How health technology assessment can help to address challenges in drug repurposing: a conceptual framework.

Drug repurposing faces various challenges that can impede its success. We developed a framework outlining key challenges in drug repurposing to explore when and how health technology assessment (HTA) methods can address them. We identified 20 drug-repurposing challenges across the categories of data access, research and development, collaboration, business case, regulatory and legal challenges. Early incorporation of HTA methods, including literature review, empirical research, stakeholder consultation, health economic evaluation and uncertainty assessment, can help to address these challenges. HTA methods canassess the value proposition of repurposed drugs, inform further research and ultimately help to bring cost-effective repurposed drugs to patients.

Software with artificial intelligence-derived algorithms for analysing CT brain scans in people with a suspected acute stroke: a systematic review and cost-effectiveness analysis.

Background: Artificial intelligence-derived software technologies have been developed that are intended to facilitate the review of computed tomography brain scans in patients with suspected stroke. Objectives: To evaluate the clinical and cost-effectiveness of using artificial intelligence-derived software to support review of computed tomography brain scans in acute stroke in the National Health Service setting. Methods: Twenty-five databases were searched to July 2021. The review process included measures to minimise error and bias. Results were summarised by research question, artificial intelligence-derived software technology and study type. The health economic analysis focused on the addition of artificial intelligence-derived software-assisted review of computed tomography angiography brain scans for guiding mechanical thrombectomy treatment decisions for people with an ischaemic stroke. The de novo model (developed in R Shiny, R Foundation for Statistical Computing, Vienna, Austria) consisted of a decision tree (short-term) and a state transition model (long-term) to calculate the mean expected costs and quality-adjusted life-years for people with ischaemic stroke and suspected large-vessel occlusion comparing artificial intelligence-derived software-assisted review to usual care. Results: A total of 22 studies (30 publications) were included in the review; 18/22 studies concerned artificial intelligence-derived software for the interpretation of computed tomography angiography to detect large-vessel occlusion. No study evaluated an artificial intelligence-derived software technology used as specified in the inclusion criteria for this assessment. For artificial intelligence-derived software technology alone, sensitivity and specificity estimates for proximal anterior circulation large-vessel occlusion were 95.4% (95% confidence interval 92.7% to 97.1%) and 79.4% (95% confidence interval 75.8% to 82.6%) for Rapid (iSchemaView, Menlo Park, CA, USA) computed tomography angiography, 91.2% (95% confidence interval 77.0% to 97.0%) and 85.0 (95% confidence interval 64.0% to 94.8%) for Viz LVO (Viz.ai, Inc., San Fransisco, VA, USA) large-vessel occlusion, 83.8% (95% confidence interval 77.3% to 88.7%) and 95.7% (95% confidence interval 91.0% to 98.0%) for Brainomix (Brainomix Ltd, Oxford, UK) e-computed tomography angiography and 98.1% (95% confidence interval 94.5% to 99.3%) and 98.2% (95% confidence interval 95.5% to 99.3%) for Avicenna CINA (Avicenna AI, La Ciotat, France) large-vessel occlusion, based on one study each. These studies were not considered appropriate to inform cost-effectiveness modelling but formed the basis by which the accuracy of artificial intelligence plus human reader could be elicited by expert opinion. Probabilistic analyses based on the expert elicitation to inform the sensitivity of the diagnostic pathway indicated that the addition of artificial intelligence to detect large-vessel occlusion is potentially more effective (quality-adjusted life-year gain of 0.003), more costly (increased costs of £8.61) and cost-effective for willingness-to-pay thresholds of £3380 per quality-adjusted life-year and higher. Limitations and conclusions: The available evidence is not suitable to determine the clinical effectiveness of using artificial intelligence-derived software to support the review of computed tomography brain scans in acute stroke. The economic analyses did not provide evidence to prefer the artificial intelligence-derived software strategy over current clinical practice. However, results indicated that if the addition of artificial intelligence-derived software-assisted review for guiding mechanical thrombectomy treatment decisions increased the sensitivity of the diagnostic pathway (i.e. reduced the proportion of undetected large-vessel occlusions), this may be considered cost-effective. Future work: Large, preferably multicentre, studies are needed (for all artificial intelligence-derived software technologies) that evaluate these technologies as they would be implemented in clinical practice. Study registration: This study is registered as PROSPERO CRD42021269609. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR133836) and is published in full in Health Technology Assessment; Vol. 28, No. 11. See the NIHR Funding and Awards website for further award information.

Stroke is a serious life-threatening medical condition caused by a blood clot or haemorrhage in the brain. Quick and effective management, including a brain scan, of the patients with suspected stroke can make a big difference in their outcome. Artificial intelligence-derived computer programmes exist that are intended to help with the interpretation of computed tomography scans of the brain in stroke. We undertook a thorough review of the existing research into the effectiveness and value for money of using these programmes to help doctors and other specialists to interpret computed tomography brain scans. We found very little evidence to tell us how well artificial intelligence-derived computer programmes work in practice. Some studies have looked at artificial intelligence-derived computer programmes on their own (i.e. not taken together with a doctor's judgement, as they were designed to be used). Other studies have looked at what happens to patients who are treated for stroke when artificial intelligence-derived computer programmes are used; these studies provide no information about whether using artificial intelligence-derived computer programmes may have led to patients who could have benefitted from treatment being missed. It is unclear how well artificial intelligence-derived software-assisted review works when added to current clinical practice.

Consolidated Health Economic Evaluation Reporting Standards - Value of Information (CHEERS-VOI): Explanation and Elaboration.

OBJECTIVES: Although the ISPOR Value of Information (VOI) Task Force's reports outline VOI concepts and provide good-practice recommendations, there is no guidance for reporting VOI analyses. VOI analyses are usually performed alongside economic evaluations for which the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 Statement provides reporting guidelines. Thus, we developed the CHEERS-VOI checklist to provide reporting guidance and checklist to support the transparent, reproducible, and high-quality reporting of VOI analyses. METHODS: A comprehensive literature review generated a list of 26 candidate reporting items. These candidate items underwent a Delphi procedure with Delphi participants through 3 survey rounds. Participants rated each item on a 9-point Likert scale to indicate its relevance when reporting the minimal, essential information about VOI methods and provided comments. The Delphi results were reviewed at 2-day consensus meetings and the checklist was finalized using anonymous voting. RESULTS: We had 30, 25, and 24 Delphi respondents in rounds 1, 2, and 3, respectively. After incorporating revisions recommended by the Delphi participants, all 26 candidate items proceeded to the 2-day consensus meetings. The final CHEERS-VOI checklist includes all CHEERS items, but 7 items require elaboration when reporting VOI. Further, 6 new items were added to report information relevant only to VOI (eg, VOI methods applied). CONCLUSIONS: The CHEERS-VOI checklist should be used when a VOI analysis is performed alongside economic evaluations. The CHEERS-VOI checklist will help decision makers, analysts and peer reviewers in the assessment and interpretation of VOI analyses and thereby increase transparency and rigor in decision making.

Oral Azacitidine for Maintenance Treatment of Acute Myeloid Leukaemia After Induction Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Celgene) of oral azacitidine (ONUREG), as part of the Single Technology Appraisal (STA) process, to submit evidence for the clinical effectiveness and cost-effectiveness of oral azacitidine for maintenance treatment of acute myeloid leukaemia (AML) after induction therapy compared with watch-and-wait plus best supportive care (BSC) and midostaurin. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review on the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations and describes the development of the NICE guidance by the Appraisal Committee. In the QUAZAR AML-001 trial, oral azacitidine significantly improved overall survival (OS) versus placebo: median OS gain of 9.9 months (24.7 months versus 14.8 months; hazard ratio (HR) 0.69 (95% CI 0.55-0.86), p < 0.001). The median time to relapse was also better for oral azacitidine, and the incidences of TEAEs were similar for the two arms. The company excluded two of the comparators listed in the scope, low-dose cytarabine and subcutaneous azacitidine, informed only by clinical expert opinion, leaving only best supportive care (BSC) and midostaurin for the FLT3-ITD and/or FLT3-TKD (FLT3 mutation)-positive subgroup. An ITC comparing oral azacitidine to midostaurin as maintenance therapy in the appropriate subgroup demonstrated that the OS and relapse-free survival (RFS) HRs were favourable for oral azacitidine when compared with midostaurin. However, in the only available trial of midostaurin as maintenance treatment in AML that was used for this ITC, subjects were not randomised at the maintenance phase, but at induction, which posed a substantial risk of bias. The revised and final probabilistic incremental cost-effectiveness ratio (ICER) presented by the company, including a commercial arrangement, was £32,480 per quality-adjusted life year (QALY) gained for oral azacitidine versus watch-and-wait plus BSC. Oral azacitidine was dominant versus midostaurin in the FLT-3 subgroup. The ERG's concerns included the approach of modelling haematopoietic stem cell transplantation (HSCT), the generalisability of the population and the number of cycles of consolidation therapy pre-treatment in the QUAZAR AML-001 trial to UK clinical practice, and uncertainty in the relapse utility. The revised and final ERG base case resulted in a similar probabilistic ICER of £33,830 per QALY gained versus watch-and-wait plus BSC, but with remaining uncertainty. Oral azacitidine remained dominant versus midostaurin in the FLT-3 subgroup. After the second NICE appraisal committee meeting, the NICE Appraisal Committee recommended oral azacitidine (according to the commercial arrangement), within its marketing authorisation, as an option for maintenance treatment for AML in adults who are in complete remission, or complete remission with incomplete blood count recovery, after induction therapy with or without consolidation treatment, and cannot have or do not want HSCT.

Comprehensive Review of Methods to Assess Uncertainty in Health Economic Evaluations.

Uncertainty assessment is a cornerstone in model-based health economic evaluations (HEEs) that inform reimbursement decisions. No comprehensive overview of available uncertainty assessment methods currently exists. We aimed to review methods for uncertainty assessment for use in model-based HEEs, by conducting a snowballing review. We categorised all methods according to their stage of use relating to uncertainty assessment (identification, analysis, communication). Additionally, we classified identification methods according to sources of uncertainty, and subdivided analysis and communication methods according to their purpose. The review identified a total of 80 uncertainty methods: 30 identification, 28 analysis, and 22 communication methods. Uncertainty identification methods exist to address uncertainty from different sources. Most identification methods were developed with the objective to assess related concepts such as validity, model quality, and relevance. Almost all uncertainty analysis and communication methods required uncertainty to be quantified and inclusion of uncertainties in probabilistic analysis. Our review can help analysts and decision makers in selecting uncertainty assessment methods according to their aim and purpose of the assessment. We noted a need for further clarification of terminology and guidance on the use of (combinations of) methods to identify uncertainty and related concepts such as validity and quality. A key finding is that uncertainty assessment relies heavily on quantification, which may necessitate increased use of expert elicitation and/or the development of methods to assess unquantified uncertainty.

Filgotinib for Treating Moderately to Severely Active Ulcerative Colitis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence invited the manufacturer (Galapagos) of filgotinib (Jyseleca®), as part of the Single Technology Appraisal process, to submit evidence for the clinical effectiveness and cost effectiveness of filgotinib for treating moderately to severely active ulcerative colitis in adults who have had an inadequate response, loss of response or were intolerant to a previous biologic agent or conventional therapy. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group. This paper summarises the company submission, presents the Evidence Review Group's critical review on the clinical and cost-effectiveness evidence in the company submission, highlights the key methodological considerations and describes the development of the National Institute for Health and Care Excellence guidance by the Appraisal Committee. The company submission included one relevant study for the comparison of filgotinib versus placebo: the SELECTION trial. As there was no head-to-head evidence with any of the comparators, the company performed two separate network meta-analyses, one for the biologic-naïve population and one for the biologic-experienced population, and for both the induction and maintenance phases. The Evidence Review Group questioned the validity of the maintenance network meta-analysis because it assumed all active treatments to be comparators in this phase, which is not in line with clinical practice. The economic analysis used a number of assumptions that introduced substantial uncertainty, which could not be fully explored, for instance, the assumption that a risk of loss of response would be independent of health state and constant over time. Company and Evidence Review Group results indicate that at its current price, and disregarding confidential discounts for comparators and subsequent treatments, filgotinib dominates some comparators (golimumab and adalimumab in the company base case, all but intravenous and subcutaneous vedolizumab in the Evidence Review Group's base case) in the biologic-naïve population. In the biologic-experienced population, filgotinib dominates all comparators in both the company and the Evidence Review Group's base case. Results should be interpreted with caution as some important uncertainties were not included in the modelling. These uncertainties were mostly centred around the maintenance network meta-analysis, loss of response, health-related quality-of-life estimates and modelling of dose escalation. The National Institute for Health and Care Excellence recommended filgotinib within its marketing authorisation, as an option for treating moderately to severely active ulcerative colitis in adults when conventional or biological treatment cannot be tolerated, or if the disease has not responded well enough or has stopped responding to these treatments, and if the company provides filgotinib according to the commercial arrangement.

The value of maintaining cognition in patients with mild cognitive impairment: The innovation headroom and potential cost-effectiveness of roflumilast.

INTRODUCTION: Early health-technology assessment can support discussing scarce resource allocation among stakeholders. We explored the value of maintaining cognition in patients with mild cognitive impairment (MCI) by estimating: (1) the innovation headroom and (2) the potential cost effectiveness of roflumilast treatment in this population. METHODS: The innovation headroom was operationalized by a fictive 100% efficacious treatment effect, and the roflumilast effect on memory word learning test was assumed to be associated with 7% relative risk reduction of dementia onset. Both were compared to Dutch setting usual care using the adapted International Pharmaco-Economic Collaboration on Alzheimer's Disease (IPECAD) open-source model. RESULTS: The total innovation headroom expressed as net health benefit was 4.2 (95% bootstrap interval: 2.9-5.7) quality-adjusted life years (QALYs). The potential cost effectiveness of roflumilast was k€34 per QALY. DISCUSSION: The innovation headroom in MCI is substantial. Although the potential cost effectiveness of roflumilast treatment is uncertain, further research on its effect on dementia onset is likely valuable.

Belimumab for Treating Active Autoantibody-Positive Systemic Lupus Erythematosus: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (GlaxoSmithKline [GSK]) of Benlysta (belimumab) to submit evidence regarding its clinical and cost effectiveness, for the review and possible extension of a previously conditionally approved intravenous formulation of belimumab for the treatment of active autoantibody-positive systemic lupus erythematosus (SLE). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review of the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the NICE Appraisal Committee.This appraisal is different to the previous appraisal in three ways: (1). This appraisal expands its definition of 'high disease activity'. (2). In TA397, belimumab was approved, with a managed access arrangement (MAA), for adults only. This appraisal includes subjects aged 5 years or older. (3). The original appraisal included an intravenous formulation only, but the current appraisal also includes a new subcutaneous formulation in the form of a prefilled pen.The company was required to collect real-world data from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR), including data on the efficacy, safety, and effect on health-related quality of life of belimumab versus rituximab. This appraisal considers these data as well as additional clinical trial evidence presented in the company's updated submission to address uncertainties identified during the original appraisal. The ERG identified three major concerns with the evidence presented on the clinical effectiveness in the current submission; namely, short follow-up in the main comparative trials (BLISS-SC, BLISS-52 and BLISS-76); using the propensity score-matching (PSM) analysis in calibrating the cost-effectiveness model can severely bias the results in favour of belimumab; and BILAG-BR data are not suitable for a comparison of belimumab with rituximab.The main issue in the economic analysis was the uncertainty about long-term disease activity progression and resulting organ damage. The company's approach of calibrating modelled organ damage to longer-term data analysed using the PSM analysis was methodologically inappropriate. The final analysis comparing belimumab with standard treatment for the intravenous formulation resulted in an incremental cost-effectiveness ratio of £12,335 per quality-adjusted life-year (QALY) gained and £30,278 per QALY gained in the company's and ERG's base-case analyses, respectively. For the subcutaneous formulation, the final analysis resulted in £8480 per QALY gained and £29,313 per QALY gained in the company's and ERG's base-case analyses, respectively. NICE recommended belimumab in both intravenous and subcutaneous formulations as an add-on treatment option for active autoantibody-positive SLE in the HDA-2 subgroup.

Mogamulizumab for Previously Treated Mycosis Fungoides and Sézary Syndrome: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Kyowa Kirin) of mogamulizumab (Poteligeo®), as part of the single technology appraisal process, to submit evidence for its clinical and cost-effectiveness for previously treated mycosis fungoides (MF) and Sézary syndrome (SS). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre, was commissioned to act as the independent evidence review group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review of the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations and describes the development of the NICE guidance by the Appraisal Committee. Based on a systematic literature review, one randomised controlled trial, MAVORIC, was identified showing favourable results in patients with MF and SS. However, MAVORIC compared mogamulizumab to vorinostat, which is not standard care in the NHS, and there is uncertainty due to the study design, specifically crossover of patients. Based on a "naïve comparison of results from the vorinostat arm of the MAVORIC study and the physician's choice arm (methotrexate or bexarotene i.e. United Kingdom [UK] standard treatments) of the ALCANZA study as well as comparison to Phase II bexarotene data", the company considered vorinostat to be "a reasonable proxy for current standard of care in the NHS". The ERG considered, based on the limited data available, that the comparability of vorinostat (MAVORIC) and physician's choice (ALCANZA) could not be established. In response to the Appraisal Consultation Document, the company provided an unanchored matched adjusted indirect comparison (MAIC) of mogamulizumab with UK standard care by analysing Hospital Episode Statistics (HES) data. However, given the high risk of bias of an unanchored MAIC, these results needed to be regarded with a considerable degree of caution. The economic analysis suffered from uncertainty because there was no trial evidence on the comparator in the England and Wales National Health Service (NHS), and it was unclear to what extent the trial (MAVORIC) comparator (vorinostat) was comparable to standard care, referred to as established clinical management (ECM) in the NHS. The evidence for overall survival had not reached maturity and was confounded by treatment switching, for which different crossover adjustment methods produced large variations in life years. Caregiver utilities were applied in the analysis, but there was a lack of guidance on their application and whether these were indicated in this appraisal. After consultation, the company updated the economic analysis with the MAIC. Incremental cost-effectiveness ratios comparing mogamulizumab against ECM were (depending on whether the HES or MAVORIC comparison were used) £31,030 or £32,634 per quality-adjusted life years (QALYs) gained according to the company's base case and £38,274 or £80,555 per QALY gained according to the ERG's base case. NICE did not recommend mogamulizumab for treating MF or SS in adults who have had at least one previous systemic treatment. This decision was subsequently appealed, and an appeal decision has been reached.

Implementation Barriers to Value of Information Analysis in Health Technology Decision Making: Results From a Process Evaluation.

OBJECTIVES: Value of information (VOI) analysis can support health technology assessment decision making, but it is a long way from being standard use. The objective of this study was to understand barriers to the implementation of VOI analysis and propose actions to overcome these. METHODS: We performed a process evaluation of VOI analysis use within decision making on tomosynthesis versus digital mammography for use in the Dutch breast cancer population screening. Based on steering committee meeting attendance and regular meetings with analysts, we developed a list of barriers to VOI use, which were analyzed using an established diffusion model. We proposed actions to address these barriers. Barriers and actions were discussed and validated in a workshop with stakeholders representing patients, clinicians, regulators, policy advisors, researchers, and the industry. RESULTS: Consensus was reached on groups of barriers, which included characteristics of VOI analysis itself, stakeholder's attitudes, analysts' and policy makers' skills and knowledge, system readiness, and implementation in the organization. Observed barriers did not only pertain to VOI analysis itself but also to formulating the objective of the assessment, economic modeling, and broader aspects of uncertainty assessment. Actions to overcome these barriers related to organizational changes, knowledge transfer, cultural change, and tools. CONCLUSIONS: This in-depth analysis of barriers to implementation of VOI analysis and resulting actions and tools may be useful to health technology assessment organizations that wish to implement VOI analysis in technology assessment and research prioritization. Further research should focus on application and evaluation of the proposed actions in real-world assessment processes.

Filgotinib for Moderate to Severe Rheumatoid Arthritis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Gilead) of filgotinib (JyselecaTM), as part of the single technology appraisal process, to submit evidence for its clinical and cost effectiveness for the treatment of patients with moderate to severe rheumatoid arthritis (RA). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review of the clinical- and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the NICE Appraisal Committee. The evidence for filgotinib was based on two good-quality international randomised controlled trials. In FINCH 1, filgotinib was compared with placebo, and in FINCH 2, filgotinib was compared with adalimumab and placebo. As there was no head-to-head evidence with most active comparators, the company performed two separate network meta-analyses (NMAs), one for the conventional disease-modifying antirheumatic drugs-inadequate response population and one for the biological disease-modifying antirheumatic drugs-inadequate response population. The outcomes analysed were American College of Rheumatology response criteria at weeks 12 and 24, and European League Against Rheumatism response criteria at 24 weeks. The statistical methods used to perform the NMAs were valid and were in line with previous NICE appraisals. Results of the NMAs are confidential and cannot be reported here, but they were uncertain due to heterogeneity of the included studies. The economic analysis of the patient population with moderate RA suffered from limited evidence on the progression from moderate to severe health states. For the moderate RA population, the final analyses comparing filgotinib, with or without methotrexate, against standard of care resulted in incremental cost-effectiveness ratios of around £20,000 per quality-adjusted life-year gained in the company's and ERG's base-case and scenario analyses. NICE recommended filgotinib in combination with methotrexate or as monotherapy when methotrexate is contraindicated, or if people cannot tolerate it, for patients with moderate RA whose disease had responded inadequately to two or more conventional disease-modifying antirheumatic drugs (DMARDs). For the severe RA population, in view of the higher or similar net health benefits that filgotinib provided versus its comparators, NICE recommended filgotinib with or without methotrexate for patients whose disease had responded inadequately to two or more conventional DMARDs, who had been treated with one or more biological DMARDs, if rituximab was not an option, or after treatment with rituximab.

State of the ART? Two New Tools for Risk Communication in Health Technology Assessments.

PURPOSE: Outcomes of health technology assessments (HTA) are uncertain, and decision-making is associated with a risk. This risk, consisting of the probability of making a wrong decision and its impact, is rarely considered in HTA. This hampers transparent and consistent risk assessment and management. The aim of this study was to develop risk communication tools in the context of health technology decision-making under uncertainty. METHODS: We performed a scoping review of tools for uncertainty and risk communication within HTA using citation pearl-growing. We developed two tools, drawing on existing publications on risk and uncertainty communication for inspiration. Individual semi-structured interviews with HTA stakeholders were performed to identify potential improvements in usefulness, user-friendliness, and information adequacy. Tools were amended and further evaluated in a real-world HTA and workshop with HTA stakeholders. RESULTS: The identified risk communication tools did not include non-quantified uncertainties, and did not link to risk management strategies. We developed two tools: the Assessment of Risk Table (ART), for a summary of quantified and non-quantified uncertainties and the resulting risk assessment, and the Appraisal of Risk Chart (ARCH), for linking net benefit and risk outcomes to appropriate risk management strategies. Stakeholders appreciated the usefulness of the tools. They also highlighted that more information on local policy options was required for optimal risk management use, and HTA processes may need adapting. CONCLUSION: The risk communication tools presented here can help assess risk, facilitate communication between analysts and decision-makers, and guide the appropriate use of available risk management strategies.

Exploring the Feasibility of Comprehensive Uncertainty Assessment in Health Economic Modeling: A Case Study.

OBJECTIVES: Decision makers adopt health technologies based on health economic models that are subject to uncertainty. In an ideal world, these models parameterize all uncertainties and reflect them in the cost-effectiveness probability and risk associated with the adoption. In practice, uncertainty assessment is often incomplete, potentially leading to suboptimal reimbursement recommendations and risk management. This study examines the feasibility of comprehensive uncertainty assessment in health economic models. METHODS: A state transition model on peripheral arterial disease treatment was used as a case study. Uncertainties were identified and added to the probabilistic sensitivity analysis if possible. Parameter distributions were obtained by expert elicitation, and structural uncertainties were either parameterized or explored in scenario analyses, which were model averaged. RESULTS: A truly comprehensive uncertainty assessment, parameterizing all uncertainty, could not be achieved. Expert elicitation informed 8 effectiveness, utility, and cost parameters. Uncertainties were parameterized or explored in scenario analyses and with model averaging. Barriers included time and resource constraints, also of clinical experts, and lacking guidance regarding some aspects of expert elicitation, evidence aggregation, and handling of structural uncertainty. The team's multidisciplinary expertise and existing literature and tools were facilitators. CONCLUSIONS: While comprehensive uncertainty assessment may not be attainable, improvements in uncertainty assessment in general are no doubt desirable. This requires the development of detailed guidance and hands-on tutorials for methods of uncertainty assessment, in particular aspects of expert elicitation, evidence aggregation, and handling of structural uncertainty. The issue of benefits of uncertainty assessment versus time and resources needed remains unclear.

High-sensitivity troponin assays for early rule-out of acute myocardial infarction in people with acute chest pain: a systematic review and economic evaluation.

BACKGROUND: Early diagnosis of acute myocardial infarction is important, but only 20% of emergency admissions for chest pain will actually have an acute myocardial infarction. High-sensitivity cardiac troponin assays may allow rapid rule out of myocardial infarction and avoid unnecessary hospital admissions. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of high-sensitivity cardiac troponin assays for the management of adults presenting with acute chest pain, in particular for the early rule-out of acute myocardial infarction. METHODS: Sixteen databases were searched up to September 2019. Review methods followed published guidelines. Studies were assessed for quality using appropriate risk-of-bias tools. The bivariate model was used to estimate summary sensitivity and specificity for meta-analyses involving four or more studies; otherwise, random-effects logistic regression was used. The health economic analysis considered the long-term costs and quality-adjusted life-years associated with different troponin testing methods. The de novo model consisted of a decision tree and a state-transition cohort model. A lifetime time horizon (of 60 years) was used. RESULTS: Thirty-seven studies (123 publications) were included in the review. The high-sensitivity cardiac troponin test strategies evaluated are defined by the combination of four factors (i.e. assay, number and timing of tests, and threshold concentration), resulting in a large number of possible combinations. Clinical opinion indicated a minimum clinically acceptable sensitivity of 97%. When considering single test strategies, only those using a threshold at or near to the limit of detection for the assay, in a sample taken at presentation, met the minimum clinically acceptable sensitivity criterion. The majority of the multiple test strategies that met this criterion comprised an initial rule-out step, based on high-sensitivity cardiac troponin levels in a sample taken on presentation and a minimum symptom duration, and a second stage for patients not meeting the initial rule-out criteria, based on presentation levels of high-sensitivity cardiac troponin and absolute change after 1, 2 or 3 hours. Two large cluster randomised controlled trials found that implementation of an early rule-out pathway for myocardial infarction reduced length of stay and rate of hospital admission without increasing cardiac events. In the base-case analysis, standard troponin testing was both the most effective and the most costly. Other testing strategies with a sensitivity of 100% (subject to uncertainty) were almost equally effective, resulting in the same life-year and quality-adjusted life-year gain at up to four decimal places. Comparisons based on the next best alternative showed that for willingness-to-pay values below £8455 per quality-adjusted life-year, the Access High Sensitivity Troponin I (Beckman Coulter, Brea, CA, USA) [(symptoms > 3 hours AND < 4 ng/l at 0 hours) OR (< 5 ng/l AND Δ < 5 ng/l at 0 to 2 hours)] would be cost-effective. For thresholds between £8455 and £20,190 per quality-adjusted life-year, the Elecsys® Troponin-T high sensitive (Roche, Basel, Switzerland) (< 12 ng/l at 0 hours AND Δ < 3 ng/l at 0 to 1 hours) would be cost-effective. For a threshold > £20,190 per quality-adjusted life-year, the Dimension Vista® High-Sensitivity Troponin I (Siemens Healthcare, Erlangen, Germany) (< 5 ng/l at 0 hours AND Δ < 2 ng/l at 0 to 1 hours) would be cost-effective. CONCLUSIONS: High-sensitivity cardiac troponin testing may be cost-effective compared with standard troponin testing. STUDY REGISTRATION: This study is registered as PROSPERO CRD42019154716. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 33. See the NIHR Journals Library website for further project information.

Heart disease is a leading cause of death in the UK, with myocardial infarction (heart attack) accounting for approximately 4% of all deaths recorded in 2018. Many people attend hospital with chest pain and suspected myocardial infarction, and chest pain has been reported as the most common cause of hospital admissions in the UK, accounting for approximately 5% of all emergency admissions in 2017­18. It is important to diagnose people who are suspected of having a myocardial infarction as early as possible to ensure quick and effective treatment. However, only around 20% of emergency admissions for chest pain will actually have an myocardial infarction and there are many other possible causes of chest pain (e.g. gastro-oesophageal disorders, muscle pain, anxiety or stable ischaemic heart disease). Current practice for ruling out myocardial infarction includes blood tests taken when the patient is first seen in the emergency department and repeated after 3­6 hours or 10­12 hours, depending on the test used. Tests that can quickly tell which patients do not have myocardial infarction could therefore avoid unnecessary hospital admissions and anxiety for many people. We aimed to assess the clinical effectiveness and cost-effectiveness of high-sensitivity troponin tests, used as single tests or repeated over a short time, for the early rule out of myocardial infarction in people who present to hospital with chest pain. We found that high-sensitivity troponin tests can safely rule out myocardial infarction within the 4-hour NHS emergency department target. Health economic analyses indicated that high-sensitivity tests may be considered value for money compared with standard troponin tests, which require repeat testing at 10­12 hours.