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Background An increasing number of technologies are obtaining marketing authorisation based on sparse evidence, which causes growing uncertainty and risk within health technology reimbursement decision making. To ensure that uncertainty is considered and addressed within health technology assessment (HTA) recommendations, uncertainties need to be identifed, included in health economic models, and reported. Objective Our objective was to develop the TRansparent Uncertainty ASsessmenT (TRUST) tool for systematically identifying, assessing, and reporting uncertainties in decision models, with the aim of making uncertainties and their impact on cost efectiveness more explicit and transparent. Methods TRUST was developed by drawing on the uncertainty and risk assessment literature. To develop and validate this tool, we conducted HTA stakeholder discussion meetings and interviews and applied it in six real-world HTA case studies in the Netherlands and the UK. Results The TRUST tool enables the identifcation and categorisation of uncertainty according to its source (transparency issues, methodology issues, and issues with evidence: imprecision, bias and indirectness, and unavailability) in each model aspect. The source of uncertainty determines the appropriate analysis. The impact of uncertainties on cost efectiveness is also assessed. Stakeholders found using the tool to be feasible and of value for transparent uncertainty assessment. TRUST can be used during model development and/or model review. Conclusion The TRUST tool enables systematic identifcation, assessment, and reporting of uncertainties in health economic models and may contribute to more informed and transparent decision making in the face of uncertainty.

Background: The NVALT-11/DLCRG-02 phase III study compared PCI to observation after chemo-radiotherapy (RT) for stage III NSCLC and showed a significant decrease in the cumulative incidence of symptomatic brain metastases (BM) in the PCI arm at two years (7% vs 27% [HR 0.23]). We here performed exploratory subgroup analyses. Methods: Two year cumulative incidence rates were calculated and competing risk regression, with death of any cause as competing risk, was used to examine the time to symptomatic BM in the following subgro

We very much appreciate the interest Reifsnider et al. [1] have taken in our perspective on the single technology appraisal (STA) of abiraterone acetate (tradename Zytiga) plus prednisolone (AAP) acetate for the treatment of chemotherapynaı ¨ve metastatic castration-resistant prostate cancer (mCRPC) prepared for the UK National Institute for Health and Care Excellence (NICE) [2, 3]. Here, we respond to the aspects highlighted by Reifsnider et al. [1] and correct factual inaccuracies in their reasoning. The main issues are printed in italics [1]. These points relate to (1) the statistical significance of the COU-AA-302 survival results and (2) the justification of the discrete-event simulation (DES) approach utilised by the company. Reifsnider et al. also highlight aspects that are unrelated to these main points, and we discuss these separately.

Background: The costs of performing research are an important input in value of information (VOI) analyses but are difficult to assess. Objective: The aim of this study was to investigate the costs of research, serving two purposes: (1) estimating research costs for use in VOI analyses; and (2) developing a costing tool to support reviewers of grant proposals in assessing whether the proposed budget is realistic. Methods: For granted study proposals from the Netherlands Organization for Health Research and Development (ZonMw), type of study, potential cost drivers, proposed budget, and general characteristics were extracted. Regression analysis was conducted in an attempt to generate a ‘predicted budget’ for certain combinations of cost drivers, for implementation in the costing tool. Results: Of 133 drug-related research grant proposals, 74 were included for complete data extraction. Because an association between cost drivers and budgets was not confirmed, we could not generate a predicted budget based on regression analysis, but only historic reference budgets given certain study characteristics. The costing tool was designed accordingly, i.e. with given selection criteria the tool returns the range of budgets in comparable studies. This range can be used in VOI analysis to estimate whether the expected net benefit of sampling will be positive to decide upon the net value of future research. Conclusion: The absence of association between study characteristics and budgets may indicate inconsistencies in the budgeting or granting process. Nonetheless, the tool generates useful information on historical budgets, and the option to formally relate VOI to budgets. To our knowledge, this is the first attempt at creating such a tool, which can be complemented with new studies being granted, enlarging the underlying database and keeping estimates up to date.

Background: Value of information (VOI) is a tool that can be used to inform decisions concerning additional research in healthcare. VOI estimates the value of obtaining additional information and indicates the optimal design for additional research. Although it is recognized as good practice in handling uncertainty, it is still hardly used in decision making in the Netherlands. Objective: This paper aims to examine the potential value of VOI, barriers and facilitators and the way forward with the use of VOI in the decision-making process for reimbursement of pharmaceuticals in the Netherlands. Methods: Three focus group interviews were conducted with researchers, policy makers, and representatives of pharmaceutical companies. Results: The results revealed that although all stakeholders recognize the relevance of VOI, it is hardly used and many barriers to the performance and use of VOI were identified. One of these barriers is that not all uncertainties are easily incorporated in VOI, and the results may be biased if structural uncertainties are ignored. Furthermore, not all research designs indicated by VOI may be feasible in practice. Conclusions: To fully embed VOI into current decision-making processes, a threshold incremental cost-effectiveness ratio and guidelines that clarify when and how VOI should be performed are needed. In addition, it should be clear to all stakeholders how the results of VOI are used in decision making.

__Background__ Allergy is a form of immune-mediated exaggerated sensitivity (hypersensitivity) to a substance that is either inhaled, swallowed, injected or comes into contact with the skin. Foreign substances that provoke allergies are called allergens. It has been claimed that multiplex allergen testing may help in diagnosing the cause of symptoms in patients with an unclear cause of allergy or who are allergic to more than one substance. __Objectives__ To evaluate multiplex allergen testing [devices that can measure the presence of multiple immunoglobulin E (IgE) antibodies in a patient’s blood at the same time], by assessing (1) clinical effectiveness (allergy symptoms, incidence of acute exacerbations, mortality, adverse events of testing and treatment, health-care presentations or admissions, health-related quality of life); (2) effects on treatment (diet, immunotherapy medications, other potential testing); (3) any additional diagnostic information provided by multiplex allergen testing; and (4) cost-effectiveness (cost of different assessment strategies). __Methods__ Fifteen databases were searched from 2005 to April 2015, including MEDLINE (via OvidSp), MEDLINE In-Process Citations, MEDLINE Daily Update, PubMed (National Library of Medicine), EMBASE, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA) database, Science Citation Index (SCI), Conference Proceedings Citation Index-Science (CPCI-S), BIOSIS Previews, Latin American and Caribbean Health Sciences Literature (LILACS), National Institute for Health Research (NIHR) HTA programme, and the US Food and Drug Administration (FDA); supplementary searches of conference proceedings and trials registries were performed. Review methods followed published guidance from the Cochrane Collaboration and the Centre for Reviews and Dissemination, University of York, UK. The meth

Background The primary indication for this assessment is the early rule-out of acute myocardial infarction (AMI) in people presenting with acute chest pain and suspected, but not confirmed, non-ST segment elevation myocardial infarction (NSTEMI). Cardiac troponins (cTns) I and T are used as markers of AMI. They are intended for use in conjunction with clinical history-taking and electrocardiography monitoring. Elevated troponin (Tn) levels are associated with an increased risk of adverse cardiac outcomes. However, the optimal sensitivity of standard Tn assays for AMI occurs several (10–12) hours after the onset of symptoms. Two high-sensitivity cardiac troponin (hs-cTn) assays are currently available for use in the NHS in England and Wales: ARCHITECT high-sensitivity troponin I assay (Abbott Diagnostics, Chicago, IL, USA) and the Elecsys troponin T high-sensitive assay (Roche Diagnostics GmbH, Mannheim, Germany). One additional assay, AccuTnI+3 troponin I assay (Beckman Coulter, Brea, CA, USA), was included in the scope for this assessment pending CE marking; CE marking has now been confirmed. These assays are able to detect lower levels of Tn in the blood with an

Background: Determination of the presence or absence of bacterial infection is important to guide appropriate therapy and reduce antibiotic exposure. Procalcitonin (PCT) is an inflammatory marker that has been suggested as a marker for bacterial infection. Objectives: To assess the clinical effectiveness and cost-effectiveness of adding PCT testing to the information used to guide antibiotic therapy in adults and children (1) with confirmed or highly suspected sepsis in intensive care and (2) presenting to the emergency department (ED) with suspected bacterial infection. Methods: Twelve databases were searched to June 2014. Randomised controlled trials were assessed for quality using the Cochrane Risk of Bias tool. Summary relative risks (RRs) and weighted mean differences (WMDs) were estimated using random-effects models. Heterogeneity was assessed visually using forest plots and statistically using the I2 and Q statistics and investigated through subgroup analysis. The cost-effectiveness of PCT testing in addition to current clinical practice was compared with current clinical practice using a decision tree with a 6 months’ time horizon. Results: Eighteen studies (36 reports) were included in the systematic review. PCT algorithms were associated with reduced antibiotic duration [WMD -3.19 days, 95% confidence interval (CI) -5.44 to -0.95 days, I2 = 95.2%; four studies], hospital stay (WMD -3.85 days, 95% CI -6.78 to -0.92 days, I2 = 75.2%; four studies) and a trend towards reduced intensive care unit (ICU) stay (WMD -2.03 days, 95% CI -4.19 to 0.13 days, I2 = 81.0%; four studies). There were no differences for adverse clinical outcomes. PCT algorithms were associated with a reduction in the proportion of adults (RR 0.77, 95% CI 0.68 to 0.87; seven studies) and children (RR 0.86, 95% CI 0.80 to 0.93) receiving antibiotics, reduced antibiotic duration (two studies). There were no differences for adverse clinical outcomes. All but one of the studies in the ED were co

Background: Value of information (VOI) is a tool that can be used to inform decisions concerning additional research in healthcare. VOI estimates the value of obtaining additional information and indicates the optimal design for additional research. Although it is recognized as good practice in handling uncertainty, it is still hardly used in decision making in the Netherlands. Objective: This paper aims to examine the potential value of VOI, barriers and facilitators and the way forward with the use of VOI in the decision-making process for reimbursement of pharmaceuticals in the Netherlands. Methods: Three focus group interviews were conducted with researchers, policy makers, and representatives of pharmaceutical companies. Results: The results revealed that although all stakeholders recognize the relevance of VOI, it is hardly used and many barriers to the performance and use of VOI were identified. One of these barriers is that not all uncertainties are easily incorporated in VOI, and the results may be biased if structural uncertainties are ignored. Furthermore, not all research designs indicated by VOI may be feasible in practice. Conclusions: To fully embed VOI into current decision-making processes, a threshold incremental cost-effectiveness ratio and guidelines that clarify when and how VOI should be performed are needed. In addition, it should be clear to all stakeholders how the results of VOI are used in decision making.

__Abstract__ Background: Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Some epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutations make tumours responsive to treatment with EGFR-TK inhibitors (EGFR-TKIs) but less responsive to treatment with standard chemotherapy. Patients with NSCLC are therefore tested for EGFR-TK tumour gene mutations to inform treatment decisions. There are a variety of tests available to detect these mutations. The different tests vary in the specific mutations that they attempt to detect, the amount of tumour cells needed for the test to work, the time that it takes to give a result, the error rate of the test, and the cost of the test. Objective: To compare the performance and cost-effectiveness of EGFR-TK mutation tests used to identify previously untreated adults with locally advanced or metastatic NSCLC, who may benefit from first-line treatment with TKIs. Data sources: Twelve databases to August 2012 [including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations and Daily Update (OvidSP), EMBASE, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment database (HTA), Science Citation Index (SCI), Latin American and Caribbean Health Sciences Literature (LILACS), BIOSIS Previews, NIHR Health Technology Assessment programme, PROSPERO (International Prospective Register of Systematic Reviews)], research registers and conference proceedings. A web-based survey gathered data on technical performance of EGFR-TK mutation tests. Methods: Randomised controlled trials were assessed for methodological quality using the Cochrane risk of bias tool. Diagnostic accuracy studies were assessed using QUADAS-2. There were insufficient data for me