cost-utility analysis of eprosartan compared to enalapril in primary prevention and nitrendipine in secondary prevention in Europe--the HEALTH model.

OBJECTIVE: To investigate the cost-utility of eprosartan versus enalapril (primary prevention) and versus nitrendipine (secondary prevention) on the basis of head-to-head evidence from randomized controlled trials. METHODS: The HEALTH model (Health Economic Assessment of Life with Teveten for Hypertension) is an object-oriented probabilistic Monte Carlo simulation model. It combines a Framingham-based risk calculation with a systolic blood pressure approach to estimate the relative risk reduction of cardiovascular and cerebrovascular events based on recent meta-analyses. In secondary prevention, an additional risk reduction is modeled for eprosartan according to the results of the MOSES study ("Morbidity and Mortality after Stroke--Eprosartan Compared to Nitrendipine for Secondary Prevention"). Costs and utilities were derived from published estimates considering European country-specific health-care payer perspectives. RESULTS: Comparing eprosartan to enalapril in a primary prevention setting the mean costs per quality adjusted life year (QALY) gained were highest in Germany (Euro 24,036) followed by Belgium (Euro 17,863), the UK (Euro 16,364), Norway (Euro 13,834), Sweden (Euro 11,691) and Spain (Euro 7918). In a secondary prevention setting (eprosartan vs. nitrendipine) the highest costs per QALY gained have been observed in Germany (Euro 9136) followed by the UK (Euro 6008), Norway (Euro 1695), Sweden (Euro 907), Spain (Euro -2054) and Belgium (Euro -5767). CONCLUSIONS: Considering a Euro 30,000 willingness-to-pay threshold per QALY gained, eprosartan is cost-effective as compared to enalapril in primary prevention (patients >or=50 years old and a systolic blood pressure >or=160 mm Hg) and cost-effective as compared to nitrendipine in secondary prevention (all investigated patients).