Sophie Beale

The clinical effectiveness and cost-effectiveness of testing for cytochrome P450 polymorphisms in patients with schizophrenia treated with antipsychotics: a systematic review and economic evaluation

OBJECTIVE To determine whether testing for cytochrome P450 (CYP) polymorphisms in adults entering antipsychotic treatment for schizophrenia leads to improvement in outcomes, is useful in medical, personal or public health decision-making, and is a cost-effective use of health-care resources. DATA SOURCES The following electronic databases were searched for relevant published literature: Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, EMBASE, Health Technology Assessment database, ISI Web of Knowledge, MEDLINE, PsycINFO, NHS Economic Evaluation Database, Health Economic Evaluation Database, Cost-effectiveness Analysis (CEA) Registry and the Centre for Health Economics website. In addition, publicly available information on various genotyping tests was sought from the internet and advisory panel members. REVIEW METHODS A systematic review of analytical validity, clinical validity and clinical utility of CYP testing was undertaken. Data were extracted into structured tables and narratively discussed, and meta-analysis was undertaken when possible. A review of economic evaluations of CYP testing in psychiatry and a review of economic models related to schizophrenia were also carried out. RESULTS For analytical validity, 46 studies of a range of different genotyping tests for 11 different CYP polymorphisms (most commonly CYP2D6) were included. Sensitivity and specificity were high (99-100%). For clinical validity, 51 studies were found. In patients tested for CYP2D6, an association between genotype and tardive dyskinesia (including Abnormal Involuntary Movement Scale scores) was found. The only other significant finding linked the CYP2D6 genotype to parkinsonism. One small unpublished study met the inclusion criteria for clinical utility. One economic evaluation assessing the costs and benefits of CYP testing for prescribing antidepressants and 28 economic models of schizophrenia were identified; none was suitable for developing a model to examine the cost-effectiveness of CYP testing. CONCLUSIONS Tests for determining genotypes appear to be accurate although not all aspects of analytical validity were reported. Given the absence of convincing evidence from clinical validity studies, the lack of clinical utility and economic studies, and the unsuitability of published schizophrenia models, no model was developed; instead key features and data requirements for economic modelling are presented. Recommendations for future research cover both aspects of research quality and data that will be required to inform the development of future economic models.

Survival Analysis and Extrapolation Modeling of Time-to-Event Clinical Trial Data for Economic Evaluation: An Alternative Approach

A recent publication includes a review of survival extrapolation methods used in technology appraisals of treatments for advanced cancers. The author of the article also noted shortcomings and inconsistencies in the analytical methods used in appraisals. He then proposed a survival model selection process algorithm to guide modelers’ choice of projective models for use in future appraisals. This article examines the proposed algorithm and highlights various shortcomings that involve questionable assumptions, including researchers’ access to patient-level data, the relevance of proportional hazards modeling, and the appropriateness of standard probability functions for characterizing risk, which may mislead practitioners into employing biased structures for projecting limited data in decision models. An alternative paradigm is outlined. This paradigm is based on the primacy of the experimental data and adherence to the scientific method through hypothesis formulation and validation. Drawing on extensive experience of survival modeling and extrapolation in the United Kingdom, practical advice is presented on issues of importance when using data from clinical trials terminated without complete follow-up as a basis for survival extrapolation.

Cost-effectiveness of Rosiglitazone Combination Therapy for the Treatment of Type 2 Diabetes Mellitus in the UK

AbstractIntroduction: Recent clinical trial results have demonstrated that, in patients with type 2 diabetes, second-line treatment of rosiglitazone in combination with metformin can lead to significant improvements in the control of fasting plasma glucose/glycosylated haemoglobin A1c (HbA1c) after the failure of metformin monotherapy. Our objective was to assess the cost-effectiveness of the use of rosiglitazone in combination with metformin in overweight and obese patients with type 2 diabetes in the UK, failing to maintain glycaemic control with metformin monotherapy compared with conventional care using metformin in combination with sulfonylurea. Methods: The Diabetes Decision Analysis of Cost — type 2 (DiDACT) model, an established long-term economic model of type 2 diabetes, which projects the relationship between treatment and HbA1c over extended periods, was used to determine the health outcomes and economic impact for matched age and sex cohorts of 1000 patients with type 2 diabetes. The perspective was that of the UK National Health Service and all costs were in UK pounds sterling. Results: Treatment with rosiglitazone in combination with metformin provides better glycaemic control over the remaining lifetime of patients than metformin and sulfonylurea combination therapy. Patients treated with rosiglitazone combination therapy were predicted to have a longer life expectancy, gaining 123 and 140 additional life years per 1000 patients in the obese and overweight cohorts, respectively. Improvements in morbidity and a delay in the start of insulin therapy resulted in a projected improvement in quality of life. These effects combine with projected improved survival to yield 131 and 209 additional quality-adjusted life-years (QALYs) per 1000 patients in the obese and overweight cohorts, respectively. Discounted incremental cost-effectiveness ratios were estimated at £16 700 per QALY gained for the obese cohort and £11 600 per QALY gained for the overweight cohort. Conclusion: The model predicts that rosiglitazone in combination with metformin is a cost-effective treatment in the UK for both obese and overweight patients failing on metformin monotherapy, compared with conventional therapy using metformin in combination with sulfonylurea.

A Model of Long-term Metabolic Progression of Type 2 Diabetes Mellitus for Evaluating Treatment Strategies

AbstractAim: To develop a novel metabolic computer model of the natural lifetime progression of type 2 diabetes that generates dynamic risk factor trajectories consistent with prespecified lifetime therapeutic strategies, in order to enhance the long-term economic and outcome modelling of type 2 diabetes and its complications. Methods: The main model drivers of progressive disease were changes in insulin sensitivity and islet β-cell function derived from an analysis of follow-up results from the Belfast Diet Study. These were related to clinical measures through an adaptation of the homeostasis model assessment. Established causal relationships estimating body mass index, lipids and blood pressure from measures of glycaemia and plasma insulin were calibrated using Third National Health and Nutrition Examination Survey (USA) data, standardizing for age, sex, ethnicity and smoking. The effects of individual interventions were calibrated using published trial evidence, in line with the current understanding of the main modes of action of each agent. Results: A comparison of the effects of common therapies using the model showed both similarities and differences. Large improvements in glycaemic control from lifestyle modifications, further enhanced by oral glucose-lowering drugs or insulin, were reproduced. Projections comparing lifetime therapeutic strategies suggest that simple guidelines may not always be valid. Conclusion: This novel mathematical model using evidence from the long-term natural history of type 2 diabetes is able to project the expected effects of various antihyperglycaemic therapies. Coupled with an economic model, this metabolic model may provide a mechanism for healthcare professionals and policymakers to evaluate different long-term strategies for the management of type 2 diabetes.

The clinical effectiveness and cost-effectiveness of the PROGENSA® prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation

BACKGROUND There is no single definitive test to identify prostate cancer in men. Biopsies are commonly used to obtain samples of prostate tissue for histopathological examination. However, this approach frequently misses cases of cancer, meaning that repeat biopsies may be necessary to obtain a diagnosis. The PROGENSA(®) prostate cancer antigen 3 (PCA3) assay (Hologic Gen-Probe, Marlborough, MA, USA) and the Prostate Health Index (phi; Beckman Coulter Inc., Brea, CA, USA) are two new tests (a urine test and a blood test, respectively) that are designed to be used to help clinicians decide whether or not to recommend a repeat biopsy. OBJECTIVE To evaluate the clinical effectiveness and cost-effectiveness of the PCA3 assay and the phi in the diagnosis of prostate cancer. DATA SOURCES Multiple publication databases and trial registers were searched in May 2014 (from 2000 to May 2014), including MEDLINE, EMBASE, The Cochrane Library, ISI Web of Science, Medion, Aggressive Research Intelligence Facility database, ClinicalTrials.gov, International Standard Randomised Controlled Trial Number Register and World Health Organization International Clinical Trials Registry Platform. REVIEW METHODS The assessment of clinical effectiveness involved three separate systematic reviews, namely reviews of the analytical validity, the clinical validity of these tests and the clinical utility of these tests. The assessment of cost-effectiveness comprised a systematic review of full economic evaluations and the development of a de novo economic model. SETTING The perspective of the evaluation was the NHS in England and Wales. PARTICIPANTS Men suspected of having prostate cancer for whom the results of an initial prostate biopsy were negative or equivocal. INTERVENTIONS The use of the PCA3 score or phi in combination with existing tests (including histopathology results, prostate-specific antigen level and digital rectal examination), multiparametric magnetic resonance imaging and clinical judgement. RESULTS In addition to documents published by the manufacturers, six studies were identified for inclusion in the analytical validity review. The review identified issues concerning the precision of the PCA3 assay measurements. It also highlighted issues relating to the storage requirements and stability of samples intended for analysis using the phi assay. Fifteen studies met the inclusion criteria for the clinical validity review. These studies reported results for 10 different clinical comparisons. There was insufficient evidence to enable the identification of appropriate test threshold values for use in a clinical setting. In addition, the implications of adding either the PCA3 assay or the phi to clinical assessment were not clear. Furthermore, the addition of the PCA3 assay or the phi to clinical assessment plus magnetic resonance imaging was not found to improve discrimination. No published papers met the inclusion criteria for either the clinical utility review or the cost-effectiveness review. The results from the cost-effectiveness analyses indicated that using either the PCA3 assay or the phi in the NHS was not cost-effective. LIMITATIONS The main limitations of the systematic review of clinical validity are that the review conclusions are over-reliant on findings from one study, the descriptions of clinical assessment vary widely within reviewed studies and many of the reported results for the clinical validity outcomes do not include either standard errors or confidence intervals. CONCLUSIONS The clinical benefit of using the PCA3 assay or the phi in combination with existing tests, scans and clinical judgement has not yet been confirmed. The results from the cost-effectiveness analyses indicate that the use of these tests in the NHS would not be cost-effective. STUDY REGISTRATION This study is registered as PROSPERO CRD42014009595. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Prasugrel (Efient®) with percutaneous coronary intervention for treating acute coronary syndromes (review of TA182): systematic review and economic analysis.

BACKGROUND Acute coronary syndromes (ACSs) are life-threatening conditions associated with acute myocardial ischaemia. There are three main types of ACS: ST segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI) and unstable angina (UA). One treatment for ACS is percutaneous coronary intervention (PCI) plus adjunctive treatment with antiplatelet drugs. Dual therapy antiplatelet treatment [aspirin plus either prasugrel (Efient(®), Daiichi Sankyo Company Ltd UK/Eli Lilly and Company Ltd), clopidogrel or ticagrelor (Brilique(®), AstraZeneca)] is standard in UK clinical practice. Prasugrel is the focus of this review. OBJECTIVES The remit is to appraise the clinical effectiveness and cost-effectiveness of prasugrel within its licensed indication for the treatment of ACS with PCI and is a review of National Institute for Health and Care Excellence technology appraisal TA182. DATA SOURCES Four electronic databases (MEDLINE, EMBASE, The Cochrane Library, PubMed) were searched from database inception to June 2013 for randomised controlled trials (RCTs) and to August 2013 for economic evaluations comparing prasugrel with clopidogrel or ticagrelor in ACS patients undergoing PCI. METHODS Clinical outcomes included non-fatal and fatal cardiovascular (CV) events, adverse effects of treatment and health-related quality of life (HRQoL). Cost-effectiveness outcomes included incremental cost per life-year gained and incremental cost per quality-adjusted life-year (QALY) gained. An independent economic model assessed four mutually exclusive subgroups: ACS patients treated with PCI for STEMI and with and without diabetes mellitus and ACS patients treated with PCI for UA or NSTEMI and with and without diabetes mellitus. RESULTS No new RCTs were identified beyond that reported in TA182. TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocardial Infarction 38) compared prasugrel with clopidogrel in ACS patients scheduled for PCI. No relevant economic evaluations were identified. Our analyses focused on a key subgroup of patients: those aged < 75 years who weighed > 60 kg (no previous stroke or transient ischaemic attack). For the primary composite end point (death from CV causes, non-fatal myocardial infarction or non-fatal stroke) statistically significantly fewer events occurred in the prasugrel arm (8.3%) than in the clopidogrel arm (11%). No statistically significant difference in major bleeding events was noted. However, there was a significant difference in favour of clopidogrel when major and minor bleeding events were combined (3.0 vs. 3.9%). No conclusions could be drawn regarding HRQoL. The results of sensitivity analyses confirmed that it is likely that, for all four ACS subgroups, within 5-10 years prasugrel is a cost-effective treatment option compared with clopidogrel at a willingness-to-pay threshold of £20,000 to £30,000 per QALY gained. At the full 40-year time horizon, all estimates are < £10,000 per QALY gained. LIMITATIONS Lack of data precluded a clinical comparison of prasugrel with ticagrelor; the comparative effectiveness of prasugrel compared with ticagrelor therefore remains unknown. The long-term modelling exercise is vulnerable to major assumptions about the continuation of early health outcome gains. CONCLUSION A key strength of the review is that it demonstrates the cost-effectiveness of prasugrel compared with clopidogrel using the generic price of clopidogrel. Although the report demonstrates the cost-effectiveness of prasugrel compared with clopidogrel at a threshold of £20,000 to £30,000 per QALY gained, the long-term modelling is vulnerable to major assumptions regarding long-term gains. Lack of data precluded a clinical comparison of prasugrel with ticagrelor; the comparative effectiveness of prasugrel compared with ticagrelor therefore remains unknown. Well-audited data are needed from a long-term UK clinical registry on defined ACS patient groups treated with PCI who receive prasugrel, ticagrelor and clopidogrel. STUDY REGISTRATION This study is registered as PROSPERO CRD42013005047. FUNDING The National Institute for Health Research Health Technology Assessment programme.

The Initial Evaluation of the Scottish Telecare Development Program

In 2006 the Scottish Government provided just over £8 million to help 32 health and social care partnerships to develop telecare services. This paper presents a summary of the 2007–2008 evaluation of the Scottish Telecare Development. This evaluation focused on measuring overall program progress toward eight predefined Scottish Telecare Development objectives. Results indicate that the initial investment has resulted in significant savings to the health and social care sectors. Additionally, telecare provides opportunities to promote independence and improve the quality of life of service users and their informal carers. However, some caution needs to be taken in interpreting the findings as results are based on self-reported performance from partnerships, and many of the reported monetary “savings” are actually efficiency savings and are unlikely, in practice, to be cash-releasing.

A scoping study to explore the cost-effectiveness of next-generation sequencing compared with traditional genetic testing for the diagnosis of learning disabilities in children

BACKGROUND Learning disability (LD) is a serious and lifelong condition characterised by the impairment of cognitive and adaptive skills. Some cases of LD with unidentified causes may be linked to genetic factors. Next-generation sequencing (NGS) techniques are new approaches to genetic testing that are expected to increase diagnostic yield. OBJECTIVES This scoping study focused on the diagnosis of LD in children and the objectives were to describe current pathways that involve the use of genetic testing; collect stakeholder views on the changes in service provision that would need to be put in place before NGS could be used in clinical practice; describe the new systems and safeguards that would need to be put in place before NGS could be used in clinical practice; and explore the cost-effectiveness of using NGS compared with conventional genetic testing. METHODS A research advisory group was established. This group provided ongoing support by e-mail and telephone through the lifetime of the study and also contributed face-to-face through a workshop. A detailed review of published studies and reports was undertaken. In addition, information was collected through 33 semistructured interviews with key stakeholders. RESULTS NGS techniques consist of targeted gene sequencing, whole-exome sequencing (WES) and whole-genome sequencing (WGS). Targeted gene panels, which are the least complex, are in their infancy in clinical settings. Some interviewees thought that during the next 3-5 years targeted gene panels would be superseded by WES. If NGS technologies were to be fully introduced into clinical practice in the future a number of factors would need to be overcome. The main resource-related issues pertaining to service provision are the need for additional computing capacity, more bioinformaticians, more genetic counsellors and also genetics-related training for the public and a wide range of staff. It is also considered that, as the number of children undergoing genetic testing increases, there will be an increase in demand for information and support for families. The main issues relating to systems and safeguards are giving informed consent, sharing unanticipated findings, developing ethical and other frameworks, equity of access, data protection, data storage and data sharing. There is little published evidence on the cost-effectiveness of NGS technologies. The major barriers to determining cost-effectiveness are the uncertainty around diagnostic yield, the heterogeneity of diagnostic pathways and the lack of information on the impact of a diagnosis on health care, social care, educational support needs and the wider family. Furthermore, as NGS techniques are currently being used only in research, costs and benefits to the NHS are unclear. CONCLUSIONS NGS technologies are at an early stage of development and it is too soon to say whether they can offer value for money to the NHS as part of the LD diagnostic process. Substantial organisational changes, as well as new systems and safeguards, would be required if NGS technologies were to be introduced into NHS clinical practice. Considerable further research is required to establish whether using NGS technologies to diagnose learning disabilities is clinically effective and cost-effective. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Reporting methodological search filter performance comparisons: a literature review.

BACKGROUND Methodological search filters are tools for retrieving database records reporting studies which use a specific research method. Choosing a filter is likely to be based on filter performance data. This review examines which measures are reported, and the way that filter performance is presented, in filter comparisons. METHODS Studies were identified from the current content and pending update (2010) of a filter website. Eligible studies compared two or more methodological search filters designed to identify randomised controlled trials, diagnostic test accuracy studies, systematic reviews or economic evaluations. RESULTS Eighteen studies met the inclusion criteria. The number of filters compared in a single study ranged from 2 to 38. The most commonly reported measures were sensitivity/recall and precision. All studies displayed results in tables and gave results as percentages or proportions. Two studies supplemented results tables with graphical displays of data: a bar graph of the proportion of retrieved and missed gold standard references per filter; a forest plot of the overall sensitivity and specificity of each filter. CONCLUSIONS Sensitivity/recall and precision are the most frequently reported performance measures. This review highlights the potential for presenting results in novel and innovative ways to aid filter selection.

Should we invest in environmental interventions to encourage physical activity in England? An economic appraisal

BACKGROUND The Department of Health in England asked the National Institute for Health and Clinical Excellence (NICE) to develop guidance on environmental interventions that promote physical activity. The economic appraisals summarized in this study informed the development of that guidance. In view of the difficulties inherent in applying conventional health economic evaluation techniques to public health interventions, the economic appraisal employed a multi-faceted approach. METHODS The analyses comprised of three components. Two cost-utility analyses; the first used a life-time disease progression model which sought to take into account the long-term benefits of physical activity on health outcomes, whereas the second used data from a regression analysis which captured some of the short-term, process benefits of physical activity which might manifest themselves in terms of improved mental health and wellbeing. The third approach was a cost-benefit analysis that took into account benefits beyond healthcare. RESULTS The cost-utility approaches generated cost-effectiveness estimates ranging between £100 and £10 000 per QALY depending on the level of effectiveness of the intervention and the proportion of the intervention cost that was deemed to be attributable to health. The standardized cost-benefit ratio was 11:1. CONCLUSION The findings present a consistent case to support environmental interventions that promote increased physical activity in the sedentary adult population. However, some degree of caution should be taken in interpreting the findings due to the limitations of the evidence upon which they are based. Further consideration should also be given to the relative merits of alternative approaches to assessing the value of changes to the built environment that might also benefit health as a positive externality.