A systematic review of the clinical effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer.

Our aim was to evaluate the clinical effectiveness of chemotherapy treatments currently licensed in Europe and recommended by the National Institute for Health and Care Excellence (NICE) for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). A systematic search of MEDLINE, EMBASE and the Cochrane Library for randomised controlled trials (RCTs) published from 2001 to 2010 was carried out. Relative treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using standard meta-analysis and mixed treatment comparison methodology. A total of 23 RCTs were included: 18 trials compared platinum-based chemotherapy, two compared pemetrexed and three compared gefitinib. There are no statistically significant differences in OS between any of the four third-generation chemotherapy regimens. There is statistically significant evidence that pemetrexed+platinum increases OS compared with gemcitabine+platinum. There are no statistically significant differences in OS between gefitinib and docetaxel+platinum or between gefitinib and paclitaxel+platinum. There is a statistically significant improvement in PFS with gefitinib compared with docetaxel+platinum and gefitinib compared with paclitaxel+platinum. Due to reduced generic pricing, third-generation chemotherapy regimens (except vinorelbine) are still competitive options for most patients. This research provides a comprehensive evidence base, which clinicians and decision-makers can use when deciding on the optimal first-line chemotherapy treatment regimen for patients diagnosed with locally advanced or metastatic NSCLC.

Improving valuation sampling of EQ-5D health states.

BACKGROUND: The original valuation exercise which formed the basis of the UK EQ-5D time trade-off social tariff of health states, employed a sampling scheme involving 43 health states. Neither that study, nor other published international valuations studies have used explicit quantifiable criteria to justify the choice of sampled states. New criteria are proposed and methods described to aid researchers in designing improved sampling schemes for future EQ-5D sampling exercises. METHOD: Four such criteria are described, and applied to assess the merits of four sampling schemes previously reported, using three large observational databases to quantify relative performance. An alternative sampling design conforming to these criteria is described, which aims to generate improved performance. RESULTS: Previous published approaches are shown to perform poorly against the measured criteria. The alternative sampling design is demonstrated to provide superior performance on all measures. CONCLUSION: Future valuation exercises using sampled health states based on this approach may be expected to offer benefits in terms of greater precision, avoidance of bias in favour of less severe states, and a higher proportion of research observations valued directly rather than dependent on extrapolation modelling.

Drug-eluting stents versus bare metal stents for angina or acute coronary syndromes.

BACKGROUND: Coronary artery stents are tiny tubular devices used to 'scaffold' vessels open during percutaneous transluminal coronary angioplasty (PTCA). Restenosis (re-narrowing) of vessels treated with stents is a problem; in order to reduce restenosis, stents that elute drugs over time are now available. However these drug-eluting stents are more expensive and there is a need to assess their clinical benefits prior to recommending their use. OBJECTIVES: To examine evidence from randomised controlled trials (RCTs) to assess the impact of drug eluting stents (DES) compared to bare metal stents (BMS) in the reduction of cardiac events. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 4), MEDLINE (1990 - April 2009) and EMBASE (1980 - January 2009) were searched. We carried out handsearching (electronic and manual) up to January 2008. SELECTION CRITERIA: We included RCTs comparing DES with BMS used in conjunction with PTCA techniques in the review. Participants were adults with stable angina or acute coronary syndrome (ACS). We considered published and unpublished sources and included them if they reported outcome data of interest. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data, assessed trial quality assessment and checked decisions within the group. Data extraction included composite event rates (major adverse cardiac event, target vessel failure); death; acute myocardial infarction (AMI); target lesion revascularisation (TLR); target vessel revascularisation (TVR) and thrombosis. Data synthesis included meta-analysis of composite event rate, death, AMI and revascularisation rates, presented as odds ratios with 95% confidence intervals (CI) using a fixed-effect model. We assessed heterogeneity between trials. MAIN RESULTS: We included more than 14,500 patients in 47 RCTs. There were no statistically significant differences in death, AMI or thrombosis between DES and BMS. For composite events, TLR and TVR reductions were evident with use of sirolimus, paclitaxel, everolimus, dexamethasone, zotarolimus and (to a limited extent) tacrolimus-eluting stents. These effects are demonstrated in the longer term follow up. Subgroup analyses (e.g. diabetics) largely mirrored these findings. AUTHORS' CONCLUSIONS: Drug-eluting stents releasing sirolimus, paclitaxel, dexamethasone and zotarolimus reduce composite cardiac events. However, this reduction is due largely to reductions in repeat revascularisation rates as there is no evidence of a significant effect on rates of death, MI or thrombosis. The increased cost of drug-eluting stents and lack of evidence of their cost-effectiveness means that various health funding agencies are having to limit or regulate their use in relation to price premium.

Lenvatinib and sorafenib for differentiated thyroid cancer after radioactive iodine: a systematic review and economic evaluation.

BACKGROUND: Thyroid cancer is a rare cancer, accounting for only 1% of all malignancies in England and Wales. Differentiated thyroid cancer (DTC) accounts for ≈94% of all thyroid cancers. Patients with DTC often require treatment with radioactive iodine. Treatment for DTC that is refractory to radioactive iodine [radioactive iodine-refractory DTC (RR-DTC)] is often limited to best supportive care (BSC). OBJECTIVES: We aimed to assess the clinical effectiveness and cost-effectiveness of lenvatinib (Lenvima®; Eisai Ltd, Hertfordshire, UK) and sorafenib (Nexar®; Bayer HealthCare, Leverkusen, Germany) for the treatment of patients with RR-DTC. DATA SOURCES: EMBASE, MEDLINE, PubMed, The Cochrane Library and EconLit were searched (date range 1999 to 10 January 2017; searched on 10 January 2017). The bibliographies of retrieved citations were also examined. REVIEW METHODS: We searched for randomised controlled trials (RCTs), systematic reviews, prospective observational studies and economic evaluations of lenvatinib or sorafenib. In the absence of relevant economic evaluations, we constructed a de novo economic model to compare the cost-effectiveness of lenvatinib and sorafenib with that of BSC. RESULTS: Two RCTs were identified: SELECT (Study of [E7080] LEnvatinib in 131I-refractory differentiated Cancer of the Thyroid) and DECISION (StuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine-refractory thyrOid caNcer). Lenvatinib and sorafenib were both reported to improve median progression-free survival (PFS) compared with placebo: 18.3 months (lenvatinib) vs. 3.6 months (placebo) and 10.8 months (sorafenib) vs. 5.8 months (placebo). Patient crossover was high (≥ 75%) in both trials, confounding estimates of overall survival (OS). Using OS data adjusted for crossover, trial authors reported a statistically significant improvement in OS for patients treated with lenvatinib compared with those given placebo (SELECT) but not for patients treated with sorafenib compared with those given placebo (DECISION). Both lenvatinib and sorafenib increased the incidence of adverse events (AEs), and dose reductions were required (for > 60% of patients). The results from nine prospective observational studies and 13 systematic reviews of lenvatinib or sorafenib were broadly comparable to those from the RCTs. Health-related quality-of-life (HRQoL) data were collected only in DECISION. We considered the feasibility of comparing lenvatinib with sorafenib via an indirect comparison but concluded that this would not be appropriate because of differences in trial and participant characteristics, risk profiles of the participants in the placebo arms and because the proportional hazard assumption was violated for five of the six survival outcomes available from the trials. In the base-case economic analysis, using list prices only, the cost-effectiveness comparison of lenvatinib versus BSC yields an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £65,872, and the comparison of sorafenib versus BSC yields an ICER of £85,644 per QALY gained. The deterministic sensitivity analyses show that none of the variations lowered the base-case ICERs to < £50,000 per QALY gained. LIMITATIONS: We consider that it is not possible to compare the clinical effectiveness or cost-effectiveness of lenvatinib and sorafenib. CONCLUSIONS: Compared with placebo/BSC, treatment with lenvatinib or sorafenib results in an improvement in PFS, objective tumour response rate and possibly OS, but dose modifications were required to treat AEs. Both treatments exhibit estimated ICERs of > £50,000 per QALY gained. Further research should include examination of the effects of lenvatinib, sorafenib and BSC (including HRQoL) for both symptomatic and asymptomatic patients, and the positioning of treatments in the treatment pathway. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017055516. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

WHAT WAS THE PROBLEM?: Differentiated thyroid cancer is a common type of thyroid cancer. For many patients, radioactive iodine is an effective treatment; however, for some patients, the treatment stops working or becomes unsafe. Two new drugs, lenvatinib (Lenvima®; Eisai Ltd, Hertfordshire, UK) and sorafenib (Nexar®; Bayer HealthCare, Leverkusen, Germany), may be new treatment options. WHAT DID WE DO?: We reviewed the clinical evidence of lenvatinib and sorafenib. We also estimated the costs and benefits of treatment. WHAT DID WE FIND?: Compared with no treatment, treatment with lenvatinib or sorafenib may increase the time that people live with thyroid cancer before their disease gets worse; however, both drugs are expensive and may have unpleasant side effects. WHAT DOES THIS MEAN?: At their published (undiscounted) prices, lenvatinib or sorafenib may not be considered to provide good value for money to the NHS.

Eribulin for Treating Locally Advanced or Metastatic Breast Cancer After One Chemotherapy Regimen: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Eribulin is a recommended treatment option for locally advanced or metastatic breast cancer (LABC/MBC) in adults whose disease has progressed after at least two chemotherapy regimens. The National Institute for Health and Care Excellence (NICE) invited the manufacturer of eribulin (Halaven®; Eisai Ltd) to submit evidence for the clinical and cost effectiveness of eribulin for treating LABC/MBC after one chemotherapy regimen in accordance with the institute's Single Technology Appraisal (STA) process. This article presents a summary of the company's evidence, Evidence Review Group (ERG) review and resulting NICE guidance (TA515), issued 28 March 2018. Clinical evidence for eribulin versus capecitabine in LABC/MBC was derived from a subgroup of 392 patients with human epidermal growth factor receptor (HER2)-negative disease which had progressed after only one prior chemotherapy regimen for LABC/MBC in the phase III, randomised, controlled Study 301 (n = 1102). Overall survival (OS) but not progression-free survival (PFS) was improved for patients treated with eribulin versus capecitabine in this subgroup. Using the discounted patient access scheme price for eribulin, the company developed a de novo economic model. In the base case, the incremental cost-effectiveness ratio (ICER) for eribulin versus capecitabine was £36,244 per quality-adjusted life year (QALY) gained. However, the ERG identified several problematic issues relating to modelling OS and PFS, drug costing and utility values, and made ten revisions to the company model. The overall impact of all ten revisions was to increase the ICER per QALY gained by £46,499. The Appraisal Committee (AC) accepted all changes made by the ERG except for the change to utility values; the AC considered that the value should be mid-way between the company's and the ERG's preferred values. A modified model was submitted by the company that included this utility value, but maintained some elements of the base case that the AC had been critical of (differential PFS between treatment arms and application of treatment cap). The new model also included a 'blended' comparator (capecitabine and vinorelbine). The AC noted there was no evidence to support a 'blended' comparator, differential PFS between treatment arms or a treatment cap. The AC therefore concluded that the most plausible ICER was likely to be £69,843 per QALY gained (derived from an ERG sensitivity analysis using the AC's preferred utility value, no differential PFS and no treatment cap). Therefore, eribulin was not recommended for treating LABC/MBC in adults who have had only one chemotherapy regimen.

Exploring the Effects of Early Censoring and Analysis of Clinical Trial Survival Data on Effectiveness and Cost-effectiveness Estimation through a Case Study in Advanced Breast Cancer.

Interim analyses of clinical trial data are frequently used to provide evidence to obtain marketing authorization for new drugs. However, results from such analyses may not reflect true estimates of relative effectiveness when trial follow-up is complete. Survival results, available at 2 time points from a breast cancer clinical trial, were compared to test the hypothesis that using immature data and a widely used right-censoring rule leads to biased survival estimates. Kaplan-Meier progression-free and overall survival data from 2 published CLEOPATRA trial reports (2012 and 2014) were digitized. Overlaying these results highlighted divergent trends. Parametric functions were fitted to both data sets but did not indicate consistent patterns that could be used as a basis for long-term extrapolation. Heavy censoring of patients in the early data cut coincides with sudden changes in hazard trends and survival patterns, supporting the hypothesis of censoring bias. This challenges the validity of estimates of clinical benefit (progression-free survival and overall survival) based on extrapolation of results from interim analyses of trial data, using a commonly employed censoring rule.

Pegylated Liposomal Irinotecan Hydrochloride Trihydrate for Treating Pancreatic Cancer After Gemcitabine: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Shire Pharmaceuticals) of pegylated liposomal irinotecan hydrochloride trihydrate (liposomal irinotecan) to submit clinical and cost-effectiveness evidence for its use in combination with 5-fluorouracil (5-FU) and folic acid/leucovorin (LV) for treating patients with pancreatic cancer following prior treatment with gemcitabine as part of the institute's Single Technology Appraisal process. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article presents a summary of the company's evidence, the ERG review and the resulting NICE guidance (TA440), issued on 26 April 2017. Clinical evidence for liposomal irinotecan + 5-FU/LV versus 5-FU/LV was derived from 236 patients with metastatic pancreatic cancer in the multinational, open-label, randomised controlled NAPOLI-1 trial. Results from analyses of progression-free survival and overall survival showed statistically significant improvements for patients treated with liposomal irinotecan + 5-FU/LV compared with those treated with 5-FU/LV. However, 5-FU/LV alone is rarely used in National Health Service clinical practice for patients with metastatic pancreatic cancer previously treated with gemcitabine. The company, ERG and Appraisal Committee (AC) all agreed that oxaliplatin + 5-FU/LV is the most commonly used treatment. Oxaliplatin + 5-FU/LV was compared with 5-FU/LV in two trials identified by the company. However, the company and the ERG both considered attempts to compare the efficacy of liposomal irinotecan + 5-FU/LV with oxaliplatin + 5-FU/LV to be methodologically flawed; not only was there heterogeneity between trials and their populations but also the proportional hazards assumption required to conduct a robust indirect treatment comparison (ITC) was violated. Nonetheless, data derived from an ITC were used to inform the company's economic model. Using the discounted patient access scheme price for liposomal irinotecan + 5-FU/LV, the company reported an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £54,412 for the comparison with oxaliplatin + 5-FU/LV. The ERG considered that the company's base-case cost-effectiveness results for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV were underestimates and should be interpreted with extreme caution. Following implementation of a number of model amendments, the ERG's modified exploratory ICER for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV was £106,898 per QALY gained. The AC accepted the majority of the ERG's amendments to the model, and also highlighted that the total QALYs for oxaliplatin + 5-FU/LV were lower than for 5-FU/LV in the company's model, which the AC considered to be clinically implausible. The AC therefore considered results from exploratory analyses, undertaken by the ERG, which included altering the QALY difference between liposomal irinotecan + 5-FU/LV and oxaliplatin + 5-FU/LV by ± 10%. These analyses resulted in ICERs for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV of between £201,019 per QALY gained to liposomal irinotecan + 5-FU/LV being dominated by oxaliplatin + 5-FU/LV. Therefore, despite uncertainty around the clinical-effectiveness evidence and cost-effectiveness results, the AC was confident that the ICER was in excess of £50,000 per QALY gained. The final guidance issued by NICE is that liposomal irinotecan + 5-FU/LV is not recommended within its marketing authorisation for treating metastatic adenocarcinoma of the pancreas in adults whose disease has progressed after gemcitabine-based therapy.

Paclitaxel as Albumin-Bound Nanoparticles with Gemcitabine for Untreated Metastatic Pancreatic Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited Celgene Ltd to submit clinical and cost-effectiveness evidence for paclitaxel as albumin-bound nanoparticles (Nab-Pac) in combination with gemcitabine (Nab-Pac + Gem) for patients with untreated metastatic pancreatic cancer. The STA was a review of NICE's 2015 guidance (TA360) in which Nab-Pac + Gem was not recommended for patients with untreated metastatic pancreatic cancer. The review was prompted by a proposed Patient Access Scheme (PAS) discount on the price of Nab-Pac and new evidence that might lead to a change in the guidance. The Liverpool Reviews and Implementation Group at the University of Liverpool was the Evidence Review Group (ERG). This article summarises the ERG's review of the company's evidence submission for Nab-Pac + Gem, and the Appraisal Committee (AC) decision. The final scope issued by NICE listed three comparators: gemcitabine monotherapy (Gem), gemcitabine in combination with capecitabine (Gem + Cap), and a combination of oxaliplatin, irinotecan, leucovorin and fluorouracil (FOLFIRINOX). Clinical evidence for the comparison of Nab-Pac + Gem versus Gem was from the phase III CA046 randomized controlled trial. Analysis of progression-free survival (PFS) and overall survival (OS) showed statistically significant improvement for patients treated with Nab-Pac + Gem versus Gem. Clinical evidence for the comparison of Nab-Pac + Gem versus FOLFIRINOX and versus Gem + Cap was derived from a network meta-analysis (NMA). Results of the NMA did not indicate a statistically significant difference in OS or PFS for the comparison of Nab-Pac + Gem versus either Gem + Cap or FOLFIRINOX. The ERG's main concerns with the clinical effectiveness evidence were difficulties in identifying the patient population for whom treatment with Nab-Pac + Gem is most appropriate, and violation of the proportional hazards (PH) assumption in the CA046 trial. The ERG highlighted methodological issues in the cost-effectiveness analysis pertaining to the modelling of survival outcomes, estimation of drug costs and double counting of adverse-event disutilities. The AC accepted all the ERG's amendments to the company's cost-effectiveness model; however, these did not make important differences to the incremental cost-effectiveness ratios (ICERs). The company's base-case ICER was £46,932 per quality-adjusted life-year (QALY) gained for the comparison of Nab-Pac + Gem versus Gem. Treatment with Nab-Pac + Gem was dominated both by treatment with Gem + Cap and with FOLFIRINOX in the company's base case. The AC concluded that the most plausible ICER for treatment with Nab-Pac + Gem versus Gem was in the range of £41,000-£46,000 per QALY gained. The AC concluded that Nab-Pac + Gem was not cost effective compared with Gem + Cap or FOLFIRINOX, and accepted that treatment with Nab-Pac + Gem met the end-of-life criteria versus Gem but did not consider Nab-Pac + Gem to meet the end-of-life criteria compared with Gem + Cap or FOLFIRINOX. The AC also concluded that although patients who would receive Nab-Pac + Gem rather than FOLFIRINOX or Gem + Cap were difficult to distinguish, they were identifiable in clinical practice. The AC recommended treatment with Nab-Pac + Gem for patients with untreated metastatic pancreatic cancer for whom other combination chemotherapies were unsuitable and who would otherwise receive Gem.

Talimogene Laherparepvec for Treating Metastatic Melanoma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Amgen) of talimogene laherparepvec (T-VEC) to submit clinical and cost-effectiveness evidence for previously untreated advanced (unresectable or metastatic) melanoma as part of the Institute's Single Technology Appraisal process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article presents a summary of the company's submission of T-VEC, the ERG review and the resulting NICE guidance (TA410), issued in September 2016. T-VEC is an oncolytic virus therapy granted a marketing authorisation by the European Commission for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (stage IIIB, IIIC and IVM1a) with no bone, brain, lung or other visceral disease. Clinical evidence for T-VEC versus granulocyte-macrophage colony-stimulating factor (GM-CSF) was derived from the multinational, open-label randomised controlled OPTiM trial [Oncovex (GM-CSF) Pivotal Trial in Melanoma]. In accordance with T-VEC's marketing authorisation, the company's submission focused primarily on 249 patients with stage IIIB to stage IV/M1a disease who constituted 57% of the overall trial population (T-VEC, n = 163 and GM-CSF, n = 86). Results from analyses of durable response rate, objective response rate, time to treatment failure and overall survival all showed marked and statistically significant improvements for patients treated with T-VEC compared with those treated with GM-CSF. However, GM-CSF is not used to treat melanoma in clinical practice. It was not possible to compare treatment with T-VEC with an appropriate comparator using conventionally accepted methods due to the absence of comparative head-to-head data or trials with sufficient common comparators. Therefore, the company compared T-VEC with ipilimumab using what it described as modified Korn and two-step Korn methods. Results from these analyses suggested that treatment with T-VEC was at least as effective as treatment with ipilimumab. Using the discounted patient access scheme (PAS) price for T-VEC and list price for ipilimumab, the company reported incremental cost-effectiveness ratios (ICERs) per quality-adjusted life-year (QALY) gained. For the comparison of treatment with T-VEC versus ipilimumab, the ICER per QALY gained was -£16,367 using the modified Korn method and -£60,271 using the two-step Korn method. The NICE Appraisal Committee (AC) agreed with the ERG that the company's methods for estimating clinical effectiveness of T-VEC versus ipilimumab were flawed and therefore produced unreliable results for modelling progression in stage IIIB to stage IVM1a melanoma. The AC concluded that the clinical and cost effectiveness of treatment with T-VEC compared with ipilimumab is unknown in patients with stage IIIB to stage IV/M1a disease. However, the AC considered that T-VEC may be a reasonable option for treating patients who are unsuitable for treatment with systemically administered immunotherapies (such as ipilimumab). T-VEC was therefore recommended by NICE as a treatment option for adults with unresectable, regionally or distantly metastatic (stage IIIB to stage IVM1a) melanoma that has not spread to bone, brain, lung or other internal organs, only if treatment with systemically administered immunotherapies is not suitable and the company provides T-VEC at the agreed discounted PAS price.

Cost-effectiveness of rosiglitazone combination therapy for the treatment of type 2 diabetes mellitus in the UK.

INTRODUCTION: Recent clinical trial results have demonstrated that, in patients with type 2 diabetes, second-line treatment of rosiglitazone in combination with metformin can lead to significant improvements in the control of fasting plasma glucose/ glycosylated haemoglobin A1c (HbA1c) after the failure of metformin monotherapy. Our objective was to assess the cost-effectiveness of the use of rosiglitazone in combination with metformin in overweight and obese patients with type 2 diabetes in the UK, failing to maintain glycaemic control with metformin monotherapy compared with conventional care using metformin in combination with sulfonylurea. METHODS: The Diabetes Decision Analysis of Cost--type 2 (DiDACT) model, an established long-term economic model of type 2 diabetes, which projects the relationship between treatment and HbA1c over extended periods, was used to determine the health outcomes and economic impact for matched age and sex cohorts of 1000 patients with type 2 diabetes. The perspective was that of the UK National Health Service and all costs were in UK pounds sterling. RESULTS: Treatment with rosiglitazone in combination with metformin provides better glycaemic control over the remaining lifetime of patients than metformin and sulfonylurea combination therapy. Patients treated with rosiglitazone combination therapy were predicted to have a longer life expectancy, gaining 123 and 140 additional life years per 1000 patients in the obese and overweight cohorts, respectively. Improvements in morbidity and a delay in the start of insulin therapy resulted in a projected improvement in quality of life. These effects combine with projected improved survival to yield 131 and 209 additional quality-adjusted life-years (QALYs) per 1000 patients in the obese and overweight cohorts, respectively. Discounted incremental cost-effectiveness ratios were estimated at pounds 16,700 per QALY gained for the obese cohort and pounds 11,600 per QALY gained for the overweight cohort. CONCLUSION: The model predicts that rosiglitazone in combination with metformin is a cost-effective treatment in the UK for both obese and overweight patients failing on metformin monotherapy, compared with conventional therapy using metformin in combination with sulfonylurea.

Cost-effectiveness of rosiglitazone oral combination for the treatment of type 2 diabetes in Germany.

AIMS/HYPOTHESIS: To assess the cost-effectiveness of rosiglitazone in combination with other oral agents for the treatment of overweight and obese patients with type 2 diabetes in Germany. METHODS: The Diabetes Decision Analysis of Cost--type 2 model was adapted for clinical practice and healthcare financing rules in Germany. The model was calibrated using Cost of Diabetes in Europe Type 2 study data and national statistics. The perspective is that of the sickness funds, and includes all hospital inpatient, ambulatory, rehabilitation, and diabetes therapy, other medications, and sickness leave. The model simulates lifetime treatment histories and associated health outcomes and costs for age and sex-matched cohorts of 1000 overweight and obese patients. The measures of effectiveness used in the analysis were life-years and quality adjusted life-years (QALYs). RESULTS: The combination therapy of rosiglitazone with metformin or sulfonylurea produces better glycaemic control than conventional care of metformin with sulfonylurea and insulin in most patients, extends the viability of oral therapy before requiring insulin, and typically leads to lifetime cost increases across all treatment types. The improvements in glycaemic control lead to survival gains and reductions in morbidity, because of the reduced risk of developing or progressing to later stages of complications. Improvements in morbidity and mortality generate additional QALYs. Costs and health outcomes combine to yield favourable incremental cost-effectiveness ratios, which fall below international 'willingness-to-pay' thresholds in the medium term. CONCLUSION: The model predicts that rosiglitazone in combination with other oral agents is a cost-effective intervention for the treatment of normal weight, overweight and obese patients with type 2 diabetes when compared with conventional care in Germany.

A model of long-term metabolic progression of type 2 diabetes mellitus for evaluating treatment strategies.

AIM: To develop a novel metabolic computer model of the natural lifetime progression of type 2 diabetes that generates dynamic risk factor trajectories consistent with prespecified lifetime therapeutic strategies, in order to enhance the long-term economic and outcome modelling of type 2 diabetes and its complications. METHODS: The main model drivers of progressive disease were changes in insulin sensitivity and islet beta-cell function derived from an analysis of follow-up results from the Belfast Diet Study. These were related to clinical measures through an adaptation of the homeostasis model assessment. Established causal relationships estimating body mass index, lipids and blood pressure from measures of glycaemia and plasma insulin were calibrated using Third National Health and Nutrition Examination Survey (USA) data, standardizing for age, sex, ethnicity and smoking. The effects of individual interventions were calibrated using published trial evidence, in line with the current understanding of the main modes of action of each agent. RESULTS: A comparison of the effects of common therapies using the model showed both similarities and differences. Large improvements in glycaemic control from lifestyle modifications, further enhanced by oral glucose-lowering drugs or insulin, were reproduced. Projections comparing lifetime therapeutic strategies suggest that simple guidelines may not always be valid. CONCLUSION: This novel mathematical model using evidence from the long-term natural history of type 2 diabetes is able to project the expected effects of various antihyperglycaemic therapies. Coupled with an economic model, this metabolic model may provide a mechanism for healthcare professionals and policymakers to evaluate different long-term strategies for the management of type 2 diabetes.

Lifetime health consequences and cost-effectiveness of rosiglitazone in combination with metformin for the treatment of type 2 diabetes in Spain.

OBJECTIVE: To assess the lifetime diabetes health consequences and cost-effectiveness in Spain of rosiglitazone in combination with metformin for the treatment of type 2 diabetes in overweight and obese patients failing to maintain glycaemic control with metformin monotherapy compared with conventional care of metformin in combination with either sulfonylureas or bedtime insulin. RESEARCH DESIGN AND METHODS: The Diabetes Decision Analysis of Cost--Type 2 was adapted for clinical practice and healthcare funding in Spain, and was calibrated with Spanish epidemiological, healthcare resource use and cost data, taking the perspective of the Spanish National Health System. The model simulates lifetime treatment histories, complications and consequences of type 2 diabetes, and associated health outcomes and costs for age and sex-matched cohorts of 1000 overweight and obese patients. The primary health outcome measures compared are glycaemic control, time to insulin, incidence and prevalence of coronary heart disease, stroke, clinical nephropathy, ulceration and amputation, and severe visual loss, and incremental life-years and quality-adjusted life-years (QALYs). RESULTS: Rosiglitazone in combination with metformin produces better glycaemic control than conventional care of metformin in combination with either sulfonylureas or bedtime insulin in most patients, and extends the viability of combination therapy by between 6 and 13 years before requiring insulin. Rosiglitazone patients have a longer life expectancy, gaining between 106 and 175 additional life-years per 1000 patients, experience fewer episodes of coronary disease and clinical nephropathy, and live for longer periods free of complications. The improvements in morbidity and mortality are projected to yield between 134 and 238 additional QALY per 1000 patients over their lifetime. Discounted incremental cost-effectiveness ratios range from euro 9406 to euro 23,514 per QALY gained. CONCLUSION: The model predicts that rosiglitazone in combination with metformin is a cost-effective intervention for the treatment of both overweight and obese patients with type 2 diabetes when compared with conventional care in Spain.

Pertuzumab in combination with trastuzumab and docetaxel for the treatment of HER2-positive metastatic or locally recurrent unresectable breast cancer.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of pertuzumab (Roche) to submit evidence for the clinical and cost effectiveness of pertuzumab + trastuzumab + docetaxel for the treatment of human epidermal growth factor receptor 2-positive (HER2+) metastatic or locally recurrent unresectable breast cancer in accordance with the Institute's Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article summarises the ERG's review of the evidence submitted by the manufacturer and provides a summary of the Appraisal Committee's (AC) initial decision. At the time of writing, final guidance had not been published by NICE. The clinical evidence was mainly derived from an ongoing phase III randomised double-blind placebo-controlled international multicentre clinical trial (CLEOPATRA), designed to evaluate efficacy and safety in 808 patients, which compared pertuzumab + trastuzumab + docetaxel (pertuzumab arm) with placebo + trastuzumab + docetaxel (control arm). Both progression-free survival (PFS) and overall survival (OS) were analysed at two data cut-off points-May 2011 (median follow-up of 18 months) and May 2012 (median follow-up of 30 months). At both time points, PFS was significantly longer in the pertuzumab arm (18.5 months compared with 12.4 months in the control arm at the first data cut-off point and 18.7 versus 12.4 months at the second data cut-off point). Assessment of OS benefit suggested an improvement for patients in the pertuzumab arm with a strong trend towards an OS benefit at the second data cut-off point; however, due to the immaturity of the OS data, the magnitude of the OS benefit was uncertain. Importantly, cardiotoxicity was not increased in patients treated with a combination of pertuzumab + trastuzumab + docetaxel. The ERG's main concern with the clinical effectiveness data was the lack of mature OS data. An additional concern of the AC was that the majority of patients in the randomised controlled trial were trastuzumab naïve, which does not reflect current clinical practice. The incremental cost-effectiveness ratios (ICERs) generated by the manufacturer's model are considered to be commercial in confidence data and therefore cannot be published. Nevertheless, the results of the manufacturer's probabilistic sensitivity analyses suggest that pertuzumab + trastuzumab + docetaxel has a 0 % probability of being cost effective at a willingness-to-pay of £30,000 per quality-adjusted life-year gained when compared with trastuzumab + docetaxel. The ERG believes that more realistic estimates of the ICERs are considerably higher, almost double those presented by the manufacturer. This is because the ERG believes that due to the manner in which the economic model is constructed, the additional survival benefit following disease progression that is generated for patients treated with pemetrexed + trastuzumab + docetaxel is unrealistic. At the time of writing, NICE had not made a final decision regarding this technology but had instead referred the issue of the assessment of technologies that are not effective at a zero price to their Decision Support Unit for advice.

Dabrafenib for Treating Unresectable, Advanced or Metastatic BRAF V600 Mutation-Positive Melanoma: An Evidence Review Group Perspective.

The National Institute for Health and Care Excellence (NICE) invited GlaxoSmithKline, the manufacturer of dabrafenib, to submit evidence for the clinical and cost effectiveness of dabrafenib for the treatment of unresectable, advanced or metastatic BRAF V600 mutation-positive melanoma in accordance with the Institute's Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article summarizes the ERG's review of the evidence submitted by the company and provides a summary of the Appraisal Committee's (AC) final decision in October 2014. The clinical evidence for dabrafenib was derived from an ongoing phase III, randomized, double-blind, placebo-controlled, international, multicentre clinical trial (BREAK-3) involving 230 patients randomized 2:1 to receive either dabrafenib or dacarbazine. A significant improvement in median progression-free survival (PFS) but not overall survival (OS) was reported in the dabrafenib arm compared with dacarbazine. Vemurafenib is considered a more appropriate comparator than is dacarbazine. The clinical evidence for vemurafenib was derived from a completed phase III, randomized, double-blind, placebo-controlled, international, multicentre clinical trial (BRIM-3) involving 675 patients randomized 1:1 to receive either vemurafenib or dacarbazine. A significant improvement in median PFS and OS was reported in the vemurafenib arm compared with dacarbazine. As there is no direct evidence comparing dabrafenib versus vemurafenib, the company presented an indirect treatment comparison (ITC) that demonstrated no statistical differences between dabrafenib and vemurafenib for PFS or OS. The ERG expressed concerns with the ITC, mainly in relation to the validity of the assumptions underpinning the methodology; the ERG concluded this resulted in findings that are unlikely to be robust or reliable. Dabrafenib and vemurafenib are both available to patients treated by the National Health Service (NHS) in England via a Patient Access Scheme (PAS) in which the costs of the drugs are discounted. Using these discounted costs, the incremental cost-effectiveness ratios (ICERs) generated by the company were £60,980 per quality-adjusted life-year (QALY) for dabrafenib versus dacarbazine and £11,046 per QALY gained for dabrafenib versus vemurafenib. The ERG considered the economic model structure developed by the company to derive the ICERs to be overly complex and based on unsubstantiated assumptions, most importantly in relation to the projection of OS. Applying the latest OS data from BREAK-3 to a less complex model structure increased the estimated ICER for dabrafenib compared with dacarbazine from £60,980 to £112,727 per QALY gained. Since the results from the ITC were considered by the ERG to be neither reliable nor robust, the ERG also considered a cost-effectiveness comparison to be inappropriate due to a lack of meaningful or reliable data. In spite of limitations in the data, the AC took the view that dabrafenib and vemurafenib were "likely" of similar clinical effectiveness. Since the overall costs of these two drugs were similar, the AC recommended the use of dabrafenib in patients with unresectable, advanced or metastatic BRAF V600 mutation-positive melanoma.

Prasugrel (Efient®) with percutaneous coronary intervention for treating acute coronary syndromes (review of TA182): systematic review and economic analysis.

BACKGROUND: Acute coronary syndromes (ACSs) are life-threatening conditions associated with acute myocardial ischaemia. There are three main types of ACS: ST segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI) and unstable angina (UA). One treatment for ACS is percutaneous coronary intervention (PCI) plus adjunctive treatment with antiplatelet drugs. Dual therapy antiplatelet treatment [aspirin plus either prasugrel (Efient(®), Daiichi Sankyo Company Ltd UK/Eli Lilly and Company Ltd), clopidogrel or ticagrelor (Brilique(®), AstraZeneca)] is standard in UK clinical practice. Prasugrel is the focus of this review. OBJECTIVES: The remit is to appraise the clinical effectiveness and cost-effectiveness of prasugrel within its licensed indication for the treatment of ACS with PCI and is a review of National Institute for Health and Care Excellence technology appraisal TA182. DATA SOURCES: Four electronic databases (MEDLINE, EMBASE, The Cochrane Library, PubMed) were searched from database inception to June 2013 for randomised controlled trials (RCTs) and to August 2013 for economic evaluations comparing prasugrel with clopidogrel or ticagrelor in ACS patients undergoing PCI. METHODS: Clinical outcomes included non-fatal and fatal cardiovascular (CV) events, adverse effects of treatment and health-related quality of life (HRQoL). Cost-effectiveness outcomes included incremental cost per life-year gained and incremental cost per quality-adjusted life-year (QALY) gained. An independent economic model assessed four mutually exclusive subgroups: ACS patients treated with PCI for STEMI and with and without diabetes mellitus and ACS patients treated with PCI for UA or NSTEMI and with and without diabetes mellitus. RESULTS: No new RCTs were identified beyond that reported in TA182. TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocardial Infarction 38) compared prasugrel with clopidogrel in ACS patients scheduled for PCI. No relevant economic evaluations were identified. Our analyses focused on a key subgroup of patients: those aged < 75 years who weighed > 60 kg (no previous stroke or transient ischaemic attack). For the primary composite end point (death from CV causes, non-fatal myocardial infarction or non-fatal stroke) statistically significantly fewer events occurred in the prasugrel arm (8.3%) than in the clopidogrel arm (11%). No statistically significant difference in major bleeding events was noted. However, there was a significant difference in favour of clopidogrel when major and minor bleeding events were combined (3.0 vs. 3.9%). No conclusions could be drawn regarding HRQoL. The results of sensitivity analyses confirmed that it is likely that, for all four ACS subgroups, within 5-10 years prasugrel is a cost-effective treatment option compared with clopidogrel at a willingness-to-pay threshold of £20,000 to £30,000 per QALY gained. At the full 40-year time horizon, all estimates are < £10,000 per QALY gained. LIMITATIONS: Lack of data precluded a clinical comparison of prasugrel with ticagrelor; the comparative effectiveness of prasugrel compared with ticagrelor therefore remains unknown. The long-term modelling exercise is vulnerable to major assumptions about the continuation of early health outcome gains. CONCLUSION: A key strength of the review is that it demonstrates the cost-effectiveness of prasugrel compared with clopidogrel using the generic price of clopidogrel. Although the report demonstrates the cost-effectiveness of prasugrel compared with clopidogrel at a threshold of £20,000 to £30,000 per QALY gained, the long-term modelling is vulnerable to major assumptions regarding long-term gains. Lack of data precluded a clinical comparison of prasugrel with ticagrelor; the comparative effectiveness of prasugrel compared with ticagrelor therefore remains unknown. Well-audited data are needed from a long-term UK clinical registry on defined ACS patient groups treated with PCI who receive prasugrel, ticagrelor and clopidogrel. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005047. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Erlotinib and gefitinib for treating non-small cell lung cancer that has progressed following prior chemotherapy (review of NICE technology appraisals 162 and 175): a systematic review and economic evaluation.

BACKGROUND: Lung cancer is the second most diagnosed cancer in the UK. Over 70% of lung cancers are non-small cell lung cancers (NSCLCs). Patients with stage III or IV NSCLC may be offered treatment to improve survival, disease control and quality of life. One-third of these patients receive further treatment following disease progression; these treatments are the focus of this systematic review. OBJECTIVES: To appraise the clinical effectiveness and cost-effectiveness of erlotinib [Tarceva(®), Roche (UK) Ltd] and gefitinib (IRESSA(®), AstraZeneca) compared with each other, docetaxel or best supportive care (BSC) for the treatment of NSCLC after disease progression following prior chemotherapy. The effectiveness of treatment with gefitinib was considered only for patients with epidermal growth factor mutation-positive (EGFR M+) disease. DATA SOURCES: Four electronic databases (EMBASE, MEDLINE, The Cochrane Library, PubMed) were searched for randomised controlled trials (RCTs) and economic evaluations. Manufacturers' evidence submissions to the National Institute for Health and Care Excellence were also considered. REVIEW METHODS: Outcomes for three distinct patient groups based on EGFR mutation status [EGFR M+, epidermal growth factor mutation negative (EGFR M-) and epidermal growth factor mutation status unknown (EGFR unknown)] were considered. Heterogeneity of the data precluded statistical analysis. A de novo economic model was developed to compare treatments (incremental cost per quality-adjusted life-year gained). RESULTS: Twelve trials were included in the review. The use of gefitinib was compared with chemotherapy (n = 6) or BSC (n = 1), and the use of erlotinib was compared with chemotherapy (n = 3) or BSC (n = 1). One trial compared the use of gefitinib with the use of erlotinib. No trials included solely EGFR M+ patients; all data were derived from retrospective subgroup analyses from six RCTs [Kim ST, Uhm JE, Lee J, Sun JM, Sohn I, Kim SW, et al. Randomized phase II study of gefitinib versus erlotinib in patients with advanced non-small cell lung cancer who failed previous chemotherapy. Lung Cancer 2012;75:82-8, V-15-32, Tarceva In Treatment of Advanced NSCLC (TITAN), BR.21, IRESSA Survival Evaluation in Lung cancer (ISEL) and IRESSA NSCLC Trial Evaluating REsponse and Survival versus Taxotere (INTEREST)]. These limited data precluded conclusions regarding the clinical effectiveness of any treatment for EGFR M+ patients. For EGFR M- patients, data were derived from the TArceva Italian Lung Optimization tRial (TAILOR) trial and Docetaxel and Erlotinib Lung Cancer Trial (DELTA). Retrospective data were also derived from subgroup analyses of BR.21, Kim et al., TITAN, INTEREST and ISEL. The only statistically significant reported results were for progression-free survival (PFS) for TAILOR and DELTA, and favoured docetaxel over erlotinib [TAILOR hazard ratio (HR) 1.39, 95% confidence interval (CI) 1.06 to 1.82; DELTA HR 1.44, 95% CI 1.08 to 1.92]. In EGFR unknown patients, nine trials (INTEREST, IRESSA as Second-line Therapy in Advanced NSCLC - KoreA, Li, Second-line Indication of Gefitinib in NSCLC, V-15-32, ISEL, DELTA, TITAN and BR.21) reported overall survival data and only one (BR.21) reported a statistically significant result favouring the use of erlotinib over BSC (HR 0.7, 95% CI 0.58 to 0.85). For PFS, BR.21 favoured the use of erlotinib when compared with BSC (HR 0.61, 95% CI 0.51 to 0.74) and the use of gefitinib was favoured when compared with BSC (HR 0.82, 95% CI 0.73 to 0.92) in ISEL. Limitations in the clinical data precluded assessment of cost-effectiveness of treatments for an EGFR M+ population by the Assessment Group (AG). The AG's economic model suggested that for the EGFR M- population, the use of erlotinib was not cost-effective compared with the use of docetaxel and compared with BSC. For EGFR unknown patients, the use of erlotinib was not cost-effective when compared with BSC. CONCLUSIONS/FUTURE WORK: The lack of clinical data available for distinct patient populations limited the conclusions of the assessment. Future trials should distinguish between patients with EGFR M+ and EGFR M- disease. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Eribulin for the treatment of advanced or metastatic breast cancer: a NICE single technology appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of eribulin (Eisai Ltd) to submit evidence for the clinical and cost effectiveness of eribulin as treatment for patients with locally advanced or metastatic breast cancer (LABC/MBC) pre-treated with at least two chemotherapy regimens. This article summarizes the review of evidence by the Evidence Review Group (ERG) and provides a summary of the NICE Appraisal Committee's (AC's) decision. The clinical evidence was derived from a multi-centred, open-label, randomized, phase III study comparing eribulin with treatment of physician's choice (TPC) in 762 patients with LABC/MBC. Clinical effectiveness results were submitted for two populations: the overall intention-to-treat (ITT) population and a subset (n = 488) that included only patients from North America, Western Europe and Australia (Region 1). For the primary endpoint of overall survival (OS), a primary analysis (after 55 % of patients had died) and an updated analysis (after 77 % of patients had died) were conducted. In the ITT population, treatment with eribulin was associated with a significant improvement in median OS compared with TPC in both primary [difference in median OS 2.5 months; hazard ratio (HR) 0.81, 95 % confidence interval (CI) 0.66-0.99] and updated analyses (2.7 months; HR 0.81, 95 % CI 0.67-0.96). A statistically significant improvement in progression-free survival (PFS) was reported for eribulin compared with TPC when assessed by the investigator (difference in median PFS 1.48 months; HR 0.76, 95 % CI 0.64-0.90), but not when assessed by the ERG (1.44 months; HR 0.87, 95 % CI 0.71-1.05). Gains in OS were greater for Region 1 patients than for the ITT population (3.1 vs. 2.7 months). Health-related quality of life (HRQoL) data suggested a benefit for eribulin responders, but was based on phase II studies. In the eribulin arm, serious adverse events included febrile neutropenia (4.2 %) and neutropenia (1.8 %), with peripheral neuropathy being the most common reason for treatment discontinuation. The manufacturer's economic evaluation using Patient Access Scheme costs reported a base-case incremental cost-effectiveness ratio (ICER) for eribulin versus TPC (Region 1) of £46,050 per quality-adjusted life year gained (corrected to £45,106 when an erroneous data entry was removed). The ERG's revised ICERs were £61,804 for Region 1 and £76,110 for the overall population. The AC concluded that the evidence had not demonstrated sufficient benefit in OS, cost effectiveness or HRQoL and that eribulin was not recommended for use in this patient group.

A model for costs of stroke services.

In industrialised countries, stroke is one of the most common causes of death and handicap, and the costs for stroke services are high. However, rational planning of stroke services and estimation of the costs of their provision are complex, even when generic pathways for stroke diagnosis and treatment are well understood. The reason is the chronic nature of cerebro-vascular disease and the cumulative effect of disabling brain injury. In this paper we describe development of a computer model for estimating the costs of stroke services, intended for use by planners and purchasers of stroke care services. The model operates by incrementing patients' experience of stroke events and their outcomes in annual steps, and is calibrated using Swedish data. We demonstrate the cost consequences by simulating three different policy changes. The model facilitates comparisons between stroke prevention, treatment and rehabilitation, and we conclude that by combining the three policy options it is possible to reduce the costs for stroke services markedly.