M. Willis

Cost Effectiveness of Becaplermin in the Treatment of Diabetic Foot Ulcers in Four European Countries

AbstractObjective: The primary objective of this study was to estimate the cost effectiveness of treating diabetic foot ulcers with becaplermin (Regranex®) plus good wound care (GWC) compared with GWC alone in a variety of European healthcare settings. A secondary objective was to analyse the effect of different treatment practices on the economics of caring for diabetic foot ulcers. Design and setting: Markov-based simulation study from the perspective of a national health system. Methods: A 12-month Markov computer simulation model was used to assess the cost effectiveness in 4 European countries of treating diabetic foot ulcers with becaplermin plus GWC versus GWC alone. Transition probabilities were taken from a prospective study of 183 patients and becaplermin efficacy was based on 20-week healing rates in a recent meta-analysis of clinical trials involving 449 patients. Country-specific treatment cost data were collected in collaboration with local economic consultations and combined with the disease model to estimate the incremental cost per ulcer-free month gained. The model was then run using hypothetical low- and high-intensity resource usage profiles to investigate the economics of caring for diabetic foot ulcers. Results: Over the course of 1 year, individuals who received becaplermin plus GWC were, on average, predicted to spend an additional 0.81 months (24% longer) free of ulcers and to experience a 9% lower risk of undergoing a lower extremity amputation than individuals who received GWC alone. Consequently, becaplermin plus GWC was estimated to be net cost saving in Sweden, Switzerland and the UK. In France, the addition of becaplermin was estimated to add

Reducing uncertainty in value-based pricing using evidence development agreements: the case of continuous intraduodenal infusion of levodopa/carbidopa (Duodopa®) in Sweden.

US19 (1999 values) for each additional ulcer-free month gained. There were substantial intercountry differences in treatment practices and the costs of treating diabetic foot ulcers. Conclusions: Becaplermin may be a cost-effective treatment for neuropathic diabetic foot ulcers in a wide range of European settings. In Sweden, Switzerland and the UK, becaplermin may even be cost saving. Substantial intercountry differences in resource patterns appear, at least partly, to be the logical outcome of differences in unit costs.

Validation of economic and health outcomes simulation model of type 2 diabetes mellitus (ECHO-T2DM)

BackgroundValue-based pricing (VBP), whereby prices are set according to the perceived benefits offered to the consumer at a time when costs and benefits are characterized by considerable uncertainty and are then reviewed ex post, is a much discussed topic in pharmaceutical reimbursement. It is usually combined with coverage with evidence development (CED), a tool in which manufacturers are granted temporary reimbursement but are required to collect and submit additional health economic data at review. Many countries, including the UK, are signalling shifts in this direction. Several countries, including Sweden, have already adopted this approach and offer good insight into the benefits and pitfalls in actual practice.ObjectiveTo describe VBP reimbursement decision making using CED in actual practice in Sweden.MethodsDecision making by The Dental and Pharmaceutical Benefits Agency (TLV) in Sweden was reviewed using a case study of continuous intraduodenal infusion of levodopa/carbidopa (Duodopa®) in the treatment of advanced Parkinson’s disease (PD) with severe motor fluctuations.ResultsThe manufacturer of Duodopa® applied for reimbursement in late 2003. While the proper economic data were not included in the submission, TLV granted reimbursement until early 2005 to provide time for the manufacturer to submit a formal economic evaluation. The re-submission with economic data was considered inadequate to judge cost effectiveness, so TLV granted an additional extension of reimbursement until August 2007, at which time conclusive data were expected. The manufacturer initiated a 3-year, prospective health economic study and a formal economic model. Data from a pre-planned interim analysis of the data were loaded into the model and the cost-effectiveness ratio was the basis of the next re-submission. TLV concluded that the data were suitable for making a definite decision and that the drug was not cost effective, deciding to discontinue reimbursement for any new patients (current patients were unaffected). The manufacturer continued to collect data and to improve the economic model and re-submitted in 2008. New data and the improved model resulted in reduced uncertainty and a lower cost-effectiveness ratio in the range of Swedish kronor (SEK)430 000 per QALY gained in the base-case analysis, ranging up to SEK900 000 in the most conservative sensitivity analysis, resulting in reimbursement being granted.DiscussionThe case of Duodopa® provides excellent insight into VBP reimbursement decision making in combination with CED and ex post review in actual practice. Publicly available decisions document the rigorous, time-consuming process (four iterations were required before a final decision could be reached). The data generated as part of the risk-sharing agreement proved correct the initial decision to grant limited coverage despite lack of economic data. Access was provided to 100 patients while evidence was generated.ConclusionsEconomic appraisal differs from clinical assessment, and decision makers benefit from analysis of naturalistic, actual practice data. Despite reviewing the initial trial-based, ‘piggy-back’ economic analysis, TLV was uncertain of the cost effectiveness in actual practice and deferred a final decision until observational data from the DAPHNE study became available. Second, acceptance of economic modelling and use of temporary reimbursement conditional on additional evidence development provide a mechanism for risk sharing between TLV and manufacturers, which enabled patient access to a drug with proven clinical benefit while necessary evidence to support claims of cost effectiveness could be generated.

Hospitalisation Utilisation and Costs in Schizophrenia Patients in Finland before and after Initiation of Risperidone Long-Acting Injection

Abstract Objective: This study constructed the Economic and Health Outcomes Model for type 2 diabetes mellitus (ECHO-T2DM), a long-term stochastic microsimulation model, to predict the costs and health outcomes in patients with T2DM. Naturally, the usefulness of the model depends upon its predictive accuracy. The objective of this work is to present results of a formal validation exercise of ECHO-T2DM. Methods: The validity of ECHO-T2DM was assessed using criteria recommended by the International Society for Pharmacoeconomics and Outcomes Research/Society for Medical Decision Making (ISPOR/SMDM). Specifically, the results of a number of clinical trials were predicted and compared with observed study end-points using a scatterplot and regression approach. An F-test of the best-fitting regression was added to assess whether it differs statistically from the identity (45°) line defining perfect predictions. In addition to testing the full model using all of the validation study data, tests were also performed of microvascular, macrovascular, and survival outcomes separately. The validation tests were also performed separately by type of data (used vs not used to construct the model, economic simulations, and treatment effects). Results: The intercept and slope coefficients of the best-fitting regression line between the predicted outcomes and corresponding trial end-points in the main analysis were −0.0011 and 1.067, respectively, and the R2 was 0.95. A formal F-test of no difference between the fitted line and the identity line could not be rejected (p = 0.16). The high R2 confirms that the data points are closely (and linearly) associated with the fitted regression line. Additional analyses identified that disagreement was highest for macrovascular end-points, for which the intercept and slope coefficients were 0.0095 and 1.225, respectively. The R2 was 0.95 and the estimated intercept and slope coefficients were 0.017 and 1.048, respectively, for mortality, and the F-test was narrowly rejected (p = 0.04). The sub-set of microvascular end-points showed some tendency to over-predict (the slope coefficient was 1.095), although concordance between predictions and observed values could not be rejected (p = 0.16). Limitations: Important study limitations include: (1) data availability limited one to tests based on end-of-study outcomes rather than time-varying outcomes during the studies analyzed; (2) complex inclusion and exclusion criteria in two studies were difficult to replicate; (3) some of the studies were older and reflect outdated treatment patterns; and (4) the authors were unable to identify published data on resource use and costs of T2DM suitable for testing the validity of the economic calculations. Conclusions: Using conventional methods, ECHO-T2DM simulated the treatment, progression, and patient outcomes observed in important clinical trials with an accuracy consistent with other well-accepted models. Macrovascular outcomes were over-predicted, which is common in health-economic models of diabetes (and may be related to a general over-prediction of event rates in the United Kingdom Prospective Diabetes Study [UKPDS] Outcomes Model). Work is underway in ECHO-T2DM to incorporate new risk equations to improve model prediction.

A Cost-Effectiveness Model of Tibolone as Treatment for the Prevention of Osteoporotic Fractures in Postmenopausal Women in Sweden

Objectives. Quantify changes in hospital resource use in Finland following initiation of risperidone long-acting injection (RLAI). Materials and Methods. A retrospective multi-center chart review (naturalistic setting) was used to compare annual hospital bed-days and hospital episodes for 177 schizophrenia patients (mean age 47.1 years, 52% female, 72% hospitalized) before and after initiation of RLAI (between January 2004 and June 2005) using the within-patient “mirror-image” study design. The base case analytical approach allocated hospital episodes overlapping the start date entirely to the preinitiation period. In order to investigate the impact of inpatient care ongoing at baseline, the change in bed-days was also estimated using an alternative analytical approached related to economic modelling. Results. In the conventional analysis, the mean annual hospitalisation costs declined by €11,900 and the number of bed-days was reduced by 40%, corresponding to 0.19 fewer hospital episodes per year. The reductions in bed-days per patient-year were similar for patients switched to RLAI as inpatients and as outpatients. In the modelling-based analysis, an 8% reduction in bed-days per year was observed. Conclusion. Despite uncertainty in the choice of analytic approach for allocating inpatient episodes that overlapping this initiation, consistent reductions in resource use are associated with the initiation of RLAI in Finland.

Validation of the Economic and Health Outcomes Model of Type 2 Diabetes Mellitus (ECHO-T2DM)

BackgroundOsteoporosis is a major cause of morbidity and mortality in the elderly and, in particular, among postmenopausal women. Hormone replacement therapy (HRT) has been shown to protect against fractures, as well as to alleviate climacteric symptoms related to menopause. Unfortunately, HRT has a number of adverse effects and many patients are noncompliant. Tibolone, a synthetic steroid with tissue-specific estrogenic, progestogenic and androgenic effects, has been shown to prevent the loss of bone mass as well as to relieve climacteric symptoms in postmenopausal women, with fewer accompanying adverse effects.ObjectiveTo estimate the economic impact in Sweden of administering tibolone 2.5 mg/day to postmenopausal women at risk for osteoporosis-related bone fractures relative to a policy of no intervention.Design and SettingModelling study performed from the national health system perspective in Sweden.MethodologyDisease modelling was used to simulate the risks of osteoporosis-related hip, vertebral and forearm fractures over time in hypothetical cohorts of postmenopausal women. The occurrence of fractures was predicted using risk functions estimated with data from actual cohorts of women in Sweden as well as the USA. Sweden-specific cost data were then used to estimate the economic impact with cost-effectiveness tools.ResultsThe model predicts that 22% of hip fractures and 13% of combined hip, vertebral and forearm fractures can be avoided over a 25-year time-period by administering tibolone to osteoporotic women. Depending on the severity of loss in bone mass and the values assumed for key parameters, estimates of the cost effectiveness of treatment range from cost saving to incremental costs per quality-adjusted life-year (QALY) gained of around SEK200 000. Delaying treatment to late menopause tends to decrease cost effectiveness.ConclusionOur findings suggest that, relative to no treatment, tibolone is a cost-effective treatment in Sweden for the prevention of fractures in women with low bone mass, especially when treatment is initiated around the onset of menopause and is administered for 5 years.

Computer modeling of diabetes and its transparency: A report on the Eighth Mount Hood Challenge

BackgroundThe Economic and Health Outcomes Model of Type 2 Diabetes Mellitus (ECHO-T2DM) was developed to address study questions pertaining to the cost-effectiveness of treatment alternatives in the care of patients with type 2 diabetes mellitus (T2DM). Naturally, the usefulness of a model is determined by the accuracy of its predictions. A previous version of ECHO-T2DM was validated against actual trial outcomes and the model predictions were generally accurate. However, there have been recent upgrades to the model, which modify model predictions and necessitate an update of the validation exercises.ObjectivesThe objectives of this study were to extend the methods available for evaluating model validity, to conduct a formal model validation of ECHO-T2DM (version 2.3.0) in accordance with the principles espoused by the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the Society for Medical Decision Making (SMDM), and secondarily to evaluate the relative accuracy of four sets of macrovascular risk equations included in ECHO-T2DM.MethodsWe followed the ISPOR/SMDM guidelines on model validation, evaluating face validity, verification, cross-validation, and external validation. Model verification involved 297 ‘stress tests’, in which specific model inputs were modified systematically to ascertain correct model implementation. Cross-validation consisted of a comparison between ECHO-T2DM predictions and those of the seminal National Institutes of Health model. In external validation, study characteristics were entered into ECHO-T2DM to replicate the clinical results of 12 studies (including 17 patient populations), and model predictions were compared to observed values using established statistical techniques as well as measures of average prediction error, separately for the four sets of macrovascular risk equations supported in ECHO-T2DM. Sub-group analyses were conducted for dependent vs. independent outcomes and for microvascular vs. macrovascular vs. mortality endpoints.ResultsAll stress tests were passed. ECHO-T2DM replicated the National Institutes of Health cost-effectiveness application with numerically similar results. In external validation of ECHO-T2DM, model predictions agreed well with observed clinical outcomes. For all sets of macrovascular risk equations, the results were close to the intercept and slope coefficients corresponding to a perfect match, resulting in high R2 and failure to reject concordance using an F test. The results were similar for sub-groups of dependent and independent validation, with some degree of under-prediction of macrovascular events.ConclusionECHO-T2DM continues to match health outcomes in clinical trials in T2DM, with prediction accuracy similar to other leading models of T2DM.

Multivariate Prediction Equations for HbA1c Lowering, Weight Change, and Hypoglycemic Events Associated with Insulin Rescue Medication in Type 2 Diabetes Mellitus: Informing Economic Modeling

Objectives: The Eighth Mount Hood Challenge (held in St. Gallen, Switzerland, in September 2016) evaluated the transparency of model input documentation from two published health economics studies and developed guidelines for improving transparency in the reporting of input data underlying model-based economic analyses in diabetes. Methods: Participating modeling groups were asked to reproduce the results of two published studies using the input data described in those articles. Gaps in input data were filled with assumptions reported by the modeling groups. Goodness of fit between the results reported in the target studies and the groups’ replicated outputs was evaluated using the slope of linear regression line and the coefficient of determination (R2). After a general discussion of the results, a diabetes-specific checklist for the transparency of model input was developed. Results: Seven groups participated in the transparency challenge. The reporting of key model input parameters in the two studies, including the baseline characteristics of simulated patients, treatment effect and treatment intensification threshold assumptions, treatment effect evolution, prediction of complications and costs data, was inadequately transparent (and often missing altogether).Not surprisingly, goodness of fit was better for the study that reported its input data with more transparency. To improve the transparency in diabetes modeling, the Diabetes Modeling Input Checklist listing the minimal input data required for reproducibility in most diabetes modeling applications was developed. Conclusions: Transparency of diabetes model inputs is important to the reproducibility and credibility of simulation results. In the Eighth Mount Hood Challenge, the Diabetes Modeling Input Checklist was developed with the goal of improving the transparency of input data reporting and reproducibility of diabetes simulation model results.

The Cost-Effectiveness Of Canagliflozin Verse Liraglutide In Patients With Type 2 Diabetes (T2dm) Failing To Achieve Glycaemic Control On Metformin Monotherapy In Ireland

BACKGROUND Type 2 diabetes mellitus (T2DM) is chronic and progressive and the cost-effectiveness of new treatment interventions must be established over long time horizons. Given the limited durability of drugs, assumptions regarding downstream rescue medication can drive results. Especially for insulin, for which treatment effects and adverse events are known to depend on patient characteristics, this can be problematic for health economic evaluation involving modeling. OBJECTIVES To estimate parsimonious multivariate equations of treatment effects and hypoglycemic event risks for use in parameterizing insulin rescue therapy in model-based cost-effectiveness analysis. METHODS Clinical evidence for insulin use in T2DM was identified in PubMed and from published reviews and meta-analyses. Study and patient characteristics and treatment effects and adverse event rates were extracted and the data used to estimate parsimonious treatment effect and hypoglycemic event risk equations using multivariate regression analysis. RESULTS Data from 91 studies featuring 171 usable study arms were identified, mostly for premix and basal insulin types. Multivariate prediction equations for glycated hemoglobin A1c lowering and weight change were estimated separately for insulin-naive and insulin-experienced patients. Goodness of fit (R2) for both outcomes were generally good, ranging from 0.44 to 0.84. Multivariate prediction equations for symptomatic, nocturnal, and severe hypoglycemic events were also estimated, though considerable heterogeneity in definitions limits their usefulness. CONCLUSIONS Parsimonious and robust multivariate prediction equations were estimated for glycated hemoglobin A1c and weight change, separately for insulin-naive and insulin-experienced patients. Using these in economic simulation modeling in T2DM can improve realism and flexibility in modeling insulin rescue medication.

PDB25 THE ECONOMIC IMPACT OF WEIGHT LOSS FOR PATIENTS WITH NEWLY DIAGNOSED TYPE 2 DIABETES MELLITUS (T2DM) IN THE US

were sourced from the literature. Both costs and outcomes were discounted at 5%. Results: Incremental costs, QALYs and ICERs for canagliflozin vs. sitagliptin were € 1,360, 0.059 QALYs and € 23,118 per QALY, respectively, in dual therapy; € 108, 0.093 QALYs and € 1,172 per QALY, respectively, in triple therapy; and € 550, 0.068 QALYs and € 8,047 per QALY, respectively, in add-on to insulin. In all three scenarios, canagliflozin was cost-effective using the acceptable willingness-to-pay threshold in Ireland. Sensitivity analyses suggest that these results are robust. ConClusions: These simulations suggest that the use of canagliflozin in patients in need of additional glycaemic control in dual, triple and add-on to insulin lines of therapy is a more efficient use of health care funds than the use of sitagliptin in the Irish setting.