BACKGROUND: the Healthy Lifestyles Programme (HeLP) trial is being conducted to determine whether a novel school-based intervention is effective and cost-effective in preventing obesity in 9-10 year-old children. This article describes the detailed statistical analysis plan for the HeLP trial, including an amendment (and rationale for amendment) made to originally planned sensitivity analyses. METHODS AND DESIGN: the HeLP trial is a definitive, pragmatic, superiority, cluster randomised controlled trial with two parallel groups and blinded outcome assessment. This update article describes in detail (1) the primary and secondary outcomes, (2) the statistical analysis principles (including which children will be included in each analysis, how the clustered nature of the study design will be accounted for, which covariates will be included in each analysis, how the results will be presented), (3) planned sensitivity analyses, planned subgroup analyses and planned adherence-adjusted analyses for the primary outcome, (4) planned analyses for the secondary outcomes and (e) planned longitudinal analyses. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) register: ISRCTN15811706. Registered on 1 May 2012.

INTRODUCTION: We develop a multidomain model to predict progression of Alzheimer's disease dementia (AD). METHODS: Data from the US National Alzheimer's Coordinating Center (n = 3009) are used to examine change in symptom status and to estimate transition probabilities between health states described using cognitive function, functional ability, and behavior. A model is used to predict progression and to assess a hypothetical treatment scenario that slows mild to moderate AD progression. RESULTS: More than 70% of participants moved state over 12 months. The majority moved in domains other than cognitive function. Over 5 years, of those alive more than half are in severe AD health states. Assessing an intervention scenario, we see fewer years in more severe health states and a potential impact (life years saved) due to mortality improvements. DISCUSSION: the model developed is exploratory and has limitations but illustrates the importance of using a multidomain approach when assessing impacts of AD and interventions.

INTRODUCTION: the Rehabilitation EnAblement in CHronic Heart Failure in patients with Heart Failure (HF) with preserved ejection fraction (REACH-HFpEF) pilot trial is part of a research programme designed to develop and evaluate a facilitated, home-based, self-help rehabilitation intervention to improve self-care and quality of life (QoL) in heart failure patients and their caregivers. We will assess the feasibility of a definitive trial of the REACH-HF intervention in patients with HFpEF and their caregivers. The impact of the REACH-HF intervention on echocardiographic outcomes and bloodborne biomarkers will also be assessed. METHODS AND ANALYSIS: a single-centre parallel two-group randomised controlled trial (RCT) with 1:1 individual allocation to the REACH-HF intervention plus usual care (intervention) or usual care alone (control) in 50 HFpEF patients and their caregivers. The REACH-HF intervention comprises a REACH-HF manual with supplementary tools, delivered by trained facilitators over 12â€
weeks. A mixed methods approach will be used to assess estimation of recruitment and retention rates; fidelity of REACH-HF manual delivery; identification of barriers to participation and adherence to the intervention and study protocol; feasibility of data collection and outcome burden. We will assess the variance in study outcomes to inform a definitive study sample size and assess methods for the collection of resource use and intervention delivery cost data to develop the cost-effectiveness analyses framework for any future trial. Patient outcomes collected at baseline, 4 and 6â€
months include QoL, psychological well-being, exercise capacity, physical activity and HF-related hospitalisation. Caregiver outcomes will also be assessed, and a substudy will evaluate impact of the REACH-HF manual on resting global cardiovascular function and bloodborne biomarkers in HFpEF patients. ETHICS AND DISSEMINATION: the study is approved by the East of Scotland Research Ethics Service (Ref: 15/ES/0036). Findings will be disseminated via journals and presentations to clinicians, commissioners and service users. TRIAL REGISTRATION NUMBER: ISRCTN78539530; Pre-results.

OBJECTIVES: to compare the effectiveness of peripheral nerve stimulation utilizing a subcutaneous lead implant technique-subcutaneous nerve stimulation (SQS) plus optimized medical management (SQS + OMM arm) vs. optimized medical management alone (OMM arm) in patients with back pain due to failed back surgery syndrome. PATIENTS AND METHODS: Patients were recruited from 21 centers, in Europe, Israel, and Australia. Eligible patients were randomized (1:1) to SQS + OMM or OMM arms. Those in the SQS arm were implanted with a neurostimulator and up to two subcutaneous percutaneous cylindrical leads in the area of pain. Patients were evaluated pre-randomization and at one, three, six, and nine months post-randomization. The primary endpoint was the proportion of subjects with a ≥50% reduction in back pain intensity ("responder") from baseline to nine months. Secondary outcomes included proportion of responders with a ≥50% reduction in back pain intensity at six months and ≥30% reduction at nine months, and the mean change from baseline in back pain intensity at six and nine months between the two arms. RESULTS: Due to the slow rate of recruitment, the study was terminated early with 116 subjects randomized. A total of 33.9% (19/56, missing: n = 20 [36%]) of subjects in the SQS + OMM arm and 1.7% (1/60, missing: n = 24 [40%]) in the OMM arm were responders at Month 9 (p 

BACKGROUND: the REtirement in ACTion (REACT) study is a multi-centre, pragmatic, two-arm, parallel-group randomised controlled trial (RCT) with an internal pilot phase. It aims to test the effectiveness and cost-effectiveness of a community, group-based physical activity intervention for reducing, or reversing, the progression of functional limitations in older people who are at high risk of mobility-related disability. METHODS/DESIGN: a sample of 768 sedentary, community-dwelling, older people aged 65 years and over with functional limitations, but who are still ambulatory (scores between 4 and 9 out of 12 in the Short Physical Performance Battery test (SPPB)) will be randomised to receive either the REACT intervention, delivered over a period of 12 months by trained facilitators, or a minimal control intervention. The REACT study incorporates comprehensive process and economic evaluation and a nested sub-study which will test the hypothesis that the REACT intervention will slow the rate of brain atrophy and of decline in cognitive function assessed using magnetic resonance imaging (MRI). Outcome data will be collected at baseline, 6, 12 and 24 months for the main study, with MRI sub-study data collected at baseline, 6 and 12 months. The primary outcome analysis (SPPB score at 24 months) will be undertaken blinded to group allocation. Primary comparative analyses will be on an intention-to-treat (ITT) basis with due emphasis placed on confidence intervals. DISCUSSION: REACT represents the first large-scale, pragmatic, community-based trial in the UK to target the non-disabled but high-risk segment of the older population with an intervention to reduce mobility-related disability. A programme that can successfully engage this population in sufficient activity to improve strength, aerobic capacity, coordination and balance would have a major impact on sustaining health and independence. REACT is also the first study of its kind to conduct a full economic and comprehensive process evaluation alongside the RCT. If effective and cost-effective, the REACT intervention has strong potential to be implemented widely in the UK and elsewhere. TRIAL REGISTRATION: ISRCTN, ID: ISRCTN45627165. Retrospectively registered on 13 June 2016. Trial sponsor: University of Bath. Protocol Version 1.5.

© 2018 the Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background Although childhood overweight and obesity prevalence has increased substantially worldwide in the past three decades, scarce evidence exists for effective preventive strategies. We aimed to establish whether a school-based intervention for children aged 9–10 years would prevent excessive weight gain after 24 months. Methods This pragmatic cluster randomised controlled trial of the Healthy Lifestyles Programme (HeLP), a school-based obesity prevention intervention, was done in 32 schools in southwest England. All state-run primary and junior schools in Devon and Plymouth (UK) with enough pupils for at least one year-5 class were eligible. Schools were assigned (1:1) using a computer-generated sequence to either intervention or control, stratified by the number of year-5 classes (one vs more than one) and the proportion of children eligible for free school meals (

© 2018 ISPOR–The Professional Society for Health Economics and Outcomes Research Objective: in economic evaluation, health outcomes are commonly quantified using quality-adjusted life-years (QALYs) derived from the preferences of a sample of the general population. It can be argued that this approach ignores the preferences of people with experience of the condition, and that patient preferences have a place in the valuation of health outcomes. Here we report the estimation of a preference-based index for an existing condition-specific preference-based measure for multiple sclerosis (MS), the MSIS-8D, based on the preferences of people with MS. Study design: Internet time trade-off (TTO) survey, eliciting preferences from people with MS. Methods: We elicited preferences from a sample of people with MS (N = 1635) across 169 MSIS-8D health states, using the TTO technique. We fitted ordinary least squares and random effects models to the survey data to estimate values for all health states described by the MSIS-8D. Results: the new patient-derived index (the MSIS-8D-P) provides values ranging from 0.893 for the best possible health state to 0.138 for the worst state. The MSIS-8D-P exhibits good discriminative validity, identifying expected significant differences between groups based on presence/absence of MS, type of MS, and duration since diagnosis. Conclusions: the MSIS-8D-P index of values for MS-specific health states provides an opportunity to estimate QALYs based on patient preferences, for use in economic evaluations of treatments for MS. More broadly, it adds to the methods and data available to consider the health-related quality of life of people with MS to inform resource allocation and individual-level decisions regarding treatments for MS.

INTRODUCTION: People with experience of the criminal justice system typically have worse physical and mental health, lower levels of mental well-being and have less healthy lifestyles than the general population. Health trainers have worked with offenders in the community to provide support for lifestyle change, enhance mental well-being and signpost to appropriate services. There has been no rigorous evaluation of the effectiveness and cost-effectiveness of providing such community support. This study aims to determine the feasibility and acceptability of conducting a randomised trial and delivering a health trainer intervention to people receiving community supervision in the UK. METHODS AND ANALYSIS: a multicentre, parallel, two-group randomised controlled trial recruiting 120 participants with 1:1 individual allocation to receive support from a health trainer and usual care or usual care alone, with mixed methods process evaluation. Participants receive community supervision from an offender manager in either a Community Rehabilitation Company or the National Probation Service. If they have served a custodial sentence, then they have to have been released for at least 2 months. The supervision period must have at least 7 months left at recruitment. Participants are interested in receiving support to change diet, physical activity, alcohol use and smoking and/or improve mental well-being. The primary outcome is mental well-being with secondary outcomes related to smoking, physical activity, alcohol consumption and diet. The primary outcome will inform sample size calculations for a definitive trial. ETHICS AND DISSEMINATION: the study has been approved by the Health and Care Research Wales Ethics Committee (REC reference 16/WA/0171). Dissemination will include publication of the intervention development process and findings for the stated outcomes, parallel process evaluation and economic evaluation in peer-reviewed journals. Results will also be disseminated to stakeholders and trial participants. TRIAL REGISTRATION NUMBERS: ISRCTN80475744; Pre-results.

Available data and models for the health-economic evaluation of treatment in Alzheimer's disease (AD) have limitations causing uncertainty to decision makers. Forthcoming treatment strategies in preclinical or early AD warrant an update on the challenges associated with their economic evaluation. The perspectives of the co-authors were complemented with a targeted review of literature discussing methodological issues and data gaps in AD health-economic modelling. The methods and data available to translate treatment efficacy in early disease into long-term outcomes of relevance to policy makers and payers are limited. Current long-term large-scale data accurately representing the continuous, multifaceted, and heterogeneous disease process are missing. The potential effect of disease-modifying treatment on key long-term outcomes such as institutionalization and death is uncertain but may have great effect on cost-effectiveness. Future research should give priority to collaborative efforts to access better data on the natural progression of AD and its association with key long-term outcomes.

BACKGROUND: Health state utility values (HSUVs) are required to calculate quality-adjusted life-years (QALYs). They are frequently derived from generic preference-based measures of health. However, such generic measures may not capture health attributes of relevance to specific conditions. In such cases, a condition-specific preference-based measure (CSPBM) may be more appropriate. OBJECTIVE: This systematic review aimed to identify all published accounts of developing CSPBMs to describe and appraise the methods used. METHOD: We undertook a systematic search (of Embase, MEDLINE, PsycINFO, Web of Science, the Cochrane Library, CINAHL, EconLit, ASSIA and the Health Management Information Consortium database) to identify published accounts of CSPBM development up to July 2015. Studies were reviewed to investigate the methods used to design classification systems, estimate HSUVs, and validate the measures. RESULTS: a total of 86 publications were identified, describing 51 CSPBMs. Around two-thirds of these were QALY measures; the remainder were designed for clinical decision making only. Classification systems for 33 CSPBMs were derived from existing instruments; 18 were developed de novo. HSUVs for 34 instruments were estimated using a 'composite' approach, involving statistical modelling; the remainder used a 'decomposed' approach based on multi-attribute utility theory. Half of the papers that described the estimation of HSUVs did not report validating their measures. CONCLUSION: Various methods have been used at all stages of CSPBM development. The choice between developing a classification system de novo or from an existing instrument may depend on the availability of a suitable existing measure, while the choice between a decomposed or composite approach appears to be determined primarily by the purpose for which the instrument is designed. The validation of CSPBMs remains an area for further development.

INTRODUCTION: Economically disadvantaged smokers not intending to stop may benefit from interventions aimed at reducing their smoking. This study assessed the effects of a behavioral intervention promoting an increase in physical activity versus usual care in a pilot randomized controlled trial. METHODS: Disadvantaged smokers who wanted to reduce but not quit were randomized to either a counseling intervention of up to 12 weeks to support smoking reduction and increased physical activity (n = 49) or usual care (n = 50). Data at 16 weeks were collected for various smoking and physical activity outcomes. Primary analyses consisted of an intention to treat analysis based on complete case data. Secondary analyses explored the impact of handling missing data. RESULTS: Compared with controls, intervention smokers were more likely to initiate a quit attempt (36 vs. 10%; odds ratio 5.05, [95% CI: 1.10; 23.15]), and a greater proportion achieved at least 50% reduction in cigarettes smoked (63 vs. 32%; 4.21 [1.32; 13.39]). Postquit abstinence measured by exhaled carbon monoxide at 4-week follow-up showed promising differences between groups (23% vs. 6%; 4.91 [0.80; 30.24]). No benefit of intervention on physical activity was found. Secondary analyses suggested that the standard missing data assumption of "missing" being equivalent to "smoking" may be conservative resulting in a reduced intervention effect. CONCLUSIONS: a smoking reduction intervention for economically disadvantaged smokers which involved personal support to increase physical activity appears to be more effective than usual care in achieving reduction and may promote cessation. The effect does not appear to be influenced by an increase in physical activity.

BACKGROUND: Collaborative care is effective for depression management in the USA. There is little UK evidence on its clinical effectiveness and cost-effectiveness. OBJECTIVE: to determine the clinical effectiveness and cost-effectiveness of collaborative care compared with usual care in the management of patients with moderate to severe depression. DESIGN: Cluster randomised controlled trial. SETTING: UK primary care practices (n = 51) in three UK primary care districts. PARTICIPANTS: a total of 581 adults aged ≥ 18 years in general practice with a current International Classification of Diseases, Tenth Edition depressive episode, excluding acutely suicidal people, those with psychosis, bipolar disorder or low mood associated with bereavement, those whose primary presentation was substance abuse and those receiving psychological treatment. INTERVENTIONS: Collaborative care: 14 weeks of 6-12 telephone contacts by care managers; mental health specialist supervision, including depression education, medication management, behavioural activation, relapse prevention and primary care liaison. Usual care was general practitioner standard practice. MAIN OUTCOME MEASURES: Blinded researchers collected depression [Patient Health Questionnaire-9 (PHQ-9)], anxiety (General Anxiety Disorder-7) and quality of life (European Quality of Life-5 Dimensions three-level version), Short Form questionnaire-36 items) outcomes at 4, 12 and 36 months, satisfaction (Client Satisfaction Questionnaire-8) outcomes at 4 months and treatment and service use costs at 12 months. RESULTS: in total, 276 and 305 participants were randomised to collaborative care and usual care respectively. Collaborative care participants had a mean depression score that was 1.33 PHQ-9 points lower [n = 230; 95% confidence interval (CI) 0.35 to 2.31; p = 0.009] than that of participants in usual care at 4 months and 1.36 PHQ-9 points lower (n = 275; 95% CI 0.07 to 2.64; p = 0.04) at 12 months after adjustment for baseline depression (effect size 0.28, 95% CI 0.01 to 0.52; odds ratio for recovery 1.88, 95% CI 1.28 to 2.75; number needed to treat 6.5). Quality of mental health but not physical health was significantly better for collaborative care at 4 months but not at 12 months. There was no difference for anxiety. Participants receiving collaborative care were significantly more satisfied with treatment. Differences between groups had disappeared at 36 months. Collaborative care had a mean cost of £272.50 per participant with similar health and social care service use between collaborative care and usual care. Collaborative care offered a mean incremental gain of 0.02 (95% CI -0.02 to 0.06) quality-adjusted life-years (QALYs) over 12 months at a mean incremental cost of £270.72 (95% CI -£202.98 to £886.04) and had an estimated mean cost per QALY of £14,248, which is below current UK willingness-to-pay thresholds. Sensitivity analyses including informal care costs indicated that collaborative care is expected to be less costly and more effective. The amount of participant behavioural activation was the only effect mediator. CONCLUSIONS: Collaborative care improves depression up to 12 months after initiation of the intervention, is preferred by patients over usual care, offers health gains at a relatively low cost, is cost-effective compared with usual care and is mediated by patient activation. Supervision was by expert clinicians and of short duration and more intensive therapy may have improved outcomes. In addition, one participant requiring inpatient treatment incurred very significant costs and substantially inflated our cost per QALY estimate. Future work should test enhanced intervention content not collaborative care per se. TRIAL REGISTRATION: Current Controlled Trials ISRCTN32829227. FUNDING: This project was funded by the Medical Research Council (MRC) (G0701013) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.

BACKGROUND: Relapses can have a major impact on the lives of people with multiple sclerosis (MS), and yet relapse-related healthcare costs have received little attention. This has limited cost-effectiveness analyses of treatments for MS and hampered decision-making regarding the funding of MS healthcare services. OBJECTIVE: to describe health/social care resource use and costs according to the frequency, severity, and endurance of MS relapses. METHODS: Data from the prospective, longitudinal UK South West Impact of Multiple Sclerosis cohort were used. A total of 11,800 questionnaires from 1441 people with MS were available, including data on relapses, contacts with health/social care professionals, and other MS-related resource use. RESULTS: the mean (SD) 6-monthly MS-related health/social care cost for individuals who reported a relapse was £519 (£949), compared to £229 (£366) for those who had not did report a relapse. Care costs varied widely dependent on the characteristics of the relapse. The mean (SD) cost when a relapse was not treated with steroids was £381 (£780), whilst the equivalent cost was £3579 (£1727) when a relapse resulted in hospitalization. CONCLUSIONS: the impact of relapses on health and social care resources and costs differs according to their frequency, length, and severity. The data provided here can be used in cost-effectiveness analyses and to inform decision-making regarding healthcare provision for people with this condition.

BACKGROUND: Multiple sclerosis (MS) is an incurable, unpredictable but typically progressive neurological condition. It is the most common cause of neurological disability in young adults. Within 15 years of diagnosis, approximately 50 % of affected people are unable to walk unaided, and over time an estimated 25 % depend on a wheelchair. Typically, people with such limited mobility are excluded from clinical trials. Severely impaired people with MS spend much of their day sitting, often with limited ability to change position. In response, secondary complications can occur including: muscle wasting, pain, reduced skin integrity, spasms, limb stiffness, constipation, and associated psychosocial problems such as depression and lowered self-esteem. Effective self-management strategies, which can be implemented relatively easily and cheaply within people's homes, are needed to improve or maintain mobility and reduce sedentary behaviour. However this is challenging, particularly in the latter stages of disease. Regular supported standing using standing frames is one potential option. METHODS/DESIGN: SUMS is a pragmatic multi-centre randomised controlled trial evaluating use of Oswestry standing frames with blinded outcome assessment and full economic evaluation. Participants will be randomly allocated (1:1) to either a home-based, self-management standing programme (with advice and support) along with their usual care or to usual care alone. Those in the intervention group will be asked to stand for a minimum of 30 min three times weekly over 20 weeks. Each participant will be followed-up at 20 and 36 weeks post baseline. The primary clinical outcome is motor function, assessed using the Amended Motor Club Assessment. The primary economic endpoint is quality-adjusted life years. The secondary outcomes include measures of explanatory physical impairments, key clinical outcomes, and health-related quality of life. An embedded qualitative component will explore participant's and carer's experiences of the standing programme. DISCUSSION: This is the first large scale multi-centre trial to assess the clinical and cost effectiveness of a home based standing frame programme for people who are severely impaired by MS. If demonstrated to be effective and cost-effective, we will use this evidence to develop recommendations for a health service delivery model which could be implemented across the United Kingdom. TRIAL REGISTRATION: ISRCTN69614598 DATE OF REGISTRATION: 3.2.16 (retrospectively registered).

BACKGROUND: Increasingly, generic preference-based measures of health-related quality of life (HRQOL) are used to estimate quality-adjusted life-years to inform resource allocation decisions. Evidence suggests that generic measures may not be appropriate for multiple sclerosis (MS). OBJECTIVES: to report the first stage in the development of an MS-specific preference-based measure to quantify the impact of MS and its treatment: deriving a health state classification system, which is amenable to valuation, from the 29-item Multiple Sclerosis Impact Scale (MSIS-29), a widely used patient-reported outcome measure in MS. METHODS: the dimensional structure of the MSIS-29 was determined using factor analysis and a conceptual framework of HRQOL in MS. Item performance was assessed, using Rasch analysis and psychometric criteria, to enable the selection of one item to represent each dimension of HRQOL covered by the MSIS-29. Analysis was undertaken using a sample (N = 529) from a longitudinal study of people with MS. Results were validated by repeating the analysis with a second sample (N = 528). RESULTS: Factor analysis confirmed the two-subscale structure of the MSIS-29. Both subscales covered several conceptually independent dimensions of HRQOL. Following Rasch and psychometric analysis, an eight-dimensional classification system named the MSIS-8D was developed. Each dimension was represented by one item with four response levels. CONCLUSIONS: Combining factor analysis with conceptual mapping, and Rasch analysis with psychometric criteria, provides a valid method of constructing a classification system for an MS-specific preference-based measure. The next stage is to obtain preference weights so that the measure can be used in studies investigating MS.

INTRODUCTION: the Rehabilitation EnAblement in CHronic Heart Failure (REACH-HF) trial is part of a research programme designed to develop and evaluate a health professional facilitated, home-based, self-help rehabilitation intervention to improve self-care and health-related quality of life in people with heart failure and their caregivers. The trial will assess the clinical effectiveness and cost-effectiveness of the REACH-HF intervention in patients with systolic heart failure and impact on the outcomes of their caregivers. METHODS AND ANALYSIS: a parallel two group randomised controlled trial with 1:1 individual allocation to the REACH-HF intervention plus usual care (intervention group) or usual care alone (control group) in 216 patients with systolic heart failure (ejection fraction

Background
Depression is associated with physical inactivity, which may mediate the relationship between depression and a range of chronic physical health conditions. However, few interventions have combined a psychological intervention for depression with behaviour change techniques, such as behavioural activation (BA), to promote increased physical activity.

Methods
To determine procedural and clinical uncertainties to inform a definitive randomised controlled trial (RCT), a pilot parallel-group RCT was undertaken within two Improving Access to Psychological Therapies (IAPT) services in South West England. We aimed to recruit 80 adults with depression and randomise them to a supported, written self-help programme based on either BA or BA plus physical activity promotion (BAcPAc). Data were collected at baseline and 4 months post-randomisation to evaluate trial retention, intervention uptake and variance in outcomes to inform a sample size calculation. Qualitative data were collected from participants and psychological wellbeing practitioners (PWPs) to assess the acceptability and feasibility of the trial methods and the intervention. Routine data were collected to evaluate resource use and cost.

Results
Sixty people with depression were recruited, and a 73 % follow-up rate was achieved. Accelerometer physical activity data were collected for 64 % of those followed. Twenty participants (33 %) attended at least one treatment appointment. Interview data were analysed for 15 participants and 9 study PWPs. The study highlighted the challenges of conducting an RCT within existing IAPT services with high staff turnover and absences, participant scheduling issues, PWP and participant preferences for cognitive focussed treatment, and deviations from BA delivery protocols. The BAcPAc intervention was generally acceptable to patients and PWPs.

Conclusions
Although recruitment procedures and data collection were challenging, participants generally engaged with the BAcPAc self-help booklets and reported willingness to increase their physical activity. A number of feasibility issues were identified, in particular the under-use of BA as a treatment for depression, the difficulty that PWPs had in adapting their existing procedures for study purposes and the instability of the IAPT PWP workforce. These problems would need to be better understood and resolved before proceeding to a full-scale RCT.

BACKGROUND: Condition-specific measures are frequently used to assess the health-related quality of life of people with multiple sclerosis (MS). Such measures are unsuitable for use in economic evaluations that require estimates of cost per quality-adjusted life-year because they are not based on preferences. OBJECTIVES: to report the estimation of a preference-based single index for an eight-dimensional instrument for MS, the Multiple Sclerosis Impact Scale - Eight Dimensions (MSIS-8D), derived from an MS-specific measure of health-related quality of life, the 29-item Multiple Sclerosis Impact Scale (MSIS-29). METHODS: We elicited preferences for a sample of MSIS-8D states (n = 169) from a sample (n = 1702) of the UK general population. Preferences were elicited using the time trade-off technique via an Internet-based survey. We fitted regression models to these data to estimate values for all health states described by the MSIS-8D. Estimated values were assessed against MSIS-29 scores and values derived from generic preference-based measures in a large, representative sample of people with MS. RESULTS: Participants reported that the time trade-off questions were easy to understand. Observed health state values ranged from 0.08 to 0.89. The best-performing model was a main effects, random effects model (mean absolute error = 0.04). Validation analyses support the performance of the MSIS-8D index: it correlated more strongly than did generic measures with MSIS-29 scores, and it discriminated effectively between subgroups of people with MS. CONCLUSIONS: the MSIS-8D enables health state values to be estimated from the MSIS-29, adding to the methods available to assess health outcomes and to estimate quality-adjusted life-years for MS for use in health technology assessment and decision-making contexts.

BACKGROUND: Telephone triage represents one strategy to manage demand for face-to-face GP appointments in primary care. However, limited evidence exists of the challenges GP practices face in implementing telephone triage. We conducted a qualitative process evaluation alongside a UK-based cluster randomised trial (ESTEEM) which compared the impact of GP-led and nurse-led telephone triage with usual care on primary care workload, cost, patient experience, and safety for patients requesting a same-day GP consultation. The aim of the process study was to provide insights into the observed effects of the ESTEEM trial from the perspectives of staff and patients, and to specify the circumstances under which triage is likely to be successfully implemented. Here we report perspectives of staff. METHODS: the intervention comprised implementation of either GP-led or nurse-led telephone triage for a period of 2-3 months. A qualitative evaluation was conducted using staff interviews recruited from eight general practices (4 GP triage, 4 Nurse triage) in the UK, implementing triage as part of the ESTEEM trial. Qualitative interviews were undertaken with 44 staff members in GP triage and nurse triage practices (16 GPs, 8 nurses, 7 practice managers, 13 administrative staff). RESULTS: Staff reported diverse experiences and perceptions regarding the implementation of telephone triage, its effects on workload, and on the benefits of triage. Such diversity were explained by the different ways triage was organised, the staffing models used to support triage, how the introduction of triage was communicated across practice staff, and by how staff roles were reconfigured as a result of implementing triage. CONCLUSION: the findings from the process evaluation offer insight into the range of ways GP practices participating in ESTEEM implemented telephone triage, and the circumstances under which telephone triage can be successfully implemented beyond the context of a clinical trial. Staff experiences and perceptions of telephone triage are shaped by the way practices communicate with staff, prepare for and sustain the changes required to implement triage effectively, as well as by existing practice culture, and staff and patient behaviour arising in response to the changes made. TRIAL REGISTRATION: Current Controlled Trials ISRCTN20687662. Registered 28 May 2009.

BACKGROUND: Health services are increasingly focused on measuring and monitoring outcomes, particularly those that reflect patients' priorities. To be meaningful, outcomes measured should be valued by patients and carers, be consistent with what health professionals seek to achieve, and be robust in terms of measurement properties. The aim of this study was (i) to seek a shared vision between families and clinicians regarding key aspects of health as outcomes, beyond mortality and morbidity, for children with neurodisability, and (ii) to appraise which multidimensional patient reported outcome measures (PROMs) could be used to assess salient health domains. METHODS: Relevant outcomes were identified from (i) qualitative research with children and young people with neurodisability and parent carers, (ii) Delphi survey with health professionals, and (iii) systematic review of PROMs. The International Classification of Functioning Disability and Health provided a common language to code aspects of health. A subset of stakeholders participated in a prioritisation meeting incorporating a Q-sorting task to discuss and rank aspects of health. RESULTS: a total of 33 pertinent aspects of health were identified. Fifteen stakeholders from the qualitative and Delphi studies participated in the prioritisation meeting: 3 young people, 5 parent carers, and 7 health professionals. Aspects of health that emerged as more important for families and targets for health professionals were: communication, emotional wellbeing, pain, sleep, mobility, self-care, independence, mental health, community and social life, behaviour, toileting and safety. Whilst available PROMs measure many aspects of health in the ICF, no single PROM captures all the key domains prioritised as for children and young people with neurodisability. The paucity of scales for assessing communication was notable. CONCLUSIONS: We propose a core suite of key outcome domains for children with neurodisability that could be used in evaluative research, audit and as health service performance indicators. Future work could appraise domain-specific PROMs for these aspects of health; a single measure assessing the key aspects of health that could be applied across paediatric neurodisability remains to be developed.

BACKGROUND: the Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial aimed to determine whether or not oral Δ(9)-tetrahydrocannabinol (Δ(9)-THC) slowed the course of progressive multiple sclerosis (MS); evaluate safety of cannabinoid administration; and, improve methods for testing treatments in progressive MS. OBJECTIVES: There were three objectives in the CUPID study: (1) to evaluate whether or not Δ(9)-THC could slow the course of progressive MS; (2) to assess the long-term safety of Δ(9)-THC; and (3) to explore newer ways of conducting clinical trials in progressive MS. DESIGN: the CUPID trial was a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were randomised in a 2 : 1 ratio to Δ(9)-THC or placebo. Randomisation was balanced according to Expanded Disability Status Scale (EDSS) score, study site and disease type. Analyses were by intention to treat, following a pre-specified statistical analysis plan. A cranial magnetic resonance imaging (MRI) substudy, Rasch measurement theory (RMT) analyses and an economic evaluation were undertaken. SETTING: Twenty-seven UK sites. PARTICIPANTS: Adults aged 18-65 years with primary or secondary progressive MS, 1-year evidence of disease progression and baseline EDSS 4.0-6.5. INTERVENTIONS: Oral Δ(9)-THC (maximum 28 mg/day) or matching placebo. ASSESSMENT VISITS: Three and 6 months, and then 6-monthly up to 36 or 42 months. MAIN OUTCOME MEASURES: Primary outcomes were time to EDSS progression, and change in Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2) 20-point physical subscale (MSIS-29phys) score. Various secondary patient- and clinician-reported outcomes and MRI outcomes were assessed. RMT analyses examined performance of MS-specific rating scales as measurement instruments and tested for a symptomatic or disease-modifying treatment effect. Economic evaluation estimated mean incremental costs and quality-adjusted life-years (QALYs). RESULTS: Effectiveness - recruitment targets were achieved. of the 498 randomised patients (332 to active and 166 to placebo), 493 (329 active and 164 placebo) were analysed. PRIMARY OUTCOMES: no significant treatment effect; hazard ratio EDSS score progression (active : placebo) 0.92 [95% confidence interval (CI) 0.68 to 1.23]; and estimated between-group difference in MSIS-29phys score (active-placebo) -0.9 points (95% CI -2.0 to 0.2 points). Secondary clinical and MRI outcomes: no significant treatment effects. Safety - at least one serious adverse event: 35% and 28% of active and placebo patients, respectively. RMT analyses - scale evaluation: MSIS-29 version 2, MS Walking Scale-12 version 2 and MS Spasticity Scale-88 were robust measurement instruments. There was no clear symptomatic or disease-modifying treatment effect. Economic evaluation - estimated mean incremental cost to NHS over usual care, over 3 years £27,443.20 per patient. No between-group difference in QALYs. CONCLUSIONS: the CUPID trial failed to demonstrate a significant treatment effect in primary or secondary outcomes. There were no major safety concerns, but unwanted side effects seemed to affect compliance. Participants were more disabled than in previous studies and deteriorated less than expected, possibly reducing our ability to detect treatment effects. RMT analyses supported performance of MS-specific rating scales as measures, enabled group- and individual person-level examination of treatment effects, but did not influence study inferences. The intervention had significant additional costs with no improvement in health outcomes; therefore, it was dominated by usual care and not cost-effective. Future work should focus on determining further factors to predict clinical deterioration, to inform the development of new studies, and modifying treatments in order to minimise side effects and improve study compliance. The absence of disease-modifying treatments in progressive MS warrants further studies of the cannabinoid pathway in potential neuroprotection. TRIAL REGISTRATION: Current Controlled Trials ISRCTN62942668. FUNDING: the National Institute for Health Research Health Technology Assessment programme, the Medical Research Council Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society and Multiple Sclerosis Trust. The report will be published in full in Health Technology Assessment; Vol. 19, No. 12. See the NIHR Journals Library website for further project information.

BACKGROUND: Telephone triage is proposed as a method of managing increasing demand for primary care. Previous studies have involved small samples in limited settings, and focused on nurse roles. Evidence is limited regarding the impact on primary care workload, costs, and patient safety and experience when triage is used to manage patients requesting same-day consultations in general practice. OBJECTIVES: in comparison with usual care (UC), to assess the impact of GP-led telephone triage (GPT) and nurse-led computer-supported telephone triage (NT) on primary care workload and cost, patient experience of care, and patient safety and health status for patients requesting same-day consultations in general practice. DESIGN: Pragmatic cluster randomised controlled trial, incorporating economic evaluation and qualitative process evaluation. SETTING: General practices (n = 42) in four regions of England, UK (Devon, Bristol/Somerset, Warwickshire/Coventry, Norfolk/Suffolk). PARTICIPANTS: Patients requesting same-day consultations. INTERVENTIONS: Practices were randomised to GPT, NT or UC. Data collection was not blinded; however, analysis was conducted by a statistician blinded to practice allocation. MAIN OUTCOME MEASURES: Primary - primary care contacts [general practice, out-of-hours primary care, accident and emergency (A&E) and walk-in centre attendances] in the 28 days following the index consultation request. Secondary - resource use and costs, patient safety (deaths and emergency hospital admissions within 7 days of index request, and A&E attendance within 28 days), health status and experience of care. RESULTS: of 20,990 eligible randomised patients (UC n = 7283; GPT n = 6695; NT n = 7012), primary outcome data were analysed for 16,211 patients (UC n = 5572; GPT n = 5171; NT n = 5468). Compared with UC, GPT and NT increased primary outcome contacts (over 28-day follow-up) by 33% [rate ratio (RR) 1.33, 95% confidence interval (CI) 1.30 to 1.36] and 48% (RR 1.48, 95% CI 1.44 to 1.52), respectively. Compared with GPT, NT was associated with a marginal increase in primary outcome contacts by 4% (RR 1.04, 95% CI 1.01 to 1.08). Triage was associated with a redistribution of primary care contacts. Although GPT, compared with UC, increased the rate of overall GP contacts (face to face and telephone) over the 28 days by 38% (RR 1.38, 95% CI 1.28 to 1.50), GP face-to-face contacts were reduced by 39% (RR 0.61, 95% CI 0.54 to 0.69). NT reduced the rate of overall GP contacts by 16% (RR 0.84, 95% CI 0.78 to 0.91) and GP face-to-face contacts by 20% (RR 0.80, 95% CI 0.71 to 0.90), whereas nurse contacts increased. The increased rate of primary care contacts in triage arms is largely attributable to increased telephone contacts. Estimated overall patient-clinician contact time on the index day increased in triage (GPT = 10.3 minutes; NT = 14.8 minutes; UC = 9.6 minutes), although patterns of clinician use varied between arms. Taking account of both the pattern and duration of primary outcome contacts, overall costs over the 28-day follow-up were similar in all three arms (approximately £75 per patient). Triage appeared safe, and no differences in patient health status were observed. NT was somewhat less acceptable to patients than GPT or UC. The process evaluation identified the complexity associated with introducing triage but found no consistency across practices about what works and what does not work when implementing it. CONCLUSIONS: Introducing GPT or NT was associated with a redistribution of primary care workload for patients requesting same-day consultations, and at similar cost to UC. Although triage seemed to be safe, investigation of the circumstances of a larger number of deaths or admissions after triage might be warranted, and monitoring of these events is necessary as triage is implemented. TRIAL REGISTRATION: Current Controlled Trials ISRCTN20687662. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 13. See the NIHR Journals Library website for further project information.

Background: in the UK, thousands of people with high cardiovascular risk are being identified by a national risk-assessment programme (NHS Health Checks). Waste the Waist is an evidence-informed, theory-driven (modified Health Action Process Approach), group-based intervention designed to promote healthy eating and physical activity for people with high cardiovascular risk. This pilot randomised controlled trial aimed to assess the feasibility of delivering the Waste the Waist intervention in UK primary care and of conducting a full-scale randomised controlled trial. We also conducted exploratory analyses of changes in weight. Methods: Patients aged 40-74 with a Body Mass Index of 28 or more and high cardiovascular risk were identified from risk-assessment data or from practice database searches. Participants were randomised, using an online computerised randomisation algorithm, to receive usual care and standardised information on cardiovascular risk and lifestyle (Controls) or nine sessions of the Waste the Waist programme (Intervention). Group allocation was concealed until the point of randomisation. Thereafter, the statistician, but not participants or data collectors were blinded to group allocation. Weight, physical activity (accelerometry) and cardiovascular risk markers (blood tests) were measured at 0, 4 and 12 months. Results: 108 participants (22% of those approached) were recruited (55 intervention, 53 controls) from 6 practices and 89% and 85% provided data at 4 and 12 months respectively. Participants had a mean age of 65 and 70% were male. Intervention participants attended 72% of group sessions. Based on last observations carried forward, the intervention group did not lose significantly more weight than controls at 12 months, although the difference was significant when co-interventions and comorbidities that could affect weight were taken into account (Mean Diff 2.6Kg. 95%CI: -4.8 to -0.3, p=0.025). No significant differences were found in physical activity. Conclusions: the Waste the Waist intervention is deliverable in UK primary care, has acceptable recruitment and retention rates and produces promising preliminary weight loss results. Subject to refinement of the physical activity component, it is now ready for evaluation in a full-scale trial. Trial registration: Current Controlled Trials ISRCTN10707899. Funding source: National Institute of Health Research.

BACKGROUND: There have been few rigorous studies on the effects of behavioural support for helping smokers to reduce who do not immediately wish to quit. While reduction may not have the health benefits of quitting, it may lead smokers to want to quit. Physical activity (PA) helps to reduce cravings and withdrawal symptoms, and also reduces weight gain after quitting, but smokers may be less inclined to exercise. There is scope to develop and determine the effectiveness of interventions to support smoking reduction and increase physical activity, for those not ready to quit. OBJECTIVE: to conduct a pilot randomised controlled trial (RCT) [Exercise Assisted Reduction then Stop (EARS) smoking study] to (1) design and evaluate the feasibility and acceptability of a PA and smoking-reduction counselling intervention [for disadvantaged smokers who do not wish to quit but do want to reduce their smoking (to increase the likelihood of quitting)], and (2) to inform the design of a large RCT to determine the clinical effectiveness and cost-effectiveness of the intervention. DESIGN: a single-centre, pragmatic, pilot trial with follow-up up to 16 weeks. A mixed methods approach assessed the acceptability and feasibility of the intervention and trial methods. Smokers were individually randomised to intervention or control arms. SETTING: General practices, NHS buildings, community venues, and the Stop Smoking Service (SSS) within Plymouth, UK. PARTICIPANTS: Aged > 18 years, smoking ≥ 10 cigarettes per day (for ≥ 2 years) who wished to cut down. We excluded individuals who were contraindicated for moderate PA, posed a safety risk to the research team, wished to quit immediately or use Nicotine Replacement Therapy, not registered with a general practitioner, or did not converse in English. INTERVENTION: We designed a client-centred, counselling-based intervention designed to support smoking reduction and increases in PA. Support sessions were delivered by trained counsellors either face to face or by telephone. Both intervention and control arms were given information at baseline on specialist SSS support available should they have wished to quit. MAIN OUTCOME MEASURES: the primary outcome was 4-week post-quit expired air carbon monoxide (CO)-confirmed abstinence from smoking. Secondary outcomes included validated behavioural, cognitive and emotional/affective and health-related quality of life measures and treatment costs. RESULTS: the study randomised 99 participants, 49 to the intervention arm and 50 to the control arm, with a 62% follow-up rate at 16 weeks. In the intervention and control arms, 14% versus 4%, respectively [relative risk = 3.57; 95% confidence interval (CI) 0.78 to 16.35], had expired CO-confirmed abstinence at least 4 and up to 8 weeks after quit day; 22% versus 6% (relative risk = 3.74; 95% CI 1.11 to 12.60) made a quit attempt; 10% versus 4% (relative risk = 92.55; 95% CI 0.52 to 12.53) achieved point-prevalent abstinence at 16 weeks; and 39% versus 20% (relative risk = 1.94; 95% CI 1.01 to 3.74) achieved at least a 50% reduction in the number of cigarettes smoked daily. The percentage reporting using PA for controlling smoking in the intervention versus control arms was 55% versus 22%, respectively at 8 weeks and 37% versus 16%, respectively, at 16 weeks. The counsellors generally delivered the intervention as planned and participants responded with a variety of smoking reduction strategies, sometimes supported by changes in PA. The intervention costs were approximately £192 per participant. Exploratory cost-effectiveness modelling indicates that the intervention may be cost-effective. CONCLUSIONS: the study provided valuable information on the resources needed to improve study recruitment and retention. Offering support for smoking reduction and PA appears to have value in promoting reduction and cessation in disadvantaged smokers not currently motivated to quit. A large RCT is needed to assess the clinical effectiveness and cost-effectiveness of the intervention in this population. TRIAL REGISTRATION: ISRCTN 13837944. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment, Vol. 18, No. 4. See the NIHR Journals Library website for further project information.

BACKGROUND: Challenges remain to find ways to support patients with depression who have low levels of physical activity (PA) to overcome perceived barriers and enhance the perceived value of PA for preventing future relapse. There is an evidence-base for behavioural activation (BA) for depression, which focuses on supporting patients to restore activities that have been avoided, but practitioners have no specific training in promoting PA. We aimed to design and evaluate an integrated BA and PA (BAcPAc) practitioner-led, written, self-help intervention to enhance both physical and mental health. METHODS/DESIGN: This study is informed by the Medical Research Council Complex Intervention Framework and describes a protocol for a pilot phase II randomised controlled trial (RCT) to test the feasibility and acceptability of the trial methods to inform a definitive phase III RCT. Following development of the augmented written self-help intervention (BAcPAc) incorporating behavioural activation with physical activity promotion, depressed adults are randomised to receive up to 12 sessions over a maximum of 4 months of either BAcPAc or behavioural activation alone within a written self-help format, which represents treatment as usual. The study is located within two 'Improving Access to Psychological Therapies' services in South West England, with both written self-help interventions supported by mental health paraprofessionals. Measures assessed at 4, 9, and 12 month follow-up include the following: CIS-R, PHQ-9, accelerometer recorded (4 months only) and self-reported PA, body mass index, blood pressure, Insomnia Severity Index, quality of life, and health and social care service use. Process evaluation will include analysis of recorded support sessions and patient and practitioner interviews. At the time of writing the study has recruited 60 patients. DISCUSSION: the feasibility outcomes will inform a definitive RCT to assess the clinical and cost-effectiveness of the augmented BAcPAc written self-help intervention to reduce depression and depressive relapse, and bring about improvements across a range of physical health outcomes. TRIAL REGISTRATION: Current Controlled Trials ISRCTN74390532, 26.03.2013.

BACKGROUND: Collaborative care is an effective treatment for the management of depression but evidence on its cost-effectiveness in the UK is lacking. AIMS: to assess the cost-effectiveness of collaborative care in a UK primary care setting. METHODS: an economic evaluation alongside a multi-centre cluster randomised controlled trial comparing collaborative care with usual primary care for adults with depression (n = 581). Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICER) were calculated over a 12-month follow-up, from the perspective of the UK National Health Service and Personal Social Services (i.e. Third Party Payer). Sensitivity analyses are reported, and uncertainty is presented using the cost-effectiveness acceptability curve (CEAC) and the cost-effectiveness plane. RESULTS: the collaborative care intervention had a mean cost of £272.50 per participant. Health and social care service use, excluding collaborative care, indicated a similar profile of resource use between collaborative care and usual care participants. Collaborative care offered a mean incremental gain of 0.02 (95% CI: -0.02, 0.06) quality-adjusted life-years over 12 months, at a mean incremental cost of £270.72 (95% CI: -202.98, 886.04), and resulted in an estimated mean cost per QALY of £14,248. Where costs associated with informal care are considered in sensitivity analyses collaborative care is expected to be less costly and more effective, thereby dominating treatment as usual. CONCLUSION: Collaborative care offers health gains at a relatively low cost, and is cost-effective compared with usual care against a decision-maker willingness to pay threshold of £20,000 per QALY gained. Results here support the commissioning of collaborative care in a UK primary care setting.

Background Fatigue is a common and troubling symptom for people with multiple sclerosis (MS). Aim to evaluate the effectiveness and cost-effectiveness of a six-session group-based programme for managing MS-fatigue (Fatigue: Applying Cognitive behavioural and Energy effectiveness Techniques to lifeStyle (FACETS)). Methods Three-centre parallel arm randomised controlled trial with economic evaluation. Patients with MS and significant fatigue were randomised to FACETS plus current local practice (FACETS) or current local practice alone (CLP), using concealed computergenerated randomisation. Participant blinding was not possible. Primary outcomes were fatigue severity (Fatigue Assessment Instrument), self-efficacy (Multiple Sclerosis- Fatigue Self-Efficacy) and disease-specific quality of life (Multiple Sclerosis Impact Scale (MSIS-29)) at 1 and 4 months postintervention (follow-up 1 and 2). Quality adjusted life years (QALYs) were calculated (EuroQoL 5- Dimensions questionnaire and the Short-form 6- Dimensions questionnaire). Results Between May 2008 and November 2009, 164 patients were randomised; primary outcome data were available for 146 (89%). Statistically significant differences favour the intervention group on fatigue selfefficacy at follow-up 1 (mean difference (MD) 9, 95% CI (4 to 14), standardised effect size (SES) 0.54, p=0.001) and follow-up 2 (MD 6, 95% CI (0 to 12), SES 0.36, p=0.05) and fatigue severity at follow-up 2 (MD -0.36, 95% CI (-0.63 to -0.08), SES -0.35, p=0.01) but no differences for MSIS-29 or QALYs. No adverse events reported. Estimated cost per person for FACETS is £453; findings suggest an incremental cost-effectiveness ratio of £2157 per additional person with a clinically significant improvement in fatigue. Conclusions FACETS is effective in reducing fatigue severity and increasing fatigue self-efficacy. However, it is difficult to assess the additional cost in terms of costeffectiveness (ie, cost per QALY) as improvements in fatigue are not reflected in the QALY outcomes, with no significant differences between FACETS and CLP. The strengths of this trial are its pragmatic nature and high external validity.

BACKGROUND: Chronic radicular pain can be effectively treated with spinal cord stimulation, but this therapy is not always sufficient for chronic back pain. Subcutaneous nerve stimulation (SQS) refers to the placement of percutaneous leads in the subcutaneous tissue within the area of pain. Case series data show that failed back surgery syndrome (FBSS) patients experience clinically important levels of pain relief following SQS and may also reduce their levels of analgesic therapy and experience functional well-being. However, to date, there is no randomized controlled trial evidence to support the use of SQS in FBSS. METHODS/DESIGN: the SubQStim study is a multicenter randomized controlled trial comparing SQS plus optimized medical management ('SQS arm') versus optimized medical management alone ('OMM arm') in patients with predominant back pain due to FBSS. Up to 400 patients will be recruited from approximately 33 centers in Europe and Australia and will be randomized 1:1 to the SQS or OMM arms. After 9 months, patients who fail to reach the primary outcome will be allowed to switch treatments. Patients will be evaluated at baseline (prior to randomization) and at 1, 3, 6, 9, 12, 18, 24, and 36 months after randomization. The primary outcome is the proportion of patients at 9 months with a ≥50% reduction in back pain intensity compared to baseline. The secondary outcomes are: back and leg pain intensity score, functional disability, health-related quality of life, patient satisfaction, patient global impression of change, healthcare resource utilization/costs, cost-effectiveness analysis and adverse events. Outcomes arms will be compared between SQS and OMM arms at all evaluation points up to and including 9 months. After the 9-month assessment visit, the main analytic focus will be to compare within patient changes in outcomes relative to baseline. DISCUSSION: the SubQStim trial began patient recruitment in November 2012. Recruitment is expected to close in late 2014. TRIAL REGISTRATION: ClinicalTrials.gov NCT01711619.

Objective to compare the clinical effectiveness of collaborative care with usual care in the management of patients with moderate to severe depression.
Design Cluster randomised controlled trial.
Setting 51 primary care practices in three primary care districts in the United Kingdom.
Participants 581 adults aged 18 years an older who met ICD-10 (international classification of diseases, 10th revision) criteria for a depressive episode on the revised Clinical Interview Schedule. We excluded acutely suicidal patients and those with psychosis, or with type I or type II bipolar disorder; patients whose low mood was associated with bereavement or whose primary presenting problem was alcohol or drug abuse; and patients receiving psychological treatment for their depression by specialist mental health services. We identified potentially eligible participants by searching computerised case records in general practices for patients with depression.
Interventions Collaborative care, including depression education, drug management, behavioural activation, relapse prevention, and primary care liaison, was delivered by care managers. Collaborative care involved six to 12 contacts with participants over 14 weeks, supervised by mental health specialists. Usual care was family doctors’ standard clinical practice.
Main outcome measures Depression symptoms (patient health questionnaire 9; PHQ-9), anxiety (generalised anxiety disorder 7; GAD-7), and quality of life (short form 36 questionnaire; SF-36) at four and 12 months; and satisfaction with service quality (client satisfaction questionnaire; CSQ-8) at four months.
Results 276 participants were allocated to collaborative care and 305 allocated to usual care. At four months, mean depression score was 11.1 (standard deviation 7.3) for the collaborative care group and 12.7 (6.8) for the usual care group. After adjustment for baseline depression, mean depression score was 1.33 PHQ-9 points lower (95% confidence interval 0.35 to 2.31, P=0.009) in participants receiving collaborative care than in those receiving usual care at four months, and 1.36 points lower (0.07 to 2.64, P=0.04) at 12 months. Quality of mental health but not physical health was significantly better for collaborative care than for usual care at four months, but not 12 months. Anxiety did not differ between groups. Participants receiving collaborative care were significantly more satisfied with treatment than those receiving usual care. The number needed to treat for one patient to drop below the accepted diagnostic threshold for depression on the PHQ-9 was 8.4 immediately after treatment, and 6.5 at 12 months.
Conclusions Collaborative care has persistent positive effects up to 12 months after initiation of the intervention and is preferred by patients over usual care.
Trial registration number ISRCTN32829227.

Design Cluster randomised controlled trial

Setting 51 UK primary care practices in three UK primary care districts

Participants 581 adults aged 18+ who met ICD-10 criteria for a depressive episode on the revised Clinical Interview Schedule. We excluded acutely suicidal patients and those with psychosis, type I or type II bi-polar disorder, patients whose low mood was associated with bereavement or whose primary presenting problem was alcohol or drug abuse, and those receiving psychological treatment for their depression by specialist mental health services. We identified potentially eligible participants by searching general practice computerised case records for patients with depression.

Interventions Collaborative care, including depression education, medication management, behavioural activation, relapse prevention, and primary care liaison delivered by care managers, as 6-12 contacts with participants over 14 weeks, supervised by mental health specialists; usual care was family doctors’ standard clinical practice.

Main outcome measures Depression symptoms (PHQ-9), anxiety (GAD-7) and quality of life (SF-36) at four and 12 months, satisfaction with service quality (CSQ-8) at four months.

Results Collaborative care participants had a mean depression score 1•33 PHQ-9 points lower (95% CI 0•35 to 2•31, p = 0•009) than those in usual care at four months and 1•36 lower (95% CI 0•07 to 2•64, p = 0•04) at 12 months after adjustment for baseline depression. Quality of mental, but not physical, health was significantly better for collaborative care at four but not 12 months, and there was no difference for anxiety. Participants receiving collaborative care were significantly more satisfied with treatment. The number needed to treat for one patient to drop below the accepted diagnostic threshold for depression on the PHQ-9 was 8.4 immediately after treatment and 6.5 at 12 months follow up.

Conclusions Collaborative care has persistent positive effects up to 12 months after initiation of the intervention and is preferred by patients over usual care.

Trial registration number: ISRCTN32829227.

PURPOSE: Attention-deficit hyperactivity disorder (ADHD) is associated with increased use of health, social and education services. There is a lack of data to quantify the economic burden of ADHD in the UK. The aim of this study was to estimate additional education, health and social care costs amongst adolescents in the UK diagnosed with ADHD. METHODS: Participants were 143, 12- to 18-year-olds from the Cardiff longitudinal ADHD study. Service use relating to mental health over the previous year was measured using the children's service interview. Individual resource use was combined with unit cost data, from national sources, to calculate costs per patient and subsequently the mean cost per patient. Mean costs, 95% confidence intervals and median use were calculated using nonparametric bootstrapping methods. RESULTS: the mean cost per adolescent for NHS, social care and education resources used in a 12-month period related to ADHD was £5,493 (£4,415.68, £6,678.61) in 2010 prices and the median was £2,327. Education and NHS resources accounted for approximately 76 and 24%, respectively. Estimated annual total UK costs are £670 million. CONCLUSIONS: the additional costs to the NHS and education system of treating adolescents remain substantial for several years after the initial ADHD diagnosis. There exists a need to develop and evaluate early interventions which have the potential to reduce the longer-term burden, particularly on education resource use.

Objectives: Chronic musculoskeletal pain and osteoarthritis can significantly limit the functional independence of individuals, and given that 25% of the population experience these problems, the socioeconomic impact is immense. Exercise and self-management have proven benefits for these conditions, but most trials tailor interventions for specific joints. Epidemiological data demonstrates that many older people with degenerative joint problems experience pain and functional difficulty in other joints, seeking further healthcare input when these present. Managing multiple joint presentations simultaneously could potentially reduce the need for repeat visits to healthcare professionals as advice is frequently the same for differing site presentations. This single-blind cluster randomised controlled trial will determine the clinical and cost-effectiveness of an exercise and self-management intervention delivered to people over-50 with either hip, knee or lower back pain, compared to 'standard' GP care. A qualitative analysis will also establish the acceptability of the intervention. Methods: 352 people with chronic degenerative musculoskeletal pain of the hip, knee or lower back will be recruited from primary care. GP surgeries will be randomised to either the intervention or control arms. Participants in the intervention arm will receive a 6-week group exercise and self-management programme facilitated by a physiotherapist in primary care. Participants allocated to the control arm will continue under 'standard' GP care. The primary outcome measure is the Dysfunction Index of the Short Musculoskeletal Functional Assessment (SMFA). Analysis: Individual patient responses will be modelled using a mixed effects linear regression, allowing for the clustering effects. Resource use and related intervention costs will be estimated and broader resource use data will be collected using a version of the Client Service Receipt Inventory adapted for musculoskeletal relevance. In addition, a cost-utility analysis will be undertaken to present an estimate of the incremental cost per QALY. A qualitative analysis investigating the acceptability of the intervention to participants and healthcare professionals will also be undertaken and thematically analysed. Ethics and dissemination: Ethical approval was received from South West 4 REC, identification number 11/SW/0053. Study findings will be disseminated via conference and journal presentation; via arthritis charitable organisations; and through local GP consortia. © 2012 Chartered Society of Physiotherapy.

BACKGROUND: Multiple sclerosis (MS) is a chronic neurological disorder, which can lead to a wide range of disabling symptoms. The condition has a significant negative impact on health-related quality of life, and the economic cost of the disease is substantial. Decision-making regarding treatments for MS, and particularly disease-modifying interventions, has been hampered by limitations in the data and evaluative framework for assessing their cost effectiveness. Whilst attention has been drawn to these weaknesses, the scope and extent of the challenges in this area have not been fully set out to date. AIMS: the aims of this review were to identify all published economic evaluations of MS treatments in order to provide a statement on the scope and characteristics of the cost-effectiveness literature in the area of MS and to provide a basis on which to suggest practical recommendations for future research to aid decision-making. METHOD: a systematic search was undertaken to identify economic evaluations of treatments for people with MS published in English up to December 2011. Included studies were reviewed to provide a comprehensive description of the characteristics of the currently applied framework for cost effectiveness in MS, with the following key methodological components considered: methods for estimating disease progression, the impact of treatment and health outcomes and costs associated with MS. RESULTS: Thirty-seven papers were identified. Most studies (n = 32) were model-based evaluations of disease-modifying drugs. All models used disability stages defined by the Expanded Disability Status Scale (EDSS) to characterise disease progression, and the impact of treatment was based on data from clinical trials and epidemiological cohorts. Outcomes were primarily based on quality-adjusted life-years (n = 22) and/or related to relapse (n = 14). Estimates for health state utility values (HSUVs), costs and the impact of treatment on the course of MS varied considerably between studies, depending on the data sources used and the methods used to incorporate data into models. The scope of the studies was narrow, with a sparsity of economic evaluations of symptomatic and/or non-pharmacological interventions; exclusion of direct non-medical, indirect and informal care costs from analyses; and a narrow view of the potential impact of treatment, concentrating on disability, according to the EDSS, and relapses. In addition, there were issues concerning how to capture losses in HSUVs due to relapses in a way that reflects their salience to people with MS, the wide variation in costs and outcomes from different sources and from potentially unrepresentative samples and modelling disease progression from natural history data from over 30 years ago. CONCLUSION: There are many complexities for those designing and reporting cost-effectiveness studies of treatments for MS. Analysts, and ultimately decision makers, face multiple data and methodological challenges. Policy makers, technology developers, clinicians, patients and researchers need to acknowledge and address these challenges and to consider recommendations that will improve the current scenario. There is a need for further research that can constructively inform decision-making regarding the funding of treatments for MS.

BACKGROUND: over the last three decades there has been a substantial increase in the proportion of children who are overweight or obese. The Healthy Lifestyles Programme (HeLP) is a novel school-based intervention, using highly interactive and creative delivery methods to prevent obesity in children. METHODS/DESIGN: We describe a cluster randomised controlled trial to evaluate the effectiveness and cost effectiveness of HeLP. The intervention has been developed using intervention mapping (involving extensive stakeholder involvement) and has been guided by the Information, Motivation, Behavioural Skills model. HeLP includes creating a receptive environment, drama activities, goal setting and reinforcement activities and runs over three school terms. Piloting showed that 9 to 10 year olds were the most receptive and participative. This study aims to recruit 1,300 children from 32 schools (over half of which will have ≥19% of pupils eligible for free school meals) from the southwest of England. Participating schools will be randomised to intervention or control groups with baseline measures taken prior to randomisation. The primary outcome is change in body mass index standard deviation score (BMI SDS) at 24 months post baseline. Secondary outcomes include, waist circumference and percent body fat SDS and proportion of children classified as overweight or obese at 18 and 24 months and objectively measured physical activity and food intake at 18 months. Between-group comparisons will be made using random effects regression analysis taking into account the hierarchical nature of the study design. An economic evaluation will estimate the incremental cost-effectiveness of HeLP, compared to control, from the perspective of the National Health Service (NHS)/third party payer. An in-depth process evaluation will provide insight into how HeLP works, and whether there is any differential uptake or engagement with the programme. DISCUSSION: the results of the trial will provide evidence on the effectiveness and cost effectiveness of the Healthy Lifestyles Programme in affecting the weight status of children. TRIAL REGISTRATION: ISRCTN15811706.

BACKGROUND: Recent years have seen an increase in primary care workload, especially following the introduction of a new General Medical Services contract in 2004. Telephone triage and telephone consultation with patients seeking health care represent initiatives aimed at improving access to care. Some evidence suggests that such approaches may be feasible but conclusions regarding GP workload, cost, and patients' experience of care, safety, and health status are equivocal. The ESTEEM trial aims to assess the clinical- and cost-effectiveness of nurse-led computer-supported telephone triage and GP-led telephone triage, compared to usual care, for patients requesting same-day consultations in general practice. METHODS/DESIGN: ESTEEM is a pragmatic, multi-centre cluster randomised clinical trial with patients randomised at practice level to usual care, computer decision-supported nurse triage, or GP-led triage. Following triage of 350-550 patients per practice we anticipate estimating and comparing total primary care workload (volume and time), the economic cost to the NHS, and patient experience of care, safety, and health status in the 4-week period following the index same-day consultation request across the three trial conditions.We will recruit all patients seeking a non-emergency same-day appointment in primary care. Patients aged 12.0-15.9 years and temporary residents will be excluded from the study.The primary outcome is the number of healthcare contacts taking place in the 4-week period following (and including) the index same-day consultation request. A range of secondary outcomes will be examined including patient flow, primary care NHS resource use, patients' experience of care, safety, and health status.The estimated sample size required is 3,751 patients (11,253 total) in each of the three trial conditions, to detect a mean difference of 0.36 consultations per patient in the four week follow-up period between either intervention group and usual care 90% power, 5% alpha, and an estimated intracluster correlation coefficient ICC of 0.05. The primary analysis will be based on the intention-to-treat principle and take the form of a random effects regression analysis taking account of the hierarchical nature of the study design. Statistical models will allow for adjustment for practice level minimisation variables and patient-level baseline covariates shown to differ at baseline. TRIAL REGISTRATION: Current Controlled Trials ISCRTN20687662.

To address the pending public health crisis due to Alzheimer's disease (AD) and related neurodegenerative disorders, the Marian S. Ware Alzheimer Program at the University of Pennsylvania held a meeting entitled "State of the Science Conference on the Advancement of Alzheimer's Diagnosis, Treatment and Care," on June 21-22, 2012. The meeting comprised four workgroups focusing on Biomarkers; Clinical Care and Health Services Research; Drug Development; and Health Economics, Policy, and Ethics. The workgroups shared, discussed, and compiled an integrated set of priorities, recommendations, and action plans, which are presented in this article. © 2012 the Alzheimer's Association. All rights reserved.

Alzheimer's disease (AD) is a chronic, progressive, neurodegenerative disease that places a heavy burden on people with the condition, their families and carers, health care systems and society in general. Health-related quality of life (HR-QOL) in patients deteriorates as the cognitive, behavioural and functional symptoms of AD develop. The human and financial cost of AD is forecast to grow rapidly as populations age, and those responsible for planning and financing health care face the challenge of allocating increasingly scarce resources against current and future interventions targeted towards AD. These include calls for early detection and diagnosis, preventative strategies, new medications, residential care, supportive care, and meeting the needs of carers as well as patients. Health care funders in many health systems now require a demonstration of the value of new interventions through a comparison of benefits in terms of improvements in HR-QOL and costs relative to those of competing or existing practices. Changes in HR-QOL provide the basis for the calculation of the quality-adjusted life-year (QALY), a key outcome used in economic evaluations to compare treatments within and between different disease conditions. The objective of this systematic review was to provide a summary of the published health state values (utilities) for AD patients and their carers that are currently available to estimate QALYs for use in health economic evaluations of interventions in AD. The health care literature was searched for articles published in English between 2000 and 2011, using keywords and variants including 'quality-adjusted life years', 'health state indicators', 'health utilities' and the specific names of generic measures of HR-QOL and health state valuation techniques. Databases searched included MEDLINE, EMBASE, NHS EED, PsycINFO and ISI Web of Science. This review identified 12 studies that reported utility values associated with health states in AD. Values for AD health states categorized according to cognitive impairment (where 1 = perfect health and 0 = dead) ranged from mild AD (0.52-0.73) to moderate AD (0.30-0.53) to severe AD (0.12-0.49). Utility values were almost all based on two generic measures of HR-QOL: the EQ-5D and Health Utility Index mark 2/3 (HUI2/3). There were no health state values estimated from condition- or disease-specific measures of HR-QOL. The review also identified 18 published cost-utility analyses (CUAs) of treatments for AD. The CUAs incorporated results from only three of the identified health state valuation studies. Twelve CUAs relied on the same study for health state values. We conclude that the literature on health state values in AD is limited and overly reliant on a single symptom (cognition) to describe disease progression. Other approaches to characterizing disease progression in AD based on multiple outcomes or dependency may be better predictors of costs and utilities in economic evaluations. Patient and proxy ratings were poorly correlated, particularly in patients with more advanced AD. However, proxy ratings displayed the validity and reliability across the entire range of AD severity needed to detect long-term changes relevant to economic evaluation. Further longitudinal research of patient and carer HR-QOL based on multidimensional measures of outcome and utilities is needed.

Background: Research on the relationship between Health Related Quality of Life (HRQoL) and physical activity (PA), to date, have rarely investigated how this relationship differ across objective and subjective measures of PA. The aim of this paper is to explore the relationship between HRQoL and PA, and examine how this relationship differs across objective and subjective measures of PA, within the context of a large representative national survey from England. Methods. Using a sample of 5,537 adults (40-60years) from a representative national survey in England (Health Survey for England 2008), Tobit regressions with upper censoring was employed to model the association between HRQoL and objective, and subjective measures of PA controlling for potential confounders. We tested the robustness of this relationship across specific types of PA. HRQoL was assessed using the summary measure of health state utility value derived from the EuroQol-5 Dimensions (EQ-5D) whilst PA was assessed via subjective measure (questionnaire) and objective measure (accelerometer- actigraph model GT1M). The actigraph was worn (at the waist) for 7days (during waking hours) by a randomly selected sub-sample of the HSE 2008 respondents (4,507 adults - 16 plus years), with a valid day constituting 10 hours. Analysis was conducted in 2010. Results: Findings suggest that higher levels of PA are associated with better HRQoL (regression coefficient: 0.026 to 0.072). This relationship is consistent across different measures and types of PA although differences in the magnitude of HRQoL benefit associated with objective and subjective (regression coefficient: 0.047) measures of PA are noticeable, with the former measure being associated with a relatively better HRQoL (regression coefficient: 0.072). Conclusion: Higher levels of PA are associated with better HRQoL. Using an objective measure of PA compared with subjective shows a relatively better HRQoL. © 2012 Anokye et al.; licensee BioMed Central Ltd.

The aim of the study was to estimate health state utility values in newly diagnosed idiopathic Parkinson's disease (PD) for use in the assessment of health-related quality-of-life (HRQL), and in the estimation of quality-adjusted life-years (QALYs). Data from 162 patients enrolled in a community-based incidence study of PD were used to estimate health state utility values. Self-report data from the EQ-5D, a generic measure of HRQL, were used to derive preference-based health state utility values. The impact of motor and non motor symptoms, and other clinical and demographic factors, on the derived EQ-5D health state values was examined in univariate and multivariate analyses. The mean health state utility value for recently diagnosed PD patients was estimated at 0.65 ± 0.27. Significant reductions in health state values were attributable to pain (-0.18), motor functioning (-0.16), depression (-0.12), and insomnia (-0.11). Depression had its greatest impact (-0.19) in patients in the less severe stages of PD (i.e. Hoehn Yahr stages ≤2.5). This study shows, through the presentation of QALY values, that there is scope to achieve significant health gains in newly diagnosed idiopathic PD patients via improved management of pain, depression and insomnia, alongside the treatment of primary motor symptoms.

BACKGROUND: Walking impairment has a major influence on the quality of life of people with multiple sclerosis (MS). The Multiple Sclerosis Walking Scale (MSWS-12) assesses the impact of MS on walking ability from the patient's perspective, but in its current form, is not amenable for use in many policy decision-making settings. OBJECTIVES: Statistical 'mapping' methods were used to convert MSWS-12 scores to EQ-5D health state values. METHODS: the relationship between the measures was estimated using cohort data from people with MS in South West England. Regression analyses were conducted, estimation errors assessed, and predictive performance of the best models tested using longitudinal data. RESULTS: Model performance was in line with that of other mapping studies, with the best-performing models being an ordinary least squares (OLS) model using MSWS-12 item scores, and an OLS model using the total MSWS-12 score and its squared term. CONCLUSIONS: a process has been described whereby data from a patient-reported outcome measure (MSWS-12) can be converted to (EQ-5D) health state values. These values may be used to consider the health-related quality of life of people with MS, to estimate quality adjusted life-years for use in effectiveness and cost-effectiveness analyses, and to inform health policy decisions.

OBJECTIVES: the 29-item Multiple Sclerosis Impact Scale (MSIS-29) is a psychometrically validated patient-reported outcome measure increasingly used in trials of treatments for multiple sclerosis. However, it is non-preference-based and not amenable for use across policy decision-making contexts. Our objective was to statistically map from the MSIS-29, version 2, to the EuroQol five-dimension (EQ-5D) and the six-dimension health state short form (derived from short form 36 health survey) (SF-6D) to estimate algorithms for use in cost-effectiveness analyses. METHODS: the relationships between MSIS-29, version 2, and EQ-5D and SF-6D scores were estimated by using data from a cohort of people with multiple sclerosis in South West England (n=672). Six ordinary least squares (OLS), Tobit, and censored least adjusted deviation (CLAD) regression analyses were conducted on estimation samples, including the use of subscale and item scores, squared and interaction terms, and demographics. Algorithms from models with the smallest estimation errors (mean absolute error [MAE], root mean square error [RMSE], normalized RMSE) were then assessed by using separate validation samples. RESULTS: Tobit and CLAD. For the EQ-5D, the OLS models including subscale squared terms, and item scores and demographics performed comparably (MAE 0.147, RMSE 0.202 and MAE 0.147, RMSE 0.203, respectively), and estimated scores well up to 3 years post-baseline. Estimation errors for the SF-6D were smaller (OLS model including squared terms: MAE 0.058, RMSE 0.073; OLS model using item scores and demographics: MAE 0.059, RMSE 0.08), and the errors for poorer health states found with the EQ-5D were less pronounced. CONCLUSIONS: We have provided algorithms for the estimation of health state utility values, both the EQ-5D and SF-6D, from scores on the MSIS-29, version 2. Further research is now needed to determine how these algorithms perform in practical decision-making contexts, when compared with observed EQ-5D and SF-6D values.

BACKGROUND: Social isolation affects a significant proportion of older people and is associated with poor health outcomes. The current evidence base regarding the effectiveness of interventions targeting social isolation is poor, and the potential utility of mentoring for this purpose has not previously been rigorously evaluated. The purpose of this study was to examine the effectiveness of a community-based mentoring service for improving mental health, social engagement and physical health for socially isolated older people. METHODS: This prospective controlled trial compared a sample of mentoring service clients (intervention group) with a matched control group recruited through general practice. One hundred and ninety five participants from each group were matched on mental wellbeing and social activity scores. Assessments were conducted at baseline and at six month follow-up. The primary outcome was the Short Form Health Survey v2 (SF-12) mental health component score (MCS). Secondary outcomes included the SF-12 physical health component score (PCS), EuroQol EQ-5D, Geriatric Depression Score (GDS-10), social activity, social support and morbidities. RESULTS: We found no evidence that mentoring was beneficial across a wide range of participant outcomes measuring health status, social activity and depression. No statistically significant between-group differences were observed at follow-up in the primary outcome (p = 0.48) and in most secondary outcomes. Identifying suitable matched pairs of intervention and control group participants proved challenging. CONCLUSIONS: the results of this trial provide no substantial evidence supporting the use of community mentoring as an effective means of alleviating social isolation in older people. Further evidence is needed on the effectiveness of community-based interventions targeting social isolation. When using non-randomised designs, there are considerable challenges in the recruitment of suitable matches from a community sample. TRIAL REGISTRATION: SCIE Research Register for Social Care 105923.

Objective: to assess the impact of exercise referral schemes on physical activity and health outcomes. Design: Systematic review and meta-analysis. Data sources: Medline, Embase, PsycINFO, Cochrane Library, ISI Web of Science, SPORTDiscus, and ongoing trial registries up to October 2009. We also checked study references. Study selection: Design: randomised controlled trials or non-randomised controlled (cluster or individual) studies published in peer review journals. Population: sedentary individuals with or without medical diagnosis. Exercise referral schemes defined as: clear referrals by primary care professionals to third party service providers to increase physical activity or exercise, physical activity or exercise programmes tailored to individuals, and initial assessment and monitoring throughout programmes. Comparators: usual care, no intervention, or alternative exercise referral schemes. Results: Eight randomised controlled trials met the inclusion criteria, comparing exercise referral schemes with usual care (six trials), alternative physical activity intervention (two), and an exercise referral scheme plus a self determination theory intervention (one). Compared with usual care, follow-up data for exercise referral schemes showed an increased number of participants who achieved 90-150 minutes of physical activity of at least moderate intensity per week (pooled relative risk 1.16, 95% confidence intervals 1.03 to 1.30) and a reduced level of depression (pooled standardised mean difference -0.82, -1.28 to -0.35). Evidence of a between group difference in physical activity of moderate or vigorous intensity or in other health outcomes was inconsistent at follow-up. We did not find any difference in outcomes between exercise referral schemes and the other two comparator groups. None of the included trials separately reported outcomes in individuals with specific medical diagnoses. Substantial heterogeneity in the quality and nature of the exercise referral schemes across studies might have contributed to the inconsistency in outcome findings. Conclusions: Considerable uncertainty remains as to the effectiveness of exercise referral schemes for increasing physical activity, fitness, or health indicators, or whether they are an efficient use of resources for sedentary people with or without a medical diagnosis.

OBJECTIVE: to assess the impact of exercise referral schemes on physical activity and health outcomes. Design Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, PsycINFO, Cochrane Library, ISI Web of Science, SPORTDiscus, and ongoing trial registries up to October 2009. We also checked study references. Study selection Design: randomised controlled trials or non-randomised controlled (cluster or individual) studies published in peer review journals. POPULATION: sedentary individuals with or without medical diagnosis. Exercise referral schemes defined as: clear referrals by primary care professionals to third party service providers to increase physical activity or exercise, physical activity or exercise programmes tailored to individuals, and initial assessment and monitoring throughout programmes. Comparators: usual care, no intervention, or alternative exercise referral schemes. RESULTS: Eight randomised controlled trials met the inclusion criteria, comparing exercise referral schemes with usual care (six trials), alternative physical activity intervention (two), and an exercise referral scheme plus a self determination theory intervention (one). Compared with usual care, follow-up data for exercise referral schemes showed an increased number of participants who achieved 90-150 minutes of physical activity of at least moderate intensity per week (pooled relative risk 1.16, 95% confidence intervals 1.03 to 1.30) and a reduced level of depression (pooled standardised mean difference -0.82, -1.28 to -0.35). Evidence of a between group difference in physical activity of moderate or vigorous intensity or in other health outcomes was inconsistent at follow-up. We did not find any difference in outcomes between exercise referral schemes and the other two comparator groups. None of the included trials separately reported outcomes in individuals with specific medical diagnoses. Substantial heterogeneity in the quality and nature of the exercise referral schemes across studies might have contributed to the inconsistency in outcome findings. Conclusions Considerable uncertainty remains as to the effectiveness of exercise referral schemes for increasing physical activity, fitness, or health indicators, or whether they are an efficient use of resources for sedentary people with or without a medical diagnosis.

OBJECTIVE: to consider the methods available to model Alzheimer's disease (AD) progression over time to inform on the structure and development of model-based evaluations, and the future direction of modelling methods in AD. METHODS: a systematic search of the health care literature was undertaken to identify methods to model disease progression in AD. Modelling methods are presented in a descriptive review. RESULTS: the literature search identified 42 studies presenting methods or applications of methods to model AD progression over time. The review identified 10 general modelling frameworks available to empirically model the progression of AD as part of a model-based evaluation. Seven of these general models are statistical models predicting progression of AD using a measure of cognitive function. The main concerns with models are on model structure, around the limited characterization of disease progression, and on the use of a limited number of health states to capture events related to disease progression over time. None of the available models have been able to present a comprehensive model of the natural history of AD. CONCLUSIONS: Although helpful, there are serious limitations in the methods available to model progression of AD over time. Advances are needed to better model the progression of AD and the effects of the disease on peoples' lives. Recent evidence supports the need for a multivariable approach to the modelling of AD progression, and indicates that a latent variable analytic approach to characterising AD progression is a promising avenue for advances in the statistical development of modelling methods.

BACKGROUND: Exercise referral schemes (ERS) aim to identify inactive adults in the primary-care setting. The GP or health-care professional then refers the patient to a third-party service, with this service taking responsibility for prescribing and monitoring an exercise programme tailored to the needs of the individual. OBJECTIVE: to assess the clinical effectiveness and cost-effectiveness of ERS for people with a diagnosed medical condition known to benefit from physical activity (PA). The scope of this report was broadened to consider individuals without a diagnosed condition who are sedentary. DATA SOURCES: MEDLINE; EMBASE; PsycINFO; the Cochrane Library, ISI Web of Science; SPORTDiscus and ongoing trial registries were searched (from 1990 to October 2009) and included study references were checked. METHODS: Systematic reviews: the effectiveness of ERS, predictors of ERS uptake and adherence, and the cost-effectiveness of ERS; and the development of a decision-analytic economic model to assess cost-effectiveness of ERS. RESULTS: Seven randomised controlled trials (UK, n = 5; non-UK, n = 2) met the effectiveness inclusion criteria, five comparing ERS with usual care, two compared ERS with an alternative PA intervention, and one to an ERS plus a self-determination theory (SDT) intervention. In intention-to-treat analysis, compared with usual care, there was weak evidence of an increase in the number of ERS participants who achieved a self-reported 90-150 minutes of at least moderate-intensity PA per week at 6-12 months' follow-up [pooled relative risk (RR) 1.11, 95% confidence interval 0.99 to 1.25]. There was no consistent evidence of a difference between ERS and usual care in the duration of moderate/vigorous intensity and total PA or other outcomes, for example physical fitness, serum lipids, health-related quality of life (HRQoL). There was no between-group difference in outcomes between ERS and alternative PA interventions or ERS plus a SDT intervention. None of the included trials separately reported outcomes in individuals with medical diagnoses. Fourteen observational studies and five randomised controlled trials provided a numerical assessment of ERS uptake and adherence (UK, n = 16; non-UK, n = 3). Women and older people were more likely to take up ERS but women, when compared with men, were less likely to adhere. The four previous economic evaluations identified suggest ERS to be a cost-effective intervention. Indicative incremental cost per quality-adjusted life-year (QALY) estimates for ERS for various scenarios were based on a de novo model-based economic evaluation. Compared with usual care, the mean incremental cost for ERS was £169 and the mean incremental QALY was 0.008, with the base-case incremental cost-effectiveness ratio at £20,876 per QALY in sedentary people without a medical condition and a cost per QALY of £14,618 in sedentary obese individuals, £12,834 in sedentary hypertensive patients, and £8414 for sedentary individuals with depression. Estimates of cost-effectiveness were highly sensitive to plausible variations in the RR for change in PA and cost of ERS. LIMITATIONS: We found very limited evidence of the effectiveness of ERS. The estimates of the cost-effectiveness of ERS are based on a simple analytical framework. The economic evaluation reports small differences in costs and effects, and findings highlight the wide range of uncertainty associated with the estimates of effectiveness and the impact of effectiveness on HRQoL. No data were identified as part of the effectiveness review to allow for adjustment of the effect of ERS in different populations. CONCLUSIONS: There remains considerable uncertainty as to the effectiveness of ERS for increasing activity, fitness or health indicators or whether they are an efficient use of resources in sedentary people without a medical diagnosis. We failed to identify any trial-based evidence of the effectiveness of ERS in those with a medical diagnosis. Future work should include randomised controlled trials assessing the cinical effectiveness and cost-effectivenesss of ERS in disease groups that may benefit from PA. FUNDING: the National Institute for Health Research Health Technology Assessment programme.

BACKGROUND: Exercise referral schemes (ERS) aim to identify inactive adults in the primary care setting. The primary care professional refers the patient to a third party service, with this service taking responsibility for prescribing and monitoring an exercise programme tailored to the needs of the patient. This paper examines the cost-effectiveness of ERS in promoting physical activity compared with usual care in primary care setting. METHODS: a decision analytic model was developed to estimate the cost-effectiveness of ERS from a UK NHS perspective. The costs and outcomes of ERS were modelled over the patient's lifetime. Data were derived from a systematic review of the literature on the clinical and cost-effectiveness of ERS, and on parameter inputs in the modelling framework. Outcomes were expressed as incremental cost per quality-adjusted life-year (QALY). Deterministic and probabilistic sensitivity analyses investigated the impact of varying ERS cost and effectiveness assumptions. Sub-group analyses explored the cost-effectiveness of ERS in sedentary people with an underlying condition. RESULTS: Compared with usual care, the mean incremental lifetime cost per patient for ERS was £169 and the mean incremental QALY was 0.008, generating a base-case incremental cost-effectiveness ratio (ICER) for ERS at £20,876 per QALY in sedentary individuals without a diagnosed medical condition. There was a 51% probability that ERS was cost-effective at £20,000 per QALY and 88% probability that ERS was cost-effective at £30,000 per QALY. In sub-group analyses, cost per QALY for ERS in sedentary obese individuals was £14,618, and in sedentary hypertensives and sedentary individuals with depression the estimated cost per QALY was £12,834 and £8,414 respectively. Incremental lifetime costs and benefits associated with ERS were small, reflecting the preventative public health context of the intervention, with this resulting in estimates of cost-effectiveness that are sensitive to variations in the relative risk of becoming physically active and cost of ERS. CONCLUSIONS: ERS is associated with modest increase in lifetime costs and benefits. The cost-effectiveness of ERS is highly sensitive to small changes in the effectiveness and cost of ERS and is subject to some significant uncertainty mainly due to limitations in the clinical effectiveness evidence base.

PURPOSE: to investigate for socially isolated older people, and older people at risk of social isolation: (1) health status and health-related quality of life (HRQL); (2) the relationship between social isolation and health status/HRQL; (3) the relationship between two alternative measures of health status/HRQL. METHODS: Older people at risk of social isolation (n = 393) completed the EQ-5D and the SF-12. Multiple regression analyses were performed to examine the relationship between levels of social isolation and health status/HRQL, controlling for demographic/clinical characteristics. The agreement between EQ-5D and SF-6D (SF-12) scores was explored using descriptive psychometric techniques. RESULTS: Health status and health state values were much lower than UK general population age-matched norms. After controlling for depression, physical co-morbidities, age, gender, living alone status, employment and accommodation, social isolation was significantly associated, to a degree that was clinically relevant, with EQ-5D DSI, SF-6D (SF-12) and SF-12 MCS scores. The potential for ceiling effects on the EQ-5D with this population was identified. CONCLUSION: This work highlights the burden that social isolation may have on the health and well-being of older people. The potential HRQL gains from addressing social isolation may be considerable, with those at risk of social isolation also a key target group.

The aims of this review were to review decision-analytic models used to evaluate interventions in idiopathic Parkinson's disease (PD), and to consider the future directions for development of methods to model the progression of PD over time. A systematic search of the healthcare literature up to June 2010 identified model-based economic evaluations in PD. The modelling methods used in the identified studies were appraised using good practice guidelines for decision-analytic modelling. The review identified 18 model-based evaluations of interventions in PD. All models evaluated treatments targeted towards the motor symptoms of PD or the motor complications of PD treatment. There were no models identified that evaluated interventions targeted towards the non-motor symptoms of PD, such as neuropsychiatric problems or autonomic dysfunction. Consequently, models characterized disease progression in PD using clinical measures of motor functioning. Most studies (n = 13) evaluated medications, three evaluated diagnostic technologies and two examined surgical procedures. Overall, the models reported structural components and data inputs appropriately and clearly, although limited evidence was provided to support choices made on the structures used in the models or the data synthesis reported. Models did not adequately consider structural uncertainty or internal/external consistency. Modelling methods used to date do not capture the full impact of PD. The emphasis in the current literature is on the motor symptoms of PD, characterizing the clinical nature of disease progression, largely neglecting the important impacts of non-motor symptoms. Modelling methods reported for the motor symptoms of PD may not be suitable for future interventions targeted towards modifying disease progression in PD across the entire spectrum of PD. More comprehensive models of disease progression, including both motor and non-motor symptoms will be needed where it is important to capture the effects of interventions more broadly.

OBJECTIVES: to assess the clinical effectiveness and cost-effectiveness of bevacizumab, combined with interferon (IFN), sorafenib tosylate, sunitinib and temsirolimus in the treatment of people with advanced and/or metastatic renal cell carcinoma (RCC). DATA SOURCES: Electronic databases, including MEDLINE, EMBASE and the Cochrane Library, were searched up to September/October 2007 (and again in February 2008). REVIEW METHODS: Systematic reviews and randomised clinical trials comparing any of the interventions with any of the comparators in participants with advanced and/or metastatic RCC were included, also phase II studies and conference abstracts if there was sufficient detail to adequately assess quality. Results were synthesised narratively and a decision-analytic Markov-type model was developed to simulate disease progression and estimate the cost-effectiveness of the interventions under consideration. RESULTS: a total of 888 titles and abstracts were retrieved in the clinical effectiveness review, including reports of eight clinical trials. Treatment with bevacizumab plus IFN or sunitinib had clinically relevant and statistically significant advantages over treatment with IFN alone, in terms of progression-free survival and tumour response, doubling median progression-free survival from approximately 5 months to 10 months. Temsirolimus had similar advantages over treatment with IFN in terms of progression-free and overall survival, increasing median overall survival from 7.3 to 10.9 months [hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.58 to 0.92)], as did sorafenib in comparison with best supportive care in terms of overall survival, progression-free survival and tumour response, with a doubling of progression-free survival (HR 0.51; 95% CI 0.43 to 0.60). However, the last was associated with an increased frequency of hypertension and hand-foot skin reaction compared with placebo. No fully published economic evaluations of any of the interventions could be located. However, estimates from the PenTAG model suggested that none of the interventions would be considered cost-effective at a willingness-to-pay threshold of 30,000 pounds per quality-adjusted life-year (QALY). Estimates of cost per QALY ranged from 71,462 pounds for sunitinib to 171,301 pounds for bevacizumab plus IFN. Although there are many similarities in the methodology and structural assumptions employed by PenTAG and the manufacturers of the interventions, in all cases the cost-effectiveness estimates from the PenTAG model were higher than those presented in the manufacturers' submissions. Cost-effectiveness estimates were particularly sensitive to variations in the estimates of treatment effectiveness, drug pricing (including dose intensity data), and health-state utility input parameters. CONCLUSIONS: Treatment with bevacizumab plus IFN and sunitinib has clinically relevant and statistically significant advantages over treatment with IFN alone in patients with metastatic RCC. In people with three of six risk factors for poor prognosis, temsirolimus had clinically relevant advantages over treatment with IFN, and sorafenib tosylate was superior to best supportive care as second-line therapy. The frequency of adverse events associated with bevacizumab plus IFN, sunitinib and temsirolimus was comparable with that seen with IFN, although the adverse event profile is different. Treatment with sorafenib was associated with a significantly increased frequency of hypertension and hand-foot syndrome. Estimates from the PenTAG model suggested that none of the interventions would be considered cost-effective at a willingness-to-pay threshold of 30,000 pounds per QALY.

OBJECTIVES: to estimate the cost-effectiveness of sorafenib (Nexavar, Bayer, Leverkusen, Germany) versus best supportive care (BSC) for second-line treatment of advanced renal cell carcinoma from the perspective of the UK National Health Service. METHODS: a decision analytic model was developed to estimate the cost-effectiveness of sorafenib. The clinical effectiveness of sorafenib versus BSC was taken from a recent randomized phase III trial. Utility values were taken from a phase II trial of sunitinib, using EQ-5D tariffs. Cost data were obtained from published literature and were based on current UK practice. The effect of parameter uncertainty on cost-effectiveness was explored through extensive one-way and probabilistic sensitivity analyses. RESULTS: Compared to BSC, sorafenib treatment resulted in an incremental cost per quality-adjusted life year (QALY) gained of pound75,398, based on an estimated mean gain of 0.27 QALYs per patient, at a mean additional cost of pound20,063 (inflated to 2007/2008). The probability that sorafenib is cost-effective compared to BSC at a willingness to pay threshold of pound30,000 per QALY is 0.0%. In sensitivity analysis, estimates of cost per QALY were sensitive to changes in the clinical effectiveness parameters, and to health state utilities and drug costs. CONCLUSIONS: Sorafenib has been shown to be clinically effective compared to BSC, offering additional health benefits; however, with a cost per QALY in excess of pound70,000, it may not be regarded as a cost-effective use of resources in some health-care settings.

OBJECTIVES: to estimate the cost-effectiveness of temsirolimus compared to interferon-alpha for first line treatment of patients with advanced, poor prognosis renal cell carcinoma, from the perspective of the UK National Health Service. METHODS: a decision-analytic model was developed to estimate the cost-effectiveness of temsirolimus. The clinical effectiveness of temsirolimus compared with interferon-alpha and the utility values (using EQ-5D tariffs) were taken from a recent phase III randomized clinical trial. Cost data were obtained from published literature and based on current UK practice. The effect of parameter uncertainty on cost-effectiveness was explored through extensive one-way and probabilistic sensitivity analyses. RESULTS: Compared to interferon-alpha, temsirolimus treatment resulted in an incremental cost per QALY gained of pound94,632; based on an estimated mean gain of 0.24 quality-adjusted life years (QALYs) per patient, at a mean additional cost of pound22,331 (inflated to 2007/8). The cost per QALY for patient subgroups ranged from pound74,369 to pound154,752. The probability that temsirolimus is cost-effective compared to interferon-alpha at a willingness to pay threshold of pound30,000 per QALY for all patient groups is expected to be close to zero. The cost per QALY was sensitive to the clinical effectiveness parameters, health state utilities, drug costs and the cost of administration of temsirolimus. CONCLUSIONS: Temsirolimus has been shown to be clinically effective compared to interferon-alpha offering additional health benefits, however, with a cost per QALY in excess of pound90,000, it may not be regarded as a cost-effective use of resources in some health care settings.

Background: Fatigue is one of the most commonly reported and debilitating symptoms of multiple sclerosis (MS); approximately two-thirds of people with MS consider it to be one of their three most troubling symptoms. It may limit or prevent participation in everyday activities, work, leisure, and social pursuits, reduce psychological well-being and is one of the key precipitants of early retirement. Energy effectiveness approaches have been shown to be effective in reducing MS-fatigue, increasing self-efficacy and improving quality of life. Cognitive behavioural approaches have been found to be effective for managing fatigue in other conditions, such as chronic fatigue syndrome, and more recently, in MS. The aim of this pragmatic trial is to evaluate the clinical and cost-effectiveness of a recently developed group-based fatigue management intervention (that blends cognitive behavioural and energy effectiveness approaches) compared with current local practice.Methods/Design: This is a multi-centre parallel arm block-randomised controlled trial (RCT) of a six session group-based fatigue management intervention, delivered by health professionals, compared with current local practice. 180 consenting adults with a confirmed diagnosis of MS and significant fatigue levels, recruited via secondary/primary care or newsletters/websites, will be randomised to receive the fatigue management intervention or current local practice. An economic evaluation will be undertaken alongside the trial. Primary outcomes are fatigue severity, self-efficacy and disease-specific quality of life. Secondary outcomes include fatigue impact, general quality of life, mood, activity patterns, and cost-effectiveness. Outcomes in those receiving the fatigue management intervention will be measured 1 week prior to, and 1, 4, and 12 months after the intervention (and at equivalent times in those receiving current local practice). A qualitative component will examine what aspects of the fatigue management intervention participants found helpful/unhelpful and barriers to change.Discussion: This trial is the fourth stage of a research programme that has followed the Medical Research Council guidance for developing and evaluating complex interventions. What makes the intervention unique is that it blends cognitive behavioural and energy effectiveness approaches. A potential strength of the intervention is that it could be integrated into existing service delivery models as it has been designed to be delivered by staff already working with people with MS. Service users will be involved throughout this research.Trial registration: Current Controlled Trials ISRCTN76517470. © 2010 Thomas et al; licensee BioMed Central Ltd.

OBJECTIVES: This study assesses the impact of the English National Health Service (NHS) Health Technology Assessment (HTA) program using the "payback" framework. METHODS: a survey of lead investigators of all research projects funded by the HTA program 1993--2003 supplemented by more detailed case studies of sixteen projects. RESULTS: of 204 eligible projects, replies were received from 133 or 65 percent. The mean number of peer-reviewed publications per project was 2.9. Seventy-three percent of projects claimed to have had had an impact on policy and 42 percent on behavior. Technology Assessment Reports for the National Institute for Health and Clinical Excellence (NICE) had fewer than average publications but greater impact on policy. Half of all projects went on to secure further funding. The case studies confirmed the survey findings and indicated factors associated with impact. CONCLUSIONS: the HTA program performed relatively well in terms of "payback." Facilitating factors included the program's emphasis on topics that matter to the NHS, rigorous methods and the existence of "policy customers" such as NICE.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of bortezomib for the treatment of multiple myeloma patients at first relapse and beyond, in accordance with the licensed indication, based upon the evidence submission from Ortho Biotech to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The outcomes stated in the manufacturer's definition of the decision problem were time to disease progression, response rate, survival and quality of life. The literature searches for clinical and cost-effectiveness studies were adequate and the one randomised controlled trial (RCT) included was of reasonable quality. Results from the RCT suggest that bortezomib increases survival and time to disease progression compared with high-dose dexamethasone (HDD) in multiple myeloma patients who have had a relapse after one to three treatments. Cost-effectiveness analysis based on the same trial and an observational study was reasonable and gave an estimated cost per life-year gained of 30,750 pounds, which ranged from 27,957 pounds to 36,747 pounds on sensitivity analysis. An attempt was made to replicate the results of the manufacturer's model and to compare the results to the Kaplan-Meier survival curve presented in the manufacturer's submission. In addition, a one-way sensitivity analysis and a probabilistic sensitivity analysis were undertaken, as well as additional scenario analyses. Based on these analyses the ERG suggests that the cost-effectiveness results presented in the manufacturer's submission may underestimate the cost per life-year gained for bortezomib therapy (versus high-dose dexamethasone) when potential UK practice and scenarios are considered. The guidance issued by NICE in June 2006 as a result of the STA states that bortezomib monotherapy for the treatment of relapsed multiple myeloma is clinically effective compared with HDD but has not been shown to be cost-effective and is not recommended for the treatment of progressive multiple myeloma in patients who have received at least one previous therapy and who have undergone, or are unsuitable for, bone marrow transplantation.

BACKGROUND: Comprising of both organisational and patient level components, collaborative care is a potentially powerful intervention for improving depression treatment in UK primary Care. However, as previous models have been developed and evaluated in the United States, it is necessary to establish the effect of collaborative care in the UK in order to determine whether this innovative treatment model can replicate benefits for patients outside the US. This Phase III trial was preceded by a Phase II patient level RCT, following the MRC Complex Intervention Framework. METHODS/DESIGN: a multi-centre controlled trial with cluster-randomised allocation of GP practices. GP practices will be randomised to usual care control or to "collaborative care" - a combination of case manager coordinated support and brief psychological treatment, enhanced specialist and GP communication. The primary outcome will be symptoms of depression as assessed by the PHQ-9. DISCUSSION: If collaborative care is demonstrated to be effective we will have evidence to enable the NHS to substantially improve the organisation of depressed patients in primary care, and to assist primary care providers to deliver a model of enhanced depression care which is both effective and acceptable to patients.

Much of the literature on distributive preferences covers specific considerations in isolation, and recent reviews have suggested that research is required to inform on the relative importance of various key considerations. Responding to this research recommendation, we explore the distributive preferences of the general public using a set of generic social value judgments. We report on a discrete choice experiment (DCE) survey, using face-to-face interviews, in a sample of the general population (n=259). The context for the survey was resource allocation decisions in the UK National Health Service, using the process of health technology appraisal as an example. The attributes used covered health improvement, value for money, severity of health, and availability of other treatments, and it is the first such survey to use cost-effectiveness in scenarios described to the general public. Results support the feasibility and acceptability of the DCE approach for the elicitation of public preferences. Choice data are used to consider the relative importance of changes across attribute levels, and to model utility scores and relative probabilities for the full set of combinations of attributes and levels in the experimental design used (n=64). Results allow the relative social value of health technology scenarios to be explored. Findings add to a sparse literature on 'social' preferences, and show that DCE data can be used to consider the strength of preference over alternative scenarios in a priority-setting context.

This study examines the preferences of a sample of the UK general public over the allocation of healthcare resources. Preferences were elicited against scenarios where alternative patient groups are competing for limited resources. Respondents were asked to make a choice between either (i) groups described according to alternative descriptions for severity of health condition, or (ii) groups described according to a broader level of disadvantage (e.g. family income). The survey used a random-location quota sampling approach, and face-to-face interview techniques. Interviews were completed with 261 people in the Southampton area of England. Results showed that the majority or respondents wanted to divide resources equally between competing groups, giving at least equal preference to the more severely affected group, and the more disadvantaged group, regardless of a stated lower potential health gain in these groups compared to alternatives. In the severity of health question 60% indicated that a unit of health gain in a severely affected patient group was of greater social value to that same unit of health gain in a moderately affected patient group, all else equal. When described by level of disadvantage, 80% of respondents stated such a preference, which indicates that they attach a greater social value to a unit of health gain in a disadvantage patient group, compared to a more advantaged group, all else equal. When given an option to 'opt out' of a difficult decision, and to 'let others choose', very few respondents (5%) took that option, suggesting that the most common stated preference of dividing resource equally between groups may be a true preference, rather than respondents avoiding difficult decisions. When interpreting the findings from the survey, results suggest that preferences reported to give priority to those more severely affected by their health, may also be a reflection of a broader preference to treat those groups classed as worse-off, in empirical studies. Results are discussed against the growing importance of the empirical ethics literature, and the growing needs of health policy makers to seek out an empirical basis upon which to consider the challenges of setting priorities in healthcare.

BACKGROUND: Two new agents have recently been licensed for use in the treatment of metastatic renal cell carcinoma (RCC) in Europe. This paper aims to systematically review the evidence from all available randomised clinical trials of sunitinib and bevacizumab (in combination with interferon-alpha (IFN-alpha)) in the treatment of advanced metastatic RCC. METHODS: Systematic literature searches were performed in six electronic databases. Bibliographies of included studies were searched for further relevant studies. Individual conference proceedings were searched using their online interfaces. Studies were selected according to the predefined criteria. All randomised clinical trials of sunitinib or bevacizumab in combination with IFN for treating advanced metastatic RCC in accordance with the European licensed indication were included. Study selection, data extraction, validation and quality assessment were performed by two reviewers with disagreements being settled by discussion. The effects of sunitinib and bevacizumab (in combination with IFN-alpha) on progression-free survival were compared indirectly using Bayesian Markov Chain Monte-Carlo (MCMC) sampling in Win BUGS, with IFN as a common comparator. RESULTS: Three studies were included. Median progression-free survival was significantly prolonged with both interventions (from approximately 5 months to between 8 and 11 months) compared with IFN. Overall survival was also prolonged, compared with IFN, although the published data are not fully mature. Indirect comparison suggests that sunitinib is superior to bevacizumab plus IFN in terms of progression-free survival (hazard ratios 0.796; 95% CI 0.63-1.0; P=0.0272). CONCLUSION: There is evidence to suggest that treatment with sunitinib and treatment with bevacizumab plus IFN has clinically relevant and statistically significant advantages over treatment with IFN alone in patients with metastatic RCC.

OBJECTIVES: to assess the clinical and cost-effectiveness of inhaled corticosteroids (ICS) alone and ICS used in combination with a long-acting beta2 agonist (LABA) in the treatment of chronic asthma in children aged under 12 years. DATA SOURCES: Major electronic bibliographic databases, e.g. MEDLINE and EMBASE, were searched up to February/March 2006 (and updated again in October 2006). REVIEW METHODS: a systematic review of clinical and cost-effectiveness studies and economic analyses were carried out. A flexible framework was used to allow different types of economic analyses as appropriate, with either a cost comparison or cost-consequence comparison conducted. RESULTS: of 5175 records identified through systematic literature searching, 34 records describing 25 studies were included (16 were fully published randomised controlled trials, six were systematic reviews, and three were post-2004 conference abstracts). The most frequently reported relevant outcomes in the 16 RCTs were peak expiratory flow rate (13 trials), FEV1 (13 trials), symptoms (13 trials), adverse events or exacerbations (13 trials), use of rescue medication (12 trials), markers of adrenal function (e.g. blood or urine cortisol concentrations) (13 trials), height and/or growth rate (seven trials) and markers of bone metabolism (two trials). In the trials that compared low-dose ICS versus ICS and high-dose ICS versus ICS, no consistent significant differences or patterns in differential treatment effect among the outcomes were evident. Where differences were statistically significant at high doses, such as for lung function and growth, they favoured formoterol fumarate (FF), but this was generally in studies that did not compare the ICS at the accepted clinically equivalent doses. Differences between the drugs in impact on adrenal suppression were only significant in two studies. At doses of 200, 400 and 800 microg/day, beclometasone dipropionate (BDP) appears to be the current cheapest ICS product both with the inclusion and exclusion of chlorofluorocarbon (CFC)-propelled products. In the trials comparing ICS at a higher dose with ICS and LABA in combination, most outcomes favoured the combined inhaler. Only the combination inhaler, Seretide Evohaler, is slightly cheaper than the weighted mean cost of all types of ICS at increased dose except BDP 400 microg/day (including CFC-propelled products). Both the combination inhalers, Seretide Accuhaler and Symbicort Turbohaler, are more expensive than the weighted mean cost for all types of ICS at a two-fold increased dose. Compared with the lowest cost preparation for each ICS drug, all the combination inhalers are always more expensive than the ICS products at increased dose. CONCLUSIONS: the limited evidence available indicates that there are no consistent significant differences in effectiveness between the three ICS licensed for use in children at either low or high dose. BDP CFC-propelled products are often the cheapest ICS currently available at both low and high dose, and may remain so even when CFC-propelled products are excluded. Exclusion of CFC-propelled products increases the mean annual cost of all budesonide (BUD) and BDP, while the overall cost differences between the comparators diminish. There is very limited evidence available for the efficacy and safety of ICS and LABAs in children. From this limited evidence, there appear to be no significant clinical differences in effects between the use of a combination inhaler versus the same drugs in separate inhalers. There is a lack of evidence comparing ICS at a higher dose with ICS and LABA in combination and comparing the combination products with each other. In the absence of any evidence concerning the effectiveness of ICS at higher dose with ICS and LABA, a cost-consequence analysis gives mixed results. There are potential cost savings with the use of combination inhalers compared to separate inhalers. At present prices, the BUD/FF combination is more expensive than those containing FP/SAL, but it is not known whether there are clinically significant differences between them. A scoping review is required to assess the requirements for additional primary research on the clinical effectiveness of treatment for asthma in children under 5 years old. Such a review could also usefully include all treatment options, pharmacological and non-pharmacological, for asthma. A direct head-to-head trial that compares the two combination therapies of FP/SAL and BUD/FF is warranted, and it is important to assess whether the addition of a LABA to a lower dose of ICS could potentially be as effective as an increased dose of ICS alone, but also be steroid sparing. There is also a need for the long-term adverse events associated with ICS use to be assessed systematically. Future trials of treatment for chronic asthma in children should aim to standardise further the way in which outcome measures are defined. There should be a greater focus on patient-centred outcomes to provide a more meaningful estimation of the impact of treatment on asthma control. Methods of reporting also require standardisation.

OBJECTIVES: to consider how the impact of the NHS Health Technology Assessment (HTA) Programme should be measured. To determine what models are available and their strengths and weaknesses. To assess the impact of the first 10 years of the NHS HTA programme from its inception in 1993 to June 2003 and to identify the factors associated with HTA research that are making an impact. DATA SOURCES: Main electronic databases from 1990 to June 2005. The documentation of the National Coordinating Centre for Health Technology Assessment (NCCHTA). Questionnaires to eligible researchers. Interviews with lead investigators. Case study documentation. REVIEW METHODS: a literature review of research programmes was carried out, the work of the NCCHTA was reviewed, lead researchers were surveyed and 16 detailed case studies were undertaken. Each case study was written up using the payback framework. A cross-case analysis informed the analysis of factors associated with achieving payback. Each case study was scored for impact before and after the interview to assess the gain in information due to the interview. The draft write-up of each study was checked with each respondent for accuracy and changed if necessary. RESULTS: the literature review identified a highly diverse literature but confirmed that the 'payback' framework pioneered by Buxton and Hanney was the most widely used and most appropriate model available. The review also confirmed that impact on knowledge generation was more easily quantified than that on policy, behaviour or especially health gain. The review of the included studies indicated a higher level of impact on policy than is often assumed to occur. The survey showed that data pertinent to payback exist and can be collected. The completed questionnaires showed that the HTA Programme had considerable impact in terms of publications, dissemination, policy and behaviour. It also showed, as expected, that different parts of the Programme had different impacts. The Technology Assessment Reports (TARs) for the National Institute for Health and Clinical Excellence (NICE) had the clearest impact on policy in the form of NICE guidance. Mean publications per project were 2.93 (1.98 excluding the monographs), above the level reported for other programmes. The case studies revealed the large diversity in the levels and forms of impacts and the ways in which they arise. All the NICE TARs and more than half of the other case studies had some impact on policy making at the national level whether through NICE, the National Screening Committee, the National Service Frameworks, professional bodies or the Department of Health. This underlines the importance of having a customer or 'receptor' body. A few case studies had very considerable impact in terms of knowledge production and in informing national and international policies. In some of these the principal investigator had prior expertise and/or a research record in the topic. The case studies confirmed the questionnaire responses but also showed how some projects led to further research. CONCLUSIONS: This study concluded that the HTA Programme has had considerable impact in terms of knowledge generation and perceived impact on policy and to some extent on practice. This high impact may have resulted partly from the HTA Programme's objectives, in that topics tend to be of relevance to the NHS and have policy customers. The required use of scientific methods, notably systematic reviews and trials, coupled with strict peer reviewing, may have helped projects publish in high-quality peer-reviewed journals. Further research should cover more detailed, comprehensive case studies, as well as enhancement of the 'payback framework'. A project that collated health research impact studies in an ongoing manner and analysed them in a consistent fashion would also be valuable.

The literature reporting economic evaluations related to the treatment of Alzheimer's disease (AD) has developed over the last decade. Most analyses have used economic models to estimate the cost effectiveness of drugs for the treatment of AD. This review considers the range of methods used in the published cost-effectiveness literature to model AD progression and the effect of interventions on the progression of AD. The review builds on and updates an earlier systematic review of cost-effectiveness studies on drugs for AD. Systematic and rigorous methods were used to search the literature for economic evaluations estimating the cost effectiveness of donepezil, rivastigmine, galantamine or memantine in AD. The literature search covered a wide range of electronic databases (e.g. MEDLINE, EMBASE), and included literature from the inception of databases up to the end of 2005. The search identified 22 published economic evaluations. An outline and brief critical review of the identified studies is provided, and thereafter the methods used to model disease progression were considered in more detail. The review employs recent guidance on good practice in decision-analytic modelling in HTA to critically review the modelling methods used. Using this guidance, the models are assessed against the broad criteria of model structure, data inputs and assessment of uncertainty and inconsistency. Concerns were noted over the model structure employed in all models. The reliance on cognitive scores to model AD, the progression of the disease, and the effect of treatment on costs and consequences is regarded as a serious limitation in almost all of the studies identified. There are also limitations over the data used to populate published models, especially around the failure of studies to document and establish the basis for the modelling of treatment effects. It is also clear that studies modelling AD progression, and subsequently the cost effectiveness of treatment, have not addressed uncertainty or consistency (internal and/or external) in sufficient detail. Further research is required on more appropriate methods for the modelling of AD progression. In the meantime, future economic evaluations of treatment need to be more explicit on the methods used to model AD, and the data used to populate models.

OBJECTIVES: to assess the clinical effectiveness and cost-effectiveness of treatments for children with idiopathic steroid-resistant nephrotic syndrome (SRNS). DATA SOURCES: Electronic databases from inception to February 2006, bibliographies of studies, and experts in the field. REVIEW METHODS: Studies were selected, quality assessed and data were extracted using recognised methods agreed a priori. Meta-analysis was undertaken where appropriate using the random effects model. Where data allowed, subgroup analysis was undertaken according to renal histopathology. RESULTS: Two systematic reviews and 11 trials were included in the clinical effectiveness review; however, the quality of reporting and methodology of the included studies was generally poor. No economic evaluations were identified. No statistically significant difference in remission rates was found between cyclophosphamide plus prednisone and prednisone alone for all children or those with focal segmental glomerulosclerosis (FSGS), also the time to response was statistically significantly less with cyclophosphamide (38.4 days versus 95.5 days). Remission rates were not statistically significantly different between intravenous and oral cyclophosphamide. Vomiting was common with intravenous cyclophosphamide, while pneumonia and alopecia occurred in the oral group. Ciclosporin statistically significantly increased the number of children with complete remission compared with placebo or supportive treatment, but not for the FSGS subgroup, adverse effects including infection and hypertension differed little between groups. No differences were found between azathioprine and placebo, with about 13% of each group having remission. Complete or partial remission occurred in six out of seven patients on the 18-month methylprednisolone regimen and three out of five patients on the 6-month regimen, for both groups renal function improved and adverse events such as hypertension and frequent infections occurred. Intravenous dexamethasone and methylprednisolone produced similar complete remission rates, partial remission rates, median time to response (about 10 days) and total number of adverse events, with hypertension as the most common. Six-hour urinary albumin and urinary albumin to creatinine ratio decreased statistically significantly with high-dose but not low-dose enalapril. Tuna fish oil was not associated with any statistically significant improvements in proteinuria, creatinine clearance, serum creatinine or lipid profiles compared with placebo. A very limited literature was found on costs associated with SRNS in children. The pharmaceutical cost of treatment varied considerably: an 8-week course of cyclophosphamide cost less than 6 pounds, while a course of ciclosporin cost almost 900 pounds per year. Treatment with tacrolimus, an alternative to ciclosporin, was estimated to cost in excess of 3400 pounds per year. Healthcare medical management costs were estimated; varying by treatment strategy, they ranged from 250 pounds to 930 pounds per year in patients not experiencing complications. Other longer term costs may also be incurred. Lack of data meant that cost-effectiveness modelling was not feasible. CONCLUSIONS: the clinical effectiveness literature on treatments for idiopathic SRNS in children is very limited. The available evidence suggests a beneficial effect of ciclosporin on remission rates and of cyclophosphamide on time to remission; however, the strength of the conclusions drawn is limited by the poor quality of the included studies. The other treatments included in this review were each evaluated by only one study, and none found a statistically significant effect. There is insufficient evidence to determine whether or not there is a clinically significant difference. The available data on costs and outcomes are sparse and do not permit the reliable modelling of the cost-effectiveness of treatments for SRNS at present. A modelling framework is suggested, should more relevant data become available. A well-designed adequately powered randomised controlled trial comparing ciclosporin with other treatments in children with SRNS without genetic mutation is required.

Alzheimer's disease (AD) is the most common form of dementia and is characterised by a worsening of cognition, functional ability, and behaviour and mood. The objective of this study was to review the clinical and cost-effectiveness of memantine for the treatment of patients with moderately severe to severe AD. To achieve this, a systematic search and review of the clinical and cost effectiveness literature for memantine was undertaken. The literature search covered the period from the inception of MEDLINE, Cochrane Library, EMBASE and other electronic databases until July 2004. The search included randomised controlled trials (RCTs) and full economic evaluations that assessed the use of memantine in patients with moderately severe to severe AD. Two published RCTs were included in this review; in one of these trials the participants were already being treated with donepezil. The two RCTs showed benefit for patients receiving memantine compared with placebo on the outcome measures of the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory modified for severe dementia, the Clinician's Interview-Based Impression of Change Plus Caregiver Input, and the Severe Impairment Battery, and that memantine appeared to be slightly more effective in patients already receiving a stable dose of donepezil. Five cost-effectiveness studies were included in the review. Although these studies reported cost reductions and improved outcomes with memantine, the evaluations were based on a number of assumptions. In conclusion, memantine appears to be beneficial when assessed using functional and global measurements. However, the effect of memantine on cognitive scores and behaviour and mood outcomes is less clear. Cost-effectiveness is dependent upon assumptions surrounding clinical effect and context-specific cost data.

BACKGROUND: the use of cholinesterase inhibitors for Alzheimer's disease (AD) is currently being appraised by the National Institute for Clinical Evidence (NICE). This article provides the latest evidence that NICE will be using as part of this appraisal process. OBJECTIVE: to provide a systematic review of the best quality evidence of the effects of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in people with mild to moderately-severe AD. DESIGN: Electronic databases were searched, references of all retrieved articles were checked, and experts were contacted for advice, peer review and to identify additional references. Randomised controlled trials (RCTs) were included if they fulfilled pre-specified criteria. Data were synthesised through a narrative review. RESULTS: Twenty-six RCTs that compared any one of the cholinesterase inhibitors with either a control group or with another cholinesterase inhibitor were included. The quality of reporting and methodology was varied. Treatment with donepezil, rivastigmine or galantamine resulted in significantly better cognitive performance using the ADAS-cog scale when compared with placebo. These findings were generally supported using the MMSE scale. Results from head to head comparisons were limited by the low number of studies and the study quality; generally showing no robust support for any one drug. Few studies evaluated quality of life. Adverse events were generally related to the gastrointestinal system, with a tendency for these to be more common in the treatment arms. CONCLUSIONS: the cholinesterase inhibitors donepezil, rivastigmine, and galantamine can delay cognitive impairment in patients with mild to moderately-severe AD for at least 6 months duration.

OBJECTIVES: the aim of this study was to assess the cost-effectiveness of drotrecogin alfa (activated) compared with best supportive care in a UK cohort of adult intensive-care patients with severe sepsis. METHODS: a systematic review of evidence on the clinical- and cost-effectiveness of drotrecogin alfa (activated) was undertaken, and a decision-analytic model was developed to estimate the cost-effectiveness of treatment in the United Kingdom. Trial data from the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study have been synthesized with other data, including UK data on severe sepsis, to estimate the costs and consequences of treatment over time. RESULTS: for patients with severe sepsis and multiple organ dysfunction, the estimates of cost per life year and cost per quality-adjusted life year (QALY) are pounds 4931 and pounds 8228, respectively. For patients with severe sepsis alone, the cost per life-year and cost per QALY are pouhds 5495 and pounds 9161, respectively. CONCLUSIONS: Whereas the therapeutic cost for drotrecogin alfa (activated) appears high (at around pounds 5000 per patient) and the potential impact on the provider budget is considerable, drotrecogin alfa (activated) is clinically effective, represents a cost-effective use of resources, and is a significant advance in the treatment of severe sepsis in patients requiring intensive care.

OBJECTIVES: to assess the clinical and cost-effectiveness of drotrecogin alfa (activated) for the treatment of adults with severe sepsis in a UK context. DATA SOURCES: Electronic databases. Data from the commercial use of the drug up to April 2002. Data from the manufacturer submission to the National Institute for Clinical Excellence (NICE). REVIEW METHODS: a systematic review of the literature and an economic evaluation were undertaken. Data were synthesised through a narrative review with full tabulation of results from included studies. RESULTS: the evidence on the effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis came primarily from one large pivotal randomised controlled trial, the PROWESS study. This study demonstrated a statistically significant absolute reduction in 28-day mortality of 6.5%. Longer term survival benefit was maintained to 90 days. By 9 months, the trend towards increased median survival was non-significant, although the survival curves did not cross. Results presented by the number of organ dysfunctions were not statistically significant, but when mortality rates for those with two or more organ failures were combined, the relative risk of death was significantly lower in those treated with drotrecogin alfa (activated) compared with placebo. However, this report highlights a number of considerations relevant to the subgroup analyses reported for the PROWESS study. Published cost-effectiveness studies of treatment with drotrecogin alfa (activated) have applied a range of methods to the estimation of benefits, estimating an incremental gain per treated patient of between 0.38 and 0.68 life-years (for patients with severe sepsis). For patients with severe sepsis and multiple organ dysfunction, the manufacturer (Eli Lilly) estimated an incremental gain of 1.115 life-years per treated patient, compared to 1.351 life-years per treated patient estimated by the Southampton Health Technology Assessments Centre (SHTAC). These latter UK analyses are based on a patient group that is more severely affected by disease, where effectiveness is greater and the baseline risk of all-cause mortality is much higher (SHTAC analysis), these factors are associated with the noted difference in effect. The three published cost-effectiveness studies report cost for US and Canadian patient groups; for those patients with severe sepsis they report the additional cost per patient treated in a range around 10,000-16,000 dollars. The manufacturer's submission reports analysis for the UK, based on 28-day survival data in patients with severe sepsis and multiple organ dysfunction (the European licence indication), with the additional mean cost per treated patient estimated to be 5106 pounds. The analysis undertaken by SHTAC, for a UK group of patients with severe sepsis and multiple organ dysfunction, estimates an additional mean cost per patient treated of 6661 pounds. The manufacturer's submission to NICE presents cost-effectiveness estimates for drotrecogin alfa (activated) in the UK, in patients with severe sepsis and multiple organ dysfunction, at 6637 pounds per quality-adjusted life-year (QALY) based on 28-day effectiveness data, and 10,937 pounds per QALY based on longer term follow-up data. SHTAC developed an independent cost-effectiveness model and estimated a base-case cost per QALY of 8228 pounds in patients with severe sepsis and multiple organ failure (based on 28-day survival data). Simulation results indicate that where the NHS is willing to pay 20,000 pounds per QALY, drotrecogin alfa (activated) is a cost-effective use of resources in 98.7% of cases. Published economic evaluations report various sensitivity analyses, with results sensitive to changes in the measure of treatment effect, but otherwise studies reported that results were robust to variations in most assumptions used in the cost-effectiveness analysis. CONCLUSIONS: Drotrecogin alfa (activated) plus best supportive care appears clinically and cost-effective compared with best supportive care alone, in a UK cohort of severe sepsis patients, and in the subgroup of more severely affected patients with severe sepsis and multiple organ failure. The introduction of drotrecogin alfa (activated) will involve a substantial additional cost to the NHS. The treatment-eligible population in England and Wales may comprise up to 16,570 patients, with an estimated annual drug acquisition cost of over 80 million pounds, excluding VAT. Further research is required on the longer term impact of drotrecogin alfa (activated) on both mortality and morbidity in UK patients with severe sepsis, on the clinical and cost-effectiveness of drotrecogin alfa (activated) in children (under 18 years) with severe sepsis, and on the effect of the timing of dosage and duration of treatment on outcomes in severe sepsis.

OBJECTIVE: to estimate the cost effectiveness (from the UK NHS and personal social services perspective) of the cholinesterase inhibitors donepezil, rivastigmine and galantamine compared with usual care in the treatment of mild to moderately severe Alzheimer's disease. Patients had a mean age of 74 years, a mean disease duration of 1 year and a mean Alzheimer's disease assessment scale-cognitive subscale score of 24. METHODS: a pharmacoeconomic model was used to predict long-term outcomes over a 5-year time horizon and to estimate the cost effectiveness of cholinesterase inhibitors for the management of Alzheimer's disease. The model structure is informed by a systematic review of the literature on the clinical and cost effectiveness of cholinesterase inhibitors and a review of the literature on the costs and outcomes associated with treatment for Alzheimer's disease. The main outcome measure used was the cost per quality-adjusted life-year (QALY) gained. All healthcare costs (excluding cholinesterase inhibitor costs) were indexed to pounds sterling (2003 values). Drug costs are 2005 values. Multivariate probabilistic sensitivity analysis and scenario analysis were undertaken to assess uncertainty in the results. RESULTS: the clinical benefits on cognition from treatment with cholinesterase inhibitors resulted in an incremental cost per QALY gained ranging from 53,780 pounds sterling to 74,735 pounds sterling, over 5 years (vs usual care). Uncertainty analysis suggests that the probability of any of these treatments having an incremental cost per QALY of < 30,000 pounds sterling is < 21%. The key determinants of cost effectiveness were the effectiveness of treatment, the mean treatment cost and the cost savings associated with an expected delay in disease progression. CONCLUSIONS: Results presented in this paper suggest that the use of cholinesterase inhibitors may not be a cost-effective use of NHS resources. Guidance from the National Institute for Health and Clinical Effectiveness (NICE) in the UK on their judgements surrounding the acceptability of technologies as an effective use of resources, indicates there would need to be special reasons for accepting cholinesterase inhibitors as a cost-effective use of NHS resources.

BACKGROUND: Topical corticosteroids remain the mainstay of treatment for atopic eczema, yet there is uncertainty over the frequency of their use in terms of clinical and cost effectiveness. OBJECTIVES: to assess the clinical and cost effectiveness of once-daily vs. more frequent use of same-potency topical corticosteroids in atopic eczema. METHODS: a systematic review of the clinical and cost-effectiveness literature was undertaken, together with a cost-minimization analysis. RESULTS: the review identified a sparse literature, comprising one previous systematic review and 10 randomized controlled trials (RCTs). No published cost-effectiveness studies were identified. RCTs were focused on potent topical corticosteroids (eight RCTs), with no trials (RCTs/controlled clinical trials) identified on mild potency products. There was broad heterogeneity in trial methods, and therefore we considered outcomes according to: (i) at least a good response or 50% improvement, and (ii) eczema rated as cleared or controlled. Studies found little difference between once-daily and more frequent use of topical corticosteroids. The literature on moderately potent and potent corticosteroids offered no basis for favouring once-daily or more frequent use, although some significant differences favouring twice-daily treatment were identified. One RCT on very potent products favoured three times daily use on the basis of clinical response, but reported no difference in the numbers with at least a good response. Given the similar outcomes seen in clinical effectiveness a cost-minimization approach was adopted to consider cost effectiveness, in order to identify the least-cost option. However, cost-minimization analysis proved complex due to wide variations in product price, with the relative cost of product comparisons by frequency proving the most important factor in determining the least-cost alternative. CONCLUSIONS: This review has not identified any clear differences in outcomes between once-daily and more frequent application of topical corticosteroids. We would encourage prescribing clinicians to consider the once-daily use of topical corticosteroids when making treatment decisions for patients with atopic eczema. However, we find that the literature on clinical effectiveness is limited and a broader understanding of compliance and phobia associated with topical steroids is needed to inform on this issue.

OBJECTIVES: to assess the clinical and cost-effectiveness of continuous subcutaneous insulin infusion (CSII) compared with multiple daily injections (MDI) in the delivery of intensive insulin therapy for the treatment of diabetes mellitus. DATA SOURCES: Electronic databases, references of retrieved articles and manufacturer submissions. Experts in the field were consulted. REVIEW METHODS: for the systematic review of clinical and cost-effectiveness, studies were assessed for inclusion according to predefined criteria by two reviewers. Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer. Data on clinical effectiveness were synthesised through a narrative review with full tabulation of all eligible studies, with meta-analysis performed where appropriate. RESULTS: Twenty studies comparing CSII with MDI were identified. Quality was generally poor. In adults with Type 1 diabetes, glycated haemoglobin improved by 0.61% (95% CI -1.29 to 0.07) in longer term studies, although this improvement was smaller when a study using bovine ultralente was excluded. A reduction in insulin dose with CSII of about 12 units per day (-11.90, 95% CI -18.16 to 5.63) was found in short-term studies, with smaller differences in longer term studies. Body weight and cholesterol levels were similar between treatments. Hypoglycaemic events did not differ significantly between CSII and MDI in most trials, but some found fewer events with CSII and one found more hypoglycaemia and hypoglycaemic coma with CSII. There was no consistency between the studies in patient preference, but progress has been made both with insulin pumps and injector pens since the publication of many of the older studies. No difference in glycated haemoglobin between CSII and MDI was found in pregnancy; one study found less insulin was required by patients with CSII, but two other studies found no significant difference. One study of adolescents found lower glycated haemoglobin and insulin dose with CSII whereas a second study found no significant difference. In CSII analogue insulin was associated with lower glycated haemoglobin levels than soluble insulin. No economic evaluations comparing CSII with MDI were identified. The estimated additional cost of CSII compared to MDI varies from GBP1091 per annum to GBP1680 per annum, according to the make of the insulin pump and the estimated life of the device. These estimates include the costs for the insulin pump, the consumables associated with delivery of CSII, and an allowance for the initial education required when patients switch from MDI to CSII. The largest component of the annual cost for CSII is the cost of consumable items (e.g. infusion sets). CONCLUSIONS: When compared with optimised MDI, CSII results in a modest but worthwhile improvement in glycated haemoglobin in adults with Type 1 diabetes. It has not been possible to establish the longer term benefits of such a difference in glycated haemoglobin, although there is an expectation that it would be reflected in a reduction in long-term complications. More immediate primary benefits from CSII may be associated with an impact on the incidence of hypoglycaemic events and the dawn phenomenon, and greater flexibility of lifestyle. However, there is limited evidence on this, and information presented to offer context on quality-of-life is based on testimonies from those patients who have had a positive experience of CSII. The estimated cost to the NHS per year for CSII would be around GBP3.5 million in England and Wales if 1% of people with Type 1 diabetes used CSII, GBP10.5 million for 3%, and GBP17.5 million for 5%. Further research should focus on wider benefits of CSII, such as flexibility of lifestyle and quality of life, and on the psychological impact of wearing a device for 24 hours every day. Research into the use of CSII in children of different ages is also needed.

OBJECTIVES: to assess the clinical and cost-effectiveness of once-daily use of topical corticosteroids versus more frequent use of same-potency topical corticosteroids in the treatment of people with atopic eczema. DATA SOURCES: Electronic databases. Bibliographies of included studies and related papers. Experts in the field. Manufacturer submissions to the National Institute for Clinical Excellence. REVIEW METHODS: Studies were assessed for inclusion according to predefined criteria by two reviewers. Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer. Clinical effectiveness data were synthesised through a narrative review with full tabulation of results. RESULTS: One RCT comparing moderately potent corticosteroids, eight RCTs comparing potent corticosteroids and one RCT comparing very potent corticosteroids were included. No RCTs or CCTs of mild corticosteroids were eligible. Most RCTs were of poor methodological quality, although two were judged to be of good quality. The only study that compared moderately potent corticosteroids found no significant difference between once- and twice-daily application. For potent corticosteroids, some statistically significant differences in numbers of patients responding to treatment were identified favouring twice-daily treatment, but these were inconsistent between physician and patient assessment and outcomes selected for analysis. Two studies found a significant improvement in some symptoms with once-daily mometasone furoate compared with twice-daily application of a different active compound, while a third study found no significant differences. One good-quality study favoured twice-daily application of fluticasone propionate ointment, while other studies found no significant difference or an improvement in one symptom but not others. The only study comparing very potent corticosteroids found a statistically significant difference in comparative clinical response in favour of three-times daily treatment, but no difference in number of patients with at least a good response. There appears to be little difference in the frequency or severity of short-term events, however data are limited. No published economic evaluations were identified. Given findings on clinical effectiveness, where outcomes from the comparators are similar, the relative cost-effectiveness of once-daily versus more frequent application of topical corticosteroids becomes a case of cost-minimisation, where the least-cost alternative should be favoured, all else being equal. Topical corticosteroid products included in this review have a wide variation in price; the cost per 30 g/30 ml varies between GBP0.60 and GBP4.88. Specific decisions on the least-cost alternative, between once-daily and more frequent application of products, will be determined by the relative price of the products being compared. Where patients can be appropriately prescribed once-daily treatment of a similarly priced product, a reduction in the quantity of topical corticosteroid used will be expected. However, issues related to pack size for prescribed products and subsequent waste (unused product) could easily erode any potential saving. The potential cost-savings on prescribed products are very small at a patient level; although given the large numbers of patients with atopic eczema, cost savings in theory could be substantial. The presence of specifically marketed 'once-daily' topical corticosteroids, which are relatively expensive (per unit price), may result in additional costs should there be a general recommendation in favour of once-daily use of topical corticosteroids, compared to more frequent use. CONCLUSIONS: the literature is very limited; that available indicates the clinical effectiveness of once-daily and more frequent application of potent topical corticosteroids is very similar, but it does not offer a basis for favouring either option. The cost-effectiveness of once-daily versus more frequent use will depend on the generalisability of the findings to the specific treatment decision and the relative product prices. The trials included in this review generally refer to moderate to severe atopic eczema, whereas most patients have mild disease, and furthermore most of the included trials report on potent topical corticosteroids (eight of 10 RCTs); therefore the generalisability of the findings is limited. Further research is required on the clinical and cost-effectiveness of once-daily versus more frequent use of same potency corticosteroids, specifically on mild potency products for mild to moderate atopic eczema. Outcomes should include quality of life and compliance.

Motor neurone disease (MND) has a severe impact on patient quality of life, especially in later stages of the disease. This study assesses the health-related quality of life (HRQL) of MND patients, and for the first time elicits health state values from patients for their present health state. A structured interview was conducted with 77 patients. Patients completed a disease specific health status measure (ALSAQ-40), a generic health status measure (EuroQol EQ-5D), a visual analogue scale (VAS) and a standard gamble (SG) exercise. The ALSAQ-40 was sensitive to disease severity. Patients' mean VAS rating of their own health ranged from 0.74 for stage 1 (early) disease severity (n = 15), to 0.37 for stage 4 (late stage) disease severity (n = 19). Utilities elicited via SG varied from a mean of 0.79 for stage 1 disease severity to a mean of 0.45 for stage 4 disease severity. The EQ-5D derived single index ranged from a mean of 0.63 for stage 1 disease severity to a mean of -0.01 for stage 4 disease severity. This study demonstrates that it is feasible and practical to obtain health state values from MND patients and it provides evidence that patients place a high value on their HRQL, even in cases where health status is very poor.

Evidence on the cost-effectiveness of healthcare interventions is increasingly required by decision-makers. Economic models can provide timely information on the long-term impact of new technologies. However, models have been criticised because of the implicit assumptions they make, in particular the methods used to extrapolate data are rarely documented. This paper presents a systematic process for choosing a method of predicting events in economic models. This process is illustrated using a model examining the cost-effectiveness of a new HMG-CoA reductase inhibitor (statin) for primary prevention of cardiovascular disease (CVD). The prediction of future CVD events is a central component of the model, and the choice of method for predicting events was an important issue in the model's development. A literature review identified 11 studies with the information required to predict CVD events. A set of criteria were developed to assess the different methods of risk estimation, covering issues like scientific validity and acceptability to decision-makers. Risk equations derived from the Framingham Heart Study were found to be most suitable for predicting future events in the economic model. The paper illustrates how the development of economic models can be made more transparent, and suggests that the process outlined may be applied to other disease areas where there are several event prediction methods to choose from. In disease areas where published methods for predicting events are not available, the process outlined can make the uncertainty this leads to explicit, and highlight where further research is required. Such transparency can help decision-makers understand the scientific basis underpinning models, and therefore make these models more acceptable and useful for health policy-making.

OBJECTIVES: to assess the clinical effectiveness and cost-effectiveness of educational interventions for patients with diabetes, compared with usual care or other educational interventions. DATA SOURCES: Electronic databases, reference lists and experts were all consulted in this study. Sponsor submissions to the National Institute of Clinical Excellence were also reviewed. REVIEW METHODS: Electronic databases were searched, references of all retrieved articles were checked for relevant studies, and experts were contacted for advice and peer review and to identify additional published and unpublished references. Randomised clinical trials (RCTs) and controlled clinical trials (CCTs) were included if they fulfilled pre-specified criteria, among which was follow-up from inception for 12 months or longer. Data were synthesised through a narrative review because the diversity of studies prevented a meta-analysis. RESULTS: Twenty-four studies (18 RCTs and six CCTs) that compared education with either a control group or with another educational intervention were included. The quality of reporting and methodology was generally found to be poor by today's standards. As part of treatment intensification, education in Type 1 diabetes (four studies) resulted in significant and long-lasting improvements in metabolic control and reductions in complications. In Type 2 diabetes (16 studies) a diversity of educational programmes did not yield consistent results on measures of metabolic control. Inconsistent results on metabolic control were also found in studies of diabetes of either type (four studies), with studies of lower quality producing significant effects. Few studies evaluated quality of life. Economic evaluations comparing education with usual care or other educational interventions were not identified. CONCLUSIONS: Education as part of intensification of treatment produces improvement in diabetic control in Type 1 diabetes. Mixed results in Type 2 diabetes mean that no clear characterisation is possible as to what features of education may be beneficial. Cost analysis and information from sponsor submissions indicated that where costs associated with patient education were in the region of 500-600 pounds sterling per patients, the benefits over time would have to be very modest to offer an attractive cost-effectiveness profile. Further research should focus on RCTs with clear designs based on explicit hypotheses and with a range of outcomes evaluated after long follow-up intervals.

Visual analog scales or rating scales are commonly used in economic evaluation to elicit preferences in order to estimate quality-adjusted life years. Values obtained from visual analog scales have been used on their own or via a transformation to map them onto one of the choice-based methods for elicting preferences, namely standard gamble or time trade-off. The arguments against using visual analog scales in economic evaluation directly or indirectly via a transformation are reviewed. It is concluded that it can only ever provide a second best solution compared with the direct use of a choice-based technique.

An important weakness of economic models in the field of osteoporosis has been the dependence on assumptions or expert judgements rather than empirical estimates for the utility values of key health events associated with osteoporosis such as hip, vertebral, wrist fracture and established osteoporosis. This paper seeks to identify the best available utility estimates for health states associated with osteoporosis and make recommendations about their use. It is based on a systematic search of the main literature databases. Studies meeting inclusion criteria have been reviewed in terms of the appropriateness of the valuation technique, the validity of the descriptive system (if one was used), the number and type of respondents, and overall quality of the study. Twenty three estimates of health state values (HSVs) were found across the four conditions from five studies. These empirical estimates were found to differ significantly from the commonly used assumptions in economic evaluation, but with a wide variation between estimates for the same state (0.32 to 0.80 for vertebral fracture states). This variation can be partly explained by the valuation technique, health state description and the background and perspective of respondent, and leaves scope for considerable discretion that could be abused. There are also problems in using values obtained from the study populations to those in economic models and the difficulty of predicting health state values in those who avoid a fracture. The review recommends a set of health state values as part of a "reference case" for use in economic models. Due to the paucity of good quality of estimates in this area, further recommendations are made regarding the design of future studies to collect HSVs relevant to economic models.

The person trade-off (PTO) technique has been suggested as a means of eliciting social preferences for health care, both the valuation of health care interventions and, more recently, to inform on the weights that society may attach to other decision-making criteria (e.g. the severity of a patients pre-treatment condition). Given the increased attention afforded to the PTO technique, this review examines the current evidence to inform on the ability of the PTO to provide a measure of social preference. Applying criteria of practicality, reliability and validity to empirical and theoretical contributions to the PTO literature, the review finds that the technique has limited empirical support. Applications of the PTO have been in a largely experimental setting, the reliability of the PTO is unproven and the empirical validity of the technique, in terms its ability to reflect actual preferences, remains unclear. In the broader context of the valuation of health states or outcomes, all techniques are open to criticism. Given this position, the review finds support for the potential of the PTO in the assessment of the societal value of health care, and it supports further empirical inquiry on the PTO.

OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a devastating disease that has serious consequences in terms of impairments and disabilities, which are expected to impact on health-related quality of life (HRQL). The aim of the present study was to assess self-reported health status and HRQL, as well as patients' own valuation of their present health state in a sample of patients with different levels of severity of ALS. METHODS: Structured interviews were conducted with 77 patients with different levels of disease severity. Patients completed a disease-specific health status measure (ALSAQ-40), a generic health status measure (EuroQol EQ-5D), visual analogue scale (VAS) rating of current health and a standard gamble (SG) exercise to provide health state utilities for their own health state. RESULTS: the results from the ALSAQ-40 and EQ-5D descriptive system indicate that patients' HRQL decreases systematically with increasing severity of disease. Patients' mean VAS rating of their own health ranged from 0.74 for stage 1 (early) disease severity, to 0.37 for stage 4 (late stage) disease severity. Utilities elicited via SG were systematically higher than VAS scores and ranged from a mean of 0.79 for stage 1 disease severity to a mean of 0.45 for stage 4 disease severity.

Given the growing need to value health-related quality of life, a review of the literature relating to health state valuation techniques was undertaken to appraise the current theoretical and empirical evidence available to inform on the techniques, to identify consensus, identify disagreement and identify important areas for future research. A systematic search of the literature was conducted, covering standard gamble (SG), time trade-off (TTO), visual analogue scale (VAS), magnitude estimation (ME) and person trade-off (PTO) techniques. The basic concepts of practicality, reliability, theoretical validity and empirical validity formed the criteria for reviewing the performance of valuation techniques. In terms of practicality and reliability, we found little evidence relating to ME and PTO. SG, TTO and VAS have been shown to be practical on a range of populations. There is little difference between the reliability of SG, TTO and VAS, and present evidence does not offer a basis to differentiate between them. When considering the theoretical basis of techniques, we conclude that choice-based methods (i.e. SG, TTO and PTO) are best placed to reflect the strength of preference for health, with the choice between these techniques depending on the study characteristics and the perspective employed. Empirical evidence relating to the theoretical perspective of the techniques has shown that there are problems with all techniques in terms of descriptive validity.

OBJECTIVE: to review the use of measures of health status in the assessment of benefits in economic evaluation, whether or not the measures were designed for this purpose. METHODS: the review was based on a systematic search of the literature. It provides a comprehensive assessment of the evidence where it exists and a balanced overview of opinion otherwise. RESULTS: over 3000 papers were identified, of which 632 were found to be relevant. The review provides a set of recommendations. These include: a checklist of questions for selecting a measure for use in economic evaluation; a list of circumstances in which non-preference-based measures can be used; and recommendations surrounding the use of health state valuation techniques and multi-attribute utility scales. CONCLUSION: These recommendations should help to identify poor economic evaluations and hence guard against inefficient conclusions being drawn regarding the provision of health services.

New and expensive therapeutic products can place great pressure on health care purchasers. Often, evidence to support the inclusion of such products in the purchasing process is lacking or confusing, yet demand can be organized and forceful. In this paper we use the example of the introduction of recombinant factor VIII (rFVIII) in the management of haemophilia A, to highlight some problems purchasers face in deciding whether to fund its use. The introduction of rFVIII involves substantial extra funding requirements and the benefits afforded by its use are unclear. Although a case can be made for the use of rFVIII on the grounds of subjective furture theoretical risks and intangible benefits, the purchasers of health care are charged with maximizing the present and obtainable benefits of the community at large, given finite resources. Guidelines produced by the United Kingdom Haemophilia Centre Directors Organization state rFVIII to be its treatment of choice for all haemophilia a patients, but offer no insight into the benefits attainable through the use of rFVIII, in terms of health outcomes. We report summary findings of Purchaser Intelligence Groups examining the use of rFVIII and offer comment on the problems associated with the implementation of therapeutic products such as rFVIII.

There are now a large number of instruments available for assessing health-related quality of life, many of which are used within economic evaluations. When considering the use of quality-of-life instruments, meaningful questions need to be asked to determine whether an instrument has been used judiciously. Such questions should consider whether the instrument is valid and suitable for the particular study question, whether the instrument is compatible with the economic evaluation framework used, and subsequently whether the conclusions presented in the study are legitimate. In order to illustrate the value of these questions we have applied them to a number of economic evaluations. The studies used were identified via a systematic review of the health economics literature. In our assessment of a sample of published material, we found that reporting is frequently unhelpful and that the inappropriate use of instruments and techniques casts doubt on the conclusions of economic evaluations. Furthermore, our systematic review of the health economics literature has shown that the general format of reported economic evaluations falls short of the commonly accepted ideal. We examined the health economics literature for 1995 and only identified a handful of studies which satisfied the economic evaluation criteria as accepted by most economists. It is hoped that raising awareness of these issues will urge evaluators, referees and publishers not to lose sight of the needs of the decision-maker when considering the detail which should be present in a reported evaluation.