The effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease (review of Technology Appraisal No. 111): a systematic review and economic model.

BACKGROUND: Alzheimer's disease (AD) is the most commonly occurring form of dementia. It is predominantly a disease of later life, affecting 5% of those over 65 in the UK. OBJECTIVES: Review and update guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine [acetylcholinesterase inhibitors (AChEIs)] and memantine within their licensed indications for the treatment of AD, which was issued in November 2006 (amended September 2007 and August 2009). DATA SOURCES: Electronic databases were searched for systematic reviews and/or metaanalyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no new includable studies. The databases searched included The Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases--Science Citation Index, Conference Proceedings Citation Index, and BIOSIS; the Centre for Reviews and Dissemination (CRD) databases--NHS Economic Evaluation Database, Health Technology Assessment, and Database of Abstracts of Reviews of Effects. REVIEW METHODS: The clinical effectiveness systematic review was undertaken following the principles published by the NHS CRD. We included RCTs whose population was people with AD. The intervention and comparators depended on disease severity, measured by the Mini Mental State Examination (MMSE). INTERVENTIONS: mild AD (MMSE 21-26)--donepezil, galantamine and rivastigmine; moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine and memantine; severe AD (MMSE < 10)--memantine. Comparators: mild AD (MMSE 21-26)--placebo or best supportive care (BSC); moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine, memantine, placebo or BSC; severe AD (MMSE < 10)--placebo or BSC. The outcomes were clinical, global, functional, behavioural, quality of life, adverse events, costs and cost-effectiveness. Where appropriate, data were pooled using pair-wise meta-analysis, multiple outcome measures, metaregression and mixedtreatment comparisons. The decision model was based broadly on the structure of the three-state Markov model described in the previous technology assessment report, based upon time to institutionalisation, parameterised with updated estimates of effectiveness, costs and utilities. RESULTS: Notwithstanding the uncertainty of our results, we found in the base case that the AChEIs are probably cost saving at a willingness-to-pay (WTP) of £'30,000 per qualityadjusted life-year (QALY) for people with mild-to-moderate AD. For this class of drugs, there is a > 99% probability that the AChEIs are more cost-effective than BSC. These analyses assume that the AChEIs have no effect on survival. For the AChEIs, in people with mild to moderate AD, the probabilistic sensitivity analyses suggested that donepezil is the most cost-effective, with a 28% probability of being the most cost-effective option at a WTP of £'30,000 per QALY (27% at a WTP of £'20,000 per QALY). In the deterministic results, donepezil dominates the other drugs and BSC, which, along with rivastigmine patches, are associated with greater costs and fewer QALYs. Thus, although galantamine has a slightly cheaper total cost than donepezil (£'69,592 vs £'69,624), the slightly greater QALY gains from donepezil (1.616 vs 1.617) are enough for donepezil to dominate galantamine.The probability that memantine is cost-effective in a moderate to severe cohort compared with BSC at a WTP of £'30,000 per QALY is 38% (and 28% at a WTP of £'20,000 per QALY). The deterministic ICER for memantine is £'32,100 per/QALY and the probabilistic ICER is £'36,700 per/QALY. LIMITATIONS: Trials were of 6 months maximum follow-up, lacked reporting of key outcomes, provided no subgroup analyses and used insensitive measures. Searches were limited to English language, The model does not include behavioural symptoms and there is uncertainty about the model structure and parameters. CONCLUSIONS: The additional clinical effectiveness evidence identified continues to suggest clinical benefit from the AChEIs in alleviating AD symptoms, although there is debate about the magnitude of the effect. Although there is also new evidence on the effectiveness of memantine, it remains less supportive of this drug's use than the evidence for AChEIs. The conclusions concerning cost-effectiveness are quite different from the previous assessment. This is because both the changes in effectiveness and costs between drug use and non-drug use underlying the ICERs are very small. This leads to highly uncertain results, which are very sensitive to change. RESEARCH PRIORITIES: RCTs to include mortality, time to institutionalisation and quality of life, powered for subgroup analysis. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Dasatinib and nilotinib for imatinib-resistant or -intolerant chronic myeloid leukaemia: a systematic review and economic evaluation.

BACKGROUND: Chronic myeloid leukaemia (CML) is a form of cancer affecting the blood, characterised by excessive proliferation of white blood cells in the bone marrow and circulating blood. In the UK, an estimated 560 new cases of CML are diagnosed each year. OBJECTIVES: The purpose of this study was to assess the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in the treatment of people with imatinib-resistant (ImR) and imatinib-intolerant (ImI) CML. A systematic review of the clinical effectiveness literature, a review of manufacturer submissions and a critique and exploration of manufacturer submissions for accelerated phase and blast crisis CML were carried out and a decision-analytic model was developed to estimate the cost-effectiveness of dasatinib and nilotinib in chronic phase CML. SYSTEMATIC REVIEW METHODS: Key databases were searched for relevant studies from their inception to June 2009 [MEDLINE (including MEDLINE In-Process & Other Non-Indexed Citations), EMBASE, (ISI Web of Science) Conference Proceedings Citation Index and four others]. One reviewer assessed titles and abstracts of studies identified by the search strategy, with a sample checked by a second reviewer. The full text of relevant papers was obtained and screened against the full inclusion criteria independently by two reviewers. Data from included studies were extracted by one reviewer and checked by a second. Clinical effectiveness studies were synthesised through narrative review. ECONOMIC EVALUATION METHODS: Cost-effectiveness analyses reported in manufacturer submissions to the National Institute of Health and Clinical Excellence were critically appraised and summarised narratively. In addition, the models for accelerated phase and blast crisis underwent a more detailed critique and exploration. Two separate decision-analytic models were developed for chronic phase CML, one simulating a cohort of individuals who have shown or developed resistance to normal dose imatinib and one representing individuals who have been unable to continue imatinib treatment owing to adverse events. One-way, multiway and probabilistic sensitivity analyses were performed to explore structural and parameter uncertainty. RESULTS: Fifteen studies were included in the systematic review. Chronic phase: effectiveness data were limited but dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic response and haematological response in both ImR and ImI populations. In terms of cost-effectiveness, it was extremely difficult to reach any conclusions regarding either agent in the ImR population. All three models (Novartis, PenTAG and Bristol-Myers Squibb) were seriously flawed in one way or another, as a consequence of the paucity of data appropriate to construct robust decision-analytic models. Accelerated and blast crisis: all available data originated from observational single-arm studies and there were considerable and potentially important differences in baseline characteristics which seriously undermined any process for making meaningful comparisons between treatments. Owing to a lack of available clinical data, de novo models of accelerated phase and blast crisis have not been developed. The economic evaluations carried out by the manufacturers of nilotinib and dasatinib were seriously undermined by the absence of evidence on high-dose imatinib in these populations. LIMITATIONS: The study has been necessarily constrained by the paucity of available clinical data, the differences in definitions used in the studies and the subsequent impossibility of undertaking a meaningful cost-effectiveness analyses to inform all policy questions. CONCLUSIONS: Dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic and haematological responses in both ImR and ImI populations. It was difficult to reach any cost-effectiveness conclusions as a consequence of the paucity of the data. Future research should include a three-way, double-blind, randomised clinical trial of dasatinib, nilotinib and high-dose imatinib.

The clinical effectiveness and cost-effectiveness of exercise referral schemes: a systematic review and economic evaluation.

BACKGROUND: Exercise referral schemes (ERS) aim to identify inactive adults in the primary-care setting. The GP or health-care professional then refers the patient to a third-party service, with this service taking responsibility for prescribing and monitoring an exercise programme tailored to the needs of the individual. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of ERS for people with a diagnosed medical condition known to benefit from physical activity (PA). The scope of this report was broadened to consider individuals without a diagnosed condition who are sedentary. DATA SOURCES: MEDLINE; EMBASE; PsycINFO; The Cochrane Library, ISI Web of Science; SPORTDiscus and ongoing trial registries were searched (from 1990 to October 2009) and included study references were checked. METHODS: Systematic reviews: the effectiveness of ERS, predictors of ERS uptake and adherence, and the cost-effectiveness of ERS; and the development of a decision-analytic economic model to assess cost-effectiveness of ERS. RESULTS: Seven randomised controlled trials (UK, n = 5; non-UK, n = 2) met the effectiveness inclusion criteria, five comparing ERS with usual care, two compared ERS with an alternative PA intervention, and one to an ERS plus a self-determination theory (SDT) intervention. In intention-to-treat analysis, compared with usual care, there was weak evidence of an increase in the number of ERS participants who achieved a self-reported 90-150 minutes of at least moderate-intensity PA per week at 6-12 months' follow-up [pooled relative risk (RR) 1.11, 95% confidence interval 0.99 to 1.25]. There was no consistent evidence of a difference between ERS and usual care in the duration of moderate/vigorous intensity and total PA or other outcomes, for example physical fitness, serum lipids, health-related quality of life (HRQoL). There was no between-group difference in outcomes between ERS and alternative PA interventions or ERS plus a SDT intervention. None of the included trials separately reported outcomes in individuals with medical diagnoses. Fourteen observational studies and five randomised controlled trials provided a numerical assessment of ERS uptake and adherence (UK, n = 16; non-UK, n = 3). Women and older people were more likely to take up ERS but women, when compared with men, were less likely to adhere. The four previous economic evaluations identified suggest ERS to be a cost-effective intervention. Indicative incremental cost per quality-adjusted life-year (QALY) estimates for ERS for various scenarios were based on a de novo model-based economic evaluation. Compared with usual care, the mean incremental cost for ERS was £169 and the mean incremental QALY was 0.008, with the base-case incremental cost-effectiveness ratio at £20,876 per QALY in sedentary people without a medical condition and a cost per QALY of £14,618 in sedentary obese individuals, £12,834 in sedentary hypertensive patients, and £8414 for sedentary individuals with depression. Estimates of cost-effectiveness were highly sensitive to plausible variations in the RR for change in PA and cost of ERS. LIMITATIONS: We found very limited evidence of the effectiveness of ERS. The estimates of the cost-effectiveness of ERS are based on a simple analytical framework. The economic evaluation reports small differences in costs and effects, and findings highlight the wide range of uncertainty associated with the estimates of effectiveness and the impact of effectiveness on HRQoL. No data were identified as part of the effectiveness review to allow for adjustment of the effect of ERS in different populations. CONCLUSIONS: There remains considerable uncertainty as to the effectiveness of ERS for increasing activity, fitness or health indicators or whether they are an efficient use of resources in sedentary people without a medical diagnosis. We failed to identify any trial-based evidence of the effectiveness of ERS in those with a medical diagnosis. Future work should include randomised controlled trials assessing the cinical effectiveness and cost-effectivenesss of ERS in disease groups that may benefit from PA. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Effect of exercise referral schemes in primary care on physical activity and improving health outcomes: systematic review and meta-analysis.

OBJECTIVE: To assess the impact of exercise referral schemes on physical activity and health outcomes. Design Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, PsycINFO, Cochrane Library, ISI Web of Science, SPORTDiscus, and ongoing trial registries up to October 2009. We also checked study references. Study selection Design: randomised controlled trials or non-randomised controlled (cluster or individual) studies published in peer review journals. POPULATION: sedentary individuals with or without medical diagnosis. Exercise referral schemes defined as: clear referrals by primary care professionals to third party service providers to increase physical activity or exercise, physical activity or exercise programmes tailored to individuals, and initial assessment and monitoring throughout programmes. Comparators: usual care, no intervention, or alternative exercise referral schemes. RESULTS: Eight randomised controlled trials met the inclusion criteria, comparing exercise referral schemes with usual care (six trials), alternative physical activity intervention (two), and an exercise referral scheme plus a self determination theory intervention (one). Compared with usual care, follow-up data for exercise referral schemes showed an increased number of participants who achieved 90-150 minutes of physical activity of at least moderate intensity per week (pooled relative risk 1.16, 95% confidence intervals 1.03 to 1.30) and a reduced level of depression (pooled standardised mean difference -0.82, -1.28 to -0.35). Evidence of a between group difference in physical activity of moderate or vigorous intensity or in other health outcomes was inconsistent at follow-up. We did not find any difference in outcomes between exercise referral schemes and the other two comparator groups. None of the included trials separately reported outcomes in individuals with specific medical diagnoses. Substantial heterogeneity in the quality and nature of the exercise referral schemes across studies might have contributed to the inconsistency in outcome findings. Conclusions Considerable uncertainty remains as to the effectiveness of exercise referral schemes for increasing physical activity, fitness, or health indicators, or whether they are an efficient use of resources for sedentary people with or without a medical diagnosis.

Computerised decision support systems in order communication for diagnostic, screening or monitoring test ordering: systematic reviews of the effects and cost-effectiveness of systems.

BACKGROUND: Order communication systems (OCS) are computer applications used to enter diagnostic and therapeutic patient care orders and to view test results. Many potential benefits of OCS have been identified including improvements in clinician ordering patterns, optimisation of clinical time, and aiding communication processes between clinicians and different departments. Many OCS now include computerised decision support systems (CDSS), which are information systems designed to improve clinical decision-making. CDSS match individual patient characteristics to a computerised knowledge base, and software algorithms generate patient-specific recommendations. OBJECTIVES: To investigate which CDSS in OCS are in use within the UK and the impact of CDSS in OCS for diagnostic, screening or monitoring test ordering compared to OCS without CDSS. To determine what features of CDSS are associated with clinician or patient acceptance of CDSS in OCS and what is known about the cost-effectiveness of CDSS in diagnostic, screening or monitoring test OCS compared to OCS without CDSS. DATA SOURCES: A generic search to identify potentially relevant studies for inclusion was conducted using MEDLINE, EMBASE, Cochrane Controlled Trials Register (CCTR), CINAHL (Cumulative Index to Nursing and Allied Health Literature), DARE (Database of Abstracts of Reviews of Effects), Health Technology Assessment (HTA) database, IEEE (Institute of Electrical and Electronic Engineers) Xplore digital library, NHS Economic Evaluation Database (NHS EED) and EconLit, searched between 1974 and 2009 with a total of 22,109 titles and abstracts screened for inclusion. REVIEW METHODS: CDSS for diagnostic, screening and monitoring test ordering OCS in use in the UK were identified through contact with the 24 manufacturers/suppliers currently contracted by the National Project for Information Technology (NpfIT) to provide either national or specialist decision support. A generic search to identify potentially relevant studies for inclusion in the review was conducted on a range of medical, social science and economic databases. The review was undertaken using standard systematic review methods, with studies being screened for inclusion, data extracted and quality assessed by two reviewers. Results were broadly grouped according to the type of CDSS intervention and study design where possible. These were then combined using a narrative synthesis with relevant quantitative results tabulated. RESULTS: Results of the studies included in review were highly mixed and equivocal, often both within and between studies, but broadly showed a beneficial impact of the use of CDSS in conjunction with OCS over and above OCS alone. Overall, if the findings of both primary and secondary outcomes are taken into account, then CDSS significantly improved practitioner performance in 15 out of 24 studies (62.5%). Only two studies covered the cost-effectiveness of CDSS: a Dutch study reported a mean cost decrease of 3% for blood tests orders (639 euros) in each of the intervention clinics compared with a 2% (208 euros) increase in control clinics in test costs; and a Spanish study reported a significant increase in the cost of laboratory tests from 41.8 euros per patient per annum to 47.2 euros after implementation of the system. LIMITATIONS: The response rate from the survey of manufacturers and suppliers was extremely low at only 17% and much of the feedback was classified as being commercial-in-confidence (CIC). No studies were identified which assessed the features of CDSS that are associated with clinician or patient acceptance of CDSS in OCS in the test ordering process and only limited data was available on the cost-effectiveness of CDSS plus OCS compared with OCS alone and the findings highly specific. Although CDSS appears to have a potentially small positive impact on diagnostic, screening or monitoring test ordering, the majority of studies come from a limited number of institutions in the USA. CONCLUSIONS: If the findings of both primary and secondary outcomes are taken into account then CDSS showed a statistically significant benefit on either process or practitioner performance outcomes in nearly two-thirds of the studies. Furthermore, in four studies that assessed adverse effects of either test cancellation or delay, no significant detrimental effects in terms of additional utilisation of health-care resources or adverse events were observed. We believe the key current need is for a well designed and comprehensive survey, and on the basis of the results of this potentially for evaluation studies in the form of cluster randomised controlled trials or randomised controlled trials which incorporate process, and patient outcomes, as well as full economic evaluations alongside the trials to assess the impact of CDSS in conjunction with OCS versus OCS alone for diagnostic, screening or monitoring test ordering in the NHS. The economic evaluation should incorporate the full costs of potentially developing, testing, and installing the system, including staff training costs. STUDY REGISTRATION: Study registration 61.

The clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia: an evidence review of the submission from Roche.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia (CLL) based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturer's searches for clinical effectiveness and cost-effectiveness data were appropriate and included all relevant studies. The submission's evidence came from a single, unpublished, well-conducted randomised controlled trial (RCT) comparing rituximab in combination with fludarabine and cyclophosphamide (R-FC) with fludarabine and cyclophosphamide (FC) alone for the first-line treatment of CLL. There was a statistically significant increase in progression-free survival (PFS) with R-FC compared with FC alone {median 39.8 months vs 32.2 months; hazard ratio [HR] 0.56 [95% confidence interval (CI) 0.43 to 0.72]}. However, the initial significant treatment benefit for R-FC compared with FC for overall survival was not maintained at a slightly longer follow-up time [median 25.4 months; adjusted HR 0.72 (95% CI 0.48 to 1.09)]. Response rates, numbers of patients with event-free survival and duration of response all favoured treatment with R-FC. Additional evidence from a mixed-treatment comparison model indicated R-FC to be significantly superior to chlorambucil alone for both PFS and overall and complete response rates. The incidence of grade 3 or 4 adverse events was higher in the R-FC arm (77%) than in the FC arm (62%). Dose modifications were also more frequent in this arm, but this did not lead to differences in treatment discontinuation. Roche used a three-state Markov model (PFS, progressed and death) to model the cost-effectiveness of R-FC compared with FC and chlorambucil alone. The model used a cycle length of 1 month and a lifetime time horizon. The approach taken to modelling was reasonable and the sources and justification of estimates were generally sound. The base-case analysis produced an incremental cost-effectiveness ratio (ICER) of 13,189 pounds per quality-adjusted life-year (QALY) for R-FC versus FC, and 6422 pounds per QALY for the comparison of R-FC versus chlorambucil, suggesting that R-FC is cost-effective at normal willingness-to-pay thresholds. One-way sensitivity analyses produced a range of ICERs from 10,249 pounds to 22,661 pounds per QALY for R-FC versus FC, and 5612 pounds and 6921 pounds per QALY for R-FC versus chlorambucil. Probabilistic sensitivity analysis results matched the deterministic results very closely. However, the sensitivity analysis did not fully investigate the uncertainty associated with differential values across arms or with the structural assumptions of the model, and utility values were not drawn from an empirical study. The NICE guidance issued as a result of the STA states that: Rituximab in combination with fludarabine and cyclophosphamide (R-FC) is recommended as an option for the first-line treatment of chronic lymphocytic leukaemia in people for whom fludarabine in combination with cyclophosphamide (FC) is considered appropriate. Rituximab in combination with chemotherapy agents other than fludarabine and cyclophosphamide is not recommended for the first-line treatment of chronic lymphocytic leukaemia.

Everolimus for the second-line treatment of advanced and/or metastatic renal cell cancer: a critique of the submission from Novartis.

This paper represents a summary of the evidence review group (ERG) report into the clinical efficacy, safety and cost-effectiveness of everolimus plus best supportive care (BSC) for the treatment of advanced renal cell carcinoma (RCC) which has progressed following or on vascular endothelial growth factor-targeted therapy (sunitinib, sorafenib, bevacizumab), compared to BSC alone. The submitting manufacturer's case for clinical effectiveness and cost-effectiveness was mainly based on a well-conducted randomised controlled trial (RCT), Renal Cell Cancer Treatment with Oral RAD001 Given Daily-1 (RECORD-1), comparing BSC plus everolimus with BSC plus placebo and a de novo economic model. The RCT indicated a marked statistically significant effect on progression-free survival. The base-case incremental cost-effectiveness ratio (ICER) estimate was 52,000 pounds per quality-adjusted life-year (this included a reduction in drug cost associated with an approved patient access scheme). The ERG undertook a critical appraisal of the submission. The ERG was generally in agreement with the submitting manufacturer concerning its estimates of effectiveness; however, there was greater concern surrounding the estimates of cost-effectiveness. The ERG judged that if potential errors in the model were corrected, the ICERs offered by the submitting manufacturer would overstate the cost-effectiveness of everolimus for the second-line treatment of metastatic RCC (that this ICER would be a higher value). Concerning the estimates of cost-effectiveness in RCC, the observations in the ERG report provide strong further support for research collecting rigorous estimates of utilities associated with the main health states likely to be experienced by patients with renal cell cancer. At the time of writing, NICE was yet to issue the Appraisal Consultation Document for this appraisal.

Bevacizumab, sorafenib tosylate, sunitinib and temsirolimus for renal cell carcinoma: a systematic review and economic evaluation.

OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of bevacizumab, combined with interferon (IFN), sorafenib tosylate, sunitinib and temsirolimus in the treatment of people with advanced and/or metastatic renal cell carcinoma (RCC). DATA SOURCES: Electronic databases, including MEDLINE, EMBASE and the Cochrane Library, were searched up to September/October 2007 (and again in February 2008). REVIEW METHODS: Systematic reviews and randomised clinical trials comparing any of the interventions with any of the comparators in participants with advanced and/or metastatic RCC were included, also phase II studies and conference abstracts if there was sufficient detail to adequately assess quality. Results were synthesised narratively and a decision-analytic Markov-type model was developed to simulate disease progression and estimate the cost-effectiveness of the interventions under consideration. RESULTS: A total of 888 titles and abstracts were retrieved in the clinical effectiveness review, including reports of eight clinical trials. Treatment with bevacizumab plus IFN or sunitinib had clinically relevant and statistically significant advantages over treatment with IFN alone, in terms of progression-free survival and tumour response, doubling median progression-free survival from approximately 5 months to 10 months. Temsirolimus had similar advantages over treatment with IFN in terms of progression-free and overall survival, increasing median overall survival from 7.3 to 10.9 months [hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.58 to 0.92)], as did sorafenib in comparison with best supportive care in terms of overall survival, progression-free survival and tumour response, with a doubling of progression-free survival (HR 0.51; 95% CI 0.43 to 0.60). However, the last was associated with an increased frequency of hypertension and hand-foot skin reaction compared with placebo. No fully published economic evaluations of any of the interventions could be located. However, estimates from the PenTAG model suggested that none of the interventions would be considered cost-effective at a willingness-to-pay threshold of 30,000 pounds per quality-adjusted life-year (QALY). Estimates of cost per QALY ranged from 71,462 pounds for sunitinib to 171,301 pounds for bevacizumab plus IFN. Although there are many similarities in the methodology and structural assumptions employed by PenTAG and the manufacturers of the interventions, in all cases the cost-effectiveness estimates from the PenTAG model were higher than those presented in the manufacturers' submissions. Cost-effectiveness estimates were particularly sensitive to variations in the estimates of treatment effectiveness, drug pricing (including dose intensity data), and health-state utility input parameters. CONCLUSIONS: Treatment with bevacizumab plus IFN and sunitinib has clinically relevant and statistically significant advantages over treatment with IFN alone in patients with metastatic RCC. In people with three of six risk factors for poor prognosis, temsirolimus had clinically relevant advantages over treatment with IFN, and sorafenib tosylate was superior to best supportive care as second-line therapy. The frequency of adverse events associated with bevacizumab plus IFN, sunitinib and temsirolimus was comparable with that seen with IFN, although the adverse event profile is different. Treatment with sorafenib was associated with a significantly increased frequency of hypertension and hand-foot syndrome. Estimates from the PenTAG model suggested that none of the interventions would be considered cost-effective at a willingness-to-pay threshold of 30,000 pounds per QALY.

Sunitinib for the treatment of gastrointestinal stromal tumours: a critique of the submission from Pfizer.

The submission's evidence for the clinical effectiveness and cost-effectiveness of sunitinib for the treatment of gastrointestinal stromal tumours (GISTs) is based on a randomised controlled trial (RCT) comparing sunitinib with placebo for people with unresectable and/or metastatic GIST after failure of imatinib and with Eastern Cooperative Oncology Group (ECOG) progression status 0-1, and an ongoing, non-comparative cohort study of a similar population but with ECOG progression status 0-4. The searches are appropriate and include all relevant studies and the RCT is of high quality. In the RCT sunitinib arm overall survival was 73 median weeks [95% confidence interval (CI) 61 to 83] versus 75 median weeks (95% CI 68 to 84) for the cohort study. However, time to tumour progression in the cohort study was different from that in the RCT sunitinib arm [41 (95% CI 36 to 47) versus 29 (95% CI 22 to 41) median weeks respectively]. Median progression-free survival with sunitinib was 24.6 weeks (95% CI 12.1 to 28.4) versus 6.4 weeks (95% CI 4.4 to 10.0) on placebo (hazard ratio 0.333, 95% CI 0.238 to 0.467, p < 0.001). The manufacturer used a three-state Markov model to model the cost-effectiveness of sunitinib compared with best supportive care for GIST patients; the modelling approach and sources and justification of estimates are reasonable. The base-case incremental cost-effectiveness ratio (ICER) was 27,365 pounds per quality-adjusted life-year (QALY) with the first cycle of sunitinib treatment not costed; when we included the cost of the first treatment cycle we estimated a base-case ICER of 32,636 pounds per QALY. Pfizer's sensitivity analysis produced a range of ICERs from 15,536 pounds per QALY to 59,002 pounds per QALY. Weaknesses of the manufacturer's submission include that the evidence is based on only one published RCT; that 84% of the RCT control population crossed over to the intervention group, giving rise to the use of unusual rank preserved structural failure time (RPSFT) analysis to correct for possible bias; and that a number of errors and omissions were made in the probabilistic sensitivity analysis, meaning that it is not possible to come to firm conclusions about the cost-effectiveness of sunitinib for GIST in this patient population. In conclusion, during the blinded phase of the RCT, overall survival was significantly longer in the sunitinib arm than in the placebo arm (hazard ratio 0.491, 95% CI 0.290 to 0.831, p <0.007). However, intention-to-treat analysis of the entire study showed no statistically significant difference in overall survival for those who received sunitinib (73 weeks) versus those who received placebo (65 weeks) (hazard ratio 0.876, 95% CI 0.679 to 1.129, p = 0.306).

The effectiveness and cost-effectiveness of methods of storing donated kidneys from deceased donors: a systematic review and economic model.

OBJECTIVE: To review the evidence for the effectiveness and cost-effectiveness of storing kidneys from deceased donors prior to transplantation, using cold static storage solutions or pulsatile hypothermic machine perfusion. DATA SOURCES: Electronic databases were searched in January 2008 and updated in May 2008 for systematic reviews and/or meta-analyses, randomised controlled trials (RCTs), other study designs and ongoing research. Sources included: Cochrane Library, MEDLINE, EMBASE, CINAHL, ISI Web of Knowledge, DARE, NRR, ReFeR, Current Controlled Trials, and (NHS) HTA. Bibliographies of articles were searched for further relevant studies, and the Food and Drugs Administration (FDA) and European Regulatory Agency Medical Device Safety Service websites were searched. Only English language papers were sought. REVIEW METHODS: The perfusion machines identified were the LifePort Kidney Transporter (Organ Recovery Systems) and the RM3 Renal Preservation System (Waters Medical Systems). The cold storage solutions reviewed were: University of Wisconsin, ViaSpan; Marshall's hypertonic citrate, Soltran; and Genzyme, Celsior. Each intervention was compared with the others as data permitted. The population was recipients of kidneys from deceased donors. The main outcomes were measures of graft survival, patient survival, delayed graft function (DGF), primary non-function (PNF), discard rates of non-viable kidneys, health-related quality of life and cost-effectiveness. Where data permitted the results of studies were pooled using meta-analysis. A Markov (state transition) model was developed to simulate the main post-transplantation outcomes of kidney graft recipients. RESULTS: Eleven studies were included: three full journal published RCTs, two ongoing RCTs [European Machine Preservation Trial (MPT) and UK Pulsatile Perfusion in Asystolic donor Renal Transplantation (PPART) study], one cohort study, three full journal published retrospective record reviews and two retrospective record reviews published as posters or abstracts only. For LifePort versus ViaSpan, no significant differences were found for DGF, PNF, acute rejection, duration of DGF, creatinine clearance or toxicity, patient survival or graft survival at 6 months, but graft survival was better at 12 months post transplant with machine perfusion (LifePort = 98%, ViaSpan = 94%, p < 0.03). For LifePort versus RM3, all outcomes favoured RM3, although the results may be unreliable. For ViaSpan versus Soltran, there were no significant differences in graft survival for cold ischaemic times up to 36 hours. For ViaSpan versus Celsior, no significant differences were found on any outcome measure. In terms of cost-effectiveness, data from the MPT suggested that machine preservation was cheaper and generated more quality-adjusted life-years (QALYs), while the PPART study data suggested that cold storage was preferable on both counts. The less reliable deterministic outputs of the cohort study suggested that LifePort would be cheaper and would generate more QALYs than Soltran. Sensitivity analyses found that changes to the differential kidney storage costs between comparators have a very low impact on overall net benefit estimates; where differences in effectiveness exist, dialysis costs are important in determining overall net benefit; DGF levels become important only when differences in graft survival are apparent between patients experiencing immediate graft function (IGF) versus DGF; relative impact of differential changes to graft survival for patients experiencing IGF as opposed to DGF depends on the relative proportion of patients experiencing each of these two outcomes. CONCLUSIONS: The conclusions drawn for the comparison of machine perfusion with cold storage depend on which trial data are used in the model. Owing to the lack of good research evidence that either ViaSpan or Soltran is better than the other, the cheaper, Soltran, may be preferable. In the absence of a cost-utility analysis, the results of our meta-analysis of the RCTs comparing ViaSpan with Celsior indicate that these cold storage solutions are equivalent. Further RCTs of comparators of interest to allow for appropriate analysis of subgroups and to determine whether either of the two machines under consideration produces better outcomes may be useful. In addition, research is required to: establish the strength and reliability of the presumed causal association between DGF and graft, and patient survival; investigate the utility impacts of renal replacement therapy; determine what the additional cost, survival and QALY impacts are of decreased or increased non-viable kidneys when discarded pre transplantation; and identify a reliable measure for predicting kidney viability from machine perfusion.

Sunitinib and bevacizumab for first-line treatment of metastatic renal cell carcinoma: a systematic review and indirect comparison of clinical effectiveness.

BACKGROUND: Two new agents have recently been licensed for use in the treatment of metastatic renal cell carcinoma (RCC) in Europe. This paper aims to systematically review the evidence from all available randomised clinical trials of sunitinib and bevacizumab (in combination with interferon-alpha (IFN-alpha)) in the treatment of advanced metastatic RCC. METHODS: Systematic literature searches were performed in six electronic databases. Bibliographies of included studies were searched for further relevant studies. Individual conference proceedings were searched using their online interfaces. Studies were selected according to the predefined criteria. All randomised clinical trials of sunitinib or bevacizumab in combination with IFN for treating advanced metastatic RCC in accordance with the European licensed indication were included. Study selection, data extraction, validation and quality assessment were performed by two reviewers with disagreements being settled by discussion. The effects of sunitinib and bevacizumab (in combination with IFN-alpha) on progression-free survival were compared indirectly using Bayesian Markov Chain Monte-Carlo (MCMC) sampling in Win BUGS, with IFN as a common comparator. RESULTS: Three studies were included. Median progression-free survival was significantly prolonged with both interventions (from approximately 5 months to between 8 and 11 months) compared with IFN. Overall survival was also prolonged, compared with IFN, although the published data are not fully mature. Indirect comparison suggests that sunitinib is superior to bevacizumab plus IFN in terms of progression-free survival (hazard ratios 0.796; 95% CI 0.63-1.0; P=0.0272). CONCLUSION: There is evidence to suggest that treatment with sunitinib and treatment with bevacizumab plus IFN has clinically relevant and statistically significant advantages over treatment with IFN alone in patients with metastatic RCC.