Generalizability of health economic evaluations : methods for multinational patient-level studies

Background: Cost-effectiveness outcomes collected in multinational health economic studies may vary across countries and geographic areas due to numerous clinical and socioeconomic factors. The between-country variability poses the question of generalizability of the cost-effectiveness estimates, i.e. applicability of the trial-wide results for the decision-making in particular jurisdiction.Objectives: The purpose of this research is to illustrate how selected methods can improve generalizability of the results of patient-level health economic studies by a) exploring between-country variability in incremental costs, effectiveness and resource use, b) calculation of trial-wide and country-level incremental cost, effectiveness and resource use while accounting for patient- and country-level covariates, and c) assessing the potential of covariates to predict cost and effectiveness estimates for the settings outside the study.Methods: Review of published health-economic evidence and international HTA guidelines was conducted to evaluate applied or recommended methods and analytical strategies to improve generalizability of the health economic outcomes. In the case study, qualitative and quantitative homogeneity test by Simon and Gail is used to explore between-country heterogeneity of the treatment effects measured by incremental costs, effectiveness, resource use (length of hospitalization) and incremental net monetary benefit. Hierarchical modelling is applied to calculate trial-wide and country-level estimates, while accounting for clustering and incorporating country- and patient-level covariates.Results: Simon and Gail test indicated qualitative homogeneity for incremental effectiveness, costs, length of hospitalization and net monetary benefit between treatment and control arms. Trial-wide and country-level mean incremental costs and effectiveness were estimated using hierarchical models with and without covariates. Results of hierarchical modelling suggested, that new treatment was more efficacious, saved costs and resource use in majority of the countries.Conclusions: Homogeneity test and hierarchical models are complementary methods to explore heterogeneity and to estimate trial-wide and country-level parameters for cost-effectiveness analysis. Hierarchical models allow for country-level estimates and adjustment for covariates. In the case study the patient-level covariates showed effect on incremental cost and effectiveness; country-level covariates had very small impact on estimates. The use of country-level covariates as predictors for incremental cost and resource use to improve generalizability of health economic studies beyond the study setting merits further investigation.