A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry's disease and mucopolysaccharidosis type 1.

OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of the administration of intravenous enzyme replacement therapy (ERT) to symptomatic patients for the prevention of long-term damage and symptoms in Fabry's disease and in mucopolysaccharidosis type 1 (MPS1). DATA SOURCES: Electronic databases from inception up to mid-2004. Contact with clinical experts. REVIEW METHODS: Relevant studies were identified and assessed using recommended quality criteria. RESULTS: The results suggested beneficial effects of ERT for Fabry's disease on measures of pain, cardiovascular function and some end-points reflecting neurosensory function. Renal function appeared to be stabilised by ERT. At present there are no utility-related health-related quality of life data on which to assess the relative health gain of ERT in MPS1. In order to be able to demonstrate the full extent of health gain from treatment, it was necessary to review the natural history of untreated patients in each disease in order to try to estimate the health loss prevented. The published information for Fabry's disease tallied with descriptions of a multi-system, life-threatening disorder particularly involving kidney, heart and brain with individual patients exhibiting many manifestations. The fragmentary information reviewed in 16 studies relevant to the natural history of MPS1 did not generate a coherent picture of disease progression and could provide little added value to published narrative reviews. For Fabry's disease, the mean cost per patient (50 kg) treated is around pounds sterling 85,000 per annum in England and Wales. The cost per patient varies considerably by dose. No published evidence reporting an economic evaluation of ERT for Fabry's disease was identified by this review. A dynamic decision model was constructed based on a birth cohort of male patients who are followed up until death. Owing to lack of information reported in the literature, many assumptions had to be applied. The key assumptions were that ERT returns patients to full health and a normal life expectancy. As far as possible, all assumptions favoured rather than detracted from the value of ERT. ERT was assumed to restore patients to full health in the base case. The estimated incremental cost-effectiveness ratio (ICER) in the base case was pounds sterling 252,000 per QALY (agalsidase beta). Univariate sensitivity analysis around the key assumptions produced ICERs ranging from pounds sterling 602,000 to pounds sterling 241,000. The base case unit cost of ERT was taken as pounds sterling 65.1/mg based on the cost of agalsidase beta. The unit cost would have had to be reduced to pounds sterling 9 to obtain an ICER of pounds sterling 30,000 per QALY. For MPS1, the mean cost per child patient (20 kg) treated is approximately pounds sterling 95,000 and an adult (70 kg) around pounds sterling 335,000 per annum in England and Wales. The cost per patient varies considerably by dose. There is no published evidence reporting an economic evaluation of ERT for MPS1 and no study was identified that reported the quality of life of MPS1 patients within a utility format. Furthermore, no or minimal information of the severity and rate of change of clinical manifestations of disease or the impact of ERT on these factors was identified. Information on the effect of ERT on mortality is also lacking owing to the relatively short time that the treatment has been available. Given this lack of data, it was not possible to develop a cost-effectiveness model of ERT treatment for MPS1 as the model would consist almost completely of assumptions based on no published evidence, leading to an incremental cost per QALY result that would be meaningless. CONCLUSIONS: Although ERT for treating the 'average' patient with Fabry's disease exceeds the normal upper threshold for cost-effectiveness seen in NHS policy decisions by over sixfold, and the value for MPS1 is likely to be of a similar order of magnitude, clinicians and the manufacturers argue that, as the disease is classified as an orphan disease under European Union legislation, it has special status, and the NHS has no option but to provide ERT. More information is required before the generalisability of the findings can be determined. Although data from the UK have been used wherever possible, this was very thin indeed. Nonetheless, even large errors in assumptions made will not reduce the ICER to anywhere near the upper level of treatments usually considered cost-effective. In order to overcome limited evidence on the natural history of the disease and the clinical effectiveness of the intervention, the establishment of disease-specific data registries is suggested to facilitate the process of technology assessment and improving patient care. These registries should attempt to include all affected patients in the UK, and collect longitudinal patient level data on clinically relevant problems, interventions received and quality of life in a utility format.

The Effects of Different Aspirin Dosing Frequencies and the Timing of Aspirin Intake in Primary and Secondary Prevention of Cardiovascular Disease: A Systematic Review.

Enhancing the effectiveness of aspirin by tailoring administration regimens is an important question among health professionals. We conducted a systematic review to evaluate the evidence on the effects of different aspirin regimens in terms of timing (chronotherapy) or frequency of dosing in the prevention of cardiovascular disease. Only two out of the 28 included studies reported long-term cardiovascular outcomes, highlighting an evidence gap that future research should address. The remaining 26 studies used surrogate outcomes.

Epigenetic biomarkers in progression from non-dysplastic Barrett's oesophagus to oesophageal adenocarcinoma: a systematic review protocol.

INTRODUCTION: Barrett's oesophagus (BO), a metaplastic condition affecting the lower oesophagus due to long-standing gastro-oesophageal reflux and chronic inflammation, is a precursor lesion for oesophageal adenocarcinoma (OADC). There is no clinical test to predict which patients with BO will progress to OADC. The British Society of Gastroenterology recommends endoscopic surveillance of patients with BO. Epigenetic changes have been well characterised in the neoplastic progression of ulcerative colitis to colonic carcinoma, another gastrointestinal cancer associated with chronic inflammation. This systematic review protocol aims to identify and evaluate studies which examine epigenetic biomarkers in BO and their association with progression to OADC. METHODS AND ANALYSIS: All prospective and retrospective primary studies, and existing systematic reviews investigating epigenetic markers including DNA methylation, histone modification, chromatin remodelling, micro and non-coding RNAs of all types will be eligible for inclusion. Eligible patients are those over the age of 18 with BO, BO with dysplasia, OADC or unspecified oesophageal cancer. A comprehensive search of bibliographic databases using combinations of text and index words relating to the population, prognostic markers and outcome will be undertaken with no language restrictions. Results will be screened by 2 independent reviewers and data extracted using a standardised proforma. The quality and risk of bias of individual studies will be assessed using the Quality in Prognostic Studies (QUIPS) tool. A narrative synthesis of all evidence will be performed with key findings tabulated. Meta-analysis will be considered where studies and reported outcomes are considered sufficiently homogeneous, both clinically and methodologically. Findings will be interpreted in the context of the quality of included studies. The systematic review will be reported according to PRISMA guidelines. ETHICS AND DISSEMINATION: This is a systematic review of completed studies and no ethical approval is required. Findings from the full systematic review will be submitted for publication and presentation at national and international conferences which will inform future research on risk stratification in patients with BO. REVIEW REGISTRATION NUMBER: CRD42016038654.

The effectiveness and cost-effectiveness of parent training/education programmes for the treatment of conduct disorder, including oppositional defiant disorder, in children.

OBJECTIVES: To assess the clinical and cost-effectiveness of parent training programmes for the treatment of children with conduct disorder (CD) up to the age of 18 years. DATA SOURCES: Electronic databases. REVIEW METHODS: For the effectiveness review, relevant studies were identified and evaluated. A quantitative synthesis of behavioural outcomes across trials was also undertaken using two approaches: vote counting and meta-analysis. The economic analysis consisted of reviewing previous economic/cost evaluations of parent training/education programmes and the economic information within sponsor's submissions; carrying out a detailed exploration of costs of parent training/education programmes; and a de novo modelling assessment of the cost-effectiveness of parent training/education programmes. The potential budget impact to the health service of implementing such programmes was also considered. RESULTS: Many of the 37 randomised controlled trials that met the review inclusion and exclusion criteria were assessed as being of poor methodological quality. Studies were clinically heterogeneous in terms of the population, type of parent training/education programme and content, setting, delivery, length and child behaviour outcomes used. Both vote counting and meta-analysis revealed a consistent trend across all studies towards short-term effectiveness (up to 4 months) of parent training/education programmes (compared with control) as measured by a change in child behaviour. Pooled estimates showed a statistically significant improvement on the Eyberg Child Behaviour Inventory frequency and intensity scales, the Dyadic Parent-Child Interaction Coding System and the Child Behaviour Checklist. No studies reported a statistically significant result favouring control over parent training/education programmes. There were few statistically significant differences between different parent training/education programmes, although there was a trend towards more intensive interventions (e.g. longer contact hours, additional child involvement) being more effective. The cost of treating CD is high, with costs incurred by many agencies. A recent study suggested that by age 28, costs for individuals with CD were around 10 times higher than for those with no problems, with a mean cost of 70,019 pounds sterling. Criminality incurs the greatest cost, followed by educational provision, foster and residential care and state benefits. Only a small proportion of these costs fall on health services. Using a 'bottom-up' costing approach, the costs per family of providing parent training/education programmes range from 629 pounds sterling to 3839 pounds sterling depending on the type and style of delivery. Using the conservative assumption that there are no cost savings from treatment, a total lifetime quality of life gain of 0.1 would give a cost per quality-adjusted life-year of between 38,393 pounds sterling and 6288 pounds sterling depending on the type of programme delivery and setting. CONCLUSIONS: Parent training/education programmes appear to be an effective and potentially cost-effective therapy for children with CD. However, the relative effectiveness and cost-effectiveness of different models (such as therapy intensity and setting) require further investigation. Further research is required on the impact of parent training/education programmes on the quality of life of children with CD and their parents/carers, as well as on longer term child outcomes.

Clinical effectiveness and cost-effectiveness of prehospital intravenous fluids in trauma patients.

OBJECTIVES: To systematically review the evidence on the effectiveness (in terms of mortality and morbidity) of prehospital intravenous (i.v.) fluid replacement, compared with no i.v. fluid replacement or delayed fluid replacement, in trauma patients with no head injury who have haemorrhage-induced hypotension due to trauma. DATA SOURCES: Electronic databases, relevant websites, handsearching, expert contacts. REVIEW METHODS: Search strategies were defined to identify randomised controlled trials (RCTs) and previous systematic reviews relating to the use of i.v. fluids in a prehospital (or other) setting compared to no fluids or delayed fluids. Inclusion and exclusion criteria were applied to identified studies, and key quality criteria of included studies were checked. Data were extracted independently by two reviewers. Economic evaluations were also systematically sought and appraised. RESULTS: Four relevant RCTs were identified, three of which were poorly designed and/or conducted. One good-quality RCT suggested that i.v. fluids may be harmful in patients with penetrating injuries. No evidence was found on the relative effectiveness of i.v. fluids in patients with blunt versus penetrating trauma. No reliable evidence was found from systematic reviews to suggest that a particular type of fluid is more beneficial compared to another type, although there was a trend favouring crystalloids over colloids. The relative costs of using i.v. fluids versus not using them were found to be very similar and changes in the use of fluids would therefore have no cost consequences for the ambulance service. A more detailed cost-effectiveness analysis would require further information on the relative consequences (mortality, morbidity) of different resuscitation strategies. CONCLUSIONS: The review found no evidence to suggest that prehospital i.v. fluid resuscitation is beneficial, and some evidence that it may be harmful. This evidence is however not conclusive, particularly for blunt trauma. A UK Consensus Statement, and to a lesser extent the UK Joint Royal Colleges Ambulance Liaison Committee guidelines represent a more cautious approach to fluid management than previously advocated and are therefore consistent with the limited evidence base. Further research is required on hypotensive (cautious) resuscitation versus delayed or no fluid replacement, particularly in blunt trauma. There is also a need for an improvement in the quality of data collection and analysis of routinely collected ambulance call-out data.

Autoantibody testing in children with newly diagnosed type 1 diabetes mellitus.

OBJECTIVES: To determine the role of autoantibody tests for autoimmune diseases in children with newly diagnosed type 1 diabetes mellitus. DATA SOURCES: MEDLINE, EMBASE and the Cochrane Library. Citation lists of included studies were scanned and relevant professional and patient websites reviewed. Laboratories and manufacturers were contacted to identify ongoing or unpublished research. REVIEW METHODS: Following scoping searches on thyroid and coeliac autoantibodies, a systematic review of autoantibody tests for diagnosis of coeliac disease was carried out. Studies were included where cohorts of untreated patients with unknown disease status were included, all patients had undergone the reference test (biopsy) and antibody tests, and sensitivity and specificity were reported or calculable. Selected studies were then evaluated against a quality checklist. Summary statistics of diagnostic accuracy, i.e. sensitivity, specificity, positive and negative likelihood ratios and diagnostic odds ratios, were calculated for all studies. A decision analytic model was developed to evaluate the cost utility of screening for coeliac disease at diagnosis of diabetes. RESULTS: All antibody tests for diagnosis of coeliac disease showed reasonably good diagnostic test accuracy. Studies reported variable measures of test accuracy, which may be due to aspects of study quality, differences in the tests and their execution in the laboratories, different populations and reference standards. The decision analytic model indicated screening for coeliac disease at diagnosis of diabetes was cost-effective. Sensitivity analyses exploring variations in the cost and disutility of gluten-free diet, the utilities attached to treated and untreated coeliac disease and the decrease in life expectancy associated with treated and untreated coeliac disease did substantially affect the cost-effectiveness of the screening strategies considered. CONCLUSIONS: In terms of test accuracy in testing for coeliac disease, immunoglobulin A (IgA) anti-endomysium is the most accurate test. If an enzyme-linked immunoassay test was required, which may be more suitable for screening purposes as it can be semi-automated, testing for IgA tissue transglutaminase is likely to be most accurate. The decision analytic model shows that the most accurate tests combined with confirmatory biopsy are the most cost-effective, whilst combinations of tests add little or no further value. There is limited information regarding test accuracy in screening populations with diabetes, and there is some uncertainty over whether the test characteristics would remain the same. Further research is required regarding the role of screening in silent coeliac disease and regarding long-term outcomes and complications of untreated coeliac disease.

Dual chamber versus single chamber ventricular pacemakers for sick sinus syndrome and atrioventricular block.

BACKGROUND: Dual chamber pacing or single chamber atrial pacing ('physiologic' pacing) is believed to have an advantage over single chamber ventricular pacing in that it resembles cardiac physiology more closely by maintaining atrioventricular (AV) synchrony and dominance of the sinus node, which in turn may reduce cardiovascular morbidity and mortality thus contributing to patient survival and quality of life. However, a significant proportion of pacemakers currently implanted are single chamber ventricular pacemakers. OBJECTIVES: The objective of this review was to assess the short- and long-term clinical effectiveness of dual chamber pacemakers compared to single chamber ventricular pacemakers in adults with AV block, sick sinus syndrome or both. An additional objective was to assess separately any potential differences in effectiveness between dual chamber pacing and single chamber atrial pacing. The clinical effectiveness of single chamber atrial pacing versus single chamber ventricular pacing was not examined. SEARCH STRATEGY: The Cochrane Controlled Trials Register (The Cochrane Library Issue 3, 2002), MEDLINE (1966 to 2002), EMBASE (1980 to 2002) and the Science Citation Index (1980 to 2002) were searched on 19th August 2002. Citation lists and web sites were checked and researchers in the field contacted. SELECTION CRITERIA: Parallel group or crossover randomised controlled trials of at least 48 hours duration comparing dual chamber pacing and single chamber ventricular pacing, and investigating cardiovascular morbidity, mortality, patient related quality of life, exercise capacity and complication rates. DATA COLLECTION AND ANALYSIS: Data was extracted onto pre-piloted data extraction forms. Quality assessment was undertaken using a checklist, with a sub-sample of quality data independently extracted by a second reviewer. Where appropriate data was available, meta-analysis was performed. Where meta-analysis was not possible, the number of studies showing a positive, neutral or negative direction of effect and statistical significance were simply counted. MAIN RESULTS: Five parallel and 26 crossover randomised controlled trials were identified. The quality of reporting was found to be poor. Pooled data from parallel studies shows a statistically non-significant preference for physiologic pacing (primarily dual chamber pacing) for the prevention of stroke, heart failure and mortality, and a statistically significant beneficial effect regarding the prevention of atrial fibrillation (odds ratio (OR) 0.79, 95% CI 0.68 to 0.93). Both parallel and crossover studies favour dual chamber pacing with regard to pacemaker syndrome (parallel: Peto OR 0.11, 95% CI 0.08 to 0.14; crossover: standardised mean difference (SMD) -0.74, 95% CI - 0.95 to -0.52). Pooled data from crossover studies shows a statistically significant trend towards dual chamber pacing being more favourable in terms of exercise capacity (SMD -0.24, 95% CI -0.03 to -0.45). No individual studies reported a significantly more favourable outcome with single chamber ventricular pacing. REVIEWERS' CONCLUSIONS: This review shows a trend towards greater effectiveness with dual chamber pacing compared to single chamber ventricular pacing, which supports the current British Pacing and Electrophysiology Group's Guidelines regarding atrioventricular block. Additional randomised controlled trial evidence from ongoing trials in this area will further inform the debate.

A systematic review and economic evaluation of subcutaneous and sublingual allergen immunotherapy in adults and children with seasonal allergic rhinitis.

BACKGROUND: Severe allergic rhinitis uncontrolled by conventional medication can substantially affect quality of life. Immunotherapy involves administering increasing doses of a specific allergen, with the aim of reducing sensitivity and symptomatic reactions. Recent meta-analyses have concluded that both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are more effective than placebo in reducing symptoms. It is uncertain which route of administration is more effective and whether or not treatment is cost-effective. OBJECTIVE: To determine the comparative clinical effectiveness and cost-effectiveness of SCIT and SLIT for seasonal allergic rhinitis in adults and children. DATA SOURCES: Electronic databases {MEDLINE, EMBASE, The Cochrane Library [Cochrane Central Register of Controlled Trials (CENTRAL)], NHS Economic Evaluation Database (NHS EED)} and trial registries (from inception up to April 2011). REVIEW METHODS: Standard systematic review methods were used for study selection, data extraction and quality assessment. Double-blind randomised, placebo-controlled trials of SCIT or SLIT, or of SCIT compared with SLIT, and economic evaluations were included. Meta-analysis and indirect comparison meta-analysis and meta-regression were carried out. A new economic model was constructed to estimate cost-utility. RESULTS: Meta-analyses found statistically significant effects for SCIT and SLIT compared with placebo across a number of outcome measures and for the vast majority of subgroup analyses (type and amount of allergen, duration of treatment). There was less evidence for children, but some results in favour of SLIT were statistically significant. Indirect comparisons did not provide conclusive results in favour of either SCIT or SLIT. Economic modelling suggested that, when compared with symptomatic treatment (ST), both SCIT and SLIT may become cost-effective at a threshold of £20,000-30,000 per quality-adjusted life-year (QALY) from around 6 years, or 5 years for SCIT compared with SLIT (NHS and patient perspective). LIMITATIONS: It is uncertain to what extent changes in the outcome measures used in the trials translate into clinically meaningful benefits. Cost-effectiveness estimates are based on a simple model, limited data and a number of assumptions, and should be seen as indicative only. CONCLUSIONS: A benefit from both SCIT and SLIT compared with placebo has been consistently demonstrated, but the extent of this effectiveness in terms of clinical benefit is unclear. Both SCIT and SLIT may be cost-effective compared with ST from around 6 years (threshold of £20,000-30,000 per QALY). Further research is needed to establish the comparative effectiveness of SCIT compared with SLIT and to provide more robust cost-effectiveness estimates. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

A systematic review and economic evaluation of the use of tumour necrosis factor-alpha (TNF-α) inhibitors, adalimumab and infliximab, for Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a severe, lifelong disease characterised by inflammation of the gastrointestinal mucosa. The impact on patients and society is high as ill health can be lifelong and can negatively affect patients' quality of life. Costs to the NHS are high, particularly for patients needing hospitalisation. Conventional treatment pathways are complex. More recently, a group of drugs called tumour necrosis factor (TNF) inhibitors (anti-TNF-α agents) have been evaluated for their effectiveness in CD. One of these, infliximab, is currently recommended by the National Institute for Health and Clinical Excellence (NICE; 2002) for patients with severe, active CD where patients are refractory to or intolerant of conventional treatment. OBJECTIVES: To investigate whether there is evidence for greater clinical effectiveness or cost-effectiveness for either adalimumab or infliximab. DATA SOURCES: Cochrane Library (Cochrane Central Register of Controlled Trials) 2007 Issue 2; MEDLINE (Ovid) 2000 to May/June 2007; MEDLINE In-Process & Other Non-Indexed Citations (Ovid) 4 June and 26 June 2007; EMBASE (Ovid) 2000 to May/June 2007. The European Medicines Agency, the US Food and Drug Administration and other relevant websites. REVIEW METHODS: Standard systematic review methods were used for study identification and selection, data extraction and quality assessment. Only randomised controlled trials (RCTs) comparing adalimumab or infliximab with standard treatment (placebo), RCTs comparing adalimumab with infliximab, or RCTs comparing different dosing regimens of either adalimumab or infliximab in adults and children with moderate-to-severe active CD intolerant or resistant to conventional treatment were eligible for inclusion. A systematic review of published studies on the cost and cost-effectiveness of adalimumab and infliximab was undertaken. The economic models of cost-effectiveness submitted by the manufacturers of both drugs were critically appraised and, where appropriate, rerun using parameter inputs based on the evidence identified by the authors of the technology asessment report. A de novo Markov state transition model was constructed to calculate the incremental cost-effectiveness ratio for adalimumab and infliximab therapy compared with standard care. RESULTS: Based on 11 trials, there was evidence from both induction and maintenance trials that both adalimumab and infliximab therapy were beneficial compared with placebo (standard care) for adults with moderate-to-severe CD and, for infliximab, for adults with fistulising CD; results were statistically significant for some time points. Between 6% and 24% (adalimumab), and 21% and 44% (infliximab) more patients achieved remission with anti-TNF-α antibodies than with placebo in the induction trials. Between 24% and 29% (adalimumab), and 14% and 24% (infliximab) more patients achieved remission with anti-TNF-α antibodies in the two large maintenance trials at reported follow-up. In fistulising CD, between 29% and 42% (induction trial) and 23% (maintenance trial) more patients achieved a > 50% reduction in fistulas with infliximab than with placebo at reported follow-up. There was no direct evidence to show that 'responders' were more likely to benefit from treatment than 'non-responders' in the longer term. Few differences were found between treatment and standard care arms for selected adverse events, though high proportions of scheduled crossovers resulted in a lack of a true placebo group in most of the maintenance trials. No published studies on the cost-effectiveness of adalimumab were identified. The four independently funded studies identified for infliximab suggested high cost-effectiveness ratios [all above £50,000/quality-adjusted life-year (QALY) for non-fistulising disease and all above £100,000/QALY for fistulising disease]. A budget impact assessment suggested that total cost to the NHS in England and Wales for induction in severe disease only could range between £17M and £92M and for maintenance for 1 year between £140M and £200M. LIMITATIONS: Regarding clinical effectiveness, there were concerns about the trial design and lack of clarity, which may have affected interpretation of results. None of the trials matched exactly the licence indications or NICE guidance, which specify the use of these drugs in patients with 'severe' disease. All trials were multicentre, and applicability to UK populations, particularly in terms of standard care being provided and in terms of patients having failed or having become intolerant to conventional treatment, was uncertain. The published economic models relied heavily on little information and data from small samples. CONCLUSIONS: Anti-TNF therapy with adalimumab or infliximab may have a beneficial effect compared with standard care on outcome measures for induction and maintenance. The findings were that for induction, both adalimumab and infliximab are cost-effective (dominant relative to standard care) in the management of severe CD, and adalimumab (but not infliximab) is cost-effective for moderate CD, according to limits generally accepted by NICE. On the basis of the analysis presented here, neither drug is likely to be cost-effective as maintenance therapy for moderate or severe disease. Perhaps, most importantly, the analysis reflected the fact that a substantial number of patients would achieve remission under standard care and that the incidence of relapse among those in remission was such that maintenance therapy would have to show greater effectiveness than at present and/or be much less costly than it currently is in order to reach the levels of generally accepted cost-effectiveness. Any future trials need to be designed to meet the particular challenges of measuring and quantifying benefit in this patient group. FUNDING: The research was funded by the HTA programme on behalf of NICE.

Rituximab for the treatment of relapsed/refractory chronic lymphocytic leukaemia.

This paper presents a summary of the evidence review group (ERG) report on the clinical effectiveness and cost-effectiveness of rituximab with chemotherapy compared to chemotherapy only for the treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) based on the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. Evidence was available in the form of one open-label, ongoing, unpublished randomised controlled trial (RCT), REACH (Rituximab in the Study of Relapsed Chronic Lymphocytic Leukemia), conducted by the manufacturer, which compared rituximab with a fludarabine and cyclophosphamide combination (R-FC) to fludarabine and cyclophosphamide (FC) only. REACH was scheduled to run for 8 years; however, the data provided were immature, with a median observation time at the time of data analysis of 2.1 years. REACH provided evidence of prolonged progression free survival with R-FC compared to FC (10 months, investigators' data), but no evidence of an overall survival benefit with R-FC. Patients refractory to fludarabine and with prior rituximab exposure were excluded from REACH and no controlled studies were identified by the ERG for these patient groups. The ERG had concerns about the structure of the economic model submitted by the manufacturer, which did not allow improvement in quality of life from treatment while in a progressed state. The manufacturer's model further assumed a divergence in cumulative deaths between the R-FC and FC treatment arms from the outset, which did not accord with observed data from REACH. When the survival advantage was removed, the manufacturer's base-case incremental cost-effectiveness ratio (ICER) changed from 15,593 pounds to between 40,000 pounds and 42,000 pounds per quality-adjusted life-year (QALY). With no survival advantage, the ICER became sensitive to changes in utility. There was no good empirical evidence on the utility of CLL patients in different states. Allowing for the possibility of a survival advantage with rituximab (although not supported by current evidence), the ERG performed further modelling, which found that rituximab would be cost-effective at 20,000 pounds/QALY (30,000 pounds/QALY) if a reduction in survival advantage relative to the manufacturer's base case of 40% (80%) was assumed. The guidance issued by NICE in July 2010 as a result of the STA recommends rituximab with FC for people with relapsed or refractory chronic lymphocytic leukaemia, except when the condition is refractory to fludarabine or where there has been previous treatment with rituximab.

Imatinib as adjuvant treatment following resection of KIT-positive gastrointestinal stromal tumours.

This is a summary of the evidence review group (ERG) report on the clinical effectiveness and cost-effectiveness of adjuvant imatinib post resection of KIT-positive gastrointestinal stromal tumours (GISTs) compared with resection only in patients at significant risk of relapse. The ERG report is based on the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The bulk of the clinical evidence submitted was in the form of one randomised controlled trial (RCT), the Z9001 trial, funded by the manufacturer, which compared resection + adjuvant imatinib for 1 year to resection only. Results were immature, with median recurrence-free survival (RFS) not yet having been reached at the time of analysis. The trial did provide evidence of a delay in disease recurrence [1-year RFS rate of 98% in the imatinib arm vs 83% in the placebo arm [hazard ratio (HR) 0.35, 95% confidence interval (CI) 0.22 to 0.53, p < 0.0001)] but no evidence of an overall survival benefit. There was no long-term evidence around the rate of imatinib resistance over time with different treatment strategies (± adjuvant treatment). The relevant patient group for this appraisal is those at significant risk of relapse. These form a subgroup of the Z9001 trial, and all information regarding this group was designated 'Commercial-in-Confidence' (CIC). Median observation time for RFS was also CIC. The manufacturer constructed a Markov model comprising 10 health states designed to estimate costs and effects of treatment over a lifetime time horizon. The manufacturer's estimate of the base-case incremental cost-effectiveness ratio (ICER) was 22,937 pounds/quality-adjusted life-year (subsequently amended by the manufacturer to 23,601 pounds). While the structure of the model reasonably reflected the natural history of the disease, the ERG had numerous concerns regarding the selection of, and assumptions around, input parameters (utilities, monthly probabilities of recurrence and death). Furthermore, the model was set up in such a way that any delay in recurrence translated directly into a survival benefit, an assumption that has no evidence base. A further assumption not supported by evidence was that any treatment benefit gained in the first year is carried on for a further 2 years at the same rate. Appropriate probabilistic sensitivity analysis was undertaken on the base case only, but not on scenario analyses, or choice of model used to estimate long-term survival data. The model was not amenable to changes in input values, thus limiting any additional analyses by the ERG to test assumptions. Due to the large number of uncertainties and assumptions, the estimated ICERs should be regarded as highly uncertain. The guidance issued by NICE in June 2010 as a result of the STA does not recommend imatinib as adjuvant treatment after resection of gastrointestinal stromal tumours, although individuals currently receiving adjuvant imatinib should have the option to continue treatment until they and their clinician consider it appropriate to stop.