Exhaled nitric oxide in the diagnosis of asthma in adults: a systematic review.

OBJECTIVES: To identify and synthesize evidence on the diagnostic accuracy of FE NO for asthma in adults. MATERIALS AND METHODS: Systematic searches (nine key biomedical databases and trial registers) were carried out on November 2014. Records were included if they recruited patients with the symptoms of asthma; used a single set of inclusion criteria; measured FE NO50 in accordance with American Thoracic Society guidelines, 2005 (off-line excluded); reported/allowed calculation of true-positive, true-negative, false-positive and false-negative patients as classified against any reference standard. Study quality was assessed using QUADAS II. Meta-analysis was planned where clinical study heterogeneity allowed. Rule-in and rule-out uses of FE NO were considered. RESULTS: A total of 4861 records were identified originally and 1312 in an update. Twenty-seven studies were included. Heterogeneity precluded meta-analysis. Results varied even within subgroups of studies. Cut-off values for the best sum of sensitivity and specificity varied from 12 to 55 p.p.b., but did not produce high accuracy. 100% sensitivity or 100% specificity was reported by some studies indicating potential use as a rule-in or rule-out strategy. CONCLUSIONS AND CLINICAL RELEVANCE: FE NO50 had variable diagnostic accuracy even within subgroups of studies with similar characteristics. Diagnostic accuracy, optimal cut-off values and best position for FE NO50 within a pathway remain poorly evidenced.

Ledipasvir-Sofosbuvir for Treating Chronic Hepatitis C: A NICE Single Technology Appraisal-An Evidence Review Group Perspective.

The National Institute for Health and Care Excellence (NICE) invited Gilead, the company manufacturing ledipasvir-sofosbuvir (LDV/SOF), to submit evidence for the clinical effectiveness and cost effectiveness of LDV/SOF for treating chronic hepatitis C. The School of Health and Related Research (ScHARR) Technology Assessment Group was commissioned as the Evidence Review Group (ERG). This paper describes the company's submission (CS), the ERG review and the subsequent decision of the NICE Appraisal Committee (AC). The ERG produced a critical review of the clinical effectiveness and cost-effectiveness evidence of LDV/SOF based upon the CS. The clinical effectiveness data for LDV/SOF were taken from ten trials: three phase III trials and seven phase II trials. Trials compared different durations of LDV/SOF, with and without ribavirin (RBV). There were no head-to-head trials comparing LDV/SOF with any comparator listed in the NICE scope. Data from the trials were mostly from populations with genotype 1 (GT1) disease, although some limited data were available for populations with genotypes 3 and 4. For GT1 treatment-naïve patients, sustained viral response for 12 weeks (SVR12) rates for LDV/SOF ranged from 93.1 to 99.4 % for subgroups of patients with non-cirrhotic disease, whilst SVR rates of 94.1 to 100 % were reported for subgroups of patients with compensated cirrhosis. For GT1 treatment-experienced patients, SVR12 rates ranging from 95.4 to 100 % were reported for subgroups of non-cirrhotic patients, and SVR rates ranging from 81.8 to 100 % were reported within subgroups of patients with compensated cirrhosis. Comparator data were not searched systematically as part of the submission, but were based on the company's previous NICE submission of sofosbuvir, with additional targeted searches. The ERG's critical appraisal of the company's economic evaluation highlighted a number of concerns. The ERG's base case analyses suggested that the incremental cost-effectiveness ratios (ICERs) for LDV/SOF (+RBV) are dependent on (a) treatment durations, (b) whether patients have been previously treated and (c) whether patients have liver cirrhosis or not. The AC concluded that it was appropriate to use the approach taken in the ERG's exploratory analyses, in line with the marketing authorisation, which considered people with and without cirrhosis separately, and estimated the cost effectiveness for each recommended treatment duration of LDV/SOF.

Colistimethate sodium powder and tobramycin powder for inhalation for the treatment of chronic Pseudomonas aeruginosa lung infection in cystic fibrosis: systematic review and economic model.

BACKGROUND: Cystic fibrosis (CF) is an inherited condition characterised by the abnormal transport of chloride ions across transporting epithelia. This leads to the production of thick sticky mucus in the lungs, pancreas, liver, intestine and reproductive tract, and an increase in the salt content in sweat. Among other problems, people with CF experience recurrent respiratory infections and have difficulties digesting food. CF affects over 9000 individuals in the UK. CF shortens life expectancy and adversely affects quality of life. In 2010, CF was recorded as the cause of 103 deaths in England and Wales. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of colistimethate sodium dry powder for inhalation (DPI) (Colobreathe(®), Forest Laboratories) and tobramycin DPI (TOBI Podhaler(®), Novartis Pharmaceuticals) for the treatment of Pseudomonas aeruginosa lung infection in CF. DATA SOURCES: Electronic databases were searched in February and March 2011 [MEDLINE, MEDLINE In-Process & Other Non-Indexed citations, EMBASE, The Cochrane Library databases, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, Conference Proceedings Citation Index (CPCI) and Bioscience Information Service (BIOSIS) Previews]. Relevant databases were searched for ongoing and unpublished studies, and bibliographies of relevant systematic reviews and the manufacturers' submissions were also hand-searched. REVIEW METHODS: A systematic review of the clinical effectiveness and cost-effectiveness of colistimethate sodium DPI and tobramycin DPI for the treatment of chronic P. aeruginosa lung infection in CF was conducted. Existing economic evidence within the literature was reviewed and a de novo health economic model was also developed. RESULTS: Three randomised controlled trials (RCTs) were included in the clinical effectiveness review. Both colistimethate sodium DPI and tobramycin DPI were reported to be non-inferior to nebulised tobramycin for the outcome forced expiratory volume in first second percentage predicted (FEV1%). It was not possible to draw any firm conclusions as to the relative efficacy of colistimethate sodium DPI compared with tobramycin DPI. The economic analysis suggests that colistimethate sodium DPI produces fewer quality-adjusted life-years (QALYs) than nebulised tobramycin. Given the incremental discounted lifetime cost of tobramycin DPI compared with nebulised tobramycin, it highly unlikely that tobramycin DPI has an incremental cost-effectiveness ratio that is better than £30,000 per QALY gained. LIMITATION: The uncertainty surrounding the short-term evidence base inevitably results in uncertainty surrounding the long-term clinical effectiveness and cost-effectiveness of colistimethate sodium DPI. CONCLUSIONS: Both DPI formulations have been shown to be non-inferior to nebulised tobramycin as measured by FEV1%. The results of these trials should be interpreted with caution owing to the means by which the results were analysed, the length of follow-up, and concerns about the ability of FEV1% to accurately represent changes in lung health. Although the increase in QALYs is expected to be lower with colistimethate sodium DPI than with nebulised tobramycin, a price for this intervention had not been agreed at the time of the assessment. Depending on the price of colistimethate sodium DPI, this results either in a situation whereby colistimethate sodium DPI is dominated by nebulised tobramycin or in one whereby the incremental cost-effectiveness of nebulised tobramycin compared with colistimethate sodium DPI is in the range of £24,000-277,000 per QALY gained. The economic analysis also suggests that, given its price, it is unlikely that tobramycin DPI has a cost-effectiveness ratio of < £30,000 per QALY gained when compared with nebulised tobramycin. A RCT to assess the longer-term (≥ 12 months) efficacy of colistimethate sodium DPI and tobramycin DPI in comparison with nebulised treatments would be beneficial. Such a study should include the direct assessment of HRQoL using a relevant preference-based instrument. Future studies should ensure that the European Medicines Agency guidelines are adhered to. In addition, high-quality research concerning the relationship between forced expiratory volume in first second % (FEV1%) predicted or other measures of lung function and survival/health-related quality of life (HRQoL) would be useful. STUDY REGISTRATION: PROSPERO CRD42011001350. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Economic modelling of diagnostic and treatment pathways in National Institute for Health and Care Excellence clinical guidelines: the Modelling Algorithm Pathways in Guidelines (MAPGuide) project.

BACKGROUND: National Institute for Health and Care Excellence (NICE) clinical guidelines (CGs) make recommendations across large, complex care pathways for broad groups of patients. They rely on cost-effectiveness evidence from the literature and from new analyses for selected high-priority topics. An alternative approach would be to build a model of the full care pathway and to use this as a platform to evaluate the cost-effectiveness of multiple topics across the guideline recommendations. OBJECTIVES: In this project we aimed to test the feasibility of building full guideline models for NICE guidelines and to assess if, and how, such models can be used as a basis for cost-effectiveness analysis (CEA). DATA SOURCES: A 'best evidence' approach was used to inform the model parameters. Data were drawn from the guideline documentation, advice from clinical experts and rapid literature reviews on selected topics. Where possible we relied on good-quality, recent UK systematic reviews and meta-analyses. REVIEW METHODS: Two published NICE guidelines were used as case studies: prostate cancer and atrial fibrillation (AF). Discrete event simulation (DES) was used to model the recommended care pathways and to estimate consequent costs and outcomes. For each guideline, researchers not involved in model development collated a shortlist of topics suggested for updating. The modelling teams then attempted to evaluate options related to these topics. Cost-effectiveness results were compared with opinions about the importance of the topics elicited in a survey of stakeholders. RESULTS: The modelling teams developed simulations of the guideline pathways and disease processes. Development took longer and required more analytical time than anticipated. Estimates of cost-effectiveness were produced for six of the nine prostate cancer topics considered, and for five of eight AF topics. The other topics were not evaluated owing to lack of data or time constraints. The modelled results suggested 'economic priorities' for an update that differed from priorities expressed in the stakeholder survey. LIMITATIONS: We did not conduct systematic reviews to inform the model parameters, and so the results might not reflect all current evidence. Data limitations and time constraints restricted the number of analyses that we could conduct. We were also unable to obtain feedback from guideline stakeholders about the usefulness of the models within project time scales. CONCLUSIONS: Discrete event simulation can be used to model full guideline pathways for CEA, although this requires a substantial investment of clinical and analytic time and expertise. For some topics lack of data may limit the potential for modelling. There are also uncertainties over the accessibility and adaptability of full guideline models. However, full guideline modelling offers the potential to strengthen and extend the analytical basis of NICE's CGs. Further work is needed to extend the analysis of our case study models to estimate population-level budget and health impacts. The practical usefulness of our models to guideline developers and users should also be investigated, as should the feasibility and usefulness of whole guideline modelling alongside development of a new CG. FUNDING: This project was funded by the Medical Research Council and the National Institute for Health Research through the Methodology Research Programme [grant number G0901504] and will be published in full in Health Technology Assessment; Vol. 17, No. 58. See the NIHR Journals Library website for further project information.

The clinical effectiveness and cost-effectiveness of cetuximab (mono- or combination chemotherapy), bevacizumab (combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of technology appraisal No.150 and part review of technology appraisal No. 118): a systematic review and economic model.

BACKGROUND: Colorectal cancer is the third most commonly diagnosed cancer in the UK after breast and lung cancer. People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as first- or second-line therapy. Recently, targeted agents have become available including anti-epidermal growth factor receptor (EGFR) agents, for example cetuximab and panitumumab, and anti-vascular endothelial growth factor (VEGF) receptor agents, for example bevacizumab. OBJECTIVE: To investigate the clinical effectiveness and cost-effectiveness of panitumumab monotherapy and cetuximab (mono- or combination chemotherapy) for Kirsten rat sarcoma (KRAS) wild-type (WT) patients, and bevacizumab in combination with non-oxaliplatin chemotherapy, for the treatment of metastatic colorectal cancer after first-line chemotherapy. DATA SOURCES: The assessment comprises a systematic review of clinical effectiveness and cost-effectiveness studies, a review and critique of manufacturer submissions and a de novo cohort-based economic analysis. For the assessment of effectiveness, a literature search was conducted in a range of electronic databases, including MEDLINE, EMBASE and The Cochrane Library, from 2005 to November 2010. REVIEW METHODS: Studies were included if they were randomised controlled trials (RCTs) or systematic reviews of RCTs of cetuximab, bevacizumab or panitumumab in participants with EGFR-expressing metastatic colorectal cancer with KRAS WT status that has progressed after first-line chemotherapy (for cetuximab and panitumumab) or participants with metastatic colorectal cancer that has progressed after first-line chemotherapy (bevacizumab). All steps in the review were performed by one reviewer and checked independently by a second. Synthesis was mainly narrative. An economic model was developed focusing on third-line and subsequent lines of treatment. Costs and benefits were discounted at 3.5% per annum. Probabilistic and univariate deterministic sensitivity analyses were performed. RESULTS: The searches identified 7745 titles and abstracts. Two clinical trials (reported in 12 papers) were included. No data were available for bevacizumab in combination with non-oxaliplatin-based chemotherapy in previously treated patients. Neither of the included studies had KRAS status performed prospectively, but the studies did report retrospective analyses of the results for the KRAS WT subgroups. Third-line treatment with cetuximab plus best supportive care or panitumumab plus best supportive care appears to have statistically significant advantages over treatment with best supportive care alone in patients with KRAS WT status. For the economic evaluation, five studies met the inclusion criteria. The base-case incremental cost-effectiveness ratio (ICER) for KRAS WT patients for cetuximab compared with best supportive care is £98,000 per quality-adjusted life-year (QALY), for panitumumab compared with best supportive care is £150,000 per QALY and for cetuximab plus irinotecan compared with best supportive care is £88,000 per QALY. All ICERs are sensitive to treatment duration. LIMITATIONS: In the specific populations of interest, there is a lack of evidence on bevacizumab, cetuximab and cetuximab plus irinotecan used second line and on bevacizumab and cetuximab plus irinotecan used third line. For cetuximab plus irinotecan treatment for KRAS WT people, there is no direct evidence on progression-free survival, overall survival and duration of treatment. CONCLUSIONS: Although cetuximab and panitumumab appear to be clinically beneficial for KRAS WT patients compared with best supportive care, they are likely to represent poor value for money when judged by cost-effectiveness criteria currently used in the UK. It would be useful to conduct a RCT for patients with KRAS WT status receiving cetuximab plus irinotecan. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Bivalirudin for the treatment of ST-segment elevation myocardial infarction: a NICE single technology appraisal.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer (The Medicines Company) of bivalirudin to submit evidence for its clinical and cost effectiveness within its licensed indication for the treatment of adults with ST-segment elevation myocardial infarction (STEMI) intended for primary percutaneous coronary intervention (PPCI), as part of NICE's single technology appraisal (STA) process. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG), which produced a review of the evidence within the manufacturer's submission to NICE. This article describes the manufacturer's submission, the ERG review and NICE's subsequent decisions. The main evidence was derived from one randomized controlled trial (RCT) of STEMI patients intended for PPCI, comparing bivalirudin with unfractionated heparin plus glycoprotein IIb/IIIa inhibitors (GPIs). Bivalirudin was associated with a significant reduction in cardiac mortality at 30 days (p = 0.03) and at 1-year follow-up (p = 0.005), and a significant reduction in major bleeding at 30 days (p < 0.001) and 1 year (p < 0.0001), compared with heparin plus GPI. Stent thrombosis up to 24 hours following PPCI was significantly (p < 0.001) more common with bivalirudin. However, there was no significant treatment effect for stent thrombosis from 1 to 30 days (p = 0.28), or at 1-year follow-up (p = 0.53). There were no significant treatment group differences at 30 days and at 1 year in stroke (p = 0.68 and p = 0.99, respectively), in myocardial infarction [MI] (p = 0.90 and p = 0.22, respectively), or in the need for the revascularization of the target vessel for ischaemia (p = 0.18 and p = 0.12, respectively). There were two decision-analytic models: the base-case scenario used 1-year follow-up data from the RCT; and a sensitivity analysis used 3-year follow-up data. Resource use was primarily drawn from this RCT. Health-related quality-of-life (HR-QOL) estimates were drawn from a UK cohort study. Both models evaluated the incremental costs and outcomes of bivalirudin compared with heparin plus GPI for patients with STEMI intended for PPCI. The analysis adopted a UK NHS perspective over a lifetime horizon. Unit costs were based on year 2009-2010 prices. The model adopted a decision-tree structure to reflect initial events for the initial period (stroke, repeat MI, minor/major bleeding events, repeat revascularization and death) and a two-state Markov component to simulate longer-term survival. The economic analysis suggested that bivalirudin is expected to dominate the heparin plus GPI strategy. This finding was consistent across the probabilistic sensitivity analysis and the vast majority of deterministic sensitivity analyses undertaken. Three exceptions to this finding were observed for the following sensitivity analyses: (1) the exclusive use of eptifibatide as the GPI (incremental cost-effectiveness ratio [ICER] = £1,764); (2) the combination of 100 % eptifibatide use, 100 % radial arterial access and no differential length between strategies for initial hospital stay (ICER = £4,106); and (3) a longer length of ward stay (increase of 0.33 days) for the initial hospitalization (ICER = £415). The Appraisal Committee (AC) gave a positive recommendation for bivalirudin for the treatment of adults with STEMI undergoing PPCI.

The clinical effectiveness and cost-effectiveness of home-based, nurse-led health promotion for older people: a systematic review.

BACKGROUND: In older age, reduction in physical function can lead to loss of independence, the need for hospital and long-term nursing or residential home care, and premature death. Home-visiting programmes for older people, carried out by nurses and other health-care professionals (e.g. occupational therapists and physiotherapists), aim to positively affect health and functional status, and may promote independent functioning of older people. OBJECTIVE: The main research question addressed by this assessment is 'What is the clinical effectiveness and cost-effectiveness of home-based, nurse-led health promotion intervention for older people in the UK?' DATA SOURCES: A comprehensive literature search was undertaken across 12 different databases and research registries from the year 2001 onwards (including MEDLINE, MEDLINE in Process & Other Non-Indexed Citations, EMBASE, Science Citation Index Expanded, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, NHS Health Economic Evaluation Database, Health Technology Assessment Database, Database of Abstracts of Reviews of Effects, Cumulative Index to Nursing and Allied Health Literature). Published systematic reviews were also hand searched to identify other trials previously published. REVIEW METHODS: Potentially relevant studies were sifted by one reviewer, and inclusion decisions were agreed among the broader research team. The methodological quality of included studies was assessed using the Cochrane Risk of Bias tool. The results of included studies were synthesised using narrative and statistical methods. A separate systematic search was undertaken to identify existing health economic analyses of home-based, nurse-led health promotion programmes. Included studies were critically appraised using a published checklist. Owing to resource constraints, a de novo health economic model was not developed. RESULTS: Eleven studies were included in the systematic review of clinical effectiveness. There was considerable heterogeneity among the studies with respect to the nature of the intervention, the nurses delivering the programmes and the populations in which the interventions were assessed. Overall, the quality of the included studies was good: all but one of the included studies were judged to be at medium or low risk of bias. Meta-analysis of eight studies suggested a statistically significant mortality benefit for the home-based health promotion groups, whereas a meta-analysis of four studies suggested non-significant benefits in terms of fewer falls in the intervention groups than in the control groups. Positive outcomes for home-based, nurse-led health promotion interventions were also reported within individual studies across several other outcomes. Only three economic studies met the criteria for inclusion in the review of cost-effectiveness. This evidence base consists of one non-randomised cost minimisation analysis and two economic evaluations undertaken alongside randomised controlled trials. Two of these studies involved an intervention targeted specifically at patients with a known underlying incurable disease, whereas the third study examined the clinical effectiveness and cost-effectiveness of early discharge in patients with a range of conditions, including fractures, neurological conditions and cardiorespiratory conditions. Each study indicated some likelihood that home-based, nurse-led health promotion may offer cost savings to the NHS and associated sectors, such as social services. However, one study did not report any comparison of health outcomes and instead simply assumed equivalence between the intervention and comparator groups, whereas the other two studies suggested at best a negligible incremental benefit in terms of preference-based health-related quality-of-life measures. LIMITATIONS: The evidence base for clinical effectiveness is subject to considerable heterogeneity. The UK economic evidence base is limited to three studies. CONCLUSIONS: On the basis of the evidence included in this systematic review, home-based, nurse-led health promotion may offer clinical benefits across a number of important health dimensions. However, it is generally unclear from the available studies which components of this type of complex intervention contribute towards individual aspects of benefit for older people. Given the limitations of the current evidence base, it remains unclear whether or not home-based health promotion interventions offer good value for money for the NHS and associated sectors. Given the considerable uncertainties in the available evidence base, it is difficult to isolate the key areas in which future research would be valuable or the exact study design required. Although this report does not identify specific studies that should be undertaken, it does set out a number of key considerations for the design of future research in this area. STUDY REGISTRATION: PROSPERO number: CRD42012002133.

Cost-effectiveness of population-based screening for colorectal cancer: a comparison of guaiac-based faecal occult blood testing, faecal immunochemical testing and flexible sigmoidoscopy.

BACKGROUND: Several colorectal cancer-screening tests are available, but it is uncertain which provides the best balance of risks and benefits within a screening programme. We evaluated cost-effectiveness of a population-based screening programme in Ireland based on (i) biennial guaiac-based faecal occult blood testing (gFOBT) at ages 55-74, with reflex faecal immunochemical testing (FIT); (ii) biennial FIT at ages 55-74; and (iii) once-only flexible sigmoidoscopy (FSIG) at age 60. METHODS: A state-transition model was used to estimate costs and outcomes for each screening scenario vs no screening. A third party payer perspective was adopted. Probabilistic sensitivity analyses were undertaken. RESULTS: All scenarios would be considered highly cost-effective compared with no screening. The lowest incremental cost-effectiveness ratio (ICER vs no screening euro 589 per quality-adjusted life-year (QALY) gained) was found for FSIG, followed by FIT euro 1696) and gFOBT (euro 4428); gFOBT was dominated. Compared with FSIG, FIT was associated with greater gains in QALYs and reductions in lifetime cancer incidence and mortality, but was more costly, required considerably more colonoscopies and resulted in more complications. Results were robust to variations in parameter estimates. CONCLUSION: Population-based screening based on FIT is expected to result in greater health gains than a policy of gFOBT (with reflex FIT) or once-only FSIG, but would require significantly more colonoscopy resources and result in more individuals experiencing adverse effects. Weighing these advantages and disadvantages presents a considerable challenge to policy makers.

Cost of care for colorectal cancer in Ireland: a health care payer perspective.

OBJECTIVE: Management options for colorectal cancer have expanded in recent years. We estimated average lifetime cost of care for colorectal cancer in Ireland in 2008, from the health care payer perspective. METHOD: A decision tree model was developed in Microsoft EXCEL. Site and stage-specific treatment pathways were constructed from guidelines and validated by expert clinical opinion. Health care resource use associated with diagnosis, treatment and follow-up were obtained from the National Cancer Registry Ireland (n=1,498 cancers diagnosed during 2004-2005) and three local hospital databases (n=155, 142 and 46 cases diagnosed in 2007). Unit costs for hospitalisation, procedures, laboratory tests and radiotherapy were derived from DRG costs, hospital finance departments, clinical opinion and literature review. Chemotherapy costs were estimated from local hospital protocols, pharmacy departments and clinical opinion. Uncertainty was explored using one-way and probabilistic sensitivity analysis. RESULTS: In 2008, the average (stage weighted) lifetime cost of managing a case of colorectal cancer was €39,607. Average costs were 16% higher for rectal (€43,502) than colon cancer (€37,417). Stage I disease was the least costly (€23,688) and stage III most costly (€48,835). Diagnostic work-up and follow-up investigations accounted for 4 and 5% of total costs, respectively. Cost estimates were most sensitive to recurrence rates and prescribing of biological agents. CONCLUSION: This study demonstrates the value of using existing data from national and local databases in contributing to estimating the cost of managing cancer. The findings illustrate the impact of biological agents on costs of cancer care and the potential of strategies promoting earlier diagnosis to reduce health care resource utilisation and care costs.

Antioxidants in the chemoprevention of colorectal cancer and colorectal adenomas in the general population: a systematic review and meta-analysis.

AIM: Antioxidants, such as vitamin A, C and E, selenium and ß-carotene, have been proposed as possible agents in the chemoprevention of colorectal cancer and have been the subject of recent trials and reviews. This review aimed to assess the present evidence on the effect of antioxidants on the incidence of colorectal neoplasms in the general population. METHOD: A systematic review of randomized controlled trials was undertaken comparing antioxidants alone or in combination with other agents vs placebo. The following databases were searched for published and unpublished literature: Cochrane Library, MEDLINE, PreMEDLINE, CINAHL, EMBASE, Web of Science, and Biological Abstracts and Research Registers. Studies were quality appraised and extracted. Meta-analysis was performed. RESULTS: Twelve studies were identified as relevant. In the nine comparing antioxidants with no antioxidants (n=148 922), there was no difference in the incidence of colorectal cancer [relative risk (RR) 1.00, 95% confidence interval (CI) 0.88-1.13]. One study assessed the effect of antioxidants on adenoma formation (n=15 538) and did not demonstrate a statistically significant effect (RR 1.47, 95% CI 0.97-2.23). Of 14 discrete analyses for different combinations of antioxidants, only one reported a statistically significant increase in relative risk of adenoma formation in participants receiving vitamin E (RR 1.74, 95% CI 1.09-1.79, P=0.02) or vitamin E plus ß-carotene (RR 1.63, 95% CI 1.01-2.63, P=0.04). Effectiveness did not seem to differ between healthy populations, participants with cardiovascular risk factors or populations exposed to smoking or asbestos. CONCLUSION: The review demonstrates that antioxidants (vitamin A, C and E, selenium and ß-carotene), as single agents, in combination with other antioxidants or in combination with other agents, are not effective in the chemoprevention of colorectal neoplasia in the general population. This questions their involvement in future randomized controlled trials of chemoprevention in colorectal cancer.

Chemoprevention of colorectal cancer: systematic review and economic evaluation.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer in the UK: incidence increases with age, median age at diagnosis being over 70 years. Approximately 25% of cases occur in individuals with a family history of CRC, including 5% caused by familial adenomatous polyposis (FAP) or hereditary non-polyposis CRC (HNPCC). Most develop from adenomatous polyps arising from the intestine lining. Individuals with these polyps undergo polypectomy and are invited for endoscopic surveillance. Screening via faecal occult blood testing has been rolled out across the UK. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of drug and micronutrient interventions for the prevention of CRC and/or adenomatous polyps. Interventions considered include: non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and cyclo-oxygenase-2 (COX-2) inhibitors; folic acid; calcium; vitamin D and antioxidants (including vitamin A, vitamin C, vitamin E, selenium and beta-carotene). Chemoprevention was assessed in the general population, in individuals at increased risk of CRC, and in individuals with FAP or HNPCC. DATA SOURCES: A systematic review identified randomised controlled trials (RCTs) assessing drug and nutritional agents for the prevention of CRC or adenomatous polyps. A separate search identified qualitative studies relating to individuals' views, attitudes and beliefs about chemoprevention. MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, CINAHL, the Cochrane Database of Systematic Reviews, Cochrane CENTRAL Register of Controlled Trials, DARE, NHS-EED (NHS Economic Evaluation Database), HTA database, Science Citation Index, BIOSIS previews and the Current Controlled Trials research register were searched in June 2008. Data were extracted by one reviewer and checked by a second. REVIEW METHODS: The synthesis methods used were systematic review and meta-analysis for RCTs and qualitative framework synthesis for qualitative studies. A health economic model was developed to assess the cost-effectiveness of chemoprevention for two populations with different levels of risk of developing CRC: the general population and an intermediate-risk population. RESULTS: The search identified 44 relevant RCTs and six ongoing studies. A small study of aspirin in FAP patients produced no statistically significant reduction in polyp number but a possible reduction in polyp size. There was a statistically significant 21% reduction in risk of adenoma recurrence [relative risk (RR) 0.79, 95% confidence interval (CI) 0.68 to 0.92] in an analysis of aspirin versus no aspirin in individuals with a history of adenomas or CRC. In the general population, a significant 26% reduction in CRC incidence was demonstrated in studies with a 23-year follow-up (RR 0.74, 95% CI 0.57 to 0.97). Non-aspirin NSAID use in FAP individuals produced a non-statistically significant reduction in adenoma incidence after 4 years of treatment and follow-up and reductions in polyp number and size. In individuals with a history of adenomas there was a statistically significant 34% reduction in adenoma recurrence risk (RR 0.66, 95% CI 0.60 to 0.72) and a statistically significant 55% reduction in advanced adenoma incidence (RR 0.45, 95% CI 0.35 to 0.58). No studies assessed the effect of non-aspirin NSAIDs in the general population. There were no studies of folic acid in individuals with FAP or HNPCC. There was no significant effect of folic acid versus placebo on adenoma recurrence (RR 1.16, 95% CI 0.97 to 1.39) or advanced adenoma incidence in individuals with a history of adenomas. In the general population there was no significant effect of folic acid on risk of CRC (RR 1.13, 95% CI 0.77 to 1.64), although studies were of relatively short duration. Calcium use by FAP patients produced no significant reduction in polyp number or disease progression. In individuals with a history of adenomas there was a statistically significant 18% reduction in risk of adenoma recurrence (RR 0.82, 95% CI 0.69 to 0.98) and a non-significant reduction in risk of advanced adenomas (RR 0.77, 95% CI 0.50 to 1.17). In the general population there was no significant effect of calcium on risk of CRC (RR 1.08, 95% CI 0.87 to 1.34), although studies were of relatively short duration. There were no studies of antioxidant use in individuals with FAP or HNPCC, and in individuals with a history of adenomas no statistically significant differences in relative risk of adenoma recurrence were found. In the general population there was no difference in incidence of CRC (RR 1.00, 95% CI 0.88 to 1.13) with antioxidant use compared with no antioxidant use. Twenty studies reported qualitative findings concerning chemoprevention. People are more likely to use NSAIDs if there is a strong perceived need. Perceptions of risk and benefit also influence decision-making and use. People have fewer concerns about using antioxidants or other supplements, but their perception of the benefits of these agents is less well-defined. The model analysis suggested that the most cost-effective age-range policy in the general population would be to provide chemoprevention to all individuals within the general population from age 50 to 60 years. The use of aspirin in addition to screening within the general population is likely to result in a discounted cost per life-year gained of around 10,000 pounds and a discounted cost per quality-adjusted life-year (QALY) gained of around 23,000 pounds compared with screening alone. In the intermediate-risk group the most economically viable age-range policy would be to provide chemoprevention to individuals following polypectomy aged 61 to 70 years. Calcium is likely to have a discounted cost per QALY gained of around 8000 pounds compared with screening alone. Although aspirin in addition to screening should be more effective and less costly than screening alone, under the current assumptions of benefits to harms of aspirin and calcium, aspirin is expected to be extendedly dominated by calcium. LIMITATIONS: Whilst a number of studies were included in the review, the duration of follow-up was generally insufficient to detect an effect on cancer incidence. Given the uncertainties and ambiguities in the evidence base, the results of the health economic analysis should be interpreted with caution. CONCLUSIONS: Aspirin and celecoxib may reduce recurrence of adenomas and incidence of advanced adenomas in individuals with an increased risk of CRC and calcium may reduce recurrence of adenomas in this group. COX-2 inhibitors may decrease polyp number in patients with FAP. There is some evidence for aspirin reducing the incidence of CRC in the general population. Both aspirin and NSAIDs are associated with adverse effects so it will be important to consider the risk-benefit ratio before recommending these agents for chemoprevention. The economic analysis suggests that chemoprevention has the potential to represent a cost-effective intervention, particularly when targeted at intermediate-risk populations following polypectomy.

Avoiding and identifying errors in health technology assessment models: qualitative study and methodological review.

BACKGROUND: Health policy decisions must be relevant, evidence-based and transparent. Decision-analytic modelling supports this process but its role is reliant on its credibility. Errors in mathematical decision models or simulation exercises are unavoidable but little attention has been paid to processes in model development. Numerous error avoidance/identification strategies could be adopted but it is difficult to evaluate the merits of strategies for improving the credibility of models without first developing an understanding of error types and causes. OBJECTIVES: The study aims to describe the current comprehension of errors in the HTA modelling community and generate a taxonomy of model errors. Four primary objectives are to: (1) describe the current understanding of errors in HTA modelling; (2) understand current processes applied by the technology assessment community for avoiding errors in development, debugging and critically appraising models for errors; (3) use HTA modellers' perceptions of model errors with the wider non-HTA literature to develop a taxonomy of model errors; and (4) explore potential methods and procedures to reduce the occurrence of errors in models. It also describes the model development process as perceived by practitioners working within the HTA community. DATA SOURCES: A methodological review was undertaken using an iterative search methodology. Exploratory searches informed the scope of interviews; later searches focused on issues arising from the interviews. Searches were undertaken in February 2008 and January 2009. In-depth qualitative interviews were performed with 12 HTA modellers from academic and commercial modelling sectors. REVIEW METHODS: All qualitative data were analysed using the Framework approach. Descriptive and explanatory accounts were used to interrogate the data within and across themes and subthemes: organisation, roles and communication; the model development process; definition of error; types of model error; strategies for avoiding errors; strategies for identifying errors; and barriers and facilitators. RESULTS: There was no common language in the discussion of modelling errors and there was inconsistency in the perceived boundaries of what constitutes an error. Asked about the definition of model error, there was a tendency for interviewees to exclude matters of judgement from being errors and focus on 'slips' and 'lapses', but discussion of slips and lapses comprised less than 20% of the discussion on types of errors. Interviewees devoted 70% of the discussion to softer elements of the process of defining the decision question and conceptual modelling, mostly the realms of judgement, skills, experience and training. The original focus concerned model errors, but it may be more useful to refer to modelling risks. Several interviewees discussed concepts of validation and verification, with notable consistency in interpretation: verification meaning the process of ensuring that the computer model correctly implemented the intended model, whereas validation means the process of ensuring that a model is fit for purpose. Methodological literature on verification and validation of models makes reference to the Hermeneutic philosophical position, highlighting that the concept of model validation should not be externalized from the decision-makers and the decision-making process. Interviewees demonstrated examples of all major error types identified in the literature: errors in the description of the decision problem, in model structure, in use of evidence, in implementation of the model, in operation of the model, and in presentation and understanding of results. The HTA error classifications were compared against existing classifications of model errors in the literature. A range of techniques and processes are currently used to avoid errors in HTA models: engaging with clinical experts, clients and decision-makers to ensure mutual understanding, producing written documentation of the proposed model, explicit conceptual modelling, stepping through skeleton models with experts, ensuring transparency in reporting, adopting standard housekeeping techniques, and ensuring that those parties involved in the model development process have sufficient and relevant training. Clarity and mutual understanding were identified as key issues. However, their current implementation is not framed within an overall strategy for structuring complex problems. LIMITATIONS: Some of the questioning may have biased interviewees responses but as all interviewees were represented in the analysis no rebalancing of the report was deemed necessary. A potential weakness of the literature review was its focus on spreadsheet and program development rather than specifically on model development. It should also be noted that the identified literature concerning programming errors was very narrow despite broad searches being undertaken. CONCLUSIONS: Published definitions of overall model validity comprising conceptual model validation, verification of the computer model, and operational validity of the use of the model in addressing the real-world problem are consistent with the views expressed by the HTA community and are therefore recommended as the basis for further discussions of model credibility. Such discussions should focus on risks, including errors of implementation, errors in matters of judgement and violations. Discussions of modelling risks should reflect the potentially complex network of cognitive breakdowns that lead to errors in models and existing research on the cognitive basis of human error should be included in an examination of modelling errors. There is a need to develop a better understanding of the skills requirements for the development, operation and use of HTA models. Interaction between modeller and client in developing mutual understanding of a model establishes that model's significance and its warranty. This highlights that model credibility is the central concern of decision-makers using models so it is crucial that the concept of model validation should not be externalized from the decision-makers and the decision-making process. Recommendations for future research would be studies of verification and validation; the model development process; and identification of modifications to the modelling process with the aim of preventing the occurrence of errors and improving the identification of errors in models.

Meta-analysis: folic acid in the chemoprevention of colorectal adenomas and colorectal cancer.

BACKGROUND: Folic acid has been identified as a possible agent for the chemoprevention of colorectal cancer. AIM: To assess the effectiveness of folic acid in reducing the recurrence of adenomas (precursors of colorectal cancer) among populations with a history of adenomas and the incidence of colorectal cancer within average-risk populations. METHODS: Systematic review of randomized controlled trials comparing folic acid alone, or with other agents, vs. placebo. Eight databases were searched for relevant trials. Meta-analysis was performed. RESULTS: The literature search retrieved 3785 citations. Six studies met the inclusion criteria. Meta-analysis of three studies in individuals with a history of adenomas showed no statistically significant difference in the relative risk of adenoma recurrence (RR 0.93, P = 0.27). A sensitivity analysis of the two higher quality trials changed the direction of effect (RR 1.16, P = 0.11). Meta-analysis of three trials in general populations demonstrated no statistically significant effect on the relative risk of colorectal cancer (RR 1.13, P = 0.54). In all three analyses, outcome event rates were higher in individuals receiving folic acid. CONCLUSION: There is no evidence that folic acid is effective in the chemoprevention of colorectal adenomas or colorectal cancer for any population.

Autologous haematopoietic stem cell transplantation for secondary progressive multiple sclerosis: an exploratory cost-effectiveness analysis.

Treatment options for secondary progressive multiple sclerosis (SPMS) are limited. Mitoxantrone is routinely used to stabilize disease progression; however, evolving evidence suggests clinical benefit from intensive treatment with autologous haematopoietic stem cell transplantation (HSCT). Given differences in cost and outcomes, preliminary cost-effectiveness studies are warranted if this approach is to be developed for more widespread application in SPMS. We developed a decision-analytic Markov model to explore the potential cost-effectiveness of autologous HSCT versus mitoxantrone in SPMS, using patient-level data from registry sources. The model evaluates the lifetime costs and health outcomes associated with disability progression and relapse. Sensitivity analyses were undertaken to examine the uncertainty surrounding cost-effectiveness outcomes. In the absence of randomised controlled trial (RCT) evidence, conditions for comparative analysis were not ideal. Under optimistic assumptions, HSCT is estimated to cost below pound3000 per quality adjusted life year gained. However, when a strict 6-month sustained progression rule is adopted, HSCT may be less effective and more expensive than mitoxantrone. The model results were sensitive to reducing procedural costs and HSCT-related mortality. We conclude that HSCT could potentially achieve an acceptable level of cost-effectiveness. However, caution should be exercised as large, high-quality RCTs comparing HSCT versus mitoxantrone are necessary to validate these findings.

Varenicline in the management of smoking cessation: a single technology appraisal.

This paper presents a summary of the submission's evidence for the clinical effectiveness and cost-effectiveness of varenicline for smoking cessation included four studies of varenicline (one of which was commercial-in-confidence) and a meta-analysis of varenicline versus nicotine replacement therapy (NRT), bupropion and placebo. Two controlled trials of 12 weeks of varenicline versus sustained-release bupropion and placebo suggested that varenicline results in a statistically significant improvement in the odds of quitting at 12 weeks [odds ratio (OR) for quit rate during last 4 weeks of the study: 1.90-1.93 (p < 0.001) varenicline versus bupropion; 3.85 (p < 0.001) varenicline versus placebo). The ORs for sustained abstinence (weeks 9-52) for varenicline versus bupropion were 1.77 (p = 0.004) and 1.46 (p = 0.057), and for varenicline versus placebo were 2.66-3.09 (p < 0.01). A placebo-controlled maintenance trial examined whether a further 12 weeks of varenicline would maintain the rate of abstinence among those successfully treated on one 12-week course [OR = 2.48 at week 24 for varenicline versus placebo (p < 0.001)]. The meta-analysis suggested that varenicline was superior to placebo and bupropion at 1 year and 3 months. Based on indirect comparisons, varenicline was reported to be superior to NRT when compared with placebo or all controls at 1 year and 3 months. The submission presented a state transition model to estimate the incremental cost-effectiveness of varenicline compared with bupropion, NRT and placebo. The model suggests that varenicline dominates bupropion, NRT and placebo.Treatment efficacy was based on a pooled analysis of 1-year quit rates from the varenicline clinical trials. Assuming a willingness-to-pay threshold range of 20,000-30,000 pounds per quality-adjusted life-year gained, the probabilistic sensitivity analysis suggests that the probability that varenicline produces the greatest amount of net benefit is 0.70. Weaknesses of the manufacturer's submission include the assumption that only a single quit attempt using a single smoking cessation intervention is made, the presence of multiple computational errors and a limited sensitivity analysis. In conclusion, varenicline is likely to be clinically and cost-effective for smoking cessation assuming that each user makes a single quit attempt. The key area of uncertainty concerns the long-term experience of subjects who have remained abstinent from smoking beyond 12 months. The guidance issued by the National Institute for Health and Clinical Excellence in July 2007 states that varenicline is recommended within its licensed indications as an option for smokers who have expressed a desire to quit smoking and that varenicline should normally be prescribed only as part of a programme of behavioral support.

Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation.

OBJECTIVES: To evaluate the clinical effectiveness and incremental cost-effectiveness of amantadine, oseltamivir and zanamivir for seasonal and post-exposure prophylaxis of influenza. DATA SOURCES: A MEDLINE search strategy was used and searches were carried out in July 2007. REVIEW METHODS: An independent health economic model was developed based on a review of existing cost-effectiveness models and clinical advice.The model draws together a broad spectrum of evidence relating to the costs and consequences associated with influenza and its prevention. Where direct evidence concerning the effectiveness of prophylaxis within specific model subgroups was lacking, the model uses estimates from mixed subgroups or extrapolates from other mutually exclusive subgroups. RESULTS: Twenty-six published references relating to 22 randomised controlled trials (RCTs) were included in the clinical effectiveness review, along with one unpublished report. Eight, six and nine RCTs were included for amantadine, oseltamivir and zanamivir respectively. The study quality was variable and gaps in the evidence base limited the assessment of the clinical effectiveness of the interventions. For seasonal prophylaxis, there was limited evidence for the efficacy of amantadine in preventing symptomatic, laboratory-confirmed influenza (SLCI) in healthy adults [relative risk (RR) 0.40, 95% confidence interval (CI) 0.08-2.03]. Oseltamivir was effective in preventing SLCI, particularly when used in at-risk elderly subjects (RR 0.08, 95% CI 0.01-0.63). The preventative efficacy of zanamivir was most notable in at-risk adults and adolescents (RR 0.17, 95% CI 0.07-0.44), and healthy and at-risk elderly subjects (RR 0.20, 95% CI 0.02-1.72). For post-exposure prophylaxis, data on the use of amantadine were again limited: in adolescents an RR of 0.10 (95% CI 0.03-0.34) was reported for the prevention of SLCI. Oseltamivir was effective in households of mixed composition (RR 0.19, 95% CI 0.08-0.45). The efficacy of zanamivir in post-exposure prophylaxis within households was also reported (RR 0.21, 95% CI 0.13-0.33). Interventions appeared to be well tolerated. Limited evidence was available for the effectiveness of the interventions in preventing complications and hospitalisation and in minimising length of illness and time to return to normal activities. No clinical effectiveness data were identified for health-related quality of life or mortality outcomes. With the exception of at-risk children, the incremental cost-utility of seasonal influenza prophylaxis is expected to be in the range 38,000-428,000 pounds per QALY gained (depending on subgroup). The cost-effectiveness ratios for oseltamivir and zanamivir as post-exposure prophylaxis are expected to be below 30,000 pounds per QALY gained in healthy children, at-risk children, healthy elderly and at-risk elderly individuals. Despite favourable clinical efficacy estimates, the incorporation of recent evidence of viral resistance to amantadine led to it being dominated in every economic comparison. CONCLUSIONS: All three interventions showed some efficacy for seasonal and post-exposure prophylaxis. However, weaknesses and gaps in the clinical evidence base are directly relevant to the interpretation of the health economic model and rendered the use of advanced statistical analyses inappropriate. These data limitations should be borne in mind in interpreting the findings of the review.

Predicting the impact of the screening programme for colorectal cancer in the UK.

OBJECTIVES: Screening for colorectal cancer by biennial testing for faecal occult blood is being introduced in the UK from 2007. We examine the likely impact of the programme, in terms of reduced mortality, lives saved and changes in incidence, over the next 20 years. SETTING: Projections of incidence and mortality of colorectal cancer in England, and the policy that has been adopted for screening in England (biennial at ages 60-69 from 2007, then 60-74 in 2010). METHODS: The results are based on the output of a simulation model that has been used to examine cost-effectiveness of screening policy options, with two scenarios regarding compliance with screening; both assume that 20% of the population will never attend for screening, but attendance of those who do is modelled either as a random 60% or 80%, at each screening round. RESULTS: The decrease in mortality rates expected 20 years after introducing screening is 13-17% in men and 12-15% in women (depending on the attendance levels). The model predicts an initial rise in incidence, followed (after six to seven years) by a fall, so that there is little net change in the number of cases detected over a 20-year period. CONCLUSION: Percentage changes in mortality seem modest, but the projected saving in terms of numbers of lives is not negligible--1800-2400 per year by 2025 in England (equivalent numbers are 2200-2700 in all over the UK). Newer screening modalities may improve on these projected results.