Advances in Addressing Patient Heterogeneity in Economic Evaluation: A Review of the Methods Literature.

Cost-effectiveness analyses commonly use population or sample averages, which can mask key differences across subgroups and may lead to suboptimal resource allocation. Despite there being several new methods developed over the last decade, there is no recent summary of what methods are available to researchers. This review sought to identify advances in methods for addressing patient heterogeneity in economic evaluations and to provide an overview of these methods. A literature search was conducted using the Econlit, Embase and MEDLINE databases to identify studies published after 2011 (date of a previous review on this topic). Eligible studies needed to have an explicit methodological focus, related to how patient heterogeneity can be accounted for within a full economic evaluation. Sixteen studies were included in the review. Methodologies were varied and included regression techniques, model design and value of information analysis. Recent publications have applied methodologies more commonly used in other fields, such as machine learning and causal forests. Commonly noted challenges associated with considering patient heterogeneity included data availability (e.g., sample size), statistical issues (e.g., risk of false positives) and practical factors (e.g., computation time). A range of methods are available to address patient heterogeneity in economic evaluation, with relevant methods differing according to research question, scope of the economic evaluation and data availability. Researchers need to be aware of the challenges associated with addressing patient heterogeneity (e.g., data availability) to ensure findings are meaningful and robust. Future research is needed to assess whether and how methods are being applied in practice.

Development and evaluation of a de-escalation training intervention in adult acute and forensic units: the EDITION systematic review and feasibility trial.

Background: Containment (e.g. physical restraint and seclusion) is used frequently in mental health inpatient settings. Containment is associated with serious psychological and physical harms. De-escalation (psychosocial techniques to manage distress without containment) is recommended to manage aggression and other unsafe behaviours, for example self-harm. All National Health Service staff are trained in de-escalation but there is little to no evidence supporting training's effectiveness. Objectives: Objectives were to: (1) qualitatively investigate de-escalation and identify barriers and facilitators to use across the range of adult acute and forensic mental health inpatient settings; (2) co-produce with relevant stakeholders an intervention to enhance de-escalation across these settings; (3) evaluate the intervention's preliminary effect on rates of conflict (e.g. violence, self-harm) and containment (e.g. seclusion and physical restraint) and understand barriers and facilitators to intervention effects. Design: Intervention development informed by Experience-based Co-design and uncontrolled pre and post feasibility evaluation. Systematic reviews and qualitative interviews investigated contextual variation in use and effects of de-escalation. Synthesis of this evidence informed co-design of an intervention to enhance de-escalation. An uncontrolled feasibility trial of the intervention followed. Clinical outcome data were collected over 24 weeks including an 8-week pre-intervention phase, an 8-week embedding and an 8-week post-intervention phase. Setting: Ten inpatient wards (including acute, psychiatric intensive care, low, medium and high secure forensic) in two United Kingdom mental health trusts. Participants: In-patients, clinical staff, managers, carers/relatives and training staff in the target settings. Interventions: Enhancing de-escalation techniques in adult acute and forensic units: Development and evaluation of an evidence-based training intervention (EDITION) interventions included de-escalation training, two novel models of reflective practice, post-incident debriefing and feedback on clinical practice, collaborative prescribing and ward rounds, practice changes around admission, shift handovers and the social and physical environment, and sensory modulation and support planning to reduce patient distress. Main outcome measures: Outcomes measured related to feasibility (recruitment and retention, completion of outcome measures), training outcomes and clinical and safety outcomes. Conflict and containment rates were measured via the Patient-Staff Conflict Checklist. Clinical outcomes were measured using the Attitudes to Containment Measures Questionnaire, Attitudes to Personality Disorder Questionnaire, Violence Prevention Climate Scale, Capabilities, Opportunities, and Motivation Scale, Coercion Experience Scale and Perceived Expressed Emotion in Staff Scale. Results: Completion rates of the proposed primary outcome were very good at 68% overall (excluding remote data collection), which increased to 76% (excluding remote data collection) in the post-intervention period. Secondary outcomes had high completion rates for both staff and patient respondents. Regression analyses indicated that reductions in conflict and containment were both predicted by study phase (pre, embedding, post intervention). There were no adverse events or serious adverse events related to the intervention. Conclusions: Intervention and data-collection procedures were feasible, and there was a signal of an effect on the proposed primary outcome. Limitations: Uncontrolled design and self-selecting sample. Future work: Definitive trial determining intervention effects. Trial registration: This trial is registered as ISRCTN12826685 (closed to recruitment). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/101/02) and is published in full in Health Technology Assessment; Vol. 28, No. 3. See the NIHR Funding and Awards website for further award information. Context: Conflict (a term used to describe a range of potentially unsafe events including violence, self-harm, rule-breaking, medication refusal, illicit drug and alcohol use and absconding) in mental health settings causes serious physical and psychological harm. Containment interventions which are intended to minimise harm from violence (and other conflict behaviours) such as restraint, seclusion and rapid tranquilisation can result in serious injuries to patients and, occasionally, death. Involvement in physical restraint is the most common cause of serious physical injury to National Health Service mental health staff in the United Kingdom. Violence to staff results in substantial costs to the health service in sickness and litigation payments. Containment interventions are also expensive (e.g. physical restraint costs mental health services £6.1 million and enhanced observations £88 million per annum). Despite these harms, recent findings indicate containment interventions such as seclusion and physical restraint continue to be used frequently in mental health settings. Clinical trials have demonstrated that interventions can reduce containment without increasing violence and other conflict behaviours (e.g. verbal aggression, self-harm). Substantial cost-savings result from reducing containment use. De-escalation, as an intervention to manage aggression and potential violence without restrictive practices, is a core intervention. 'De-escalation' is a collective term for a range of psychosocial techniques designed to reduce distress and anger without the need to use 'containment' interventions (measures to prevent harm through restricting a person's ability to act independently, such as physical restraint and seclusion). Evidence indicates that de-escalation involves ensuring conditions for safe intervention and effective communication are established, clarifying and attempting to resolve the patient's concern, conveyance of respect and empathy and regulating unhelpful emotions such as anxiety and anger. Despite featuring prominently in clinical guidelines and training policy domestically and internationally and being a component of mandatory National Health Service training, there is no evidence-based model on which to base training. A systematic review of de-escalation training effectiveness and acceptability conducted in 2015 concluded: (1) no model of training has demonstrated effectiveness in a sufficiently rigorous evaluation, (2) the theoretical underpinning of evaluated models was often unclear and (3) there has been inadequate investigation of the characteristics of training likely to enhance acceptability and uptake. Despite all National Health Service staff being trained in de-escalation there have been no high-quality trials evaluating the effectiveness and cost-effectiveness of training. Feasibility studies are needed to establish whether it is possible to conduct a definitive trial that can determine the clinical, safety and cost-effectiveness of this intervention.

Mental health hospitals are stressful places for patients and staff. Patients are often detained against their will, in places that are noisy, unfamiliar and frightening. Violence and self-injury happen quite frequently. Sometimes staff physically restrain patients or isolate patients in locked rooms (called seclusion). While these measures might sometimes be necessary to maintain safety, they are psychologically and physically harmful. To help reduce the use of these unsafe measures, staff are trained in communication skills designed to reduce anger and distress without using physical force. Professionals call these skills 'de-escalation'. Although training in de-escalation is mandatory, there is no good evidence to say whether it works or not, or what specific techniques staff should be trained in. The Enhancing de-escalation techniques in adult acute and forensic units: Development and evaluation of an evidence-based training intervention (EDITION) project aimed to develop and evaluate a de-escalation training programme informed by research evidence. We interviewed over one hundred people who either worked in or received treatment in a mental health hospital. These people were clear that the training should target key sources of interpersonal and environmental stress that prevent de-escalation from working. We also reviewed all the scientific studies on de-escalation and training, aiming to identify the elements of training that are most likely to increase use of de-escalation. Then, in partnership with current mental health service users and clinical staff, we developed the training programme. Training was delivered to more than 270 staff working in 10 different wards in mental health hospitals. We measured rates of violence, self-injury and use of physical restraint and seclusion 8 weeks before staff received training and 16 weeks after they received training (24 weeks of data collection in total). Analysis of these data showed that these unsafe events were occurring significantly less frequently after training than they were before training, which raised the possibility that the training was helping to reduce harm.

Development of a cost of illness inventory questionnaire for children with autism spectrum disorder in South Asia.

BACKGROUND: The economic burden of autism is substantial and includes a range of costs, including healthcare, education, productivity losses, informal care and respite care, among others. In India, approximately, 2 million children aged 2-9 years have autism. Given the likely substantial burden of illness and the need to identify effective and cost-effective interventions, this research aimed to produce a comprehensive cost of illness inventory (COII) suitable for children with autism in South Asia (India) to support future research. METHODS: A structured and iterative design process was followed to create the COII, including literature reviews, interviews with caregivers, pilot testing and translation. Across the development of the COII, thirty-two families were involved in the design and piloting of the tool. The COII was forward translated (from English to Hindi) and back translated. Each stage of the process of development of the COII resulted in the further refinement of the tool. RESULTS: Domains covered in the final COII include education, childcare, relocation, healthcare contacts (outpatient, inpatient, medical emergencies, investigations and medication), religious retreats and rituals, specialist equipment, workshops and training, special diet, support and care, certification, occupational adjustments and government rebates/schemes. Administration and completion of the COII determined it to be feasible to complete in 35 minutes by qualified and trained researchers. The final COII is hosted by REDCap Cloud and is a bilingual instrument (Hindi and English). CONCLUSIONS: The COII was developed using experiences gathered from an iterative process in a metropolitan area within the context of one low- and middle-income country (LMIC) setting, India. Compared to COII tools used for children with autism in high-income country settings, additional domains were required, such as complimentary medication (e.g. religious retreats and homeopathy). The COII will allow future research to quantify the cost of illness of autism in India from a broad perspective and will support relevant economic evaluations. Understanding the process of developing the questionnaire will help researchers working in LMICs needing to adapt the current COII or developing similar questionnaires.

A review of economic evaluations of health care for people at risk of psychosis and for first-episode psychosis.

BACKGROUND: Preventing psychotic disorders and effective treatment in first-episode psychosis are key priorities for the National Institute for Health and Care Excellence. This review assessed the evidence base for the cost-effectiveness of health and social care interventions for people at risk of psychosis and for first-episode psychosis. METHODS: Electronic searches were conducted using the PsycINFO, MEDLINE and Embase databases to identify relevant published full economic evaluations published before August 2020. Full-text English-language studies reporting a full economic evaluation of a health or social care intervention aiming to reduce or prevent symptoms in people at risk of psychosis or experiencing first-episode psychosis were included. Screening, data extraction, and critical appraisal were performed using pre-specified criteria and forms based on the NHS Economic Evaluation Database (EED) handbook and Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist for economic evaluations. The protocol was registered on the PROSPERO database (CRD42018108226). Results were summarised qualitatively. RESULTS: Searching identified 1,628 citations (1,326 following the removal of duplications). After two stages of screening 14 studies met the inclusion criteria and were included in the review. Interventions were varied and included multidisciplinary care, antipsychotic medication, psychological therapy, and assertive outreach. Evidence was limited in the at-risk group with only four identified studies, though all interventions were found to be cost-effective with a high probability (> 80%). A more substantial evidence base was identified for first-episode psychosis (11 studies), with a focus on early intervention (7/11 studies) which again had positive conclusions though with greater uncertainty. CONCLUSIONS: Study findings generally concluded interventions were cost-effective. The evidence for the population who are at-risk of psychosis was limited, and though there were more studies for the population with first-episode psychosis, limitations of the evidence base (including generalisability and heterogeneity across the methods used) affect the certainty of conclusions.

Acknowledging Patient Heterogeneity in Economic Evaluations in Schizophrenia: A Systematic Review.

OBJECTIVES: Schizophrenia is a severe mental illness with heterogeneous etiology, range of symptoms, and course of illness. Cost-effectiveness analysis often applies averages from populations, which disregards patient heterogeneity even though there are a range of methods available to acknowledge patient heterogeneity. This review evaluates existing economic evaluations of interventions in schizophrenia to understand how patient heterogeneity is currently reflected in economic evaluation. METHODS: Electronic searches of MEDLINE, Embase, and PsycINFO via Ovid and the Health Technology Assessment database were run to identify full economic evaluations of interventions aiming to reduce the symptoms associated with schizophrenia. Two levels of screening were used, and explicit inclusion criteria were applied. Prespecified data extraction and critical appraisal were performed. RESULTS: Seventy-six relevant studies were identified. More than half (41 of 76) of the articles acknowledged patient heterogeneity in some way through discussion or methods. There was a range of patient characteristics considered, including demographics and socioeconomic factors (eg, age, educational level, ethnicity), clinical characteristics (eg, symptom severity, comorbidities), and preferences (eg, preferences related to outcomes or symptoms). Subgroup analyses were rarely reported (8 of 76). CONCLUSIONS: Patient heterogeneity was frequently mentioned in studies but was rarely thoroughly investigated in the identified economic evaluations. When investigated, included patient characteristics and methods were found to be heterogeneous. Understanding and acknowledging patient heterogeneity may alter the conclusions of cost-effectiveness evaluations; subsequently, we would encourage further research in this area.

Factors Limiting Subgroup Analysis in Cost-Effectiveness Analysis and a Call for Transparency.

The use of population averages in cost-effectiveness analysis may hide important differences across subgroups, potentially resulting in suboptimal resource allocation, reduced population health and/or increased health inequalities. We discuss the factors that limit subgroup analysis in cost-effectiveness analysis and propose more thorough and transparent reporting. There are many issues that may limit whether subgroup analysis can be robustly included in cost-effectiveness analysis, including challenges with prespecifying and justifying subgroup analysis, identifying subgroups that can be implemented (identified and targeted) in practice, resource and data requirements, and statistical and ethical concerns. These affect every stage of the design, development and reporting of cost-effectiveness analyses. It may not always be possible to include and report relevant subgroups in cost effectiveness, e.g. due to data limitations. Reasons for not conducting subgroup analysis may be heterogeneous, and the consequences of not acknowledging patient heterogeneity can be substantial. We recommend that when potentially relevant subgroups have not been included in a cost-effectiveness analysis, authors report this and discuss their rationale and the limitations of this. Greater transparency of subgroup reporting should provide a starting point to overcoming these challenges in future research.

Protocol for the economic evaluation of metacognitive therapy for cardiac rehabilitation participants with symptoms of anxiety and/or depression.

INTRODUCTION: Cardiac rehabilitation (CR) is offered to reduce the risk of further cardiac events and to improve patients' health and quality of life following a cardiac event. Psychological care is a common component of CR as symptoms of depression and/or anxiety are more prevalent in this population, however evidence for the cost-effectiveness of current interventions is limited. Metacognitive therapy (MCT), is a recent treatment development that is effective in treating anxiety and depression in mental health settings and is being evaluated in CR patients. This protocol describes the planned approach to the economic evaluation of MCT for CR patients. METHODS AND ANALYSIS: The economic evaluation work will consist of a within-trial analysis and an economic model. The PATHWAY Group MCT study has been prospectively designed to collect comprehensive self-reported resource use and health outcome data, including the EQ-5D, within a randomised controlled trial study design (UK Clinical Trials Gateway). A within-trial economic evaluation and economic model will compare the cost-effectiveness of MCT plus usual care (UC) to UC, from a health and social care perspective in the UK. The within-trial analysis will use intention-to-treat and estimate total costs and quality-adjusted life-years (QALYs) for the trial follow-up. Single imputation will be used to impute missing baseline variables. Multiple imputation will be used to impute values missing at follow-up. Items of resource use will be multiplied by published national healthcare costs. Regression analysis will be used to estimate net costs and net QALYs and these estimates will be bootstrapped to generate 10 000 net pairs of costs and QALYs to inform the probability of cost-effectiveness. A decision analytical economic model will be developed to synthesise trial data with the published literature over a longer time frame. Sensitivity analysis will explore uncertainty. Guidance of the methods for economic models will be followed and dissemination will adhere to reporting guidelines. ETHICS AND DISSEMINATION: The economic evaluation includes a within-trial analysis. The trial which included the collection of this data was reviewed and approved by Ethics. Ethics approval was obtained by the Preston Research Ethics Committee (project ID 156862). The modelling analysis is not applicable for Ethics as it will use data from the trial (secondary analysis) and the published literature. Results of the main trial and economic evaluation will be published in the peer-reviewed National Institute for Health Research (NIHR) journals library (Programme Grants for Applied Research), submitted to a peer-reviewed journal and presented at appropriate conferences. TRIAL REGISTRATION NUMBER: ISRCTN74643496; Pre-results.

Health State Values of Deaf British Sign Language (BSL) Users in the UK: An Application of the BSL Version of the EQ-5D-5L.

BACKGROUND: Deaf people experience health inequalities compared to hearing populations. The EQ-5D, a widely used, standardised, generic measure of health status, which is available in over 100 languages, was recently translated into British Sign Language (BSL) and initial validation conducted. Using data from this previous study of the EQ-5D-5L BSL we aimed to assess (1) whether responses to the EQ-5D differed between a sample of Deaf BSL users and the general population (2) whether socio-demographic characteristics and clinical measures were associated with EQ-5D index scores in Deaf BSL users and (3) the impact of psychological distress and depression on health status in Deaf BSL users. METHODS: Published population tariffs were applied to the EQ-5D-5L BSL, using the crosswalk methodology, to estimate health state values. Descriptive statistics (mean, SD, 95% CIs) compared Deaf BSL signer participants' (n = 92) responses to data from the general population. Descriptive statistics and linear regression analyses were used to identify associations between Deaf participants' EQ-5D index scores, socio-demographic characteristics, physical health and depression. Descriptive statistics compared the BSL index scores for people with psychological distress/depression to those from two cross-sectional, population-based surveys. RESULTS: Using the EQ-5D, Deaf participants had lower mean health-state values (0.78; 95% CI 0.72-0.83; n = 89) than people participating in the 2017 Health Survey for England (0.84; 95% CI 0.83-0.84; n = 7169). Unlike larger studies, such as the Health Survey for England sample, there was insufficient evidence to assess whether Deaf participants' EQ-5D health state values were associated with their demographic characteristics. Nevertheless, analysis of the BSL study data indicated long-standing physical illness was associated with lower health-state values (ordinary least squares coefficient = - 0.354; 95% CI - 0.484, - 0.224; p < 0.01; n = 82). Forty-three percent of our Deaf participants had depression. Participants with depression had reduced health status (0.67; 95% CI 0.58-0.77; n = 36) compared to those with no psychological distress or depression (0.87; 95% CI 0.61-0.67; n = 36). CONCLUSIONS: The study highlights reduced health in the Deaf signing population, compared to the general population. Public health initiatives focused on BSL users, aiming to increase physical and mental health, are needed to address this gap.

Long-term clinical and cost-effectiveness of collaborative care (versus usual care) for people with mental-physical multimorbidity: cluster-randomised trial.

BACKGROUND: Collaborative care can support the treatment of depression in people with long-term conditions, but long-term benefits and costs are unknown.AimsTo explore the long-term (24-month) effectiveness and cost-effectiveness of collaborative care in people with mental-physical multimorbidity. METHOD: A cluster randomised trial compared collaborative care (integrated physical and mental healthcare) with usual care for depression alongside diabetes and/or coronary heart disease. Depression symptoms were measured by the symptom checklist-depression scale (SCL-D13). The economic evaluation was from the perspective of the English National Health Service. RESULTS: 191 participants were allocated to collaborative care and 196 to usual care. At 24 months, the mean SCL-D13 score was 0.27 (95% CI, -0.48 to -0.06) lower in the collaborative care group alongside a gain of 0.14 (95% CI, 0.06-0.21) quality-adjusted life-years (QALYs). The cost per QALY gained was £13 069. CONCLUSIONS: In the long term, collaborative care reduces depression and is potentially cost-effective at internationally accepted willingness-to-pay thresholds.Declaration of interestNone.

Cost-effectiveness of cardiac rehabilitation: a systematic review.

Patients may be offered cardiac rehabilitation (CR), a supervised programme often including exercises, education and psychological care, following a cardiac event, with the aim of reducing morbidity and mortality. Cost-constrained healthcare systems require information about the best use of budget and resources to maximise patient benefit. We aimed to systematically review and critically appraise economic studies of CR and its components. In January 2016, validated electronic searches of the National Health Service Economic Evaluation Database (NHS EED), Health Technology Assessment, PsycINFO, MEDLINE and Embase databases were run to identify full economic evaluations published since 2001. Two levels of screening were used and explicit inclusion criteria were applied. Prespecified data extraction and critical appraisal were performed using the NHS EED handbook and Drummond checklist. The majority of studies concluded that CR was cost-effective versus no CR (incremental cost-effectiveness ratios (ICERs) ranged from $1065 to $71 755 per quality-adjusted life-year (QALY)). Evidence for specific interventions within CR was varied; psychological intervention ranged from dominant (cost saving and more effective) to $226 128 per QALY, telehealth ranged from dominant to $588 734 per QALY and while exercise was cost-effective across all relevant studies, results were subject to uncertainty. Key drivers of cost-effectiveness were risk of subsequent events and hospitalisation, hospitalisation and intervention costs, and utilities. This systematic review of studies evaluates the cost-effectiveness of CR in the modern era, providing a fresh evidence base for policy-makers. Evidence suggests that CR is cost-effective, especially with exercise as a component. However, research is needed to determine the most cost-effective design of CR.

A systematic review of economic evaluations of seasonal influenza vaccination for the elderly population in the European Union.

OBJECTIVES: The Council of the European Union (EU) has recommended that action should be taken to increase influenza vaccination in the elderly population. The aims were to systematically review and critically appraise economic evaluations for influenza vaccination in the elderly population in the EU. METHODS: Electronic searches of the NHS Economic Evaluation, Health Technology Assessment, MEDLINE and Embase databases were run to identify full economic evaluations. Two levels of screening were used, with explicit inclusion criteria applied by two independent reviewers at each stage. Prespecified data extraction and critical appraisal were performed on identified studies. Results were summarised qualitatively. RESULTS: Of the 326 search results, screening identified eight relevant studies. Results varied widely, with the incremental cost-effectiveness ratio ranging from being both more effective and cheaper than no intervention to costing €4 59 350 per life-year gained. Cost-effectiveness was most sensitive to variations in influenza strain, vaccination type and strategy, population and modelling characteristics. CONCLUSIONS: Most studies suggest that vaccination is cost-effective (seven of eight studies identified at least one cost-effective scenario). All but one study used economic models to synthesise data from different sources. The results are uncertain due to the methods used and the relevance and robustness of the data used. Sensitivity analysis to explore these aspects was limited. Integrated, controlled prospective clinical and economic evaluations and surveillance data are needed to improve the evidence base. This would allow more advanced modelling techniques to characterise the epidemiology of influenza more accurately and improve the robustness of cost-effectiveness estimates.

Long-term cost-effectiveness of collaborative care (vs usual care) for people with depression and comorbid diabetes or cardiovascular disease: a Markov model informed by the COINCIDE randomised controlled trial.

OBJECTIVES: To evaluate the long-term cost-effectiveness of collaborative care (vs usual care) for treating depression in patients with diabetes and/or coronary heart disease (CHD). SETTING: 36 primary care general practices in North West England. PARTICIPANTS: 387 participants completed baseline assessment (collaborative care: 191; usual care: 196) and full or partial 4-month follow-up data were captured for 350 (collaborative care: 170; usual care: 180). 62% of participants were male, 14% were non-white. Participants were aged ≥18 years, listed on a Quality and Outcomes Framework register for CHD and/or type 1 or 2 diabetes mellitus, with persistent depressive symptoms. Patients with psychosis or type I/II bipolar disorder, actively suicidal, in receipt of services for substance misuse, or already in receipt of psychological therapy for depression were excluded. INTERVENTION: Collaborative care consisted of evidence-based low-intensity psychological treatments, delivered over 3 months and case management by a practice nurse and a Psychological Well Being Practitioner. OUTCOME MEASURES: As planned, the primary measure of cost-effectiveness was the incremental cost-effectiveness ratio (cost per quality-adjusted life year (QALY)). A Markov model was constructed to extrapolate the trial results from short-term to long-term (24 months). RESULTS: The mean cost per participant of collaborative care was £317 (95% CI 284 to 350). Over 24 months, it was estimated that collaborative care was associated with greater healthcare usage costs (net cost £674 (95% CI -30 953 to 38 853)) and QALYs (net QALY gain 0.04 (95% CI -0.46 to 0.54)) than usual care, resulting in a cost per QALY gained of £16 123, and a likelihood of being cost-effective of 0.54 (willingness to pay threshold of £20 000). CONCLUSIONS: Collaborative care is a potentially cost-effective long-term treatment for depression in patients with comorbid physical and mental illness. The estimated cost per QALY gained was below the threshold recommended by English decision-makers. Further, long-term primary research is needed to address uncertainty associated with estimates of cost-effectiveness. TRIAL REGISTRATION NUMBER: ISRCTN80309252; Post-results.

Valuing the economic benefits of complex interventions: when maximising health is not sufficient.

Complex interventions, involving interlinked packages of care, challenge the application of current methods of economic evaluation that focus on measuring only health gain. Complex interventions may be problematic on two levels. The complexity means the intervention may not fit into one of the current appraisal systems, and/or maximising health is not the only objective. This paper discusses the implications of a programme of work that focused on clinical genetics services, as an example of a complex intervention, and aimed to identify the following: the attributes that comprise both health and non-health aspects of benefits and whether it is possible to evaluate such an intervention using current National Institute for Health and Clinical Excellence appraisal processes. Genetic services and tests are a good example of a complex intervention and have broader objectives than just health gain, which may usefully be measured using the concept related to capability, which we have called 'empowerment'. Further methodological work is required to identify the trade-off between non-health (empowerment) and health benefits for other complex interventions. We do not advocate a move away from QALY maximisation but do suggest that there is a need for a more considered approach that can take account of the perceived value for non-health attributes for some complex interventions.

The validity and responsiveness of generic utility measures in rheumatoid arthritis: a review.

OBJECTIVE: Cost-utility analysis is increasingly important as healthcare providers aim to invest scarce resources in interventions offering the greatest health benefit. The ability to attach utility values to health states is essential, and is increasingly performed using generic scales. However, the evidence regarding the validity of generic utility scales in rheumatoid arthritis (RA) is unclear. We summarize and review evidence on the validity and comparative performance of generic utility scales in RA. METHODS: We searched the English-language medical literature for studies using utilities in RA between 1980 and mid-2006. Reports describing primary evidence of the validity or performance of a generic utility scale in RA were selected, summarized, and reviewed using the OMERACT filter. RESULTS: In total 923 articles were identified, of which 228 reported the use of utility scales in RA; 26 studies related to the validation or evidence of generic utility scales in RA, the EQ-5D, Health Utility Index-2 (HUI2) and HUI3, SF-6D, and Quality of Well-Being Scale. The EQ-5D, HUI2 and HUI3, and SF-6D all have consistent evidence of construct validity and responsiveness in RA, but each has limitations. CONCLUSION: The EQ-5D and HUI3 have been the most extensively studied instruments and show validity and responsiveness for use in RA, but both instruments have limitations. The SF-6D is relatively new and appears to have potential for use in milder RA, but needs further evaluation. More longitudinal head-to-head evaluation of measures is needed across the spectrum of RA disease severity to further investigate their comparative properties, and to seek consensus on the best utility measure for use in economic evaluation.

A randomized controlled trial of the cost-utility of second-generation antipsychotics in people with psychosis and eligible for clozapine.

OBJECTIVE: To assess whether clozapine is likely to be more cost-effective than other second-generation antipsychotics (SGAs) in people with schizophrenia. METHODS: An integrated clinical and economic multicenter, rater-blind, randomized controlled trial (RCT) compared clozapine to the class of other SGAs, using the perspectives of the National Health Service, social support services, and patients. The practice setting was secondary and primary care in the United Kingdom; patients were followed for 1 year. Incremental cost-effectiveness ratios (ICERs), net benefit statistics, and cost acceptability curves were estimated. RESULTS: The ICER for clozapine was 33,240 pound per quality-adjusted life-year (QALY) (range 23,000-70,000 pound for the sensitivity analyses). The proportion of simulations when clozapine was more cost-effective than other SGAs reached 50% if decision-makers are prepared to pay 30,000 pound to 35,000 pound per QALY. This is at the top of the range of acceptable willingness-to-pay values per QALY implied by decisions taken by the National Institute for Health and Clinical Excellence (NICE). CONCLUSIONS: This study adds to a limited body of evidence comparing clozapine to other SGAs and is the first economic and clinical RCT to compare clozapine to the class of other SGAs using the lower cost of generic clozapine and a pragmatic trial design. Policy decisions by the NICE suggest that additional reasons would be needed to accept clozapine as effective and efficient if it had a high probability of having ICERs more than 35,000 pound per QALY. The results and limitations of the analysis suggest that there is still a need for further economic evaluation of clozapine.

Costing day case anesthesia: obtaining accurate patient-based costs for adults and children.

OBJECTIVES: This study proposes the method requirements for a valid costing study in anesthesia to allow differences to be identified between treatments and uses these method requirements to design and conduct a robust costing study. METHODS: A prospective, patient-based costing study was carried out in adult and pediatric day surgery in the United Kingdom. The perspective was that of the National Health Service and the patient. Data were collected for each patient until 7 days after hospital discharge. RESULTS: Data were collected for 1063 adults and 322 children undergoing day surgery between October 1999 and January 2001. Statistically significant differences were found only between variable costs, which accounted for 11.4 percent and 9.0 percent of adult and pediatric costs, respectively. There were no differences in length of stay, fixed costs, or semi-fixed costs. Differences were not found in total costs in adults but were found in children. By day 7, postdischarge primary and secondary care costs were not different between groups in either study. No differences were found in costs to patients or parents. CONCLUSIONS: The use of prospective, patient-based cost data enabled the detection of differences in variable costs between difference anesthetic regimens in day surgery. The stochastic nature of the data provided a measure of variability around mean cost estimates. Practice patterns in the study reflected normal practice in the United Kingdom so the costing data have direct clinical relevance. The use of different anesthetic agents only affected variable costs and had no effect on larger cost drivers such as length of stay or staff input.

The value of the managed entry of new drugs: a case study of donepezil.

OBJECTIVE: A United Kingdom Department of Health directive (EL[94]72) asked Health Authorities to manage the entry of new drugs into practice. There seem to be costs associated with the decision-making process of managed entry, but no clear evidence of benefit to patient populations. The objective of this study was to assess the potential costs and outcomes of different models of managed entry, using the example of donepezil in the North West Health Region of the U.K. National Health Service. This is a preliminary study designed to identify the key pieces of information required to evaluate the value of managed entry. METHODS: Decision analytic models of three Health Authorities' approaches to manage the entry of donepezil were used to estimate the expected costs and effectiveness of the process. Resource use data were obtained from published sources and the relevant Health Authority. Probabilistic sensitivity analysis was used to determine the robustness of the results. RESULTS: The process of managed entry of donepezil was associated with higher expected costs and higher expected outcome than no managed entry. The 95% confidence intervals for the net expected costs and net expected outcomes were relatively narrow and did not cross zero, which suggests a statistical difference between managed entry and no managed entry for donepezil. The incremental cost-effectiveness ratios for managed entry of donepezil indicate that, compared with no managed entry, there were substantial differences between the different models used in the three study sites. The expected cost per unit of cognitive function gained was between 18,000 pounds sterling in study site 001 to 28,000 pounds sterling in study site 010. The expected cost per person with a clinically significant improvement was between 140,000 pounds sterling and 230,000 pounds sterling. The expected cost per QALY ranged from 470,000 pounds sterling to 19.3 million pounds sterling. CONCLUSIONS: Managed entry does not appear to be a worthwhile mechanism to introduce drugs into practice. However, poor accessibility and availability of data means that the results are highly uncertain. The lack of data presents serious obstacles for both researchers and policy makers wishing to develop evidence-based policy and practice.

How to undertake a clinically relevant systematic review in a rapidly evolving field. Magnetic resonance angiography.

OBJECTIVES: The aim was to determine which generations of the evolving technology of magnetic resonance angiography (MRA) are currently of clinical relevance in two clinical applications. Our purpose was to plan a systematic review that would be valuable both to purchasers driven by cost-effectiveness and to practicing clinicians. METHODS: Information was gathered from a search of major bibliographic databases, from a short questionnaire sent to 500 U.K. vascular radiologists and vascular surgeons, and from local clinical experts. We asked which of the MRA techniques were currently used and, assuming availability, what would be their technique of choice. RESULTS: There were 206 published articles that satisfied preliminary inclusion criteria: 69 discussed 2D time of flight (TOF); 47, 3D TOF; and 38, contrast-enhanced techniques. There were 162 questionnaires returned (60 radiologists, 102 surgeons). Of the total respondents, 77/162 (48%) used MRA in the assessment of carotid artery stenosis; 47/77 (61%) used 2D TOF; 32/77 (42%), 3D TOF; and 26/77 (34%), contrast-enhanced techniques. Thirty-five of 162 (22%) respondents used MRA in the assessment of peripheral vascular disease (PVD); 15/35 (43%) used 2D TOF, 4/35 (11%) used 3D TOF, and 22/35 (63%) used contrast-enhanced techniques. For those wishing to use MRA, contrast-enhanced techniques were the method of choice. CONCLUSIONS: The TOF methods that represent earlier generations of the technology remain clinically relevant, and will therefore be included in our systematic review. To ensure complete and relevant coverage in reviews of other evolving technologies, it would be advisable to obtain data for guidance in a similar way.