The cost-effectiveness of follow-up strategies after cancer treatment: a systematic literature review.

Introduction: The cost of treatment and follow-up of cancer patients in the UK is substantial. In a budget-constrained system such as the NHS, it is necessary to consider the cost-effectiveness of the range of management strategies at different points on cancer patients' care pathways to ensure that they provide adequate value for money. Sources of data: We conducted a systematic literature review to explore the cost-effectiveness of follow-up strategies of patients previously treated for cancer with the aim of informing UK policy. All papers that were considered to be economic evaluations in the subject areas described above were extracted. Areas of agreement: The existing literature suggests that intensive follow-up of patients with colorectal disease is likely to be cost-effective, but the opposite holds for breast cancer. Areas of controversy: Interventions and strategies for follow-up in cancer patients were variable across type of cancer and setting. Drawing general conclusions about the cost-effectiveness of these interventions/strategies is difficult. Growing points: The search identified 2036 references but applying inclusion/exclusion criteria a total of 44 articles were included in the analysis. Breast cancer was the most common (n = 11) cancer type followed by colorectal (n = 10) cancer. In general, there were relatively few studies of cost-effectiveness of follow-up that could influence UK guidance. Where there was evidence, in the most part, NICE guidance broadly reflected this evidence. Areas timely to develop research: In terms of future research around the timing, frequency and composition of follow-ups, this is dependent on the type of cancer being considered. Nevertheless, across most cancers, the possibility of remote follow-up (or testing) by health professionals other than hospital consultants in other settings appears to warrant further work.

Are preferences over health states informed?

BACKGROUND: The use of preference-elicitation tasks for valuing health states is well established, but little is known about whether these preferences are informed. Preferences may not be informed because individuals with little experience of ill health are asked to value health states. The use of uninformed preferences in cost-effectiveness can result in sub-optimal resource allocation. The aim of this study was to pilot a novel method to assess whether members of the public are informed about health states they value in preference-elicitation tasks. METHODS: The general public was said to be informed if the expectations of the public about the effect of ill health on people's lives were in agreement with the experience of patients. Sixty-two members of the public provided their expectations of the consequences of ill health on five life domains (activities, enjoyment, independence, relationships, and avoiding being a burden). A secondary dataset was used to measure patient experience on those five consequences. RESULTS: There were differences between the expectations of the public and the experience of patients. For example, for all five life consequences the public underestimated the effects of problems in usual activities compared to problems in mobility. They also underestimated the effect of 'anxiety or depression' compared to physical problems on enjoyment of life and on the quality of personal relationships. CONCLUSIONS: This proof-of-concept study showed that it is possible to test whether preferences are informed. This study should be replicated using a larger sample. The findings suggest that preferences over health states in this sample are not fully informed because the participants do not have accurate expectations about the consequences of ill health. These uninformed preferences may not be adequate for allocation of public resources, and research is needed into methods to make them better informed.

How do individuals value health states? A qualitative investigation.

Despite the importance of health state values in informing resource allocation in health care, there is arguably little known about how individuals value health. Previous studies have shown that a variety of non-health factors and beliefs are important in valuing health, but there is less evidence in the literature about how individuals' beliefs affect their preferences or what role non-health factors play in the process of forming preferences. This study investigated the thought processes of 21 U.K. based participants in March 2013 who valued health states using semi-structured interviews and a think-aloud protocol, with the aim to better understand the relationship between health states, the individual's underlying beliefs, and the individual's preferences. Participants followed several stages in valuing health. First, participants interpreted the health states more concretely, relying on their imagination and their experience of ill health. Participants judged how the concrete health problems combined with their personal interests, circumstances, and environment would affect them personally. Ultimately, participants valued health by estimating and weighing the non-health consequences of the health states. Six consequences were most frequently mentioned: activities, enjoyment, independence, relationships, dignity, and avoiding being a burden. At each stage participants encountered difficulties and expressed concerns. The findings have implications for methods of describing health, for example, whether the focus should be on health or a broader notion of well-being and capability. This is because the consequences are similar to the domains of broader measures such as the ICECAP measures for adults and older people, and the Warwick-Edinburgh Mental Wellbeing Scale. The findings suggest the need for testing whether individuals are informed about the health states they are valuing. Participants valued health by estimating the non-health consequences of health states and these estimates relied on individuals' beliefs about the interaction of the health state and their personal and social circumstances.

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.

Ezetimibe for the treatment of hypercholesterolaemia: a systematic review and economic evaluation.

OBJECTIVES: To review the clinical and cost-effectiveness of ezetimibe as a combination therapy or monotherapy for the treatment of primary hypercholesterolaemia in the UK. DATA SOURCES: Twelve electronic databases were searched from inception to June 2006. 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 the clinical efficacy evidence was undertaken following recommended guidelines. A Markov model was developed to explore the costs and health outcomes associated with ezetimibe treatment. RESULTS: No published clinical outcome trials (> 12 weeks) were identified. In the absence of clinical end-point data from trials, 13 (of which five were multi-arm) phase III multi-centre randomised controlled trials (RCTs) (of varying methodological quality) of short-term duration (12-48 weeks) with surrogate end-point data were included. For patients not adequately controlled with a statin alone, a meta-analysis of six studies showed that a fixed-dose combination of ezetimibe and statin treatment was associated with a statistically significant reduction in low-density lipoprotein cholesterol (LDL-c) and total cholesterol (Total-c) compared with statin alone (p < 0.00001). Four studies (not eligible for meta-analysis) that titrated (either forced or stepwise) the statin doses to LDL-c targets generally showed that the co-administration of ezetimibe and statin was significantly more effective in reducing plasma LDL-c concentrations than statin monotherapy (p < 0.05 for all studies). For patients where a statin is not considered appropriate, a meta-analysis of seven studies demonstrated that ezetimibe monotherapy significantly reduced LDL-c levels compared with placebo (p < 0.00001). There were no statistically significant differences in LDL-c-lowering effects across different subgroups. Ezetimibe therapy (either in combination with a statin or monotherapy) appeared to be well tolerated compared to statin monotherapy or placebo, respectively. No ezetimibe studies reported data on health-related quality of life (HRQoL). There was a wide range in the economic results depending on the treatment strategies evaluated. When comparing ezetimibe monotherapy with no treatment in individuals with baseline LDL-c values of 3.0-4.0 mmol/l, the results range from 21,000 pounds to 50,000 pounds per quality-adjusted life-year (QALY). Results for individuals with baseline LDL-c values over 5.0 mmol/l are below 30,000 pounds per QALY. When comparing the costs and benefits of adding ezetimibe to ongoing statin treatment compared with maintaining statin treatment at the current dose, the majority of results are above values generally considered to be cost-effective (range 19,000 pounds to 48,000 pounds per QALY). Based on the evidence available, when comparing the costs and benefits associated with adding ezetimibe to ongoing statin treatment compared with a switch to a more potent statin, the results are governed by the difference in the cost of the treatment regimens compared and results range from 1500 pounds to 116,000 pounds per QALY. CONCLUSIONS: The short-term RCT clinical evidence demonstrated that ezetimibe was effective in reducing LDL-c when administered as monotherapy or in combination with a statin. However, when used as a monotherapy, ezetimibe is less effective than statins in lowering LDL-c. Given the limitations in the effectiveness data, there is great uncertainty in the economic results. These suggest that ezetimibe could be a cost-effective treatment for individuals with high baseline LDL-c values, for patients with diabetes and for individuals with heterozygous familial hypercholesterolaemia. Long-term clinical outcome studies are needed to allow more precise cost-effectiveness estimates to be calculated.

Use of evidence in economic decision models: practical issues and methodological challenges.

This paper outlines the current 'state of play' regarding the use of evidence in decision modelling and highlights both practical issues and methodological challenges related to identifying, combining and reporting evidence to inform decision model parameters and structure. Based on discussions at two MRC HSRC-funded workshops consisting of 37 experts from a range of disciplines (i.e. decision-makers, health economists, information specialists, operations researchers and statisticians), it aims to derive a multi-disciplinary standpoint on the appropriate use of evidence in economic decision models and, where applicable, offer some suggestions for good modelling practice. Gaps in the established methodology knowledge base are identified for future research.

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.

Effects of restricted feeding of beef heifers during the postweaning period on growth, efficiency, and ultrasound carcass characteristics.

Traits used for identification of replacement beef heifers and feeding levels provided during postweaning development may have major financial implications due to effects on maintenance requirements and level of lifetime production. The current study evaluated the effects of 2 levels of feeding during the postweaning period on growth, G:F, and ultrasound carcass measurements of heifers, and the associations among these traits. Heifers (1/2 Red Angus, 1/4 Charolais, and 1/4 Tarentaise) born in 3 yr were randomly assigned to a control (fed to appetite; n = 205) or restricted (fed at 80% of that consumed by controls adjusted to a common BW basis; n = 192) feeding during a 140-d postweaning period. Heifers were individually fed a diet of 68% corn silage, 18% alfalfa, and protein-mineral supplement (DM basis) in pens equipped with Calan gates. Ultrasound measurements of LM area, intramuscular fat, and subcutaneous fat thickness over the LM were made on d 140 (382 +/- 0.8 d of age). Average daily DMI was 4.1 and 5.6 kg/d for restricted and control heifers, respectively (P < 0.001). Feed restriction decreased (P < 0.001) BW (292 vs. 314 kg), ADG (0.52 vs. 0.65 kg/d), LM area (55 vs. 59 cm2), intramuscular fat (3.2 vs. 3.5%), and subcutaneous fat thickness over the LM (3.2 vs. 3.9 mm), but increased G:F (0.12 vs. 0.11) when compared with control at the end of the 140-d study. The magnitude of the associations of DMI with ADG (r = 0.32 vs. 0.21), 140-d BW (r = 0.78 vs. 0.36), hip height (r = 0.57 vs. 0.17), LMA (r = 0.30 vs. 0.18), and BCS (r = 0.17 vs. 0.11) was greater in restricted- than control-fed heifers. Variance of residual feed intake, calculated within each treatment, was greater (P < 0.01) in control (0.088) than restricted (0.004) heifers, and magnitude of association between residual feed intake and average DMI was greater in control (r = 0.88) than restricted (r = 0.41) heifers. Pregnancy rate tended (P = 0.11) to be reduced in heifers that had been developed on restricted feeding (86.3 +/- 2.3 vs. 91.5 +/- 2.3%). However, ADG was greater (P < 0.001) in restricted than control heifers (0.51 vs. 0.46 kg/d) while grazing native range in the 7 mo after restriction. In summary, restricted heifers consumed 22% less feed on a per-pregnant-heifer basis during the development period and had a greater magnitude of association between DMI and several growth-related traits at the end of the 140-d postweaning feeding period, which is indicative of improved efficiency.

Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer.

OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of bevacizumab and cetuximab in the treatment of individuals with metastatic colorectal cancer (CRC). DATA SOURCES: Searches of main electronic databases were conducted in April and May 2005. REVIEW METHODS: For the assessment of bevacizumab, trials were included if they recruited participants with untreated metastatic CRC for first-line treatment. Only trials comparing bevacizumab in combination with irinotecan and/or established fluorouracil (5-FU)-containing or releasing regimens given as first-line therapy were included. For the assessment of cetuximab, trials were included if they recruited participants with epidermal growth-factor receptor-expressing metastatic CRC who had previously failed irinotecan-including therapy. Independent cost-effectiveness models of bevacizumab and cetuximab were developed using survival modelling methods. RESULTS: Adding bevacizumab to irinotecan in combination with 5-FU/folic acid (FA) plus irinotecan resulted in a statistically significant increase in median overall survival (OS) of 4.7 months. Adding bevacizumab to 5-FU/FA resulted in a non-significant increase in median OS of 3.7 months within one study and 7.7 months in another. Adding bevacizumab to irinotecan, fluorouracil and leucovorin (IFL) resulted in a statistically significant increase in median progression-free survival (PFS) of 4.4 months. Adding bevacizumab to 5-FU/FA resulted in a statistically significant increase in median PFS of 3.7 months, and a statistically significant increase in time to disease progression of 3.8 months compared to FU/FA alone. An overall tumour response rate of 44.8% was reported for bevacizumab plus IFL compared to 34.8% for IFL plus placebo. This addition was statistically significant. The addition of bevacizumab to 5-FU/FA resulted in a significant difference in tumour response rate within one study, but not another. Bevacizumab in combination with IFL or 5-FU/FA was observed to result in an increase of grade 3/4 adverse events. The independent health economic assessment suggests that the cost-effectiveness of bevacizumab plus IFL is unlikely to be better than pound 46,853 per life-year gained (LYG); the cost-utility of bevacizumab plus IFL is unlikely to be better than pound 62,857 per quality-adjusted life-year (QALY) gained. The cost-effectiveness of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 84,607 per LYG; the cost-utility of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 88,658 per QALY gained. A Phase II trial reported a median OS duration of 8.6 months for patients receiving cetuximab plus irinotecan, plus a median time to progression of 4.1 months, a tumour response rate of 22.9% and suggested that treatment with cetuximab in combination with irinotecan is associated with significantly more adverse events (any grade 3 or grade 4 adverse event) than cetuximab monotherapy. The single arm study of cetuximab plus irinotecan reported a median OS duration of 8.4 months, a median time to progression of 2.9 months and a tumour response rate of 15.2%. The cost-effectiveness model suggested that the expected survival duration of patients receiving cetuximab plus irinotecan is 0.79 years (9.5 months) when the proposed continuation rule is applied. In order for cetuximab plus irinotecan to achieve a cost-utility ratio of pound 30,000 per QALY gained, treatment with cetuximab plus irinotecan must provide an additional 0.65 life years (7.8 months) over treatment with active/best supportive care, implying that survival in the active/best supportive care group must be 0.14 life years (1.7 months) or less. CONCLUSIONS: The trials indicate that bevacizumab in combination with 5-FU/FA, and bevacizumab in combination with IFL, is clinically effective in comparison to standard chemotherapy options for the first-line treatment of metastatic CRC. The health economic analysis suggests that the marginal cost-utility of bevacizumab plus IFL versus IFL is unlikely to be better than pound 62,857 per QALY gained, and the marginal cost-utility of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 88,658 per QALY gained. There is no direct evidence to demonstrate whether cetuximab in combination with irinotecan improves health-related quality of life or OS in comparison to active/best supportive care or oxaliplatin plus 5-FU/FA, although the evidence on tumour response rates suggests that cetuximab plus irinotecan has some clinical activity. While it is difficult to suggest whether cetuximab represents value for money, indirect comparisons suggest that the incremental cost-utility of cetuximab plus irinotecan is unlikely to be better than pound 30,000 per QALY gained. This review highlights a number of areas for further research, including clarifying the true impact of first-line bevacizumab in combination with irinotecan and/or infusional 5-FU/FA, without subsequent bevacizumab treatment following disease progression, on OS in patients with metastatic CRC who are representative of the typical population of CRC patients in England and Wales. Further research concerning the impact of therapies on health-related quality of life is essential.

Cost-effectiveness of oxaliplatin and capecitabine in the adjuvant treatment of stage III colon cancer.

For many years, the standard treatment for stage III colon cancer has been surgical resection followed by 5-fluorouracil in combination with folinic acid (5-FU/LV). Ongoing clinical trial evidence suggests that capecitabine and oxaliplatin (in combination with 5-FU/LV) may improve disease-free survival and overall survival when compared against 5-FU/LV alone in the adjuvant setting. This study evaluates the cost-effectiveness profiles of these two regimens in comparison to standard chemotherapy, using evidence from two international randomised controlled trials. Survival modelling techniques were employed to extrapolate survival curves from the two trials in order to estimate the long-term benefits of alternative treatment options over the remaining lifetime of patients. The health economic analysis suggests that capecitabine is expected to produce greater health gains at a lower cost than 5-FU/LV. Oxaliplatin in combination with 5-FU/LV is estimated to cost pounds 2970 per additional QALY gained when compared to 5-FU/LV alone. Future research should attempt to elucidate uncertainties concerning the optimal roles of capecitabine and/or oxaliplatin in the adjuvant setting in order to achieve the maximum level of clinical benefit.

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.

Psychological therapies including dialectical behaviour therapy for borderline personality disorder: a systematic review and preliminary economic evaluation.

OBJECTIVES: To summarise the available evidence on the clinical effectiveness and cost-effectiveness of psychological therapies including dialectical behaviour therapy (DBT) for borderline personality disorder (BPD). DATA SOURCES: Electronic databases were searched up to March 2005. REVIEW METHODS: Relevant studies were assessed using standard checklists and data were abstracted by two reviewers using standardised forms. Separate economic evaluations were undertaken for six selected randomised controlled trials (RCTs). Cost-effectiveness was assessed in terms of cost per parasuicide event avoided in all six trials and cost per quality-adjusted life-year (QALY) in four of them. All results are at 2003-4 prices and for 12 months follow-up. RESULTS: Nine RCTs and one non-RCT of moderate to poor quality were identified in the clinical effectiveness review. They provided some evidence that DBT is more effective than treatment as usual (TAU) for the treatment of chronically parasuicidal and drug-dependent borderline women; that DBT-orientated therapy is more effective than client-centred therapy (CCT) for the treatment of BPD; and that DBT is as effective as comprehensive validation therapy plus 12-Step for the treatment of opioid-dependent borderline women. There was also some evidence that partial hospitalisation is more effective than TAU in the treatment of BPD, good evidence that manual-assisted cognitive behavioural therapy (MACT) is no more effective than TAU in the treatment of BPD and some evidence that interpersonal group therapy is no more effective than individual mentalisation-based partial hospitalisation (MBT) for the treatment of BPD. However, these results should be interpreted with caution as not all studies were primarily targeted to borderline symptoms and there were considerable differences between the studies. The assessment of cost-effectiveness found a mix of results in the four trials of DBT, along with the high levels of uncertainty and the limitations in the analyses. The findings do not support the cost-effectiveness of DBT though they suggest it has the potential to be cost-effective. The results for MBT are promising, though again surrounded by a high degree of uncertainty and for MACT, the analysis suggests that the intervention is unlikely to be cost-effective. CONCLUSIONS: The overall efficacy of psychological therapies is promising; however, at this stage the evidence is inconclusive. The cost-effectiveness of the intervention in six RCTs examined, however, does not support the cost-effectiveness of DBT although potential is suggested. There is a need for considerable research in this area. This research should involve appropriately powered head-to-head RCTs of psychological therapies; a survey of current practice and the use of the full range of services by people with BPD to inform future economic analyses; full resource-use data collected in the context of pragmatic clinical trials; psychometric assessment of the validity of the EQ-5D or other generic and condition-specific preference-based measures in BPD, and the development of a more formal cost-effectiveness model using the above data.

Clinical effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review.

OBJECTIVES: To evaluate the clinical and cost-effectiveness of tandem mass spectrometry (MS)-based neonatal screening for inborn errors of metabolism (IEM). DATA SOURCES: Fourteen electronic bibliographic databases covering biomedical, science, economic and grey literature, the reference lists of relevant articles and abstracts of conference proceedings and 18 health services research-related resources. REVIEW METHODS: This review is an update of two previous HTA reports of neonatal screening for IEM. These reports have been updated by a systematic review of published research (between 1995 and January 2002) on neonatal screening of inherited metabolic disorders using tandem MS. This was supplemented by a search for economic literature and the application of a modelling exercise to investigate the economics of using tandem MS within a neonatal screening programme in the UK. RESULTS: Evidence from the reviews of IEM found that the UK screening programme for phenylketonuria (PKU) was well established and there was universal agreement that neonatal screening for PKU was justified. Of the many other disorders that can be detected by tandem MS, the best candidate condition for a new screening programme was medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency. For many other IEM that can be detected by tandem MS, robust clinical evidence was limited. Cost-effectiveness analysis using economic modelling indicated that substituting the use of tandem MS for existing technologies for the screening of PKU alone could not be justified. However, results from the economic modelling indicate that the addition of screening for MCAD deficiency as part of a neonatal screening programme for PKU using tandem MS would be economically attractive. Using an operational range of 50,000-60,000 specimens per system per year, the mean incremental cost for PKU and MCAD deficiency screening combined using tandem MS from the model was -23,312 British pounds for each cohort of 100,000 neonates screened. This cost saving is associated with a mean incremental gain of 59 life-years. Additional economic modelling using the available evidence does not support including other inherited metabolic diseases within a neonatal screening programme at present. CONCLUSIONS: The evidence appears to support the introduction of tandem MS into a UK neonatal screening programme for PKU and MCAD deficiency combined. Tandem MS has the potential for simultaneous multi-disease screening using a single analytical technique. Although the marginal cost of extending the programme to include other conditions may be relatively small, the application of this new technology to PKU and MCAD deficiency screening does not imply the wholesale inclusion of all disorders detectable by tandem MS. It is suggested that the primary focus of further research should be on the long-term effectiveness of treatment strategies on adverse outcomes (disabilities and impairments) under conventional management and the potential impact of early diagnosis using tandem MS.

Clinical and cost-effectiveness of new and emerging technologies for early localised prostate cancer: a systematic review.

OBJECTIVES: To evaluate the clinical and cost-effectiveness of new and emerging technologies for early, localised prostate cancer. DATA SOURCES: Electronic databases, reference lists of relevant articles and various health services research-related resources. REVIEW METHODS: A list of new and emerging technologies was identified and agreed. A systematic review was undertaken and selected studies were reviewed against a set of criteria. An economic model was developed and used to compare the specified newer treatments with the traditional approaches. RESULTS: For neoadjuvant hormonal therapy, no evidence of benefit was seen in terms of biochemical disease-free survival. For adjuvant hormonal therapy, there was no evidence of benefit in terms of survival, but some conflicting evidence that higher risk patients may benefit. The largest number of studies reported results for brachytherapy, where some evidence suggested that it may be more effective than standard treatments for lower risk patients, although less effective for intermediate- and high-risk patients, in terms of biochemical disease-free survival. Lower quality evidence reported fewer complications than for standard treatments. Higher quality evidence suggested that disease-specific quality of life (QoL) for brachytherapy patients was lower than for patients receiving standard treatments. The review of three-dimensional conformal radiotherapy (3D-CRT) considered treatment-related morbidity, where significantly fewer gastrointestinal complications occurred than with standard radiotherapy. It was suggested that higher radiation doses achieved better disease control, although patient characteristics were often reported as independent indicators of control. The review of intensity-modulated conformal radiotherapy suggested that late gastrointestinal toxicity may be reduced compared with 3D-CRT. For cryotherapy, high rates of impotence were reported. Owing to the paucity and poor quality of evidence identified for other interventions, conclusions regarding their clinical effectiveness cannot be drawn. Cost-effectiveness estimates were based on the impact of adverse events on quality-adjusted life-years and the assessment was restricted to brachytherapy, 3D-CRT and cryotherapy compared with standard treatments. Of the new treatments included, only cryotherapy appeared not to be potentially cost-effective compared with traditional treatments, owing to the associated high incidence of impotence. CONCLUSIONS: The results of the clinical effectiveness review should be viewed in the context of the quality of the available evidence. Very few randomised controlled trials (RCTs) were identified, with the majority of included studies being descriptive case series, open to patient selection bias and measuring surrogate end-points with short-term follow-up. It is difficult therefore to draw conclusions on the relative benefits or otherwise of the newer technologies owing to the lack of substantive evidence of any quality and the lack of comparisons between the newer technologies and with standard treatments. Given the lack of high-quality clinical evidence with long-term follow-up and the uncertainty surrounding the assumptions in the economic analysis, the following areas are recommended for further research: RCTs with sufficient follow-up to measure benefits in terms of overall survival to include QoL measurement to establish trade-offs between potential adverse events and benefits of treatment; the identification of prognostic risk factors among men diagnosed with early prostate cancer; QoL studies to compare the utility of health states among patients on active monitoring, patients receiving treatment and the comparable healthy population; the relationship between surrogate end-points and survival; and the adoption of standard definitions for adverse events.

Economic modelling of different treatment strategies for haemophilia A with high-responding inhibitors.

This paper reports a systematic review of the cost-effectiveness of treatment options in patients with haemophilia A with inhibitors. As very little relevant published evidence was identified, an economic modelling exercise was undertaken to calculate the cost-effectiveness of different strategies in the treatment of high-responding haemophilia A patients with inhibitors. A decision analysis approach was used to model the expected lifetime clinical outcomes and costs of the more common regimens currently used in UK in treating severe haemophiliacs with inhibitors. The model attempts to reflect the outcomes of clinical events, costs and life expectancy for each different treatment regimen for haemophilic boys with inhibitors who are high responders (defined as inhibitor level >/=10 BU) throughout their life. The basic model structure is centred on a Markov decision process, which was used to simulate, at quarter-yearly intervals, the movement through discrete health states and their complications. The model allows a comparison of cost-effectiveness between three immune tolerance induction (ITI) regimens (Bonn, Mälmo and Low-Dose protocols) and against a relevant 'on-demand' (OD) regimen. It also shows the cost-effectiveness of different OD regimens using different bypassing agents. The results of the economic modelling indicate that treating haemophilia A patients who have high-responding inhibitors OD with recombinant activated factor VII is cost-effective compared to treatment with activated prothrombin complex concentrates. However, when OD treatment regimens are compared with the three ITI protocols, the Malmö ITI protocol is the preferred treatment strategy, generating more quality adjusted life-years (QALYs) and less cost than either an OD regimen or the Bonn or Low-Dose ITI protocols.

Effectiveness and cost-effectiveness of prognostic markers in prostate cancer.

This paper demonstrates how economic modelling can be used to derive estimates of the cost-effectiveness of prognostic markers in the management of clinically localised and moderately graded prostate cancer. The model uses a Markov process and is populated using published evidence and local data. The robustness of the results has been tested using sensitivity analysis. Three treatment policies of 'monitoring' (observation), radical prostatectomy, or a selection-based management policy using DNA-ploidy as an experimental marker, have been evaluated. Modelling indicates that a policy of managing these tumours utilising experimental markers has an estimated cost per quality-adjusted life year (QALY) of pound 12 068. Sensitivity analysis shows the results to be relatively sensitive to quality-of-life variables. If novel and experimental markers can achieve specificity in excess of 80%, then a policy of radical surgery for those identified as being at high risk and conservative treatment for the remainder would be both better for patients and cost-effective. The analysis suggests that a radical prostatectomy treatment policy for the moderately graded tumours (Gleason grades -7) modelled in this paper may be inferior to a conservative approach in the absence of reliable prognostic markers, being both more costly and yielding fewer QALYs.

Systematic review of the clinical and cost effectiveness of digital hearing aids.

The aim of the present study was to systematically review the clinical and cost effectiveness of hearing aids which use digital signal processing relative to other forms of hearing aid technology, in particular analogue-based aids. A comprehensive search for randomized controlled trials, randomized crossover trials and economic studies was undertaken. Trial quality assessment and data extraction were undertaken by two independent reviewers. Eight trials comparing digital to non-digital devices were identified--one randomized controlled trial and seven randomized crossover trials. The majority of these studies were of small sample size and of poor methodological quality. In the majority of cases (nine out of 13), there was no evidence of a significant difference in either laboratory scores (nine out of 13 outcomes assessed) or user function/quality of life scores (six out of nine outcomes assessed) between digital and non-digital devices. In addition, there was no significant difference in patient preference for digital compared to control aids (relative risk 1.93; 95% CI 0.70-5.35) when pooled across studies. No cost-effectiveness studies directly comparing digital to non-digital devices were identified. In conclusion, the evidence identified by this review provides no significant evidence of the clinical benefit of digital devices compared to analogue-based aids. However, these results are difficult to generalize to current UK practice as the analogue aids and types of fitting in the trials are not those typically used in the NHS.