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Background To limit the use of antimicrobials without disincentivising the development of novel antimicrobials, there is interest in establishing innovative models that fund antimicrobials based on an evaluation of their value as opposed to the volumes used. The aim of this project was to evaluate the population-level health benefit of ceftazidime-avibactam in the NHS in England, for the treatment of severe aerobic Gram-negative bacterial infections when used within its licensed indications. The results were used to inform National Institute for Health and Care Excellence guidance in support of commercial discussions regarding contract value between the manufacturer and NHS England. Methods The health benefit of ceftazidime-avibactam was first derived for a series of high-value clinical scenarios. These represented uses that were expected to have a significant impact on patients’ mortality risks and health-related quality of life. Patient-level costs and health-related quality of life of ceftazidime-avibactam under various usage scenarios compared with alternative management strategies in the high-value clinical scenarios were quantified using decision modelling. Results were reported as incremental net health effects expressed in quality-adjusted life-years, which were scaled to 20-year population in quality-adjusted life-years using infection number forecasts based on data from Public Health England. The outcomes estimated for the high-value clinical scenarios were extrapolated to other expected uses for ceftazidime-avibactam. Results The clinical effectiveness of ceftazidime-avibactam relative to its comparators was estimated by synthesising evidence on susceptibility of the pathogens of interest to the antimicrobials in a network meta-analysis. In the base case, ceftazidime-avibactam was associated with a statistically significantly higher susceptibility relative to colistin (odds ratio 7.24, 95% credible interval 2.58 to 20.94). The remainder of the treatments were associated with lower susceptibility than colistin (odds ratio < 1). The results were sensitive to the definition of resistance and the studies included in the analysis. In the base case, patient-level benefit of ceftazidime-avibactam was between 0.08 and 0.16 quality-adjusted life-years, depending on the site of infection and the usage scenario. There was a high degree of uncertainty surrounding the benefits of ceftazidime-avibactam across all subgroups, and the results were sensitive to assumptions in the meta-analysis used to estimate susceptibility. There was substantial uncertainty in the number of infections that are suitable for treatment with ceftazidime-avibactam, so population-level results are presented for a range of scenarios for the current infection numbers, the expected increases in infections over time, and rates of emergence of resistance. The population-level benefit varied substantially across the scenarios, from 531 to 2342 quality-adjusted life-years over 20 years. Conclusion This work has provided quantitative estimates of the value of ceftazidime-avibactam within its areas of expected usage within the NHS. Limitations Given existing evidence, the estimates of the value of ceftazidime-avibactam are highly uncertain. Future work Future evaluations of antimicrobials would benefit from improvements to NHS data linkages, research to support appropriate synthesis of susceptibility studies, and application of routine data and decision modelling to assess enablement value. Study registration No registration of this study was undertaken. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Policy Research Programme (NIHR award ref: NIHR135592), conducted through the Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions, PR-PRU-1217-20401, and is published in full in Health Technology Assessment; Vol. 28, No. 73. See the NIHR Funding and Awards website for further award information. Plain language summary This project tested new methods for estimating the value to the NHS of an antimicrobial, ceftazidime-avibactam (CAZ-AVI), so its manufacturer could be paid fairly even if very little drug is used in order to reduce the risk of bacteria becoming resistant to the product. Clinicians said that the greatest benefit of CAZ-AVI is when used for complicated urinary tract infections (cUTI) and pneumonia acquired within hospitals caused by bacteria called Enterobacterales, with a resistance mechanism called OXA-48. Because there were no relevant clinical trial data, we estimated how effective CAZ-AVI and alternative treatments were by doing a systematic literature review of studies that grew bacteria from infections in the laboratory and tested the drugs on them. We linked this to data estimating the long-term health and survival of patients. Some evidence was obtained by asking clinicians detailed questions about what they thought the effects would be based on their experience and the available evidence. We included the side effects of the alternative treatments, some of which can cause kidney damage. We estimated how many infections there would be in the UK, whether they would increase over time and how resistance to treatments may change over time. Clinicians told us that they would also use CAZ-AVI to treat intra-abdominal and bloodstream infections. We estimated how many of these infections there would be, and assumed the same health benefits as for cUTI and HAP/VAP, respectively. The total value to the NHS was calculated using these estimates. We also considered whether we had missed any additional elements of value. We estimated that the value to the NHS was £11 million to £47 million over 20 years. This reflects the maximum the NHS could pay for use of CAZ-AVI if the health lost as a result of making these payments rather than funding other NHS services is not to exceed the health benefits of using this antimicrobial. However, these estimates are uncertain due to limitations with the evidence used to produce them and assumptions that had to be made. Scientific summary Background This evaluation is one of two performed as part of a pilot conducted by the National Institute for Health and Care Excellence (NICE), NHS England (NHSE) and NHS Improvement to assess the feasibility of innovative models that pay for antimicrobials (AMs) based on an evaluation of their value to the NHS as opposed to the volumes used. These projects informed commercial discussions regarding contract value for a period of up to 10 years. This report details the evaluation phase for ceftazidime with avibactam (CAZ-AVI, brand name Avycaz), a fixed-dose combination medication composed of ceftazidime, a cephalosporin antibiotic, and avibactam, a beta-lactamase inhibitor manufactured by Pfizer which received a marketing authorisation in June 2016 for treatment in adults and paediatric patients (> 3 months) for complicated intra-abdominal infections (cIAI), complicated UTI (cUTI), hospital-acquired pneumonia, including ventilator-associated pneumonia (HAP/VAP), bacteraemia (adults only) associated with the aforementioned infections and treatment of infections caused by aerobic Gram-negative organisms with limited treatment options. Aim and objectives The aim of this evaluation is to assess the value of CAZ-AVI to the NHS in England when used within its licensed indications. Specific objectives are: To identify two high-value clinical scenarios (HVCSs) for which CAZ-AVI is expected to impact on mortality risks and improve health-related quality of life To undertake an ‘evidence mapping’ exercise and relevant systematic literature reviews to characterise the available clinical effectiveness evidence for the use of CAZ-AVI in the HVCSs. To establish an appropriate decision-analytic model to quantify the costs and health benefits of the use of CAZ-AVI under various usage scenarios compared with usage scenarios involving other available AMs in the HVCSs. The decision-analytic model was required to estimate costs and health effects at both the individual level and the aggregate population level, providing population incremental net health effects (INHEs). Drawing on the systematic reviews and evidence synthesis, national-level data on healthcare-associated infections, and other sources as needed, identify evidence to populate the decision-analytic models. To use structured expert elicitation as necessary to supplement the available evidence to populate the decision-analytic models. To use available evidence and where necessary expert opinion to quantitatively extrapolate estimated population INHEs associated with CAZ-AVI in the HVCSs to other expected uses for the product within the product’s licensed indications. Expected usage and high-value clinical scenarios To control the spread of resistance to CAZ-AVI and to preserve its long-term viability as an effective treatment option against highly resistant pathogens, CAZ-AVI was expected to be used in a narrower group of patients than permitted by its license. This evaluation characterised the value of CAZ-AVI in two steps. First, decision modelling assessed quantitatively the value of CAZ-AVI in a set of ‘high-value clinical scenarios’ (HVCSs). Secondly, rescaling was used to provide a quantitative assessment of value in the overall population expected to receive CAZ-AVI in the English NHS, including scenarios outside the HVCSs. The HVCSs were scenarios where there was currently significant burden from resistant infections, and where CAZ-AVI was expected to offer significant improvements over existing treatments in terms of efficacy and/or safety. The HVCSs focus on the following patient populations: Empiric setting (ES): infections strongly suspected to be caused by oxacillinase-48 (OXA-48) Enterobacterales in patients with hospital-acquired pneumonia or ventilator-associated pneumonia (HAP/VAP). The pathogen, resistance mechanism and antibiotic susceptibility have not yet been established but treatment is initiated immediately due to the severity of the infection. Microbiology-directed setting (MDS): patients with an infection confirmed to be caused by OXA-48 Enterobacterales, where antibiotic susceptibility testing results were available, and where the site of infection was HAP/VAP or cUTI. The resourcing for this project was equivalent to that of a diagnostic assessment review or multiple technology assessment for NICE, but the levels of analysis extend beyond the typical focus of those evaluations, to include population-level health effects now and over time, as well as across several indications and settings. The analyses are inevitably constrained by the time and resources available for the project. Clinical evidence Methods A mapping review was undertaken to establish available evidence and ascertain which approach to estimating comparative effectiveness could inform an economic model. Reviews 1 and 2 considered RCTs and observational studies in patients with HAP/VAP or cUTI infections caused by OXA-48 Enterobacterales or suspected to be caused by carbapenem-resistant Enterobacterales. In Review 3 in vitro susceptibility studies of OXA-48 Enterobacterales isolates which reported the proportion of isolates from any infection site that were susceptible to the HVCS treatment and at least one relevant comparator (colistin, meropenem, tigecycline, aztreonam, fosfomycin, gentamicin, amikacin, tobramycin) were sought. Systematic searches across relevant databases (MEDLINE, EMBASE and Centre for Review and Dissemination (CRD) database) were conducted in March 2021. EEPRU also considered evidence submitted by Pfizer and Public Health England (PHE). After mapping, only Review 3 was pursued, since there was insufficient evidence from Reviews 1 and 2 (see details in Results below). Risk-of-bias assessment was performed using a bespoke tool developed for this evaluation. A random-effects NMA of susceptibility studies was conducted. Subgroup and sensitivity analyses were planned to investigate the impact of clinical sources of heterogeneity including: inclusion criteria (use of resistance to a comparator to select study sample); co-carriage of MBLs; the proportion who were carbapenem-sensitive; whether the sample was recruited consecutively; and what laboratory methods and breakpoints were used to assess susceptibility. Review 4 aimed to provide evidence on the link between susceptibility and clinical outcomes and Review 5 between susceptibility and long-term outcomes in the sites of interest. Review 6 aimed to assess the safety of CAZ-AVI. Results The mapping reviews of RCT and observational studies identified insufficient evidence to inform an assessment of clinical effectiveness since the RCTs included very small numbers of OXA-48 Enterobacterales infections and did not report these data as a subgroup analysis and the observational data were not reported separately for the sites of interest (cUTI and HAP/VAP), the studies were small and highly heterogeneous with respect to prognostic factors, and individual patient data (IPD) were not available within the timeframe of this evaluation. In the review of susceptibility studies, 28 data sources met the initial inclusion criteria. One, from PHE, which included isolates submitted voluntarily to the antimicrobial resistance and healthcare-associated infections (AMRHAI) reference laboratory, had high relevance, but several limitations. EEPRU therefore included a broader set of evidence synthesised using network meta-analysis (NMA). Sixteen studies and data sources met the inclusion criteria. In the synthesis, CAZ-AVI was associated with a statistically significantly higher susceptibility relative to colistin [odds ratio (OR) 7.24, 95% credible interval (CrI) 2.58 to 20.94]. The remainder of the treatments were associated with lower susceptibility than colistin (OR < 1). Heterogeneity was extremely high [standard deviation (SD) 1.56, 95% CrI 1.28 to 1.93] and sensitivity analyses were conducted to investigate the sources of heterogeneity. The evidence network using EUCAST methods and breakpoints to assess susceptibility was selected as the base-case analysis to inform the economic evaluation since heterogeneity was lower and there was a clinical rationale to support restricting to studies that had used EUCAST laboratory methods and breakpoints as these are more commonly used in England. A scenario analysis was planned to include the result from the full analysis set. A further scenario was planned restricted to studies with no-MBLs and that had used EUCAST laboratory methods and breakpoints, which left one study (Vazquez-Ucha et al.). A further scenario analysis was planned using the PHE data alone, due to its high relevance to the evaluation. Review 4 identified two studies that reported mortality or hospital length of stay conditional on susceptibility to empiric treatment and were selected for use in the ES model. No useful evidence relating to the MDS was identified. Review 5 did not identify any relevant literature, but an unpublished study (CARBAR) was submitted by Shionogi during the parallel appraisal of cefiderocol. Review 6 indicated that CAZ-AVI does not appear to increase the risk of acute kidney injury (AKI), C. difficile, or any other serious adverse events (SAE), compared to non-toxic comparators (i.e. comparators that were not colistin or an aminoglycoside). No study reported a comparison of CAZ-AVI exclusively with colistin or aminoglycosides. Event rates were generally very low or zero. Discussion of clinical evidence: there were some limitations to the approach selected and analyses done. Key limitations include: susceptibility could be considered, at best, a surrogate outcome; linking data were limited and not specific to the pathogen–mechanism combination, and expert elicitation had to be relied upon to evidence the link in the MDS; uncertainties relating to the determination and application of breakpoints and the NMA results were associated with high levels of heterogeneity. Economic evidence Methods No published existing economic evaluations that assessed the use of CAZ-AVI in the HVCSs or areas of expected usage were identified. The manufacturer’s cost-effectiveness model estimated that introduction of CAZ-AVI was associated with an expected INHE benefit of approximately 20,000 quality-adjusted life-years (QALYs) over a 10-year time horizon, based on a cost-effectiveness threshold of £30,000 per QALY. EEPRU considered the model to contain several strong assumptions and it assumed a much broader population of patients would receive CAZ-AVI than considered appropriate by clinical advisors to EEPRU. Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions developed a de novo decision-analytic model to predict the cost and health consequences (summarised as population-level INHEs) of introducing CAZ-AVI within the HVCSs. These estimates assumed CAZ-AVI was supplied free of charge to the NHS, and use an estimate of health opportunity cost of £20,000/QALY. This quantitative analysis comprises three components assessing INHEs of the HVCSs at the patient level, INHEs of the HVCSs at the population level, and how INHEs within the HVCSs might appropriately be rescaled to reflect expected usage across the English NHS. The patient-level component characterises the cost, mortality and morbidity consequences of introducing CAZ-AVI over a patient’s lifetime. Separate but related models were developed for the ES and MDS. In the ES, treatment with CAZ-AVI was compared to non-colistin/aminoglycoside-based treatment and colistin/aminoglycoside-based treatment (considered more toxic). In the MDS, outcomes in the overall microbiology-directed cohort using CAZ-AVI were compared to outcomes using existing AMs only. In the ES, outcomes were modelled both for patients in whom OXA-48 Enterobacterales suspicion was confirmed and for those in whom this suspicion turned out to be incorrect. The probability of having the suspected pathogen/resistance mechanism was informed by national surveillance data supplied by PHE. The key driver of effectiveness was in vitro susceptibility (see evidence syntheses above). A combination of evidence from the literature and structured expert elicitation informed the model. Higher rates of AKI for colistin and aminoglycoside-based therapy (compared to other agents, including CAZ-AVI) were informed by published systematic reviews. Lifetime costs, quality of life and mortality were predicted accounting for the highly comorbid nature of the patient population and the increased risk of chronic kidney disease resulting from AKI. The population-level component used a forecast-based approach to aggregate the patient-level predictions to the population-level accounting for the size of, and growth over time in, the eligible patient population within each HVCS. This component also reflects how resistance is likely to develop to CAZ-AVI and existing AMs over time. Predictions were presented for patients initiated on treatment over the next 20 years. National surveillance data were used to estimate current numbers of patients within the HVCS and to forecast growth in patient numbers over time. A series of scenarios reflect the potential emergence of resistance to CAZ-AVI. Changes in resistance to existing AMs over time were not modelled due to the sparsity of evidence available to inform these forecasts. Predicted overall population INHEs corresponding to the expected use of CAZ-AVI in the English NHS were generated by rescaling the population INHEs from the HVCSs to reflect additional areas of expected usage (known or suspected OXA-48 Enterobacterales bloodstream and intra-abdominal infections). Rescaling was based on surveillance data on population size and expert assessments of the similarity in per-patient INHEs between the HVCSs and these additional sites of interest. The literature on the economic evaluation of AMs has described a range of elements of value associated with these products that are not relevant to evaluations of other healthcare interventions. We summarised the extent to which these elements of value were captured within the quantitative estimates and, where this has not been possible, whether they were likely to substantively modify the quantitative estimates of value presented. Results Patient-level INHEs in the HVCS The benefits of CAZ-AVI are driven by similar susceptibility but improved safety compared to colistin/aminoglycoside-based treatments, and, in the ES, by higher susceptibility than non-colistin/aminoglycoside-based treatment. The two most significant sources of uncertainty relate to the ES and are (1) the susceptibility evidence and (2) the proportion of patients in the ES who are suspected of having OXA-48 Enterobacterales who are later confirmed to have this resistant pathogen. CAZ-AVI generated INHEs of 0.16 QALYs per patient in the ES (range across scenarios 0.00–0.26) and 0.08 (0.05–0.12) in the microbiology-directed settings. Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions were unable to select a base case for the population-level results. Population-level results are, therefore, presented for two different approaches to estimating current infection numbers (based on different methods to classify infections from clinical specimen sites), two alternative approaches to forecasting infections over time (based on whether observed trends are assumed to persist indefinitely or not) and three different trajectories with respect to CAZ-AVI resistance emergence (1%, 5% and 10% at 20 years). Across these scenarios, population INHEs varied from 531 to 2342 QALYs. The population size estimates are subject to additional uncertainties relating to the challenges of inferring patient population size from microbiology data and in forecasting population size in the future. Estimates were generated using a number of strong assumptions about the generalisability of patient-level INHEs between settings, for example, that patient-level INHEs for bloodstream infections can be generalised to HAP/VAP infections. These assumptions were based on discussions with clinical experts. Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions considers that it is possible that CAZ-AVI use will facilitate additional or at least more prompt receipt of required treatments/procedures for certain groups and therefore provide additional enablement value not captured within the model estimates of INHEs. The magnitude of these enablement benefits remains highly uncertain. Conclusion Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions’s quantitative assessment of value of CAZ-AVI was associated with a base-case population INHE across its areas of expected usage of 531–2342 QALYs over 20 years. These values were informed by interlinked decision-analytic models informed by systematic reviews of the literature and evidence synthesis, additional national data provided by PHE, structured expert elicitation and, where necessary, assumptions informed by clinical opinion. The quantitative estimates of the value for CAZ-AVI within the areas of expected usage within the NHS indicate that the maximum amount the NHS could pay for CAZ-AVI was £11 million to £47 million if the health lost as a result of making these payments rather than funding other NHS services is not to exceed the health benefits of using CAZ-AVI. The high level of uncertainty could be addressed via further research; however, the appropriateness of amending payments to reflect revised estimates of value requires further consideration. A broader and important question is ‘what would represent the “optimal” scope of usage for CAZ-AVI?’ Further methodological and quantitative work is required to address this question. Study registration No registration of this study was undertaken. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Policy Research Programme (NIHR award ref: NIHR135592), conducted through the Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions, PR-PRU-1217-20401, and is published in full in Health Technology Assessment; Vol. 12, No. 73. See the NIHR Funding and Awards website for further award information.

Background To limit the use of antimicrobials without disincentivising the development of novel antimicrobials, there is interest in establishing innovative models that fund antimicrobials based on an evaluation of their value as opposed to the volumes used. The aim of this project was to evaluate the population-level health benefit of cefiderocol in the NHS in England, for the treatment of severe aerobic Gram-negative bacterial infections when used within its licensed indications. The results were used to inform the National Institute for Health and Care Excellence guidance in support of commercial discussions regarding contract value between the manufacturer and NHS England. Methods The health benefit of cefiderocol was first derived for a series of high-value clinical scenarios. These represented uses that were expected to have a significant impact on patients’ mortality risks and health-related quality of life. The clinical effectiveness of cefiderocol relative to its comparators was estimated by synthesising evidence on susceptibility of the pathogens of interest to the antimicrobials in a network meta-analysis. Patient-level costs and health outcomes of cefiderocol under various usage scenarios compared with alternative management strategies were quantified using decision modelling. Results were reported as incremental net health effects expressed in quality-adjusted life-years, which were scaled to 20-year population values using infection number forecasts based on data from Public Health England. The outcomes estimated for the high-value clinical scenarios were extrapolated to other expected uses for cefiderocol. Results Among Enterobacterales isolates with the metallo-beta-lactamase resistance mechanism, the base-case network meta-analysis found that cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.32, 95% credible intervals 0.04 to 2.47), but the result was not statistically significant. The other treatments were also associated with lower susceptibility than colistin, but the results were not statistically significant. In the metallo-beta-lactamase Pseudomonas aeruginosa base-case network meta-analysis, cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.44, 95% credible intervals 0.03 to 3.94), but the result was not statistically significant. The other treatments were associated with no susceptibility. In the base case, patient-level benefit of cefiderocol was between 0.02 and 0.15 quality-adjusted life-years, depending on the site of infection, the pathogen and the usage scenario. There was a high degree of uncertainty surrounding the benefits of cefiderocol across all subgroups. There was substantial uncertainty in the number of infections that are suitable for treatment with cefiderocol, so population-level results are presented for a range of scenarios for the current infection numbers, the expected increases in infections over time and rates of emergence of resistance. The population-level benefits varied substantially across the base-case scenarios, from 896 to 3559 quality-adjusted life-years over 20 years. Conclusion This work has provided quantitative estimates of the value of cefiderocol within its areas of expected usage within the NHS. Limitations Given existing evidence, the estimates of the value of cefiderocol are highly uncertain. Future work Future evaluations of antimicrobials would benefit from improvements to NHS data linkages; research to support appropriate synthesis of susceptibility studies; and application of routine data and decision modelling to assess enablement value. Study registration No registration of this study was undertaken. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Policy Research Programme (NIHR award ref: NIHR135591), conducted through the Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions, PR-PRU-1217-20401, and is published in full in Health Technology Assessment; Vol. 28, No. 28. See the NIHR Funding and Awards website for further award information. Plain language summary This project tested new methods for estimating the value to the NHS of an antimicrobial, cefiderocol, so its manufacturer could be paid fairly even if very little drug is used in order to reduce the risk of bacteria becoming resistant to the product. Clinicians said that the greatest benefit of cefiderocol is when used for complicated urinary tract infections and pneumonia acquired within hospitals caused by two types of bacteria (called Enterobacterales and Pseudomonas aeruginosa), with a resistance mechanism called metallo-beta-lactamase. Because there were no relevant clinical trial data, we estimated how effective cefiderocol and alternative treatments were by doing a systematic literature review of studies that grew bacteria from infections in the laboratory and tested the drugs on them. We linked this to data estimating the long-term health and survival of patients. Some evidence was obtained by asking clinicians detailed questions about what they thought the effects would be based on their experience and the available evidence. We included the side effects of the alternative treatments, some of which can cause kidney damage. We estimated how many infections there would be in the UK, whether they would increase over time and how resistance to treatments may change over time. Clinicians told us that they would also use cefiderocol to treat intra-abdominal and bloodstream infections, and some infections caused by another bacteria called Stenotrophomonas. We estimated how many of these infections there would be, and assumed the same health benefits as for other types of infections. The total value to the NHS was calculated using these estimates. We also considered whether we had missed any additional elements of value. We estimated that the value to the NHS was £18–71 million over 20 years. This reflects the maximum the NHS could pay for use of cefiderocol if the health lost as a result of making these payments rather than funding other NHS services is not to exceed the health benefits of using this antimicrobial. However, these estimates are uncertain due to limitations with the evidence used to produce them and assumptions that had to be made. Scientific summary This section reproduces and adapts, with permission, content previously published as part of the study protocol (Harnan SE, Woods B, Schmitt L, Kearns B, Srivastava T, Scope A, et al. Protocol for the technology evaluation of cefiderocol for treating severe aerobic Gram-negative bacterial infections. Health Technol Assess 2021.) Background The National Institute for Health and Care Excellence (NICE), NHS England and NHS Improvement are currently undertaking a project to assess the feasibility of innovative models that pay for antimicrobials (AMs) based on an evaluation of their value to the NHS as opposed to the volumes used. This project involves evaluation of two AMs to inform commercial discussions regarding contract value for a period of up to 10 years. This report details the evaluation phase of this project for cefiderocol (Fetcroja), which is manufactured by Shionogi. Cefiderocol is an injectable siderophore cephalosporin and received a marketing authorisation in April 2020 for treating infections due to aerobic Gram-negative organisms in adults with limited treatment options. Aim and objectives The aim of this evaluation is to assess the value of cefiderocol to the NHS in England when used within its licensed indications. Specific objectives are: To identify two high-value clinical scenarios (HVCSs), within its broad licensed indications, for which cefiderocol is expected to have a significant impact on patients’ outcomes in terms of reducing mortality risks and improving health-related quality of life (HRQoL). To undertake an ‘evidence mapping’ exercise and relevant systematic literature reviews to characterise the available clinical effectiveness evidence for the use of cefiderocol in the HVCSs. To establish an appropriate decision-analytic model to quantify the costs and health benefits of the use of cefiderocol under various usage scenarios compared with usage scenarios involving other available AMs in the HVCSs. The decision-analytic model was required to estimate costs and health effects at both the individual level and the aggregate population level, providing population-level incremental net health effects (INHEs). Drawing on the systematic reviews and evidence synthesis, national-level data on healthcare-associated infections and other sources as needed, to identify evidence to populate the decision-analytic models. To use structured expert elicitation as necessary to supplement the available evidence to populate the decision-analytic models. To use available evidence and, where necessary, expert opinion quantitatively to extrapolate estimated population-level INHEs associated with cefiderocol in the HVCSs to other expected uses for the product within the product’s licensed indications. Expected usage and high-value clinical scenarios The licensed indication for cefiderocol is broad. In practice, to control the spread of resistance to cefiderocol and to preserve its long-term viability as an effective treatment option against highly resistant pathogens, cefiderocol may be used in a more restricted group of patients than permitted by its license. Quantifying the health and cost implications of using cefiderocol across anticipated NHS usage, even within this restricted population, remains challenging, as the use is expected in infections which differ in causative organism (pathogen, resistance mechanism), site of the infection, healthcare setting and other patient characteristics. This evaluation characterises the value of cefiderocol across its range of expected uses via a two-step approach. First, decision modelling is used quantitatively to assess the value of cefiderocol in a set of scenarios defined by features of the pathogen, site of infection, healthcare setting and other patient characteristics, considered to represent important uses of cefiderocol; referred to as the HVCSs. Second, rescaling is used to estimate how this evidence can be used to provide quantitative assessments of value in the overall population expected to receive cefiderocol, including patients who fall outside the HVCSs but who are relevant to determining the overall value of cefiderocol to the English NHS. The HVCSs were selected to reflect areas of clinical use where there is a current significant burden from resistant infections, and cefiderocol is expected to offer significant improvements over existing treatments in terms of efficacy and/or safety. The HVCSs were selected based on feedback from the manufacturer, clinical advisors to the Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions (EEPRU) and broader stakeholders involved in the NICE scoping process. The HVCSs focus on the following patient populations: Empiric setting (ES): patients with an infection strongly suspected to be caused by metallo-beta-lactamase (MBL)-producing Enterobacterales or MBL-producing Pseudomonas aeruginosa in patients with hospital-acquired pneumonia or ventilator-associated pneumonia (HAP/VAP). In this patient group, the pathogen, resistance mechanism and antibiotic susceptibility have not yet been established, but treatment is initiated immediately due to the severity of the infection. Microbiology-directed setting (MDS): patients with an infection confirmed to be caused by MBL Enterobacterales or MBL P. aeruginosa, where antibiotic susceptibility testing results are available, and where the site of infection is HAP/VAP or complicated urinary tract infection (cUTI). The resourcing for this project was equivalent to that of a diagnostic assessment review or multiple technology assessment for NICE, but the levels of analysis extend from the typical focus of those evaluations on a single type of patient for one indication and setting. In this evaluation, we also include population-level health effects now and over time, and across several indications and settings. The objective is to use appropriate analyses of the available evidence at every level, but the detail in those analyses is inevitably constrained by the time and resources available for the project. Clinical evidence Methods There are evidential challenges when evaluating the use of new or nearly new AMs to treat infections caused by multidrug-resistant (MDR) pathogens. Randomised controlled trials (RCTs) are of generally low relevance as they tend not to recruit patients with MDR pathogens. Therefore, relative treatment effects between the intervention and comparator cannot be generalised to MDR pathogens, as this may overestimate the efficacy of the comparator. It was anticipated that RCTs were unlikely to be the primary source of evidence. Therefore, a mapping review was undertaken to establish available evidence and ascertain which approach to estimating comparative effectiveness could inform an economic model. Reviews 1 and 2 considered RCTs and observational studies of cefiderocol in patients with HAP/VAP or cUTI infections caused by MBL Enterobacterales or P. aeruginosa or suspected to be caused by carbapenem-resistant Enterobacterales or P. aeruginosa. In Review 3, in vitro susceptibility studies were considered. These studies provide evidence on the proportion of isolates that are susceptible to treatments and comparators as an indication of relative efficacy. Susceptibility studies were considered eligible if they reported susceptibility for MBL Enterobacterales or P. aeruginosa isolates, from any infection site (clinical advisors indicated that infection site was not associated with susceptibility profile), and reported susceptibility to cefiderocol and at least one comparator as defined by the HVCSs (colistin, meropenem, tigecycline, aztreonam, fosfomycin, gentamicin, amikacin, tobramycin). Susceptibility studies test isolates in vitro to ascertain the minimum concentration of any given treatment that is needed to inhibit growth of the microbe [the minimum inhibitory concentration (MIC)]. If this is below the clinical breakpoint published by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) [or by the Clinical Laboratory Standards Institute (CLSI) from the USA], the isolate is considered susceptible, and is likely to respond to treatment in vivo. In the UK, the British Society for Antimicrobial Chemotherapy (BSAC) recommends use of EUCAST guidelines. Systematic searches across relevant databases [MEDLINE, EMBASE and Centre for Review and Dissemination (CRD) database] were conducted in March 2021. EEPRU also considered evidence submitted by Shionogi and Public Health England (PHE). After mapping, only Review 3 was pursued, since there was insufficient evidence from Reviews 1 and 2. Risk of bias assessment was performed using a bespoke tool developed for this evaluation. No studies of fosfomycin were identified. An additional rapid review was conducted to identify studies reporting the susceptibility of fosfomycin and at least one other HVCS comparator. A random-effects network meta-analysis (NMA) of susceptibility studies was conducted to allow a comprehensive synthesis of evidence on all relevant treatments. A different network was constructed for each subgroup of pathogens (MBL Enterobacterales and MBL P. aeruginosa), since susceptibility profiles were expected to differ. For each of these, a network was constructed using EUCAST breakpoints and another using CLSI breakpoints. The EUCAST networks were considered the main analysis, while the CLSI networks were considered in sensitivity analyses. Sensitivity analyses were also conducted to test assumptions around the inclusion of comparators in the network, to assess the impact of missed data on the analysis, and prioritising PHE data where possible as these are from English isolates and, therefore, have the highest relevance. Two additional reviews were conducted to provide evidence on the link between susceptibility and clinical outcomes (Review 4) and between susceptibility and long-term outcomes (Review 5) in the sites of interest. A further review (Review 6) was conducted to identify any important safety implications of cefiderocol. Results The reviews of RCT and observational studies identified insufficient evidence to inform an assessment of clinical effectiveness. One RCT did report subgroup data relating to MBLs, but the subgroup was small (n = 16 in the cefiderocol arm, n = 7 in the best available therapy arm) and was, therefore, not used due to the chance of baseline imbalances introducing bias. The key limitations of the observational studies that were identified included small numbers of MBL infections (range n = 2–17 patients), high levels of heterogeneity with respect to prognostic factors, and data not being reported for the sites of interest. Review 3 identified in vitro susceptibility studies in relatively large samples of MBL Enterobacterales or P. aeruginosa isolates obtained from a range of clinical sites of infection. Three studies (SIDERO CR, SIDERO WT and Johnston et al.) reporting data for cefiderocol and at least one comparator met the inclusion criteria and were synthesised. The separate review of fosfomycin identified 10 studies. In the MBL Enterobacterales EUCAST analysis, cefiderocol was associated with a lower susceptibility relative to colistin [odds ratio (OR) 0.32, 95% credible intervals (CrI) 0.04 to 2.47], but the result was not statistically significant. Fosfomycin had a similar OR (OR 0.34, 95% CrI 0.06 to 1.96) compared to colistin as cefiderocol. The remainder of the treatments were also associated with lower susceptibility than colistin, but the results were not statistically significant. In the MBL P. aeruginosa EUCAST analysis, cefiderocol was associated with a lower susceptibility relative to colistin (OR 0.44, 95% CrI 0.03 to 3.94), but the result was not statistically significant. The remainder of the treatments were associated with no susceptibility. Heterogeneity was high in both networks. In the sensitivity analyses using CLSI breakpoints, where the breakpoint for cefiderocol is higher, cefiderocol was associated with a higher susceptibility relative to colistin. However, the results were very uncertain in some of the NMAs due to sparse data and a large number of treatment arms with either zero or 100% susceptibility. Review 4 (link between susceptibility and clinical outcomes) identified two studies that reported mortality or hospital length of stay (LoS) conditional on susceptibility to empiric treatment and were selected for use in the model for the ES. No useful evidence relating to the MDS was identified. Review 5 (link between susceptibility and long-term clinical outcomes) did not identify any relevant literature, but an unpublished study (CARBAR) was submitted by Shionogi that contained useful data. Review 6 indicated that cefiderocol does not appear to increase the risk of acute kidney injury (AKI), Clostridium difficile, or any other serious adverse events, compared to non-toxic comparators (i.e. comparators other than colistin or an aminoglycoside). No study reported a comparison of cefiderocol exclusively to colistin or aminoglycosides. Event rates were generally very low or zero. Discussion of clinical evidence: There were limitations to the approach selected and analyses done. Key limitations include: susceptibility could be considered, at best, a surrogate outcome, but no pre-specified criteria for judging the suitability of the surrogate or the linking evidence were applied; linking data were limited and not specific to the pathogen-mechanism combination, and expert elicitation had to be relied upon to evidence the link in the MDS; uncertainties relating to the determination and application of breakpoints; and the NMAs results were associated with high levels of heterogeneity. Economic evidence Methods No published existing economic evaluations assessed the use of cefiderocol in the HVCSs or areas of expected usage. The manufacturer did not submit a cost-effectiveness model. A de novo decision-analytic model was developed to predict the cost and health consequences of introducing cefiderocol within the HVCSs. These were summarised as INHEs. These are estimates of the quality-adjusted life-years (QALYs) associated with introducing cefiderocol if it was supplied free of charge to the NHS, taking in to account both its health benefits and the health benefits of freeing up NHS resources (e.g. via reduced time in hospital) calculated using an estimate of health opportunity cost of £20,000/QALY. This means that for every £20,000 saved, 1 QALY of health can be generated within the NHS. The estimates of INHE will be used in subsequent negotiations to determine an appropriate payment level for cefiderocol. This quantitative analysis comprises three components: an assessment of the INHEs of introducing cefiderocol within the HVCSs at the patient level; an assessment of INHEs within the HVCSs at the population level; and an assessment of how population-level INHEs within the HVCSs might appropriately be rescaled to reflect expected usage across the English NHS. The patient-level component is structured similarly to decision models developed as part of other NICE processes and characterises the cost, mortality and morbidity consequences of introducing cefiderocol over a patient’s lifetime. Separate but related models are developed for the ES and MDS. In the ES, empiric treatment with cefiderocol is compared to: empiric treatment with a non-colistin/aminoglycoside-based treatment (MBL P. aeruginosa only); empiric treatment with colistin/aminoglycoside-based treatment (considered more toxic). In the MDS, we compare outcomes in the overall microbiology-directed cohort who receive tailored therapy with cefiderocol available as a treatment option, to outcomes when this cohort receive tailored therapy with existing AMs only. In the ES, patients are suspected to have a MDR infection, so it is necessary to model outcomes for both patients in whom this suspicion is confirmed and for those in whom this suspicion turns out to be incorrect. The probability of having the suspected pathogen/resistance mechanism is informed by Second-Generation Surveillance System (SGSS) national surveillance data supplied by PHE for this evaluation. The key driver of effectiveness is in vitro susceptibility as estimated via the evidence syntheses discussed above. Higher susceptibility reduces mortality and LoS in hospital. These relationships are based on a combination of evidence from the literature and structured expert elicitation. Colistin or aminoglycoside-based therapy is expected to be associated with higher rates of AKI than other agents (including cefiderocol), which has significant consequences for patients’ short- and long-term mortality, morbidity and costs. Safety differences between colistin or aminoglycoside-based therapy and other agents are, therefore, modelled using evidence from published systematic reviews. Lifetime costs, quality of life and mortality were predicted accounting for the highly comorbid nature of the patient population and the increased risk of chronic kidney disease (CKD) resulting from AKI. The population-level component uses a forecast-based approach to aggregate the patient-level predictions to the population level accounting for the size of, and growth over time in, the eligible patient population in England within each HVCS. This component also reflects how resistance is likely to develop to cefiderocol and existing AMs over time. Predictions of population-level INHE are presented for patients initiated on treatment over the next 20 years. Current numbers of patients within the HVCSs were based on evidence from SGSS. Future growth in the number of patients in the HVCSs was based on statistical forecasting models fitted to time-series data from a national reference laboratory data set supplied by PHE for this evaluation. A series of scenarios reflects the potential emergence of resistance to cefiderocol. We did not model changes in resistance to existing AMs over time due to the sparsity of evidence available to inform these forecasts. Predicted overall population-level INHEs corresponding to the expected use of cefiderocol in the English NHS were generated by rescaling the population-level INHEs from the HVCSs to reflect additional areas of expected usage. These included patients with bloodstream and intra-abdominal infections (BSIs and IAIs) known or suspected to be caused by MBL Enterobacterales or MBL P. aeruginosa, and patients with infections caused by Stenotrophomonas across a range of sites (HAP/VAP, cUTI, BSIs and IAIs). This rescaling was based on population size estimates from SGSS and the use of expert opinion to inform the similarity in patient-level INHEs between the patients falling within the HVCSs and these additional sites and pathogens of interest. The literature on the economic evaluation of AMs has described a range of elements of value associated with these products that are not relevant to evaluations of other healthcare interventions. We also, therefore, summarise the extent to which these elements of value are captured within the quantitative estimates and, where this has not been possible, whether they are likely to substantively modify the quantitative estimates of value presented. Results Patient-level INHEs in the HVCS For HAP/VAP patients treated empirically, the base-case INHEs (0.15 QALYs) are similar in patients with suspected MBL Enterobacterales, and those with suspected P. aeruginosa. The results were very sensitive to the proportion of patients who have MBL Enterobacterales, use of the CLSI breakpoints, AKI risk, AKI-related mortality and long-term survival (range across scenarios: 0.00–0.23 QALYs). For patients treated in the MDS, the base-case INHEs associated with cefiderocol are much higher for MBL P. aeruginosa (0.15 QALYs for HAP/VAP and cUTI) than MBL Enterobacterales (0.02 QALYs for HAP/VAP and cUTI) as the latter patient group has a higher probability of being susceptible to a non-colistin/aminoglycoside-based treatment, and hence not requiring treatment with cefiderocol. There is a large degree of uncertainty in the patient-level INHE in the MBL P. aeruginosa population (range across scenarios 0.01–0.25). This reflects uncertainties in the susceptibility to non-colistin/aminoglycoside-based treatments. Results in the MBL P. aeruginosa populations are subject to additional uncertainty due to limitations in the evidence base for the comparators (fosfomycin plus meropenem and fosfomycin plus colistin), as fosfomycin does not have an established breakpoint for P. aeruginosa, making links to clinical outcomes more tenuous. Furthermore, the available evidence to inform the relative susceptibility of fosfomycin was based on very small studies (n = 7 in the EUCAST and n = 20 in the CLSI networks). We were unable to select a base case for the population-level results. Population-level results are, therefore, presented for two different approaches to estimating infection numbers (based on different methods to classify infections from clinical specimen sites); two alternative approaches to forecasting increases in infections over time (based on whether observed trends are assumed to persist indefinitely or not); and three different trajectories with respect to resistance emergence to cefiderocol (1%, 5% and 10% at 20 years). Across these scenarios, population-level INHEs range from 896 to 3559 QALYs. The results are particularly sensitive to the assumption about which clinical specimen sites are indicative of HAP/VAP. A substantial part of the value of cefiderocol (20 to 38% depending on scenario) is generated among patients with Stenotrophomonas who were outside of the HVCSs considered by EEPRU. Departures from the base-case assumptions in the patient-level model also had substantial effects on the mean population-level INHEs. The population size estimates used to generate the estimates of population-level INHEs are subject to additional uncertainties relating to the completeness of the national data, whether all tested patients would fall within the HVCS population for empiric treatment, the potential double counting of samples from the same infectious episode and inherent uncertainties in forecasting population size over time. In addition, estimates of population-level INHEs were generated using a number of strong assumptions about how evidence can be generalised between settings. Namely, that patient-level INHE of cefiderocol in patients with BSI can be approximated based on outcomes in HAP/VAP patients, and that the patient-level INHE of cefiderocol in patients with IAI can be proxied by that in patients with cUTI. These assumptions were based on discussions with clinical experts. Based on the available evidence, we concluded that diversity value, transmission value and spectrum value were unlikely to be significant drivers of population-level INHEs for cefiderocol. Insurance value was captured for the HVCS, though the benefits of cefiderocol use in novel future outbreaks were not captured and remain highly uncertain. EEPRU considers that it is possible that cefiderocol use will facilitate additional or at least more prompt receipt of required treatments/procedures for certain groups but that the magnitude of these enablement benefits remains highly uncertain. Conclusion The quantitative assessment of value in this report indicates that cefiderocol is associated with a base-case population-level INHE across its areas of expected usage of 896 to 3559 QALYs over 20 years. T

Abstract Objective The objective of this study was to assess the feasibility and acceptability of institutionalizing Health Technology Assessment (HTA) in Malawi. Methods This study employed a document review and qualitative research methods, to understand the status of HTA in Malawi. This was complemented by a review of the status and nature of HTA institutionalization in selected countries.Qualitative research employed a Focus Group Discussion (FGD ) with 7 participants, and Key Informant Interviews (KIIs) with12 informants selected based on their knowledge and expertise in policy processes related to HTA in Malawi.Data extracted from the literature was organized in Microsoft Excel, categorized according to thematic areas and analyzed using a literature review framework. Qualitative data from KIIs and the FGD was analyzed using a thematic content analysis approach. Results Some HTA processes exist and are executed through three structures namely: Ministry of Health Senior Management Team, Technical Working Groups, and Pharmacy and Medicines Regulatory Authority (PMRA) with varyingdegrees of effectiveness.The main limitations of current HTA mechanisms include limited evidence use, lack of a standardized framework for technology adoption, donor pressure, lack of resources for the HTA process and technology acquisition, laws and practices that undermine cost-effectiveness considerations. KII and FGD results showed overwhelming demand for strengthening HTA in Malawi, with a stronger preference for strengthening coordination and capacity of existing entities and structures. Conclusion The study has shown that HTA institutionalization is acceptable and feasible in Malawi. However, the current committee based processes are suboptimal to improve efficiency due to lack of a structured framework. A structured HTA framework has the potential to improve processes in pharmaceuticals and medical technologies decision-making.In the short to medium term, HTA capacity building should focus on generating demand and increasing capacity in cost-effectiveness assessments. Country-specific assessments should precede HTA institutionalization as well as recommendations for new technology adoptions.

Aims Guidelines for suspected cardiac chest pain have used historical risk stratification tools, advocating invasive coronary angiography (ICA) first-line in those at highest risk. We aimed to determine whether different strategies to manage suspected stable angina affected medium-term cardiovascular event rates and patient-reported quality of life (QoL) measures.Methods CE-MARC 2, a three-arm parallel group trial, randomised patients with suspected stable cardiac chest pain and a Duke Clinical pretest likelihood of coronary artery disease between 10% and 90%. Patients were randomised to either first-line cardiovascular magnetic resonance (CMR), single-photon emission computed tomography (SPECT) or the UK National Institute for Health and Care Excellence (NICE) CG95 (2010) guidelines-directed care. For the three arms, 1-year and 3-year first major adverse cardiovascular event (MACE) rates and QoL assessed by the Seattle Angina Questionnaire, Short Form 12 (V.12) Questionnaire and EuroQol-5 Dimension Questionnaire were recorded.Results 1202 patients were randomised to CMR (n=481), SPECT (n=481) and NICE (n=240). Forty-two patients (18 CMR, 18 SPECT, 6 NICE) experienced one or more MACEs. The percentage rates (95% CIs) of MACE in the CMR, SPECT and NICE groups at 3 years were 3.7% (2.4%, 5.8%), 3.7% (2.4%, 5.8%) and 2.1% (0.9%, 4.8%), respectively. QoL scores did not significantly differ across domains.Conclusion Despite a fourfold increase in referrals for ICA, the NICE CG95 (2010) guidelines risk-stratified care strategy did not significantly reduce 3-year MACE or improve QoL, as compared with functional imaging with CMR or SPECT.Trial registration number ClinicalTrials.gov Registry (NCT01664858).

Background. Antimicrobial resistance (AMR) is a global public health threat. The wider implications of AMR, such as the impact of antibiotic resistance (ABR) on surgical procedures, are yet to be quantified. The objective of this study was to produce a conceptual modeling framework to provide a basis for estimating the current and potential future consequences of ABR for surgical procedures in England. Design. A framework was developed using literature-based evidence and structured expert elicitation. This was applied to populations undergoing emergency repair of the neck of the femur and elective colorectal resection surgery. Results. The framework captures the implications of increasing ABR by allowing for higher rates of surgical site infection (SSI) as the effectiveness of antibiotic prophylaxis wanes and worsened outcomes following SSIs to reflect reduced antibiotic treatment effectiveness. The expert elicitation highlights the uncertainty in quantifying the impact of ABR, reflected in the results. A hypothetical SSI rate increase of 14% in a person undergoing emergency repair of the femur could increase costs by 39% (−2% to 108% credible interval [CI]) and decrease quality-adjusted life-years by 11% (0.4% to 62% CI) over 15 y. Conclusions. The modeling framework is a starting point for addressing the implication of ABR on the outcomes and costs of surgeries. Due to clinical uncertainty highlighted in the expert elicitation process, the numerical outputs of the case studies should not be focused on but rather the framework itself, illustration of the evidence gaps, the benefit of expert elicitation in quantifying parameters with limited data, and the potential magnitude of the impact of ABR on surgical procedures. Implications. The framework can be used to support research surrounding the health and cost burden of ABR in England. Highlights The modeling framework is a starting point for assessing the health and cost impacts of antibiotic resistance on surgeries in England. Formulating a framework and synthesizing evidence to parameterize data gaps provides targets for future research. Once data gaps are addressed, this modeling framework can be used to feed into overall estimates of the health and cost burden of antibiotic resistance and evaluate control policies.

Health technology assessment (HTA) offers a set of analytical tools to support health systems' decisions about resource allocation. Although there is increasing interest in these tools across the world, including in some middle-income countries, they remain rarely used in low-income countries (LICs). In general, the focus of HTA is narrow, mostly limited to assessments of efficacy and cost-effectiveness. However, the principles of HTA can be used to support a broader series of decisions regarding new health technologies. We examine the potential for this broad use of HTA in LICs, with a focus on Malawi. We develop a framework to classify the main decisions on health technologies within health systems. The framework covers decisions on identifying and prioritizing technologies for detailed assessment, deciding whether to adopt an intervention, assessing alternative investments for implementation and scale-up, and undertaking further research activities. We consider the relevance of the framework to policymakers in Malawi and we use two health technologies as examples to investigate the main barriers and enablers to the use of HTA methods. Although the scarcity of local data, expertise, and other resources could risk limiting the operationalisation of HTA in LICs, we argue that even in highly resource constrained health systems, such as in Malawi, the use of HTA to support a broad range of decisions is feasible and desirable.

BackgroundA pressing need exists to develop vaccines for neglected diseases, including leishmaniasis. However, the development of new vaccines is dependent on their value to two key players-vaccine developers and manufacturers who need to have confidence in the global demand in order to commit to research and production; and governments (or other international funders) who need to signal demand based on the potential public health benefits of the vaccine in their local context, as well as its affordability. A detailed global epidemiological analysis is rarely available before a vaccine enters a market due to lack of resources as well as insufficient global data necessary for such an analysis. Our study seeks to bridge this information gap by providing a generalisable approach to estimating the commercial and public health value of a vaccine in development relying primarily on publicly available Global Burden of Disease (GBD) data. This simplified approach is easily replicable and can be used to guide discussions and investments into vaccines and other health technologies where evidence constraints exist. The approach is demonstrated through the estimation of the demand curve for a future leishmaniasis vaccine.Methodology/principal findingsWe project the ability to pay over the period 2030-2040 for a vaccine preventing cutaneous and visceral leishmaniasis (CL / VL), using an illustrative set of countries which account for most of the global disease burden. First, based on previous work on vaccine demand projections in these countries and CL / VL GBD-reported incidence rates, we project the potential long-term impact of the vaccine on disability-adjusted life years (DALYs) averted as a result of reduced incidence. Then, we apply an economic framework to our estimates to determine vaccine affordability based on the abilities to pay of governments and global funders, leading to estimates of the demand and market size. Based on our estimates, the maximum ability-to-pay of a leishmaniasis vaccine (per course, including delivery costs), given the current estimates of incidence and population at risk, is higher than $5 for 25-30% of the countries considered, with the average value-based maximum price, weighted by quantity demanded, being $5.7-6 [$0.3 - $34.5], and total demand of over 560 million courses.Conclusion/significanceOur results demonstrate that both the quantity of vaccines estimated to be required by the countries considered as well as their ability-to-pay could make a vaccine for leishmaniasis commercially attractive to potential manufacturers. The methodology used can be equally applied to other technology developments targeting health in developing countries.

Abstract Background Prolonged acute hospital stays are a problem for older people and for health services. Failure to effectively manage the psychological and social aspects of illness is an important cause of prolonged hospital stay. Proactive Psychological Medicine (PPM) is a new way of providing psychiatry services to medical wards which is proactive, focussed, intensive and integrated with medical care. The primary aim of PPM is to reduce the time older people spend in hospital because of unmanaged psychological and social problems. The HOME Study will test the effectiveness and cost-effectiveness of PPM. Methods/design The study is a two-arm, parallel-group, randomised, controlled superiority trial with linked health economic analysis and an embedded process evaluation. The target population is people aged 65 years and older admitted to acute hospitals. Participants will be randomly allocated to either usual care plus PPM or usual care alone. The primary outcome is the number of days spent as an inpatient in a general hospital in the month following randomisation. Secondary outcomes include quality of life, cognitive function, independent functioning, symptoms of anxiety and depression, and experience of hospital stay. The cost-effectiveness of usual care plus PPM compared with usual care alone will be assessed using quality-adjusted life-years as an outcome as well as costs from the NHS perspective. Discussion This update to the published trial protocol gives a detailed plan of the statistical and economic analysis of The HOME Study. Trial registration ISRCTN registry, ISRCTN86120296 . Registered on 3 January 2018.

Abstract Background Prolonged acute hospital stays are a major problem for older people and for health services. Failure to effectively manage the psychological and social aspects of illness is an important cause of prolonged hospital stays. Proactive Psychological Medicine (PPM) is a new way of providing psychiatry services to medical wards. PPM is proactive, focussed, intensive and integrated with medical care. A major aim of PPM is to reduce the time older people spend in hospital because of unmanaged psychological and social problems. The HOME Study will test the effectiveness and cost-effectiveness of PPM. Methods/design A two-arm parallel-group randomised controlled superiority trial, with a linked health economic analysis and an embedded process evaluation, will be conducted at three sites. A total of 3588 participants will be recruited and randomised to usual care or usual care plus PPM. The primary outcome is the number of days spent as an inpatient in a general hospital in the month (30 days) post-randomisation. Secondary outcomes for each participant (measured at 1 and 3 months) include quality of life, independent functioning, symptoms of anxiety and depression, cognitive function, and their experience of the hospital stay. Discussion The trial has been designed to produce findings that are generalisable to all older medical inpatients (including those with cognitive impairment). It will provide information on the effectiveness and cost-effectiveness of PPM, which we hope will be of value to patients, clinicians, managers and service planners. Trial registration ISRCTN86120296 . Registered on 3 January 2018.

A recent systematic review identified few papers on the economic evaluation of systems for emergency transport of acutely ill or injured patients. In addition, we found no articles dealing with the methodological challenges posed by such studies in low-income or middle-income countries. We therefore carried out an analysis of issues that are of particular salience to this important topic. This is an intellectual study in which we develop models, identify their limitations, suggest potential extensions to the models and discuss priorities for empirical studies to populate models. First, we develop a general model to calculate changes in survival contingent on the reduced time to treatment that an emergency transport system is designed to achieve. Second, we develop a model to estimate transfer times over an area that will be served by a proposed transfer system. Third, we discuss difficulties in obtaining parameters with which to populate the models. Fourth, we discuss costs, both direct and indirect, of an emergency transfer service. Fifth, we discuss the issue that outcomes other than survival should be considered and that the effects of a service are a weighted sum over all the conditions and severities for which the service caters. Lastly, based on the above work, we identify priorities for research. To our knowledge, this is the first study to identify and frame issues in the health economics of acute transfer systems and to develop models to calculate survival rates from basic parameters, such as time delay/survival relationships, that vary by intervention type and context.

Abstract Background Fenestrated endovascular aneurysm repair (fEVAR) is a new approach for complex abdominal aortic aneurysms, limited to a few specialist centers, with limited evidence base. We developed a cost-effectiveness decision model of fEVAR compared to open surgical repair (OSR) to investigate the likely direction of costs and benefits and inform further research projects on this technology. Methods A systematic review with meta-analysis and a four-state Markov model were used to estimate the cost-effectiveness of fEVAR versus OSR. We used a recent coverage with evidence development framework to characterize the main sources of uncertainty and inform decisions about the type of further research that would be most worthwhile and feasible. Results Seven observational comparative studies were identified, of which four presented odds ratios adjusted for confounders. The odds ratios for operative mortality varied widely between studies. Assuming a central estimate of the odds ratio of 0.54 (95% CI 0.05–6.24), the decision model estimated that the incremental cost per quality adjusted life year (QALY) was £74,580/QALY with a probability of 9 and 16% of being cost-effective at standard cost-effectiveness thresholds of £20,000/QALY and £30,000/QALY, respectively. The Expected Value of Perfect Information over 10 years at a threshold of £20,000/QALY was £11.2 million. Operative mortality contributed to most of the uncertainty in the decision model. Conclusions In the case of “maturing technologies”, decision modelling indicates the likely direction of costs and benefits and guides the development of further research projects. In our analysis of fEVAR versus OSR, decision uncertainty, particularly around operative mortality, might be effectively resolved by a short-term RCT, or possibly a well-conducted comparative observational study. Decision makers may consider that a conditional coverage decision is warranted with assessments required to make this type of recommendation depending on local priorities and circumstances.

BackgroundThe iDSI reference case, originally published in 2014, aims to improve the quality and comparability of cost-effectiveness analyses (CEA). This study assesses whether the development of the guideline is associated with an improvement in methodological and reporting practices for CEAs using disability-adjusted life-years (DALYs).MethodsWe analyzed the Tufts Medical Center Global Health CEA Registry to identify cost-per-DALY averted studies published from 2011 to 2017. Among each of 11 principles in the iDSI reference case, we translated all methodological specifications and reporting standards into a series of binary questions (satisfied or not satisfied) and awarded articles one point for each item satisfied. We then calculated methodological and reporting adherence scores separately as a percentage of total possible points, measured as normalized adherence score (0% = no adherence; 100% = full adherence). Using the year 2014 as the dissemination period, we conducted a pre-post analysis. We also conducted sensitivity analyses using: 1) optional criteria in scoring, 2) alternate dissemination period (2014-2015), and 3) alternative comparator classification.ResultsArticles averaged 60% adherence to methodological specifications and 74% adherence to reporting standards. While methodological adherence scores did not significantly improve (59% pre-2014 vs. 60% post-2014, p = 0.53), reporting adherence scores increased slightly over time (72% pre-2014 vs. 75% post-2014, pConclusionsThe iDSI reference case has substantial potential to serve as a useful resource for researchers and policy-makers in global health settings, but greater effort to promote adherence and awareness is needed to achieve its potential.

Abstract Background Network meta-analysis methods, which are an extension of the standard pair-wise synthesis framework, allow for the simultaneous comparison of multiple interventions and consideration of the entire body of evidence in a single statistical model. There are well-established advantages to using individual patient data to perform network meta-analysis and methods for network meta-analysis of individual patient data have already been developed for dichotomous and time-to-event data. This paper describes appropriate methods for the network meta-analysis of individual patient data on continuous outcomes. Methods This paper introduces and describes network meta-analysis of individual patient data models for continuous outcomes using the analysis of covariance framework. Comparisons are made between this approach and change score and final score only approaches, which are frequently used and have been proposed in the methodological literature. A motivating example on the effectiveness of acupuncture for chronic pain is used to demonstrate the methods. Individual patient data on 28 randomised controlled trials were synthesised. Consistency of endpoints across the evidence base was obtained through standardisation and mapping exercises. Results Individual patient data availability avoided the use of non-baseline-adjusted models, allowing instead for analysis of covariance models to be applied and thus improving the precision of treatment effect estimates while adjusting for baseline imbalance. Conclusions The network meta-analysis of individual patient data using the analysis of covariance approach is advocated to be the most appropriate modelling approach for network meta-analysis of continuous outcomes, particularly in the presence of baseline imbalance. Further methods developments are required to address the challenge of analysing aggregate level data in the presence of baseline imbalance.

Background: Men with suspected prostate cancer usually undergo transrectal ultrasound (TRUS)-guided prostate biopsy. TRUS-guided biopsy can cause side effects and has relatively poor diagnostic accuracy. Multiparametric magnetic resonance imaging (mpMRI) used as a triage test might allow men to avoid unnecessary TRUS-guided biopsy and improve diagnostic accuracy. Objectives: To (1) assess the ability of mpMRI to identify men who can safely avoid unnecessary biopsy, (2) assess the ability of the mpMRI-based pathway to improve the rate of detection of clinically significant (CS) cancer compared with TRUS-guided biopsy and (3) estimate the cost-effectiveness of a mpMRI-based diagnostic pathway. Design: A validating paired-cohort study and an economic evaluation using a decision-analytic model. Setting: Eleven NHS hospitals in England. Participants: Men at risk of prostate cancer undergoing a first prostate biopsy. Interventions: Participants underwent three tests: (1) mpMRI (the index test), (2) TRUS-guided biopsy (the current standard) and (3) template prostate mapping (TPM) biopsy (the reference test). Main outcome measures: Diagnostic accuracy of mpMRI, TRUS-guided biopsy and TPM-biopsy measured by sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) using primary and secondary definitions of CS cancer. The percentage of negative magnetic resonance imaging (MRI) scans was used to identify men who might be able to avoid biopsy. Results: Diagnostic study – a total of 740 men were registered and 576 underwent all three tests. According to TPM-biopsy, the prevalence of any cancer was 71% [95% confidence interval (CI) 67% to 75%]. The prevalence of CS cancer according to the primary definition (a Gleason score of ≥ 4 + 3 and/or cancer core length of ≥ 6 mm) was 40% (95% CI 36% to 44%). For CS cancer, TRUS-guided biopsy showed a sensitivity of 48% (95% CI 42% to 55%), specificity of 96% (95% CI 94% to 98%), PPV of 90% (95% CI 83% to 94%) and NPV of 74% (95% CI 69% to 78%). The sensitivity of mpMRI was 93% (95% CI 88% to 96%), specificity was 41% (95% CI 36% to 46%), PPV was 51% (95% CI 46% to 56%) and NPV was 89% (95% CI 83% to 94%). A negative mpMRI scan was recorded for 158 men (27%). Of these, 17 were found to have CS cancer on TPM-biopsy. Economic evaluation – the most cost-effective strategy involved testing all men with mpMRI, followed by MRI-guided TRUS-guided biopsy in those patients with suspected CS cancer, followed by rebiopsy if CS cancer was not detected. This strategy is cost-effective at the TRUS-guided biopsy definition 2 (any Gleason pattern of ≥ 4 and/or cancer core length of ≥ 4 mm), mpMRI definition 2 (lesion volume of ≥ 0.2 ml and/or Gleason score of ≥ 3 + 4) and cut-off point 2 (likely to be benign) and detects 95% (95% CI 92% to 98%) of CS cancers. The main drivers of cost-effectiveness were the unit costs of tests, the improvement in sensitivity of MRI-guided TRUS-guided biopsy compared with blind TRUS-guided biopsy and the longer-term costs and outcomes of men with cancer. Limitations: The PROstate Magnetic resonance Imaging Study (PROMIS) was carried out in a selected group and excluded men with a prostate volume of > 100 ml, who are less likely to have cancer. The limitations in the economic modelling arise from the limited evidence on the long-term outcomes of men with prostate cancer and on the sensitivity of MRI-targeted repeat biopsy. Conclusions: Incorporating mpMRI into the diagnostic pathway as an initial test prior to prostate biopsy may (1) reduce the proportion of men having unnecessary biopsies, (2) improve the detection of CS prostate cancer and (3) increase the cost-effectiveness of the prostate cancer diagnostic and therapeutic pathway. The PROMIS data set will be used for future research; this is likely to include modelling prognostic factors for CS cancer, optimising MRI scan sequencing and biomarker or translational research analyses using the blood and urine samples collected. Better-quality evidence on long-term outcomes in prostate cancer under the various management strategies is required to better assess cost-effectiveness. The value-of-information analysis should be developed further to assess new research to commission. Trial registration: Current Controlled Trials ISRCTN16082556 and NCT01292291. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 39. See the NIHR Journals Library website for further project information. This project was also supported and partially funded by the NIHR Biomedical Research Centre at University College London (UCL) Hospitals NHS Foundation Trust and UCL and by The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research Biomedical Research Centre and was co-ordinated by the Medical Research Council’s Clinical Trials Unit at UCL (grant code MC_UU_12023/28). It was sponsored by UCL. Funding for the additional collection of blood and urine samples for translational research was provided by Prostate Cancer UK.

Objectives: The Medical Outcomes Study HIV Health Survey (MOS-HIV) is frequently used in HIV clinical trials; however, scores generated from the MOS-HIV are not suited for cost-effectiveness analyses as they do not assign utility values to health states. Our objective was to estimate and externally validate several mapping algorithms to predict Health Utilities Index Mark 3 (HUI3) and EQ-5D-3L utility values from the MOS-HIV. Methods: We developed and validated mapping algorithms using data from two HIV clinical trials. Data from the first trial (n = 367) formed the estimation data set for the HUI3 (4,610 observations) and EQ-5D-3L (4,662 observations) mapping algorithms; data from the second trial (n = 168) formed the HUI3 (1,135 observations) and EQ-5D-3L (1,152 observations) external validation data set. We compared ordinary least squares (OLS) models of increasing complexity with the more flexible two-part, beta regression, and finite mixture models. We assessed model performance using mean absolute error (MAE) and mean squared error (MSE). Results: The OLS model that used MOS-HIV dimension scores along with squared terms gave the best HUI3 predictions (mean observed 0.84; mean predicted 0.80; MAE 0.0961); the finite mixture model gave the best EQ-5D-3L predictions (mean observed 0.90; mean predicted 0.88; MAE 0.0567). All models produced higher prediction errors at the lower end of the HUI3 and EQ-5D-3L score ranges (

BACKGROUND:There is limited information on the costs and benefits of alternative adjunct non-pharmacological treatments for knee osteoarthritis and little guidance on which should be prioritised for commissioning within the NHS. This study estimates the costs and benefits of acupuncture, braces, heat treatment, insoles, interferential therapy, laser/light therapy, manual therapy, neuromuscular electrical stimulation, pulsed electrical stimulation, pulsed electromagnetic fields, static magnets and transcutaneous electrical nerve Stimulation (TENS), based on all relevant data, to facilitate a more complete assessment of value. METHODS:Data from 88 randomised controlled trials including 7,507 patients were obtained from a systematic review. The studies reported a wide range of outcomes. These were converted into EQ-5D index values using prediction models, and synthesised using network meta-analysis. Analyses were conducted including firstly all trials and secondly only trials with low risk of selection bias. Resource use was estimated from trials, expert opinion and the literature. A decision analytic model synthesised all evidence to assess interventions over a typical treatment period (constant benefit over eight weeks or linear increase in effect over weeks zero to eight and dissipation over weeks eight to 16). RESULTS:When all trials are considered, TENS is cost-effective at thresholds of £20-30,000 per QALY with an incremental cost-effectiveness ratio of £2,690 per QALY vs. usual care. When trials with a low risk of selection bias are considered, acupuncture is cost-effective with an incremental cost-effectiveness ratio of £13,502 per QALY vs. TENS. The results of the analysis were sensitive to varying the intensity, with which interventions were delivered, and the magnitude and duration of intervention effects on EQ-5D. CONCLUSIONS:Using the £20,000 per QALY NICE threshold results in TENS being cost-effective if all trials are considered. If only higher quality trials are considered, acupuncture is cost-effective at this threshold, and thresholds down to £14,000 per QALY.

Background: There has been an increase in the utilisation of acupuncture in recent years, yet the evidence base is insufficiently well established to be certain about its clinical effectiveness and cost-effectiveness. Addressing the questions related to the evidence base will reduce uncertainty and help policy- and decision-makers with regard to whether or not wider access is appropriate and provides value for money. Aim: Our aim was to establish the most reliable evidence on the clinical effectiveness and cost-effectiveness of acupuncture for chronic pain by drawing on relevant evidence, including recent high-quality trials, and to develop fresh evidence on acupuncture for depression. To extend the evidence base we synthesised the results of published trials using robust systematic review methodology and conducted a randomised controlled trial (RCT) of acupuncture for depression. Methods and results: We synthesised the evidence from high-quality trials of acupuncture for chronic pain, consisting of musculoskeletal pain related to the neck and low back, osteoarthritis of the knee, and headache and migraine, involving nearly 18,000 patients. In an individual patient data (IPD) pairwise meta-analysis, acupuncture was significantly better than both sham acupuncture (p

Background: Gestational diabetes mellitus (GDM) is associated with a higher risk of important adverse outcomes. Practice varies and the best strategy for identifying and treating GDM is unclear. Aim: To estimate the clinical effectiveness and cost-effectiveness of strategies for identifying and treating women with GDM. Methods: We analysed individual participant data (IPD) from birth cohorts and conducted systematic reviews to estimate the association of maternal glucose levels with adverse perinatal outcomes; GDM prevalence; maternal characteristics/risk factors for GDM; and the effectiveness and costs of treatments. The cost-effectiveness of various strategies was estimated using a decision tree model, along with a value of information analysis to assess where future research might be worthwhile. Detailed systematic searches of MEDLINE® and MEDLINE In-Process & Other Non-Indexed Citations®, EMBASE, Cumulative Index to Nursing and Allied Health Literature Plus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment database, NHS Economic Evaluation Database, Maternity and Infant Care database and the Cochrane Methodology Register were undertaken from inception up to October 2014. Results: We identified 58 studies examining maternal glucose levels and outcome associations. Analyses using IPD alone and the systematic review demonstrated continuous linear associations of fasting and post-load glucose levels with adverse perinatal outcomes, with no clear threshold below which there is no increased risk. Using IPD, we estimated glucose thresholds to identify infants at high risk of being born large for gestational age or with high adiposity; for South Asian (SA) women these thresholds were fasting and post-load glucose levels of 5.2 mmol/l and 7.2 mmol/l, respectively and for white British (WB) women they were 5.4 and 7.5 mmol/l, respectively. Prevalence using IPD and published data varied from 1.2% to 24.2% (depending on criteria and population) and was consistently two to three times higher in SA women than in WB women. Lowering thresholds to identify GDM, particularly in women of SA origin, identifies more women at risk, but increases costs. Maternal characteristics did not accurately identify women with GDM; there was limited evidence that in some populations risk factors may be useful for identifying low-risk women. Dietary modification additional to routine care reduced the risk of most adverse perinatal outcomes. Metformin (Glucophage,® Teva UK Ltd, Eastbourne, UK) and insulin were more effective than glibenclamide (Aurobindo Pharma – Milpharm Ltd, South Ruislip, Middlesex, UK). For all strategies to identify and treat GDM, the costs exceeded the health benefits. A policy of no screening/testing or treatment offered the maximum expected net monetary benefit (NMB) of £1184 at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year (QALY). The NMB for the three best-performing strategies in each category (screen only, then treat; screen, test, then treat; and test all, then treat) ranged between –£1197 and –£1210. Further research to reduce uncertainty around potential longer-term benefits for the mothers and offspring, find ways of improving the accuracy of identifying women with GDM, and reduce costs of identification and treatment would be worthwhile. Limitations: We did not have access to IPD from populations in the UK outside of England. Few observational studies reported longer-term associations, and treatment trials have generally reported only perinatal outcomes. Conclusions: Using the national standard cost-effectiveness threshold of £20,000 per QALY it is not cost-effective to routinely identify pregnant women for treatment of hyperglycaemia. Further research to provide evidence on longer-term outcomes, and more cost-effective ways to detect and treat GDM, would be valuable. Study registration: This study is registered as PROSPERO CRD42013004608. Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Standard-of-care antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection uses a combination of drugs, until now considered essential to minimise treatment failure and development of drug resistance. Protease inhibitors (PIs) are potent with a high genetic barrier to resistance and have the potential for use as monotherapy after viral load (VL) suppression achieved on combination therapy. However, longer-term resistance and toxicity risks are uncertain. Objective: To compare the effectiveness, toxicity profile and cost-effectiveness of PI monotherapy with those of standard-of-care triple therapy in a pragmatic long-term clinical trial. Design: Open-label, parallel-group, randomised controlled trial. Setting: Forty-three HIV clinical centres in the UK NHS. Participants: HIV-positive adults taking standard combination ART with a suppressed VL for ≥ 6 months. Interventions: Patients were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected ritonavir-boosted PI monotherapy (PI-mono), with prompt return to combination therapy in the event of VL rebound. Main outcome measures: The primary outcome was reduction of future drug options, defined as new intermediate-/high-level resistance to one or more drugs to which the patient’s virus was considered to be sensitive at trial entry (non-inferiority comparison, 10% margin). Secondary outcomes included confirmed virological rebound, serious drug- or disease-related complications, total grade 3 or 4 adverse events (AEs), neurocognitive function change, cluster of differentiation 4 (CD4) cell count change, change in health-related quality of life, cardiovascular risk change, health-care costs and health economic analysis. Results: In total, 587 participants were randomised (77% male, 68% white) to OT (n = 291) or PI-mono (n = 296) and followed for a median of 44 months, of whom 2.7% withdrew/were lost to follow-up. One or more episodes of confirmed VL rebound were observed in eight patients (Kaplan–Meier estimate 3.2%) in the OT group and 95 patients (35.0%) in the PI-mono group [absolute risk difference 31.8%, 95% confidence interval (CI) 24.6% to 39.0%; p

Background: Cost-effectiveness analysis involves the comparison of the incremental cost-effectiveness ratio of a new technology, which is more costly than existing alternatives, with the cost-effectiveness threshold. This indicates whether or not the health expected to be gained from its use exceeds the health expected to be lost elsewhere as other health-care activities are displaced. The threshold therefore represents the additional cost that has to be imposed on the system to forgo 1 quality-adjusted life-year (QALY) of health through displacement. There are no empirical estimates of the cost-effectiveness threshold used by the National Institute for Health and Care Excellence. Objectives: (1) To provide a conceptual framework to define the cost-effectiveness threshold and to provide the basis for its empirical estimation. (2) Using programme budgeting data for the English NHS, to estimate the relationship between changes in overall NHS expenditure and changes in mortality. (3) To extend this mortality measure of the health effects of a change in expenditure to life-years and to QALYs by estimating the quality-of-life (QoL) associated with effects on years of life and the additional direct impact on QoL itself. (4) To present the best estimate of the cost-effectiveness threshold for policy purposes. Methods: Earlier econometric analysis estimated the relationship between differences in primary care trust (PCT) spending, across programme budget categories (PBCs), and associated disease-specific mortality. This research is extended in several ways including estimating the impact of marginal increases or decreases in overall NHS expenditure on spending in each of the 23 PBCs. Further stages of work link the econometrics to broader health effects in terms of QALYs. Results: The most relevant ‘central’ threshold is estimated to be £12,936 per QALY (2008 expenditure, 2008–10 mortality). Uncertainty analysis indicates that the probability that the threshold is

New evidence on the clinical effectiveness of acupuncture plus usual care (acupuncture) and counselling plus usual care (counselling) for patients with depression suggests the need to investigate the health-related quality of life and costs of these treatments to understand whether they should be considered a good use of limited health resources.The cost-effectiveness analyses are based on the Acupuncture, Counselling or Usual care for Depression (ACUDep) trial results. Statistical analyses demonstrate a difference in mean quality adjusted life years (QALYs) and suggest differences in mean costs which are mainly due to the price of the interventions. Probabilistic sensitivity analysis is used to express decision uncertainty. Acupuncture and counselling are found to have higher mean QALYs and costs than usual care. In the base case analysis acupuncture has an incremental cost-effectiveness ratio (ICER) of £4,560 per additional QALY and is cost-effective with a probability of 0.62 at a cost-effectiveness threshold of £20,000 per QALY. Counselling compared with acupuncture is more effective and more costly with an ICER of £71,757 and a probability of being cost-effective of 0.36. A scenario analysis of counselling versus usual care, excluding acupuncture as a comparator, results in an ICER of £7,935 and a probability of 0.91.Acupuncture is cost-effective compared with counselling or usual care alone, although the ranking of counselling and acupuncture depends on the relative cost of delivering these interventions. For patients in whom acupuncture is unavailable or perhaps inappropriate, counselling has an ICER less than most cost-effectiveness thresholds. However, further research is needed to determine the most cost-effective treatment pathways for depressed patients when the full range of available interventions is considered.

Depression is a significant cause of morbidity. Many patients have communicated an interest in non-pharmacological therapies to their general practitioners. Systematic reviews of acupuncture and counselling for depression in primary care have identified limited evidence. The aim of this study was to evaluate acupuncture versus usual care and counselling versus usual care for patients who continue to experience depression in primary care.In a randomised controlled trial, 755 patients with depression (Beck Depression Inventory BDI-II score ≥ 20) were recruited from 27 primary care practices in the North of England. Patients were randomised to one of three arms using a ratio of 2.2.1 to acupuncture (302), counselling (302), and usual care alone (151). The primary outcome was the difference in mean Patient Health Questionnaire (PHQ-9) scores at 3 months with secondary analyses over 12 months follow-up. Analysis was by intention-to-treat. PHQ-9 data were available for 614 patients at 3 months and 572 patients at 12 months. Patients attended a mean of ten sessions for acupuncture and nine sessions for counselling. Compared to usual care, there was a statistically significant reduction in mean PHQ-9 depression scores at 3 months for acupuncture (-2.46, 95% CI -3.72 to -1.21) and counselling (-1.73, 95% CI -3.00 to -0.45), and over 12 months for acupuncture (-1.55, 95% CI -2.41 to -0.70) and counselling (-1.50, 95% CI -2.43 to -0.58). Differences between acupuncture and counselling were not significant. In terms of limitations, the trial was not designed to separate out specific from non-specific effects. No serious treatment-related adverse events were reported.In this randomised controlled trial of acupuncture and counselling for patients presenting with depression, after having consulted their general practitioner in primary care, both interventions were associated with significantly reduced depression at 3 months when compared to usual care alone.Controlled-Trials.com ISRCTN63787732 Please see later in the article for the Editors' Summary.

Background: Coronavirus disease 2019 (COVID-19) is resurgent in the UK and health and economic costs of the epidemic continue to rise. There is a need to understand the health and economic costs of different courses of action. Methods: We combine modelling, economic analysis and a user-friendly interface to contrast the impact and costs of different testing strategies: two levels of testing within the current test-trace-isolate (TTI) strategy (testing symptomatic people, tracing and isolating everyone) and a strategy where TTI is combined with universal testing (UT; i.e. additional population testing to identify asymptomatic cases). We also model effective coverage of face masks. Results: Increased testing is necessary to suppress the virus after lockdown. Partial reopening accompanied by scaled-up TTI (at 50% test and trace levels), full isolation and moderately effective coverage of masks (30% reduction in overall transmission) can reduce the current resurgence of the virus and protect the economy in the UK. Additional UT from December 2020 reduces the epidemic dramatically by Jan 2021 when combined with enhanced TTI (70% test-trace levels) and full isolation. UT could then be stopped; continued TTI would prevent rapid recurrence. This TTI+UT combination can suppress the virus further to save ~20,000 more lives and avoid ~£90bn economic losses, though costs ~£8bn more to deliver. We assume that all traced and lab-confirmed cases are isolated. The flexible interface we have developed allows exploration of additional scenarios, including different levels of reopening of society after the second lockdown in England as well as different levels of effective mask coverage. Conclusions: Our findings suggest that increased TTI is necessary to suppress the virus and protect the economy after the second lockdown in England. Additional UT from December 2020 reduces the epidemic dramatically by Jan 2021 and could then be stopped, as continued TTI would prevent rapid recurrence.