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.

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.

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.

The use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer: systematic review and economic evaluation.

OBJECTIVES: To evaluate three technologies for the management of advanced colorectal cancer: (1) first-line irinotecan combination [with 5-fluorouracil (5-FU)] or second-line monotherapy; (2) first- or second-line oxaliplatin combination (again, with 5-FU); and (3) raltitrexed, where 5-FU is inappropriate. To examine the role of irinotecan and oxaliplatin in reducing the extent of incurable disease before curative surgery (downstaging). SOURCES: Ten electronic bibliographic databases covering the period up to August 2004. METHODS: Searches identified existing studies of the effectiveness and economics of the technologies and any studies that evaluated any of the indications outlined above were included. Data were extracted and assessed generic components of methodological quality. Survival outcomes were meta-analysed. RESULTS: Seventeen trials were found, of varying methodological quality. Compared with 5-FU, first-line irinotecan improved overall survival (OS) by 2-4 months (p=0.0007), progression-free survival (PFS) by 2-3 months (p<0.00001) and response rates (p<0.001). It offered a different toxicity profile and no quality of life (QoL) advantage. However, second-line irinotecan compared with 5-FU improved OS by 2 months (p=0.035) and PFS by 1 month (p=0.03), and provided a better partial response rate, but with more toxicities and no QoL advantage. Compared with second-line best supportive care, irinotecan improved OS by 2 months (p=0.0001), had a different toxicity profile and maintained baseline QoL longer, but with no overall difference. The addition of oxaliplatin to second-line 5-FU is associated with a borderline significant improvement in overall survival (p<0.07); a significantly higher response rate (<0.0001); and more serious toxicities. There is no evidence for a significant difference in QoL. Schedules with treatment breaks may not reduce clinical effectiveness but reduce toxicity. The addition of oxaliplatin to second-line 5-FU also saw no improvement in OS (p<0.07), better PFS (by 2.1 months, p=0.0001), an 8.9% higher response rate (p<0.0001), more toxicities and no QoL advantage. There was no significant difference in OS or PFS between first-line irinotecan and oxaliplatin combinations except when 5-FU was delivered by bolus injection, when oxaliplatin provided better OS (p=0.032) and response rates (p=0.032), but not PFS (p=0.169). The regimens had different toxicity profiles and neither conferred a QoL advantage. When compared to 5-FU, raltitrexed is associated with no significant difference in overall or progression-free survival; no significant difference in response rates; more vomiting and nausea, but less diarrhoea and mucositis; no significant difference in, or worse QoL. Raltitrexed treatment was cut short in two out of four included trials due to excess toxic deaths. 5-FU followed by irinotecan was inferior to any other sequence. First-line irinotecan/5-FU combination improved OS and PFS, although further unplanned therapy exaggerated the OS effect size. Staged combination therapy (combination oxaliplatin followed by combination irinotecan or vice versa) provided the best OS and PFS, although there was no head-to-head comparison against other treatment plans. In the only trial to use three active chemotherapies in any staged combination, median OS was over 20 months. In another study, the longest median OS from a treatment plan using two active agents was 16.2 months. Where irinotecan or oxaliplatin were used with 5-FU to downstage people with unresectable liver metastases, studies consistently showed response rates of around 50%. Resection rates ranged from 9 to 35% with irinotecan and from 7 to 51% with oxaliplatin. In the one study that compared the regimens, oxaliplatin enabled more resections (p=0.02). Five-year OS rates of 5-26% and disease-free survival rates of 3-11% were reported in studies using oxaliplatin. Alone or in combination, 5-FU was more effective and less toxic when delivered by continuous infusion. Existing economic models were weak because of the use of unplanned second-line therapies in their trial data: the survival benefits in patients on such trials cannot be uniquely attributed to the allocated therapy. Consequently, the economic analyses are either limited to the use of PES (at best, a surrogate outcome) or are subject to confounding. Weaknesses in cost components, the absence of direct in-trial utility estimates and the limited use of sensitivity analysis were identified. Improvements to the methodologies used in existing economic studies are presented. Using data from two trials that planned treatment sequences, an independent economic evaluation of six plans compared with first-line 5-FU followed on progression by second-line irinotecan monotherapy (NHS standard treatment) is presented. 5-FU followed on progression by irinotecan combination cost 13,174 pounds per life-year gained (LYG) and 10,338 pounds per quality-adjusted life-year (QALY) gained. Irinotecan combination followed on progression by additional second-line therapies was estimated to cost 12,418 pounds per LYG and 13,630 pounds per QALY gained. 5-FU followed on progression by oxaliplatin combination was estimated to cost 23,786 pounds per LYG and 31,556 pounds per QALY gained. Oxaliplatin combination followed on progression by additional second-line therapies was estimated to cost 43,531 pounds per LYG and 67,662 pounds per QALY gained. Evaluations presented in this paragraph should be interpreted with caution owing to missing information on the costs of salvage therapies in the trial from which data were drawn. Irinotecan combination followed on progression by oxaliplatin combination cost 12,761 pounds per LYG and 16,663 pounds per QALY gained. Oxaliplatin combination followed on progression by irinotecan combination cost 16,776 pounds per LYG and 21,845 pounds per QALY gained. The evaluation suggests that these two sequences have a cost-effectiveness profile that is favourable in comparison to other therapies currently funded by the NHS. However, the differences in OS observed between the two trials from which data were taken may be a result of heterogeneous patient populations, unbalanced protocol-driven intensity biases or other differences between underlying health service delivery systems. CONCLUSIONS: Treatment with three active therapies appears most clinically effective and cost-effective. NHS routine data could be used to validate downstaging findings and a meta-analysis using individual patient-level data is suggested to validate the optimal treatment sequence.

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.

The cost-effectiveness of bevacizumab in the first-line treatment of metastatic colorectal cancer in England and Wales.

BACKGROUND: Bevacizumab is a humanised monoclonal antibody, which has demonstrated significant activity in metastatic colorectal cancer. The aim of this study is to estimate the cost-effectiveness of adding bevacizumab to chemotherapy for patients with untreated metastatic colorectal cancer. METHODS: A decision-analytic model was developed to estimate the lifetime costs and benefits of adding bevacizumab to irinotecan plus FU/LV (IFL) or 5-FU/LV alone. Effectiveness outcomes, health utilities and resource use data were derived from recent bevacizumab RCTs and from the literature. RESULTS: Adding bevacizumab to IFL costs approximately pound62,857 per QALY gained. Adding bevacizumab to 5-FU/LV costs approximately pound88,436 per QALY gained. The acquisition cost of bevacizumab is a key determinant of its cost-effectiveness. The probability that bevacizumab has a cost-effectiveness ratio that is better than pound30,000 per QALY gained is close to zero. CONCLUSIONS: Given high acquisition costs in relation to clinical benefits, bevacizumab is unlikely to represent a cost-effective use of NHS resources.

A review and critique of modelling in prioritising and designing screening programmes.

OBJECTIVES: To undertake a structured review and critical appraisal of methods for the model-based cost-utility analysis of screening programmes. Also to develop guidelines and an assessment checklist of good practice in the development of screening models. DATA SOURCES: Major electronic databases of healthcare and operational research literatures were searched up to June 2003. REVIEW METHODS: Searches of the literature were undertaken to identify applied and methodological studies of economic evaluations of healthcare screening programmes. All applied screening models were also reviewed in three broad disease areas (cancer, cardiovascular disease and diabetes), as well as antenatal screening. A second-level review focused on particular aspects of the modelling process through case study assessments of screening models for three specific disease areas (colorectal cancer, abdominal aortic aneurysms and antenatal screening for haemoglobinopathies). A separate literature review of studies reporting the utility effects of screening was also undertaken. Guidelines and an assessment checklist for good practice for screening modelling were developed. RESULTS: Few relevant methodological studies were identified, and no studies reporting direct empirical comparisons of alternative methodologies were retrieved. From the review of disease-based screening models, it was apparent that many alternative modelling methods had been applied, including some relatively new approaches that had not been widely disseminated. Natural history modelling is the preferred approach. Alternative modelling approaches were generally only used to extrapolate the observed effects of screening and were unsuitable for evaluating unobserved screening options. More complex model structures may incorporate important additional aspects of the disease natural history, although any benefits should outweigh the consequences of additional unobservable input parameters and increased complexity in implementing the model. No direct comparisons of more detailed and less detailed screening model structures informed areas in which more realistic representations of the disease process may be most beneficial, so only general aspects of good practice could be defined. Two structural aspects that were not well handled by existing screening models included post-diagnosis disease progression and screening uptake. Most models described the former using historical mortality rates, rather than treatment models that are representative of current treatment patterns for different stages of the disease. Constant screening uptake rates were applied to all screening programmes and attendance was not linked to disease incidence or progression. Evidence exists to inform a more detailed representation of screening uptake. The most commonly applied modelling techniques were cohort Markov models and individual sampling simulation models. Individual sampling simulation models may provide more flexibility in their representation of a screening decision problem, but any benefits should outweigh the consequences of the need to assess both variability and uncertainty. Complex mathematical models describing input parameters as continuous variables have analysed the cost-effectiveness of screening; these require further development to estimate the cost-utility of screening directly, or to inform a more detailed representation of the preclinical section of a natural history model (with a traditional state-based model describing pathways' post-clinical presentation). Calibration is a common aspect of screening models, whereby models are fitted to observed data describing outputs of the model in order to populate unobserved input parameters. The review concluded that the estimation of a reference case input parameter set is not recommended. CONCLUSIONS: The review of methods for the model-based cost-utility analysis of screening programmes identified the natural history modelling approach as the preferred general method of evaluation for screening programmes. State transition models have generally been used to represent disease natural histories, with individual sampling models more prevalent than in treatment intervention evaluations. No comparative methodological studies were identified, so no empirical data were available to inform the relative merits of alternative methodologies. The defined guidelines and assessment checklist are informed, therefore, by theoretical interpretations of the impact of alternative approaches to different components of the modelling process when applied to the cost-utility analysis of screening programmes. Further research is needed into methods with the potential to improve the accuracy of screening models, and to respond to the needs of model users.

The clinical and cost-effectiveness of oxaliplatin and capecitabine for the adjuvant treatment of colon cancer: systematic review and economic evaluation.

OBJECTIVES: To assess the clinical and cost-effectiveness of oxaliplatin in combination with 5-fluorouracil/leucovorin (5-FU/LV), and capecitabine monotherapy (within their licensed indications), as adjuvant therapies in the treatment of patients with Stage III (Dukes' C) colon cancer after complete surgical resection of the primary tumour, as compared with adjuvant chemotherapy with an established fluorouracil-containing regimen. DATA SOURCES: Ten electronic bibliographic databases were searched from inception to January 2005. Searches were supplemented by hand searching relevant articles, sponsor and other submissions of evidence to the National Institute of Health and Clinical Excellence and conference proceedings. REVIEW METHODS: A systematic review and meta-analysis (where appropriate) of clinical efficacy evidence and a cost-effectiveness review and economic modelling were carried out. Marginal costs, life years gained and cost-effectiveness acceptability curves were estimated. Probabilistic sensitivity analysis was used to generate information on the likelihood that each of the interventions was optimal. RESULTS: Three randomised active-controlled trials, of varying methodological quality, were included in the review. The MOSAIC trial and NSABP C-07 study considered the addition of oxaliplatin to adjuvant treatment (albeit administered in different 5-FU/LV regimens) and the X-ACT study compared oral capecitabine with bolus 5-FU/LV alone. A review of the available evidence indicated that in patients with Stage III colon cancer, oxaliplatin in combination with an infusional de Gramont schedule of 5-FU/LV (FOLFOX4) was more effective in preventing and delaying disease recurrence than infusional 5-FU/LV alone (de Gramont regimen). Serious adverse events and treatment discontinuations due to toxicity were more evident with oxaliplatin-based regimens (FOLFOX4 and FLOX regimen) than infusional or bolus 5-FU/LV alone (de Gramont and Roswell Park regimen). Oral capecitabine was at least equivalent in disease-free survival to the bolus Mayo Clinic 5-FU/LV regimen for patients with resected Stage III colon cancer. Although, the safety and tolerability profile of capecitabine was superior to that of the Mayo Clinic 5-FU/LV regimen, it has not been evaluated in comparison with other less toxic 5-FU/LV regimens currently in common use in the UK. Based on the assumptions and survival analysis methods used, the cost-effectiveness analysis using economic modelling estimated that capecitabine was a dominating strategy and resulted in a cost-saving of approximately pound 3320 per patient in comparison with the Mayo Clinic 5-FU/LV regimen, while also providing an additional 0.98 quality-adjusted life-years (QALYs) over a 50-year model time horizon. Oxaliplatin in combination with 5-FU/LV (FOLFOX4 regimen) is estimated to cost an additional pound 2970 per QALY gained when compared with the de Gramont 5-FU/LV regimen and demonstrated superior survival outcomes with marginal costs. The uncertainty analysis suggests that both interventions have a high probability of being cost-effective at a threshold of both pound 20,000 and pound 30,000. An indirect comparison of the FOLFOX4 and Mayo Clinic 5-FU/LV regimens suggests that the use of FOLFOX4 in place of the Mayo Clinic 5-FU/LV regimen would cost an additional pound 5777 per QALY gained. An incremental cost-effectiveness ratio (ICER) is estimated to be approximately pound 13,000 per QALY gained from treatment with FOLFOX4 compared with capecitabine. However, if the Mayo Clinic and the de Gramont 5-FU/LV regimens are assumed to be equivalent in terms of effectiveness, the ICER of FOLFOX4 in comparison with capecitabine may be greater than pound 30,000 per QALY. CONCLUSIONS: The evidence suggests that both capecitabine and FOLFOX4 are clinically effective and cost-effective in comparison with 5-FU/LV regimens (Mayo Clinic and de Gramont schedules). Further research is suggested into the effectiveness, tolerability, patient acceptability and costs of different oxaliplatin/fluoropyrimidine schedules in the adjuvant setting; the effects of treatment duration on efficacy; adverse events; resource data collection strategies and reporting of summary statistics; subgroups benefiting most from adjuvant chemotherapy; and methods for estimating mean survival.

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.

A systematic review of the clinical effectiveness of pioglitazone in the treatment of type 2 diabetes mellitus.

BACKGROUND: Pioglitazone is a member of a recently developed class of glucose-lowering agents, the thiazolidinediones, used in the treatment of type 2 diabetes mellitus. In the United States, it is approved for use both as monotherapy and in combination with metformin, a sulfonylurea, or insulin; in Europe, it is approved for use in combination with metformin or a sulfonylurea but not insulin. OBJECTIVE: This article presents a systematic review of the published literature on the effectiveness of pioglitazone in the treatment of type 2 diabetes, both as monotherapy and in combination with other antidiabetic agents. METHODS: The peer-reviewed English- and foreign-language literature was searched using MEDLINE, PubMED, EMBASE, Science Citation Index, the Cochrane Database of Systematic Reviews, the Cochrane Controlled Trials Register, the UK National Health Service Centre for Reviews and Dissemination databases, and the Office of Health Economics Health Economic Evaluations Database. Searches were not limited to specific publication types, study designs, dates, or languages. The latest search was performed in March 2001. For a trial to be included in the review, at least 1 outcome measure had to involve the effects of pioglitazone on glycemic control or cardiovascular risk factors, or its side effects. Because of the heterogeneity of studies, no formal meta-analysis was performed. RESULTS: Eleven studies met the inclusion criteria, 6 involving pioglitazone monotherapy and 5 involving combination therapy. Full reports were available for only 6 of the 11 studies. No studies directly compared pioglitazone with other antidiabetic drugs. Both as monotherapy and in combination therapy, pioglitazone produced decreases in blood glucose levels (up to 95 mg/dL) and glycosylated hemoglobin (up to 2.6%). At doses of > or = 30 mg/d, pioglitazone was associated with reductions in triglyceride levels (-30-70 mg/dL) and increases in high-density lipoprotein cholesterol (HDL-C) levels (-4-5 mg/dL). Pioglitazone treatment was associated with significant weight gain (up to 4 kg over 16 weeks). Adverse effects included mild edema (in up to 11.7% of patients) and a clinically nonsignificant decrease in hemoglobin concentrations. Abnormal results on liver function testing were no more common in treated patients than in control groups. CONCLUSIONS: Pioglitazone has been shown to reduce blood glucose levels in patients with type 2 diabetes. Although the observed decreases in triglyceride levels and increases in HDL-C levels could be expected to lead to a reduction in cardiovascular risk, the effects of weight gain may counteract this benefit. The evidence suggests that the preferred role for pioglitazone may be as an adjunct to metformin or a sulfonylurea in patients whose condition is not well controlled with monotherapy and for whom a metformin-sulfonylurea combination is contraindicated. There is a need for large-scale, long-term studies comparing the effectiveness of combination therapy that includes pioglitazone with that of other combinations of antidiabetic drugs.

The role of modelling in prioritising and planning clinical trials.

OBJECTIVES: To identify the role of modelling in planning and prioritising trials. The review focuses on modelling methods used in the construction of disease models and on methods for their analysis and interpretation. DATA SOURCES: Searches were initially developed in MEDLINE and then translated into other databases. REVIEW METHODS: Systematic reviews of the methodological and case study literature were undertaken. Search strategies focused on the intersection between three domains: modelling, health technology assessment and prioritisation. RESULTS: The review found that modelling can extend the validity of trials by: generalising from trial populations to specific target groups; generalising to other settings and countries; extrapolating trial outcomes to the longer term; linking intermediate outcome measures to final outcomes; extending analysis to the relevant comparators; adjusting for prognostic factors in trials; and synthesising research results. The review suggested that modelling may offer greatest benefits where the impact of a technology occurs over a long duration, where disease/technology characteristics are not observable, where there are long lead times in research, or for rapidly changing technologies. It was also found that modelling can inform the key parameters for research: sample size, trial duration and population characteristics. One-way, multi-way and threshold sensitivity analysis have been used in informing these aspects but are flawed. The payback approach has been piloted and while there have been weaknesses in its implementation, the approach does have potential. Expected value of information analysis is the only existing methodology that has been applied in practice and can address all these issues. The potential benefit of this methodology is that the value of research is directly related to its impact on technology commissioning decisions, and is demonstrated in real and absolute rather than relative terms; it assesses the technical efficiency of different types of research. Modelling is not a substitute for data collection. However, modelling can identify trial designs of low priority in informing health technology commissioning decisions. CONCLUSIONS: Good practice in undertaking and reporting economic modelling studies requires further dissemination and support, specifically in sensitivity analyses, model validation and the reporting of assumptions. Case studies of the payback approach using stochastic sensitivity analyses should be developed. Use of overall expected value of perfect information should be encouraged in modelling studies seeking to inform prioritisation and planning of health technology assessments. Research is required to assess if the potential benefits of value of information analysis can be realised in practice; on the definition of an adequate objective function; on methods for analysing computationally expensive models; and on methods for updating prior probability distributions.

Methods for expected value of information analysis in complex health economic models: developments on the health economics of interferon-beta and glatiramer acetate for multiple sclerosis.

OBJECTIVES: To develop methods for performing expected value of perfect information (EVPI) analysis in computationally expensive models and to report on the developments on the health economics of interferon-beta and glatiramer acetate in the management of multiple sclerosis (MS) using this methodological framework. DATA SOURCES: Electronic databases and Internet resources, reference lists of relevant articles. REVIEW METHODS: A methodological framework was developed for undertaking EVPI analysis for complex models. The framework identifies conditions whereby EVPI may be calculated numerically, where the one-level algorithm sufficiently approximates the two-level algorithm, and whereby metamodelling techniques may accurately approximate the original simulation model. Metamodelling techniques, including linear regression, neural networks and Gaussian processes (GP), were systematically reviewed and critically appraised. Linear regression metamodelling, GP metamodelling and the one-level EVPI approximation were used to estimate partial EVPIs using the ScHARR MS cost-effectiveness model. RESULTS: The review of metamodelling approaches suggested that in general the simpler techniques such as linear regression may be easier to implement, as they require little specialist expertise although may provide only limited predictive accuracy. More complex methods such as Gaussian process metamodelling and neural networks tend to use less-restrictive assumptions concerning the relationship between the model inputs and net benefits, and therefore may permit greater accuracy in estimating EVPIs. Assuming independent treatment efficacy, the 'per patient' EVPI for all uncertainty parameters within the ScHARR MS model is 8855 British pounds. This leads to a population EVPI of 86,208,936 British pounds, which represents the upper estimate for the overall EVPI over 10 years. Assuming all treatment efficacies are perfectly correlated, the overall per patient EVPI is 4271 British pounds. This leads to a population EVPI of 41,581,273 British pounds, which represents the lower estimate for the overall EVPI over 10 years. The partial EVPI analysis, undertaken using both the linear regression metamodel and Gaussian process metamodel clearly, suggests that further research is indicated on the long-term impact of these therapies on disease progression, the proportion of patients dropping off therapy and the relationship between the EDSS, quality of life and costs of care. CONCLUSIONS: The applied methodology points towards using more sophisticated metamodelling approaches in order to obtain greater accuracy in EVPI estimation. Programming requirements, software availability and statistical accuracy should be considered when choosing between metamodelling techniques. Simpler, more accessible techniques are open to greater predictive error, whilst sophisticated methodologies may enhance accuracy within non-linear models, but are considerably more difficult to implement and may require specialist expertise. These techniques have been applied in only a limited number of cases hence their suitability for use in EVPI analysis has not yet been demonstrated. A number of areas requiring further research have been highlighted. Further clinical research is required concerning the relationship between the EDSS, costs of care and health outcomes, the rates at which patients drop off therapy and in particular the impact of disease-modifying therapies on the progression of MS. Further methodological research is indicated concerning the inclusion of epidemiological population parameters within the sensitivity analysis; the development of criteria for selecting a metamodelling approach; the application of metamodelling techniques within health economic models and in the specific application to EVI analyses; and the use of metamodelling for EVSI and ENBS analysis.

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.

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 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.

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 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.