Abstract Evidence-based health-care decision making requires comparisons of all relevant competing interventions. In the absence of randomized, controlled trials involving a direct comparison of all ...treatments of interest, indirect treatment comparisons and network meta-analysis provide useful evidence for judiciously selecting the best choice(s) of treatment. Mixed treatment comparisons, a special case of network meta-analysis, combine direct and indirect evidence for particular pairwise comparisons, thereby synthesizing a greater share of the available evidence than a traditional meta-analysis. This report from the ISPOR Indirect Treatment Comparisons Good Research Practices Task Force provides guidance on the interpretation of indirect treatment comparisons and network meta-analysis to assist policymakers and health-care professionals in using its findings for decision making. We start with an overview of how networks of randomized, controlled trials allow multiple treatment comparisons of competing interventions. Next, an introduction to the synthesis of the available evidence with a focus on terminology, assumptions, validity, and statistical methods is provided, followed by advice on critically reviewing and interpreting an indirect treatment comparison or network meta-analysis to inform decision making. We finish with a discussion of what to do if there are no direct or indirect treatment comparisons of randomized, controlled trials possible and a health-care decision still needs to be made.
Abstract Evidence-based health care decision making requires comparison of all relevant competing interventions. In the absence of randomized controlled trials involving a direct comparison of all ...treatments of interest, indirect treatment comparisons and network meta-analysis provide useful evidence for judiciously selecting the best treatment(s). Mixed treatment comparisons, a special case of network meta-analysis, combine direct evidence and indirect evidence for particular pairwise comparisons, thereby synthesizing a greater share of the available evidence than traditional meta-analysis. This report from the International Society for Pharmacoeconomics and Outcomes Research Indirect Treatment Comparisons Good Research Practices Task Force provides guidance on technical aspects of conducting network meta-analyses (our use of this term includes most methods that involve meta-analysis in the context of a network of evidence). We start with a discussion of strategies for developing networks of evidence. Next we briefly review assumptions of network meta-analysis. Then we focus on the statistical analysis of the data: objectives, models (fixed-effects and random-effects), frequentist versus Bayesian approaches, and model validation. A checklist highlights key components of network meta-analysis, and substantial examples illustrate indirect treatment comparisons (both frequentist and Bayesian approaches) and network meta-analysis. A further section discusses eight key areas for future research.
Abstract Objectives Within technology appraisals, it is necessary to compare the complete set of treatments that may be used in the patient group under consideration. Randomized controlled trials are ...a key source of evidence for these comparisons. The techniques of network meta-analysis allow the networks of trial evidence to be evaluated to obtain estimates of comparative efficacy between sets of treatments. These techniques may be the only source of estimates of comparative effectiveness if trials directly comparing the treatments of interest have not been conducted, and may provide useful additional evidence if both direct and indirect comparisons exist. Methods We examined both published and draft guidelines from reimbursement and health technology appraisal bodies, and considered their recommendations using appropriate methodology for the conduct of indirect comparisons and the assessments of their validity. Results Guidelines from 33 countries were reviewed. Of these, guidelines from 9 countries—Australia, Belgium, Canada, France, Germany, Scotland, Spain, South Africa, and the United Kingdom (England and Wales)—included detailed recommendations on the conduct of network meta-analysis. The recommendations were summarized. Conclusions No two recommendations from the multiple national guidelines are mutually exclusive. It is possible to perform one network meta-analysis for submission to multiple national jurisdictions.
Abstract Objectives To demonstrate how value of information (VOI) analysis can be used to establish research priorities regarding the use of pharmacogenetic tests using CYP2D6 testing to select ...adjuvant hormonal therapy in early stage breast cancer as a case study. Methods The following four treatment pathways are compared in a Markov model: tamoxifen treatment; CYP2D6 test and treat homozygous and heterozygous wild type patients (wt/wt; wt/*4) with tamoxifen and *4/*4 patients with anastrozole (HetTam); CYP2D6 test and treat homozygous wild type patients with tamoxifen and others with anastrozole (HomTam); and anastrozole treatment. Pharmacogenetic testing efficacy is estimated by synthesizing randomized controlled trial data comparing tamoxifen to anastrozole with observational data linking CYP2D6 genotype to tamoxifen outcomes. Results In order of increasing effectiveness the comparators are tamoxifen, HetTam, HomTam, anastrozole. Health outcomes for test and treatment strategies are highly uncertain. Differences in comparator costs depend on assumptions made regarding anastrozole patent expiry. The expected value of a decision taken with perfect information is £69 to £106 million (pound sterling) for the United Kingdom depending on patent expiry assumptions and the acceptable cost-effectiveness threshold. The most valuable research (VOI £53–£82 million) elucidates the relationship between CYP2D6 genotype and tamoxifen effectiveness. It is uncertain whether values of other research designs would exceed their costs. Conclusions Retrospective analysis of one of the large adjuvant aromatase inhibitor trials is warranted to better understand any association between CYP2D6 genotype and tamoxifen outcomes. VOI approaches may be helpful for prioritising evidence needs and structuring coverage with evidence development agreements for pharmacogenetics.
Abstract Background There is an increasing number of health-care systems using economic evaluations to inform decisions about the reimbursement of health technologies. There are usually two separate ...elements of this process: assembling relevant evidence and undertaking analyses (technology assessment), and decision-making. In most systems, technology assessment is undertaken by the manufacturer of the technology. In a few, “third-party” assessment is used. Methods In the United Kingdom, the National Institute for Health and Clinical Excellence used a combination of third-party and manufacturer assessments between 1999 and 2005. After this point, a Single Technology Appraisal program (using manufacturer-based assessment) was instituted for some technologies. Here the role of third-party assessment is considered in this from of decision-making. The article reviews the requirements of economic evaluation to support decision-making, and considers the extent to which each type of assessment is likely to meet these requirements. It also attempts to address whether the two forms of assessment differ in their impact on decision-making using a comparison of the decisions made by National Institute for Health and Clinical Excellence (NICE) (under its multiple-technology appraisal system) and the Scottish Medicines Consortium (SMC), which relies on manufacturer assessment. Results The comparison is limited by the small number of technologies considered by both bodies. Nevertheless, it suggests that there are potentially important differences between the two bodies, with NICE generally placing more restrictions of the use of technologies. Conclusions The article concludes that there are potential advantages to third-party assessment, but its cost and timing may preclude its use for all new technologies. A hybrid arrangement is suggested where third-party assessment is used in particular circumstances.
Abstract Objectives To evaluate the cost-effectiveness of bendamustine compared with chlorambucil as first-line treatment for patients with chronic lymphocytic leukemia who would be considered ...unsuitable for treatment with fludarabine combination chemotherapy regimens. Methods A semi-Markov approach was used to estimate time in each health state. The model was parameterized primarily by using data from a phase III randomized, open-label trial comparing bendamustine with chlorambucil. It captured the increased progression-free survival and improved response rates with bendamustine, and the cost and quality of life impacts of postprogression treatments. The analysis was conducted from the perspective of the National Health Service in England and Wales. A lifetime (35-year) time horizon was used. Deterministic sensitivity analyses, probabilistic sensitivity analyses, and subgroup analyses in older patients and patients with poor performance status were carried out. Results The estimated incremental cost-effectiveness ratio was £11,960 per quality-adjusted life-year. None of the deterministic sensitivity analyses increased the incremental cost-effectiveness ratio by more than £2000. Subgroup analyses showed that bendamustine remained cost-effective across different patient groups. Probabilistic sensitivity analysis showed that at the £20,000 threshold, bendamustine has a 90% probability of being cost-effective. Conclusions Bendamustine represents good value for first-line treatment of patients with chronic lymphocytic leukemia who are unsuitable for treatment with fludarabine combination chemotherapy. The incremental cost-effectiveness ratio is below the thresholds commonly applied in England and Wales (£20,000–£30,000 per quality-adjusted life-year).
ABSTRACT Objective To demonstrate the importance of considering all relevant indirect data in a network meta-analysis of treatments for non–small-cell lung cancer (NSCLC). Methods A recent National ...Institute for Health and Clinical Excellence appraisal focussed on the indirect comparison of docetaxel with erlotinib in second-line treatment of NSCLC based on trials including a common comparator. We compared the results of this analysis to a network meta-analysis including other trials that formed a network of evidence. We also examined the importance of allowing for the correlations between the estimated treatment effects that can arise when analysing such networks. Results The analysis of the restricted network including only trials of docetaxel and erlotinib linked via the common placebo comparator produced an estimated mean hazard ratio (HR) for erlotinib compared with docetaxel of 1.55 (95% confidence interval CI 0.72–2.97). In contrast, the network meta-analysis produced an estimated HR for erlotinib compared with docetaxel of 0.83 (95% CI 0.65–1.06). Analyzing the wider network improved the precision of estimated treatment effects, altered their rankings and also allowed further treatments to be compared. Some of the estimated treatment effects from the wider network were highly correlated. Conclusions This empirical example shows the importance of considering all potentially relevant data when comparing treatments. Care should therefore be taken to consider all relevant information, including correlations induced by the network of trial data, when comparing treatments.
Abstract Background Decisions about the use of new technologies in health care are often based on complex economic models. Decision makers frequently make informal judgments about evidence, ...uncertainty, and the assumptions that underpin these models. Objectives Transparent interactive decision interrogator (TIDI) facilitates more formal critique of decision models by decision makers such as members of appraisal committees of the National Institute for Health and Clinical Excellence in the UK. By allowing them to run advanced statistical models under different scenarios in real time, TIDI can make the decision process more efficient and transparent, while avoiding limitations on pre-prepared analysis. Methods TIDI, programmed in Visual Basic for applications within Excel, provides an interface for controlling all components of a decision model developed in the appropriate software (e.g., meta-analysis in WinBUGS and the decision model in R) by linking software packages using RExcel and R2WinBUGS. TIDI's graphical controls allow the user to modify assumptions and to run the decision model, and results are returned to an Excel spreadsheet. A tool displaying tornado plots helps to evaluate the influence of individual parameters on the model outcomes, and an interactive meta-analysis module allows the user to select any combination of available studies, explore the impact of bias adjustment, and view results using forest plots. We demonstrate TIDI using an example of a decision model in antenatal care. Conclusion Use of TIDI during the NICE appraisal of tumor necrosis factor-alpha inhibitors (in psoriatic arthritis) successfully demonstrated its ability to facilitate critiques of the decision models by decision makers.
ABSTRACT Background Infliximab recently became the only biologic approved for use in pediatric patients with severe active Crohn's disease (CD). Objectives To estimate the cost-effectiveness of ...scheduled maintenance treatment with infliximab compared with standard care in children suffering from severe active CD over 5 years from the UK National Health Service perspective. Methods A Markov model was constructed to simulate the progression of a hypothetical cohort of CD children through predefined health states on scheduled maintenance treatment with infliximab (5 mg/kg). The data to populate the model came from infliximab trials from Targan et al., ACCENT I, and REACH. The health states included in the model were remission, responding active disease, nonresponding active disease, surgery, postsurgery remission, postsurgery complications, and death. Standard care, comprising immunomodulators, and/or corticosteroids were used as a comparator. The primary outcome was quality-adjusted life-years (QALY) estimated using the EuroQol (EQ-5D) from a European CD population. To account for the weight-based dosing of infliximab, a baseline patient weight of 40 kg that increased by 5 kg/year up to 60 kg was used. The costs and outcomes were discounted at 3.5% over a period of 5 years. Probabilistic sensitivity analyses were performed by varying the infliximab efficacy estimates, costs, and utilities. Results The incremental cost-effectiveness ratio (ICER) for infliximab treatment was £14,607 compared with standard care. The sensitivity analyses revealed the treatment effect of infliximab to be the most influential parameter with ICERs ranging from £10,480 to £37,017. Assuming a willingness to pay of £30,000 per QALY, the probability of infliximab being cost-effective is 78.6%. Conclusion Scheduled maintenance treatment with infliximab (5 mg/kg) is likely to be a cost-effective treatment in children suffering from severe active CD under an 8-week maintenance program.
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