For the Treatment of Rheumatoid Arthritis M Connock, S Tubeuf, K Malottki, a Uthman, J Round, S Bayliss, C Meads and D Moore

This is a repository copy of Bevacizumab in combination with fluoropyrimidine-based chemotherapy for the first-line treatment of metastatic colorectal cancer .

White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/43321/

Article: Whyte, S., Pandor, A., Stevenson, M. et al. (1 more author) (2010) Bevacizumab in combination with fluoropyrimidine-based chemotherapy for the first-line treatment of metastatic colorectal cancer. Health Technology Assessment , 14 (2). pp. 47-53. ISSN 1366-5278 https://doi.org/10.3310/hta14suppl2/07

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[email protected] https://eprints.whiterose.ac.uk/ Health Technology Assessment 2010; Vol. 14: Suppl. 2

Single Technology Appraisals A supplement to Health Technology Assessment Journal

In this issue irst-line treatment of chronic lymphocytic leukaemia: an evidence Certolizumab pegol for rheumatoid arthritis Capecitabine for advanced gastric cancer Rituximab for relapsed/refractory chronic lymphocytic leukaemia metastatic renal cell cancer: Rituximab for chronic lymphocytic leukaemia SUPPLEMENT Pemetrexed for locally advanced or metastatic non-small cell lung Bevacizumab in combination with luoropyrimidine-based cancer chemotherapy for the irst-line treatment of metastatic colorectal cancer

Everolimus for advanced and/or metastatic renal cell cancer Dronedarone for the treatment of atrial ibrillation and atrial lutter Bevacizumab in combination with luoropyrimidine-based chemotherapy for metastatic colorectal cancer

Dronedarone for atrial ibrillation and atrial lutter Geitinib for the irst-line treatment of locally advanced or metastatic Imatinib as adjuvant treatment following resection of KIT-positive gastrointestinal stromal tumours Geitinib for locally advanced or metastatic non-small cell lung cancer

October 2010

Health Technology Assessment NIHR HTA programme www.hta.ac.uk HTA

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The website also provides information about the HTA programme and lists the membership of the various committees. Health Technology Assessment Volume 14: Supplement 2, October 2010

iii Supplement introduction

1 Certolizumab pegol (CIMZIA®) for the treatment of rheumatoid arthritis M Connock, S Tubeuf, K Malottki, A Uthman, J Round, S Bayliss, C Meads and D Moore

11 Capecitabine for the treatment of advanced gastric cancer G Norman, M Soares, P Peura, S Rice, D Suh, K Wright, M Sculpher and A Eastwood

19 Rituximab for the treatment of relapsed/refractory chronic lymphocytic leukaemia J Dretzke, P Barton, B Kaambwa, M Connock, O Uthman, S Bayliss and C Meads

27 The clinical effectiveness and cost-effectiveness of rituximab for the irst-line treatment of chronic lymphocytic leukaemia: an evidence review of the submission from Roche C Main, M Pitt, T Moxham and K Stein

33 Pemetrexed for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer J Greenhalgh, C McLeod, A Bagust, A Boland, N Fleeman, Y Dundar, J Oyee, R Dickson, H Davis, J Green, E McKenna and M Pearson

41 Everolimus for the second-line treatment of advanced and/or metastatic renal cell cancer: a critique of the submission from Novartis M Pitt, L Crathorne, T Moxham, M Bond and C Hyde

47 Bevacizumab in combination with luoropyrimidine-based chemotherapy for the irst-line treatment of metastatic colorectal cancer S Whyte, A Pandor, M Stevenson and A Rees

55 Dronedarone for the treatment of atrial ibrillation and atrial lutter E Maund, C McKenna, M Sarowar, D Fox, M Stevenson, C Pepper, S Palmer and N Woolacott

63 Imatinib as adjuvant treatment following resection of KIT-positive gastrointestinal stromal tumours J Dretzke, J Round, M Connock, S Tubeuf, M Pennant, A Fry-Smith, C Hulme, C McCabe and C Meads

71 Geitinib for the irst-line treatment of locally advanced or metastatic non-small cell lung cancer T Brown, A Boland, A Bagust, J Oyee, J Hockenhull, Y Dundar, R Dickson, VS Ramani and C Proudlove NIHR Health Technology Assessment programme

he Health Technology Assessment (HTA) programme, part of the National Institute for Health TResearch (NIHR), was set up in 1993. It produces high-quality research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS. ‘Health technologies’ are broadly deined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care. The research indings from the HTA programme directly inluence decision-making bodies such as the National Institute for Health and Clinical Excellence (NICE) and the National Screening Committee (NSC). HTA indings also help to improve the quality of clinical practice in the NHS indirectly in that they form a key component of the ‘National Knowledge Service’. The HTA programme is needs led in that it ills gaps in the evidence needed by the NHS. There are three routes to the start of projects. First is the commissioned route. Suggestions for research are actively sought from people working in the NHS, from the public and consumer groups and from professional bodies such as royal colleges and NHS trusts. These suggestions are carefully prioritised by panels of independent experts (including NHS service users). The HTA programme then commissions the research by competitive tender. Second, the HTA programme provides grants for clinical trials for researchers who identify research questions. These are assessed for importance to patients and the NHS, and scientiic rigour. Third, through its Technology Assessment Report (TAR) call-off contract, the HTA programme commissions bespoke reports, principally for NICE, but also for other policy makers. TARs bring together evidence on the value of speciic technologies. This supplement to the Journal series contains a collection of summaries based on Evidence Review Group reports (ERGs), produced as part of NICE’s Single Technology Appraisal (STA) process. The reports are mainly based on data submissions from manufacturers and do not undergo the standard peer-review process. Some HTA research projects, including TARs, may take only months, others need several years. They can cost from as little as £40,000 to over £1 million, and may involve synthesising existing evidence, undertaking a trial, or other research collecting new data to answer a research problem. Criteria for inclusion in the HTA Journal series and Supplements Reports are published in the journal series and supplements if (1) they have resulted from work for the HTA programme, and (2) they are of a suficiently high scientiic quality as assessed by the referees and editors. Reviews in Health Technology Assessment are termed ‘systematic’ when the account of the search, appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others.

The research reported in this issue of the supplement was commissioned and funded by the HTA programme on behalf of NICE. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health. Editor-in-Chief: Professor Tom Walley CBE Series Editors: Dr Martin Ashton-Key, Professor Aileen Clarke, Professor Chris Hyde, Dr Tom Marshall, Dr John Powell, Dr Rob Riemsma and Professor Ken Stein Editorial Contact: [email protected] ISSN 1366-5278 © 2010 Queen’s Printer and Controller of HMSO This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (http://www.publicationethics.org/). This journal may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NETSCC, Health Technology Assessment, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Published by Prepress Projects Ltd, Perth, Scotland (www.prepress-projects.co.uk), on behalf of NETSCC, HTA. Printed on acid-free paper in the UK by Henry Ling Ltd, The Dorest Press, Dorchester. Health Technology Assessment 2010; Vol. 14: Suppl. 2

Supplement introduction

elcome to the ifth Supplement to the Health The independent academic input to NICE’s WTechnology Assessment journal series. The series process, which continues to be supported by the is now over 10 years old and has published more TAR centres around the UK under contract to the than 500 titles, covering a wide range of health HTA programme, is to scrutinise, critique and technologies in a diverse set of applications. In explore this dossier of evidence. general, the series publishes each technology assessment as a separate issue within each annual The papers included in this Supplement report volume. on this HTA programme funded work, and we hope that the summaries of the work carried out The Supplements depart from that format by to inform the development of NICE guidance for containing a series of shorter articles. These are all these technologies will be of interest and value to products from a ‘call-off contract’, which the HTA readers. programme holds with a range of academic centres around the UK, at the universities of Aberdeen, The papers included here contain reports of the Birmingham, Exeter, Liverpool, Shefield, position that the NICE guidance had reached Southampton and York. These centres are retained at the time of submission to Health Technology to provide a highly responsive resource, which Assessment for inclusion in this supplement. As we meets the needs of national policy makers, notably collect a series of papers together for an issue, the the National Institute for Health and Clinical process of developing NICE guidance may have Excellence (NICE). moved on further for some topics than others. Further details on the current position regarding Until recently, these HTA Technology Assessment each of the NICE Appraisals are available on the Review (TAR) centres provided academic input to NICE website (www. nice.org.uk) and we welcome policy making through independent analyses of comments on the summaries via the HTA website the impact and value of health technologies. As (www.hta.ac.uk/correspond/). many readers will be aware, the perception that the advice NICE provides to the NHS could be Professor Tom Walley made more timely has led to the development of Director, NIHR HTA programme the ‘Single Technology Appraisal’ process. In this Editor-In-Chief, Health Technology Assessment approach, manufacturers of technologies, which are, in general, pharmaceuticals close to the time Professor Ken Stein of launch, submit a dossier of evidence aiming to Chair, Editorial Board, Health Technology Assessment demonstrate effectiveness and cost-effectiveness.

iii

DOI: 10.3310/hta14suppl2/01 Health Technology Assessment 2010; Vol. 14: Suppl. 2

Certolizumab pegol (CIMZIA®) for the treatment of rheumatoid arthritis

M Connock,1 S Tubeuf,2 K Malottki,1 A Uthman,1 J Round,2 S Bayliss,1 C Meads1 and D Moore1*

1Unit of Public Health, Epidemiology and Biostatistics, University of Birmingham, Birmingham, UK 2Leeds Institute of Health Sciences, University of Leeds, Leeds, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 07/13/01

This paper presents a summary of the evidence Date of ERG submission: review group (ERG) report into the clinical 1 August 2009 effectiveness and cost-effectiveness of certolizumab TAR Centre(s): pegol (CZP) for adults with active rheumatoid West Midlands Health Technology Assessment arthritis (RA) that have not responded adequately Collaboration to treatment with conventional disease modifying List of authors: anti-rheumatic drugs (DMARDs) including M Connock, S Tubeuf, K Malottki, A Uthman, J Round, methotrexate (MTX), in accordance with the S Bayliss, C Meads and D Moore licensed indication, based upon the evidence submission from the manufacturer to the National Contact details: David Moore, Unit of Public Health, Epidemiology and Institute for Health and Clinical Excellence (NICE) Biostatistics, University of Birmingham, Edgbaston, as part of the single technology appraisal (STA) Birmingham B15 2TT, UK process. The outcome measures included American College of Rheumatology (ACR) 20, 50 and 70 E-mail: [email protected] response rates and quality of life measures after The research reported in this article of the journal 3 months and 6 months of treatment. The ERG supplement was commissioned and funded by the examined the submission’s search strategies and HTA programme on behalf of NICE as project number considered they appeared comprehensive and that 07/13/01. The assessment report began editorial review it was unlikely that relevant studies would have in December 2009 and was accepted for publication in been missed. Only English language studies were January 2010. See the HTA programme website for further considered in the submission and non-English project information (www.hta.ac.uk). This summary of the language studies relevant to the decision problem ERG report was compiled after the Appraisal Committee’s review. may possibly have been ignored. The ERG analysed the irst submitted economic model so as The views and opinions expressed therein are those of to itemise in detail clariication points that were the authors and do not necessarily relect those of the brought to the attention of the manufacturer. In Department of Health. response the manufacturer submitted a modiied Discussion of ERG reports is invited. Visit the HTA website cost-effectiveness analysis. The ERG undertook correspondence forum (www.hta.ac.uk/correspond). further analysis of this second model and other additional submitted evidence. The clinical evidence was derived from two multicentre blinded randomised controlled trials (RCTs) comparing CZP + MTX to placebo + MTX (the RAPID 1 and RAPID 2 trials). RAPID 1 lasted 52 weeks with 982 1

patients and RAPID 2 24 weeks with 619 patients. indication, where most of the relevant evidence Evidence for clinical effectiveness of CZP in mono- lies with one manufacturer or sponsor.1 Typically, therapy came from the 24-week FAST4WARD trial it is used for new pharmaceutical products close with 220 patients that compared CZP (400 mg to launch. The principal evidence for an STA is every 4 weeks) versus placebo. The three key RCTs derived from a submission by the manufacturer/ demonstrated statistically signiicant superiority sponsor of the technology. In addition, a report of CZP + MTX versus placebo + MTX and of reviewing the evidence submission is submitted CZP versus placebo with respect to a variety of by the evidence review group (ERG), an external outcomes including ACR 20, ACR 50 and ACR organisation independent of the Institute. 70 measures and quality of life measures at 3 and 6 months. On the basis of results from the indirect This paper presents a summary of the ERG report comparison meta-analyses, the manufacturer for the STA submission that considered the clinical suggested that CZP may be at least as effective as effectiveness and cost-effectiveness of certolizumab other ‘biological’ DMARD (bDMARD) comparators pegol (CZP) for adults with active rheumatoid and, in a few ACR measures at 3 and 6 months, arthritis (RA) that has not responded adequately more effective. CZP is an effective therapy for adult to treatment with conventional disease modifying RA patients whose disease has failed to respond anti-rheumatic drugs (cDMARDs) including adequately to cDMARDs including MTX or who methotrexate (MTX).2 CZP is a ‘biological’ DMARD are intolerant of MTX. The cost-effectiveness of (bDMARD) whose effectiveness could be compared CZP relative to other bDMARDs is unclear because to cDMARDs or to other bDMARDs administered the economic modelling undertaken may have within their licensed indications. ignored relevant effectiveness data and potential differences between trial populations, and so may Description of the underlying have included effectiveness results that were biased health problem in favour of CZP; underestimated uncertainty in the relative effectiveness of compared DMARDs; This section is taken from the NICE scope for this and ignored the potential inluence of differences STA. between bDMARDs with regard to adverse events and their related costs and health impacts. The Rheumatoid arthritis is a chronic, disabling NICE guidance issued in October 2009 states autoimmune disease characterised by inlammation that: the Committee is minded not to recommend of the synovial tissue of the peripheral joints, which certolizumab pegol as a treatment option for causes swelling, stiffness, pain and progressive people with RA; and the Committee recommends joint destruction. For a small proportion of people, that NICE asks the manufacturer of CZP for more inlammatory disease outside the joints (e.g. information on the clinical effectiveness and cost- eye and lung disease, vasculitis) can also pose a effectiveness of CZP for the treatment of people signiicant problem. RA is heterogeneous, it is with RA. On receipt of this information and usually a chronic relapsing condition which has a details of a patient access scheme NICE issued pattern of lare-ups followed by periods of lower inal guidance recommending CZP, under certain disease activity, but in a minority of cases the criteria, as a treatment option for people with RA. disease is constantly progressive. Most patients with RA develop damage to affected joints, with the amount of damage ranging from mild to severe. Introduction RA has a severe impact on quality of life and it is estimated that 40% of people with RA will stop The National Institute for Health and Clinical working within 5 years of diagnosis. Excellence (NICE) is an independent organisation within the NHS that is responsible for providing Rheumatoid arthritis is three times more prevalent national guidance on the treatment and care of in women than in men. It can develop at any age, people using the NHS in England and Wales. but usually starts between 40 and 60 years of age. One of responsibilities of NICE is to provide RA affects 1% of the population, or approximately guidance to the NHS on the use of selected new 400,000 people in England and Wales. Of these, and established health technologies, based on an approximately 15% have severe disease. appraisal of those technologies. People with RA are usually treated in an outpatient NICE’s single technology appraisal (STA) process setting rather than in primary care. There is is speciically designed for the appraisal of a single no cure, and treatment aims to improve quality 2 product, device or other technology, with a single of life and to prevent or reduce joint damage. Health Technology Assessment 2010; Vol. 14: Suppl. 2

Treatment for RA usually includes: non-steroidal quality-adjusted life-year (QALY) gained from CZP anti-inlammatory agents (NSAIDs) which reduce in comparison with anti-TNF agents (adalimumab, pain, fever and joint swelling/inlammation; and etanercept and inliximab) or with rituximab. DMARDS which slow the disease process and Model inputs for clinical effectiveness of the reduce joint damage. Corticosteroids may also be different bDMARDs were derived from results used to control inlammation. DMARDs are usually from ICMs and based on the American College started soon after diagnosis. MTX and sulfasalazine of Rheumatology (ACR) 20, 50 and 70 response are two commonly used DMARDs. NICE guidance rates7 after 3 months and 6 months of treatment. recommends the use of a TNF (tumour necrosis The estimated ACR response rates in the absence factor)-α inhibitor (adalimumab, etanercept and of bDMARD treatment were single point values inliximab; types of bDMARD) after the failure (no associated uncertainty) and were obtained by of two cDMARDs such as MTX and sulfasalazine. simple aggregation of the rates reported across the NICE guidance recommends the use of rituximab control arms of the included trials. (a bDMARD that depletes B cells) after the failure of a TNF inhibitor, but does not recommend the Health-related quality of life (HRQoL) utilities use of abatacept after the failure of a TNF inhibitor. for the irst 6 months of treatment were obtained by regression analysis of the relationship between Scope of the evidence ACR response and European Quality of Life-5 review group report Dimensions (EQ-5D) scores observed for European patients participating in CZP trials. Utilities while The scope for this STA was to address the clinical continuing on treatment and utility after cessation effectiveness and cost-effectiveness of CZP relative of treatment were obtained by converting Health to cDMARDs and to bDMARDs for the treatment Assessment Questionnaire measures using a of adults with active RA whose disease had not published algorithm proposed by Brennan et al.8 responded adequately to cDMARDs including Costs were mainly obtained from standard sources. MTX. The STA was initiated prior to the granting of formal marketing authorisation. The anticipated marketing authorisation for CZP speciied a dose Methods regimen of 400 mg administered subcutaneously on weeks 0, 2 and 4, followed by 200 mg every other The ERG report comprised a critical review of the week. CZP is indicated for use in ‘combination’ evidence for the clinical effectiveness and cost- therapy with MTX or as ‘monotherapy’ (without effectiveness of the technology based upon the MTX) for patients intolerant of MTX. The manufacturer’s/sponsor’s submission to NICE as acquisition cost of CZP is £357.50 per 200-mg part of the STA process. syringe, excluding VAT (value added tax). Owing to the central importance of the RAPID The key sources of evidence on clinical 1, RAPID 2 and FAST4WARD studies, these effectiveness of CZP in combination therapy were formally fully appraised by the ERG, taking came from two multicentre blinded randomised advantage of responses to requests for clariication controlled trials (RCTs) comparing CZP + MTX to from the manufacturer. placebo + MTX [the RA Prevention of Structural Damage (RAPID) 13 and RAPID 24 trials]. RAPID The ERG examined the submission’s search 1 lasted 52 weeks with 982 patients and RAPID 2 strategies and considered they appeared 24 weeks with 619 patients. Evidence for clinical comprehensive and that it was unlikely that effectiveness of CZP in mono-therapy came from relevant studies would have been missed. Only the 24-week FAST4WARD trial5 with 220 patients English language studies were considered in the that compared CZP (400 mg every 4 weeks) versus submission and non-English language studies placebo. There were no head-to-head trials that relevant to the decision problem may possibly have compared the effectiveness of CZP to the other been ignored. bDMARDs. To estimate the relative clinical effectiveness between bDMARDs the manufacturer The ERG critically appraised the submitted ICM undertook indirect comparison meta-analyses with focus on the validity of selection of studies (ICMs)6 using the results from various placebo- for inclusion, the reproducibility of results and the controlled trials of bDMARDs. exploration of heterogeneity. The ERG considered the relative merits of alternative approaches to the The manufacturer submitted a de novo economic ICM submitted. model that was used to estimate the cost per 3

The ERG analysed the irst submitted economic for clariication, others depended on new results model so as to itemise in detail clariication obtained from unprompted reanalyses of trial points that were brought to the attention of the data undertaken by the manufacturer. The main manufacturer. In response the manufacturer changes made were exclusion of adverse events, submitted a modiied cost-effectiveness analysis. exact calculation of discontinuation rates and The ERG undertook further analysis of this second modiied annual utility decrement upon cessation model and other additional submitted evidence. of bDMARD treatment. The main results from the second model are shown in Table 1. The submission also included an economic analysis encompassing Results a proposed patient access scheme. At the time, this Summary of submitted scheme was not approved by the Department of clinical evidence Health (DoH) and as such it was not considered in the irst appraisal meeting. The three key RCTs demonstrated statistically signiicant superiority of CZP + MTX versus Commentary on the robustness placebo + MTX and of CZP versus placebo with of submitted evidence respect to a variety of outcomes including ACR 20, ACR 50 and ACR 70 measures and quality of life In the three CZP trials there were large numbers measures at 3 and 6 months. of early patient withdrawals from the control arms that were imposed for lack of a rapidly established On the basis of results from the ICMs, the clinical effectiveness response. manufacturer suggested that CZP may be at least as effective as other bDMARD comparators and, In the RAPID 1 trial, of 199 patients receiving in a few ACR measures at 3 and 6 months, more placebo + MTX, 63% had withdrawn by week 16 effective. These ICM estimates were associated and 78% by the end of the trial; this compared with considerable uncertainty. Some evidence to 21% and 35%, respectively, of patients was presented that CZP inhibits progression of receiving CZP. In RAPID 2, 87% of patients in the structural damage to joints. placebo + MTX arm had withdrawn by the end of the trial (week 24). In the FAST4WARD mono- Summary of submitted cost- therapy trial, 54% of control arm patients had effectiveness evidence withdrawn by week 12 and 74% by the end of the trial at 24 weeks. The inputs for the irst model were modiied in the second model submitted. Some modiications The high withdrawal rates at early phases of the were introduced in response to NICE’s requests CZP trials, especially seen in the control arms,

TABLE 1 Base-case results from the manufacturer’s second economic model using indirect comparison effectiveness analysis

Mean cost (£) Mean QALYs ICER

Combination therapy CZP + MTX 89,158 6.654 – Etanercept + MTX 86,165 6.589 46,192 Adalimumab + MTX 86,034 6.412 12,937 Rituximab + MTX 82,940 6.362 21,345 Inliximab+ MTX 95,599 6.196 CZP dominates

Monotherapy CZP 85,424 6.305 – Etanercept 85,941 6.435 (3991)a Adalimumab 84,201 6.09 5687

CZP, certolizumab pegol; ICER, incremental cost-effectiveness ratio; MTX, methotrexate; QALYs, quality-adjusted life-years. a ICER for etanercept compared with CZP. 4 Health Technology Assessment 2010; Vol. 14: Suppl. 2

necessitated that estimates of effectiveness at later (e) The development of effectiveness input for time points required many ‘last observations’ to be the economic analysis included data for a carried forward, and somewhat compromised the bDMARD comparator omitted from the robustness of these estimates. subsequent economic analysis, raising the issue of whether data for other omitted bDMARDs Owing to a lack of head-to-head trials of different should also have been included. bDMARDs, the manufacturer undertook random (f) The development of clinical effectiveness effects ICMs to gain an estimate of their relative input for the economic analysis used a clinical effectiveness. point estimate derived by aggregation across trial control arms and sacriiced The effectiveness of CZP relative to other some of the strengths of randomisation and bDMARDs was based on ACR 20, ACR 50 and underestimated associated uncertainty. ACR 70 outcomes measured at 12 and 24 weeks in various trials analysed by ICM. The robustness of The validity of ICM rests on an assumption of these comparisons was potentially compromised by exchangeability between trials such that the the high withdrawal rates in the CZP trials relative placebo arms of the trials are interchangeable. to those observed in the other included trials. The submission lacked an assessment or discussion of clinical or statistical heterogeneity amongst For combination therapy ACR responses at 24 the trials used for ICM and did not comment on weeks, the ICM included 10 trials [two with CZP whether baseline characteristics of participants (RAPID 1 and 2), three with adalimumab, two were similar across these RCTs. As such there with inliximab and one each with etanercept, was no consideration of potential sources of non- rituximab and tocilizumab]. Seven trials were used comparability of the placebo-controlled arms of the for responses at 12 weeks [two with CZP (RAPID trials. trials), two with etanercept and one each with adalimumab, inliximab and tocilizumab]. For The ERG undertook an analysis of the monotherapy ACR responses at 12 and 24 weeks, heterogeneity amongst the control arms of the the ICM included four trials (two with adalimumab studies used in the estimation of effectiveness for and one each with CZP and etanercept). the 24-week ACR 20 outcome for combination therapy. This choice was made because it involved The reported results from the ICMs (odds ratios) the largest number of studies and the largest were associated with considerable uncertainty and number of events. The results are shown in there were some errors in the reported values for Figure 1. Data for four study level variables (chosen ACR 70. Of the 85 indirect comparisons made by the ERG) are also included in the igure. between pairs of bDMARDs, only four reached statistical signiicance. Two of these were for The control rate in the two CZP RCTs was the superiority of CZP at 24 weeks in the ACR 20 lowest amongst the 10 trials, and the I2 statistic outcome. indicated considerable heterogeneity. When the two CZP studies were omitted from the analysis, Several aspects of the ICMs reported by the the I2 statistic was reduced to 70% and the pooled manufacturer were a cause of concern: estimate increased to 28%.

(a) The inclusion and exclusion of studies for the The four study level variables that were looked ICM did not appear to be systematic. at as potential contributors to the observed (b) The inclusion of data from the included heterogeneity were: entry level MTX dose as a studies lacked some consistency. potential indicator of treatment intensity and (c) There was a possibility that relevant population differences; percentage withdrawals information from several excluded studies, for the ACR 20 outcome as indicator of including an unpublished industry sponsored completeness of data; duration of RA; and number randomised trial of CZP + MTX versus of previous DMARDs trialed as indicators of MTX + placebo (study C87014), could have possible population differences. For each of these been used in the ICM. variables the two CZP RCTs were at the extreme (d) There was insuficient consideration and of the distributions. The brief examination of exploration of underlying heterogeneity heterogeneity amongst the studies used for ICMs amongst the studies included for ICM. indicated that an indirect comparison or mixed-

MTX % Previous Disease Study mg/wk Loss DMARDs duration% Risk (95% Cl)

Certolizumab + MTX RAPID 24 12.2 79 1.2 5.6 8.66 (4.40 to 14.97) RAPID 13 13.4 62 1.4 6.2 13.57 (9.14 to 19.12)

Adalimumab + MTX ARMADA9 16.5 unclear 2 11.1 14.52 (6.86 to 25.78) Kim 200710 16.3 37.5 1 to 2 6.9 36.51 (24.73 to 49.60) Keystone 200411 16.7 30 1.4 10.9 29.50 (23.28 to 36.34)

Etanercept + MTX Weinblatt 199912 18 20 1.8 13 25.81 (12.28 to 45.89)

Inﬂiximab + MTX START13 15 17 1.3 8.4 23.97 (19.67 to 28.70) ATTEST14 16.6 3NR 8.4 41.82 (32.48 to 51.61)

Rituximab + MTX Strand 200615 13.7 8 2.6 11 37.50 (22.73 to 54.20)

Tocilizumab + MTX OPTION16 14.8 39 1.7 7.8 26.47 (20.55 to 33.08)

Overall Overall (I2 = 87.1%, p = 0.000) 23.78 (21.60 to 26.04)

0 20 40 55 % ACR 20

FIGURE 1 Risk of ACR 20 in placebo plus MTX arms of trials used for ICM at 6 months. ACR, American College of Rheumatology; CI, conidence interval; DMARDs, disease modifying anti-rheumatic drugs; MTX, methotrexate.

treatment analysis with methods that allow for Conclusions differences in control rate or baseline risk (similar to the Bayesian analyses undertaken by Nixon et Certolizumab pegol is an effective therapy for adult al.17) probably represents the preferred choice of RA patients whose disease has failed to respond methodology for the decision problem. adequately to cDMARDs including MTX or who are intolerant of MTX. Regarding the economic model, the robustness of quality of life and health-utility inputs was dificult A reasonable interpretation of the results is that to determine through lack of detail of how many there is little convincing evidence that CZP is more patients were given HRQoL questionnaires and or less effective than the comparators examined. what response rates were elicited. It was not clear how this uncertainty might affect the estimates of Patients with RA may respond differently to cost-effectiveness generated by the model. different bDMARDs and effectiveness of a bDMARD for a speciic patient is currently Adverse event costs as well as their related health unpredictable; an increase in the variety of outcomes were not included in the revised model available bDMARDs might potentially increase the although they were included in the original overall proportion of patients responsive to these submission. There was a lack of information drugs. to justify this revision, so it was unclear what sources of data were used in this exercise. An The cost-effectiveness of CZP relative to other assumption of no difference in adverse effects bDMARD is unclear because the economic between drugs (CZP, inliximab, adalimumab, modelling undertaken may have ignored relevant etanercept, rituximab) may on average be shown effectiveness data and potential differences to be reasonable, but on the basis of the submitted between trial populations, and so may have information the assumption cannot be considered included effectiveness results that were biased to be evidence based. in favour of CZP; underestimated uncertainty in

6 Health Technology Assessment 2010; Vol. 14: Suppl. 2

the relative effectiveness of compared DMARDs; • further details of how the assumed utility and ignored the potential inluence of differences decrease of 0.0025 per year when treatment is between bDMARDs with regard to adverse events discontinued was derived and their related costs and health impacts. • clariication and a full breakdown of the direct and indirect costs included in the model, Summary of NICE guidance including an explanation of why the mean cost issued as a result of the STA for the intervention and comparators differed between the original and revised models, and At the time of drafting this report, the guidance an explanation of how these changes relate to appraisal consultation document issued by NICE in costs associated with adverse events October 2009 states that: • clariication of how incorporating an estimated relationship between ACR 20, 50 and 70 would 1.1 The Committee is minded not to recommend affect cost effectiveness in the revised model. certolizumab pegol as a treatment option for people with rheumatoid arthritis (RA). Provision of an incremental cost-effectiveness analysis: 1.2 The Committee recommends that NICE asks the manufacturer of certolizumab pegol for • comparing certolizumab pegol with other more information on the clinical effectiveness and TNF-α inhibitors (that is, not including cost-effectiveness of certolizumab pegol for the rituximab) treatment of people with RA. This information • including univariate sensitivity analysis should be made available for the second Appraisal exploring the effect of lowering the estimate Committee meeting, and should cover the for the cost of administering inliximab in following issues: line with the range of costs used in previous appraisals Estimation of the clinical effectiveness of • including a comparison of all treatments certolizumab pegol relative to other TNF-α with full reporting of results of probabilistic inhibitors for the treatment of RA, including sensitivity analysis, including but not limited to consideration of uncertainty around the estimate. presentation of cost-effectiveness acceptability In order to clarify this issue the Committee curves, with all treatments plotted and a requests: scatter plot of all treatments on the same cost- effectiveness plane. • provision of a mixed-treatment comparison (MTC) analysis, rather than an indirect The manufacturer responded to the ACD with comparison meta-analysis a new submission that incorporated a MTC that • details of potentially relevant studies, including included the industry sponsored CZP study C87014 study C87014, that were excluded from the and two additional studies previously excluded analysis from the ICMs. The major change to the economic • provision of data from the C87014 trial analysis was the introduction of a DOH-approved and an assessment of the impact on the patient access scheme (PAS) that considerably incremental cost-effectiveness ratios (ICERs) reduced the initial cost of CZP treatment by when the American College of Rheumatology making early treatment syringes free of charge. (ACR) response for certolizumab pegol in combination with methotrexate is calculated The MTC more faithfully relected the inherent using data from the C87014 plus the RAPID 1 uncertainty in the estimates of relative effectiveness and 2 trials. of the compared DMARDs (Figure 2) and the PAS improved the cost-effectiveness of CZP treatment. Clariication of how the original economic model The main new cost-effectiveness results submitted was revised: are summarised in Table 2.

• further justiication of why a utility decrease The inal appraisal document for this technology of 0.037 per year after assessment of clinical was issued by NICE shortly before this article was response at 6 months was assumed in the sent to press. The appraisal document states: original model, but a utility increase of 0.0402 per year was assumed in the revised model

TABLE 2 Manufacturer’s revised cost effectiveness results incorporating mixed-treatment comparison of effectiveness and DOH-approved patient access scheme

Mean cost (£) Mean QALYs ICER

Combination therapy CZP + MTX 85,583 6.654 – Etanercept + MTX 86,165 6.589 CZP dominates Adalimumab + MTX 86,034 6.412 CZP dominates Rituximab + MTX 82,940 6.362 9072 Inliximab+ MTX 95,599 6.196 CZP dominates

Monotherapy CZP 81,849 6.305 – Etanercept 85,941 6.435 (31,582)a Adalimumab 84,201 6.09 CZP dominates

CZP, certolizumab pegol; ICER, incremental cost-effectiveness ratio; MTX, methotrexate; QALYs, quality-adjusted life-years. a ICER for etanercept compared with CZP.

INDIRECT MTC

ACR 20 odds ratio CZP + MTX vs Placebo + MTX 10.57 11.12 CZP + MTX vs Adalimumab + MTX 2.17 2.18 CZP + MTX vs Etanercept + MTX 1.56 1.54 CZP + MTX vs Infiximab + MTX 3.64 3.82 CZP + MTX vs Rituximab + MTX 2.41 2.46 CZP + MTX vs Toclizumab + MTX 2.70 2.85 ACR 50 odds ratio CZP + MTX vs Placebo + MTX 9.08 10.01 CZP + MTX vs Adalimumab + MTX 1.35 1.35 CZP + MTX vs Etanercept + MTX 0.49 0.32 CZP + MTX vs Infiximab + MTX 2.74 2.98 CZP + MTX vs Rituximab + MTX 1.75 1.84 CZP + MTX Toclizumab + MTX 1.40 1.51 ACR 70 odds ratio CZP + MTX vs Placebo + MTX 10.18 12.76 CZP + MTX vs Adalimumab + MTX 1.61 1.85 CZP + MTX vs Etanercept + MTX 0.89 0.43 CZP + MTX Infiximab + MTX 3.10 3.78 CZP + MTX vs Rituximab + MTX 1.85 1.89 CZP + MTX vs Toclizumab + MTX 0.72 0.83 0.01 0.1 110 100 Odds ratio (log scale)

FIGURE 2 Manufacturer’s results for ICM (hollow symbol) and MTC (solid symbol) with associated uncertainty: ACR 20, 50, 70 outcomes. ACR, American College of Rheumatology; CZP, certolizumab pegol; MTC, mixed-treatment comparison; MTX, methotrexate.

8 Health Technology Assessment 2010; Vol. 14: Suppl. 2

Cetolizumab pegol is recommended as an option 7. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College for the treatment of people with rheumatoid of Rheumatology. Preliminary deinition of arthritis only if: improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727–35. • certolizumab pegol is used as described for other tumour necrosis factor (TNF) inhibitor 8. Brennan A, Bansback N, Nixon R. Modelling the treatments in ‘Adalimumab, etanercept and cost effectiveness of TNF-a inhibitors in the management inliximab for the treatment of rheumatoid of rheumatoid arthritis: results from the British Society arthritis (NICE technology appraisal guidance for Rheumatology Biologics Registry. University of 130) and Shefield ScHARR; 2006. Report No.: 06/12.

• the manufacturer provides the irst 12 weeks 9. Weinblatt M, Keystone E, Furst D, Moreland L, Weisman M, Birbara C, et al. Adalimumab, a fully of certolizumab pegol (10 pre-loaded 200-mg human anti-tumor necrosis factor alpha monoclonal syringes) free of charge to all patients starting antibody, for the treatment of rheumatoid arthritis treatment. in patients taking concomitant methotrexate: The ARMADA Trial. Arthritis Rheum 2003;48:35–45.

Key references 10. Kim H-Y. A randomized, double-blind, placebo- 1. NICE. Guide to single technology (STA) controlled, phase III study of the human anti-tumor process. 2006. URL: www.nice.org.uk/page. necrosis factor antibody adalimumab administered aspx?o=STAprocessguide. as subcutaneous injections in Korean rheumatoid arthritis patients treated with methotrexate. APLAR 2. Connock MJ, Tubeuf S, Malottki K, Uthman Journal of Rheumatology 2007;10:9–16. A, Round J, Bayliss S, et al. Certolizumab pegol (CIMZIA®) for the treatment of Rheumatoid 11. Keystone E, Kavanaugh A, Sharp J, Tannenbaum Arthritis. URL: www.nice.org.uk/guidance/index. H, Hua Y, Teoh L, et al. Radiographic, Clinical, jsp?action=download&o=45795. and Functional Outcomes of Treatment with Adalimumab (a human anti-tumour necrosis 3. Keystone E, Heijde DV, Mason D, Jr., Landewe factor monoclonal antibody) in patients with R, Vollenhoven RV, Combe B, et al. Certolizumab active rheumatoid arthritis receiving concomitant pegol plus methotrexate is signiicantly more methotrexate therapy: a randomized, placebo- effective than placebo plus methotrexate in active controlled 52-week trial. Arthritis Rheum rheumatoid arthritis: Findings of a ifty-two-week, 2004;50:1400–11. phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis 12. Weinblatt M, Kremer J, Bankhurst A, Bulpitt K, Rheum 2008;58:3319–29. Fleischmann R, Fox R, et al. A Trial of Etanercept, a Recombinant Tumor Necrosis Factor Receptor: 4. Smolen J, Landewe RB, Mease P, Brzezicki J, Fc fusion protein, in patients with Rheumatoid Mason D, Luijtens K, et al. Eficacy and safety Arthritis receiving Methotrexate. N Engl J Med of certolizumab pegol plus methotrexate in 1999;340:253–9. active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann Rheum Dis 13. Westhovens R, Yocum D, Han J. The safety of 2009;68:797–804. inliximab, combined with background treatments, among patients with rheumatoid arthritis and 5. Fleischmann R, Vencovsky J, van Vollenhoven various comorbidities: a large, randomized, RF, Borenstein D, Box J, Coteur G, et al. Eficacy placebo-controlled trial. Arthritis Rheum and safety of certolizumab pegol monotherapy 2006;54:1075–86. every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic 14. Schiff M, Keiserman M. Eficacy and safety of therapy: the FAST4WARD study. Ann Rheum Dis abatacept or inliximab vs placebo in ATTEST: 2009;68:805–11. a phase III, multi-centre, randomised, double- blind, placebo-controlled study in patients with 6. Bucher HC, Guyatt GH, Grifith LE, Walter SD. The rheumatoid arthritis and an inadequate response to results of direct and indirect treatment comparisons methotrexate. Ann Rheum Dis 2008;67:1096–103. in meta-analysis of randomized controlled trials. J Clin Epidemiol 1997;50:683–91. 15. Strand V, Balbir-Gurman A, Pavelka K. Sustained beneit in rheumatoid arthritis following one

course of rituximab: improvements in physical 17. Nixon RM, Bansback N, Brennan A. Using mixed function over 2 years. Rheumatology (Oxford) treatment comparisons and meta-regression to 2006;45:1505–13. perform indirect comparisons to estimate the eficacy of biologic treatments in rheumatoid 16. Smolen JSB. Effect of interleukin-6 receptor arthritis. Stat Med 2007;26:1237–54. inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double- blind, placebo-controlled, randomised trial. Lancet 2008;371:987–97.

10 DOI: 10.3310/hta14suppl2/02 Health Technology Assessment 2010; Vol. 14: Suppl. 2

Capecitabine for the treatment of advanced gastric cancer

G Norman,* M Soares, P Peura, S Rice, D Suh, K Wright, M Sculpher and A Eastwood

Centre for Reviews and Dissemination, University of York, York, UK

*Corresponding author

Declared competing interests of authors: M Sculpher has a minority shareholding in a consulting company that has undertaken work for Roche during the last 3 years, but not in the clinical area of gastric cancer. He did not participate personally in this consultancy. M Seymour is a co-investigator in a trial (‘321GO’), which includes capecitabine as treatment for patients with advanced gastroesophageal cancer. The trial is peer reviewed and funded by Cancer Research UK, but also receives some supplementary inancial support from Roche (£50k over 2 years). M Seymour also attended the ASCO Oncology Conference last year as a guest of Roche. D Suh is also a co-investigator on the ‘321GO’ study. Roche have also offered to sponsor his trip to ASCO this year. Stephen Kelly accepted inancial support from Roche in 2008 and 2009 to attend the British Oncology Pharmacists Association Annual Symposium on behalf of the Leeds Teaching Hospitals NHS Trust Pharmacy Department.

Abstract HTA 08/85/01

This paper presents a summary of the evidence Date of ERG submission: review group (ERG) report into capecitabine for 16 February 2010 advanced gastric cancer (aGC). Capecitabine is an TAR Centre(s): oral prodrug of 5-luorouracil (5-FU). The decision CRD and CHE Technology Assessment Group problem addressed was the use of capecitabine (X) List of authors: compared to 5-FU (F), in combination regimens G Norman, M Soares, P Peura, S Rice, D Suh, with platinum agents [cisplatin (C) or oxaliplatin K Wright, M Sculpher and A Eastwood (O)] with or without epirubicin (E), in patients with Contact details: inoperable aGC. Approximately 7000 new cases Gill Norman, Centre for Reviews and Dissemination, of gastric cancer are diagnosed in England and University of York, York YO10 5DD, UK Wales every year. Of these, 80% are candidates for E-mail: [email protected] palliative chemotherapy and around 2900 receive such treatment. The standard UK practice for The research reported in this article of the journal patients with aGC who are considered it enough supplement was commissioned and funded by the HTA has consisted of a triplet regimen comprising programme on behalf of NICE as project number 08/95/01. intravenous 5-FU in combination with a platinum The assessment report began editorial review in June 2010 and was accepted for publication in July 2010. See the agent (capecitabine or oxaliplatin) and epirubicin. HTA programme website for further project information The manufacturer’s submission (MS) focused on (www.hta.ac.uk). This summary of the ERG report was direct evidence from two phase III non-inferiority compiled after the Appraisal Committee’s review. randomised controlled trials (RCTs), REAL-2 (Randomized ECF for Advanced and Locally The views and opinions expressed therein are those of the authors and do not necessarily relect those of the advanced oesophagogastric cancer-2; n = 1002) and Department of Health. ML17032 (n = 316). REAL-2 randomised patients to four regimens (ECF, ECX, EOF and EOX) to Discussion of ERG reports is invited. Visit the HTA website compare 5-FU with capecitabine and cisplatin correspondence forum (www.hta.ac.uk/correspond). with oxaliplatin, whereas ML17032 compared CX with CF. Eficacy outcomes from these trials were 11

pooled in an individual patient data (IPD) meta- Introduction analysis. Both RCTs demonstrated statistically signiicant non-inferiority of capecitabine on the The National Institute for Health and Clinical outcome of overall survival (OS) assessed in the Excellence (NICE) is an independent organisation per-protocol population; equivalent results were within the NHS that is responsible for providing also demonstrated for progression-free survival national guidance on the treatment and care of (PFS). The IPD meta-analysis found a statistically people using the NHS in England and Wales. signiicant beneit in OS for capecitabine One of the responsibilities of NICE is to provide compared with 5-FU [unadjusted hazard ratio guidance to the NHS on the use of selected new (HR): 0.87; 95% conidence interval (CI) 0.77 and established health technologies, based on an to 0.98, p = 0.027]. There was no evidence of a appraisal of those technologies. poorer safety proile for capecitabine overall, nor of any difference in quality of life (QoL) between NICE’s single technology appraisal (STA) the two luoropyrimidines. The MS included a process1 is speciically designed for the appraisal de novo economic evaluation based on a cost- of a single product, device or other technology, minimisation analysis (CMA), where the costs with a single indication, where most of the of capecitabine-based regimens were compared relevant evidence lies with one manufacturer with their equivalent 5-FU-based regimens in or sponsor (Roche). Typically, it is used for new aGC. A time horizon of 5.5 cycles (each lasting pharmaceutical products close to launch. The for 21 days) was used in the base-case analysis, principal evidence for an STA is derived from a representing the duration of treatment. The results submission by the manufacturer/sponsor of the of the manufacturer’s base-case analysis showed technology. In addition, a report reviewing the that capecitabine regimens are associated with evidence submission is prepared by the evidence mean net cost savings of £1620 (ECX vs ECF), review group (ERG), an external organisation £1572 (EOX vs EOF) and £4210 (CX vs CF). The independent of the Institute. This paper presents manufacturer failed to comment explicitly on the a summary of the ERG report for the STA entitled uncertainty around the estimates of eficacy and ‘Capecitabine for the treatment of advanced gastric on the fact that the IPD meta-analysis suggests cancer’.2 that capecitabine may actually be more effective on average. Further analyses exploring additional Description of the underlying costs incurred by the UK NHS from extending health problem survival duration showed that these are unlikely to have a material effect on conclusions. A full Gastric cancer is the 10th most commonly probabilistic analysis was not performed; however, diagnosed cancer in the UK, with approximately the evidence explored by the MS and ERG is 7000 new cases diagnosed in England and consistent in suggesting that capecitabine has a Wales every year. Of these, some 80% of patients lower mean cost than 5-FU-based regimens. The are unsuitable for curative treatment and are submission was considered to contain convincing candidates for palliative chemotherapy. It is evidence of the non-inferiority of capecitabine to estimated that just over one-half (around 2900) of 5-FU on survival; this evidence was considered these patients with advanced gastric cancer (aGC) to be applicable to UK practice. Although some receive such treatment. uncertainty remains, the ERG deemed CMA to be an appropriate framework with which to analyse The standard UK practice for patients with aGC, this decision problem. Overall cost estimates for who are considered it enough, has consisted of the CMA were generated appropriately and were a triplet regimen comprising a luoropyrimidine, robust to uncertainties regarding assumptions intravenous 5-luorouracil (5-FU) in combination and sources. At the time of writing, the guidance with a platinum agent (cisplatin or oxaliplatin) and document issued by NICE on 28 July 2010 states an anthracycline (epirubicin). that capecitabine in combination with a platinum- based regimen is recommended for the irst-line Scope of the ERG report treatment of inoperable advanced gastric cancer. The decision problem addressed was the use of capecitabine (Xeloda) in combination with platinum-based chemotherapy regimens (cisplatin or oxaliplatin) with or without epirubicin, compared with 5-FU in combination with such 12 Health Technology Assessment 2010; Vol. 14: Suppl. 2

regimens, in patients with inoperable aGC. also undertook additional sensitivity analyses Capecitabine is an oral prodrug of 5-FU, and is based on the revised base case, and conducted licensed for the irst-line treatment of aGC in a threshold analysis, evaluating the maximum combination with a platinum-based regimen. costs that the NHS would be willing to pay for the Oral chemotherapies are usually considered to extension of survival time implied by prespeciied be preferred by patients and may have fewer cost-effectiveness thresholds. associated costs and/or adverse events.

The outcome measures considered were overall Results survival (OS), progression-free survival (PFS), Summary of submitted response rates, adverse effects of treatment and clinical evidence health-related quality of life (QoL). These were assessed in direct comparisons by two open-label The MS focused on direct evidence from two phase non-inferiority randomised controlled trials III non-inferiority RCTs.3,4 (RCTs), assessing doublet or triplet regimens.3,4 Eficacy outcomes from these trials were Economic outcomes included cost per life-year pooled in an individual patient data (IPD) gained (LYG) and cost per quality-adjusted life- meta-analysis.7 REAL-2 (Randomized year (QALY) gained. The manufacturer proposed ECF for Advanced and Locally advanced evaluating the cost-effectiveness of capecitabine- oesophagogastric cancer-2) was a 2 × 2 factorial based regimens compared with 5-FU-based trial that compared 5-FU with capecitabine regimens by using cost-minimisation analyses and cisplatin with oxaliplatin.3 The following (CMAs). regimens were used: epirubicin + cisplatin + 5-FU (ECF); epirubicin + cisplatin + capecitabine Methods (ECX); epirubicin + oxaliplatin + 5-FU (EOF); and epirubicin + oxaliplatin + capecitabine The ERG report comprised a critical review of the (EOX). A second trial, ML17032, compared evidence for the clinical effectiveness and cost- cisplatin + capecitabine (CX) with cisplatin + 5-FU effectiveness of the technology, based upon the (CF).4 manufacturer’s/sponsor’s submission (MS) to NICE as part of the STA process. The ERG checked the REAL-2 found statistically signiicant non- literature searches and carried out a search for inferiority of capecitabine on the primary ongoing trials. The review methodology including outcome of OS assessed in the per-protocol inclusion criteria was appraised. The validity population adjusted [hazard ratio (HR) 0.89, 95% assessments of the included RCTs were critiqued conidence interval (CI) 0.77 to 1.02]. ML17032 and the ERG carried out its own assessment using found statistically signiicant non-inferiority of the CRD guidelines for the critical appraisal of capecitabine on the primary outcome of PFS in RCTs. the per-protocol population (adjusted HR 0.85, 95% CI 0.65 to 1.11). Statistically signiicant non- In evaluating the cost effectiveness of capecitabine, inferiority on OS (unadjusted HR 0.85, 95% CI the manufacturer used a cost-minimisation 0.64 to 1.13) was also demonstrated. approach. The ERG has thus irst commented on the appropriateness of using such methodology, The IPD meta-analysis of the intention-to-treat within this speciic decision problem, taking into (ITT) populations of the REAL-2 and ML17032 consideration NICE’s reference case methods.5 trials found a statistically signiicant beneit in OS Next, the ERG assessed the manufacturer’s de for capecitabine compared with 5-FU (unadjusted novo economic evaluation using Drummond et HR 0.87, 95% CI 0.77 to 0.98, p = 0.027).7 al.’s checklist.6 In response to the ERG’s points of clariication regarding the initial submission, the There was minimal QoL data reported in the MS. manufacturer provided additional evidence on the The REAL-2 trial was reported as assessing QoL costs of adverse events, drug acquisition inputs and using the European Organization for Research and costs of additional survival. The ERG considered Treatment of Cancer Quality of Life Questionnaire this evidence throughout. Based on the identiied C30 (EORTC-30), version 3,8 administered at limitations in the MS, the ERG revisited the base baseline, and after 3, 6, 9 and 12 months. The case according to drug use, unit costs of treatments manufacturer subsequently provided the levels and pharmacy drug preparation costs. The ERG of compliance, data on the baseline scores for all 13

subscales, and changes from baseline at 12 weeks Summary of submitted cost- and 24 weeks for the REAL-2 trial. These showed effectiveness evidence few statistically signiicant differences between the The manufacturer’s literature search identiied individual trial arms. one economic evaluation relevant to this decision problem. This was Roche’s 2007 submission to the Safety analyses showed some signiicant differences Scottish Medicines Consortium for capecitabine in in adverse events proiles between capecitabine this indication. The methods and results reported and 5-FU regimens. However, in the REAL-2 trial, are consistent with the current submission. all statistical analyses were pairwise comparisons with the ECF arm, which the trial was not powered The MS included a de novo economic evaluation to assess. Of particular note was grade 3 or 4 based on a CMA, where the costs of capecitabine- neutropenia, which occurred signiicantly more based regimens were compared with their often in the ECX arm (p < 0.05) and signiicantly equivalent 5-FU-based regimens (ECX vs ECF, less often in the EOX and EOF arms (p < 0.01) EOX vs EOF, CX vs CF) in the treatment of compared with the ECF arm; grade 3 or 4 advanced gastric cancer. A time horizon of 5.5 diarrhoea, which occurred signiicantly more often cycles (each lasting for 21 days) was used in the in the EOX and EOF arms compared with the base-case analysis, representing the duration of ECF arm (p < 0.05); and grade 3 or 4 hand–foot treatment of the alternative regimens. syndrome, which occurred signiicantly more often in the ECX arm compared with the ECF The cost-minimisation approach was based on arm (p < 0.05). In the ML17032 trial, stomatitis evidence from two clinical trials – REAL-2 and occurred more often, and with greater severity, in ML17032 – reporting that capecitabine is at least the CF arm, while hand–foot syndrome was more as effective as intravenous 5-FU (see above). The common in the CX arm. calculations considered costs relating to drug acquisition and to drug administration. The drug administration costs comprised the costs of

TABLE 1 Drug administration activities costed for each cycle of a treatment regimen and the days in each cycle (of 21 days) during which the activity takes place

ECF and ECX and Activity/component Activity cost (£) EOF EOX CF CX Line insertion 445.77 Day 1a Day 1a Drug delivery, 1st attendance; 281.45 Day 1 Day 1 Day 1b Day 1 outpatient/day case Drug delivery, subsequent 36.83 Days 7, 14 attendances; nurse cost to lush central line a change pump Drug delivery, subsequent 198.72 Days 2–4b attendances; outpatient/day case Drug delivery; inpatient stay 5 1435.64 Days 1–5c days Pump cost 38.50 Days 1, 7, 14 Transport cost (20% of patients) 28.43 Days 1, 7, 14 Day 1 Days 1–5 Pharmacy preparation ‘Complex’ Days 7, 14 Day 1 Days 1–5 Day 1 (intravenous): 41.87 ‘Complex’ ‘Simple’ ‘Complex’ ‘Simple’ ‘Simple’ (oral): 25.34

CF, cisplatin + 5-FU; CX, cisplatin + capecitabine; ECF, epirubicin + cisplatin + 5-FU; ECX, epirubicin + cisplatin + capecitabine; EOF, epirubicin + oxaliplatin + 5-FU; EOX, epirubicin + oxaliplatin + capecitabine; 5-FU, 5-luorouracil. a Line insertion was only considered at the start of the irst cycle. b Base-case activity. c Activity in scenario analysis, which replaces the outpatient/day case drug-delivery activities. Shaded cells indicate that the activity was not costed for the regimen. 14 Health Technology Assessment 2010; Vol. 14: Suppl. 2

hospital visits (central line insertion, delivery of although these patients are signiicantly younger chemotherapy, and subsequent care by a nurse than the UK aGC patient population as a whole. to lush central line and change the pump), The trial included a majority of patients who pharmacy drug preparation costs, ambulatory are outside the licensed indication, having pump costs and NHS transport costs (Table 1). advanced inoperable cancer of the oesophagus The manufacturer assumed that there were no or gastroesophageal junction. The ERG’s clinical signiicant economically important differences experts conirmed that treatment for each of these in the incidence or severity of adverse events cancers would follow the same course as that for between capecitabine and 5-FU-based regimens, advanced inoperable gastric cancer. There was also and therefore the costs of treatment-related no evidence of a statistically signiicant difference adverse events were not included in the analysis. in prognosis based on primary tumour location.9 After a request for clariications, the manufacturer presented the expected costs associated with the The ML17032 (n = 316) trial assessed doublet relevant adverse events. therapy, which the ERG’s clinical advisors indicated would be used in patients who were considered The results of the manufacturer’s base-case unable to tolerate triplet therapy. However, such analysis showed that capecitabine regimens are doublets would be given at a lower dose than was cost saving compared with their equivalent 5-FU- used in the trial. The trial population was also based regimens. The total net cost savings for unrepresentative of UK patients, being younger capecitabine-based regimens were £1620 (ECX and having a different ethnic composition. When vs ECF), £1572 (EOX vs EOF), and £4210 (CX the non-inferiority analyses of eficacy outcomes vs CF). Capecitabine remained cost saving in were performed using a margin of 1.25 relative the manufacturer’s one-way sensitivity analysis, to the eficacy of 5-FU, rather than 1.40 as the scenario analysis and worst-case analysis. The protocol had speciied, the trial had only 50% manufacturer did not conduct probabilistic power to detect statistically signiicant non- sensitivity analysis or subgroup analysis. The inferiority. submission also included a threshold analysis that explored the additional effectiveness (in terms of Both trials were necessarily open-label, and QALYs) needed for 5-FU to be considered cost- REAL-2 was unblinded for all outcomes, whereas effective. for ML1703 the MS reported blinded outcome assessment only for the primary outcome of PFS. Commentary on the robustness The ERG requested these independently assessed of submitted evidence data for the outcomes of tumour response and adverse events. The manufacturer subsequently The MS appears to include all relevant evidence supplied these data for response rates and, from completed RCTs with respect to the question although differences in the data sets were present, of eficacy; the ERG’s search revealed no additional there was no indication of systematic bias. completed RCTs, although one additional ongoing trial was located. The primary weakness of the initial MS was the limited QoL data. This is of particular importance The ERG identiied a number of issues and errors where the decision problem centres on an issue of in the review process, which had the potential clinical non-inferiority and patient preference. to exclude relevant studies. However, it did not appear that this had impacted on the results of the With respect to economic evaluation, the ERG review. deems CMA to be an appropriate framework with which to analyse the decision problem. However, it Two RCTs that directly addressed the comparison should be noted that the appropriateness of using between capecitabine and 5-FU in combination such an approach is dependent not only on clinical with platinum in the licensed population were evidence from the REAL-2 and ML17032 trials, included. but also on evidence relating to QoL and adverse events. The weaknesses identiied above regarding The REAL-2 trial was large (n = 1002), adequately the evidence presented by the manufacturer are powered, and closely relective of UK standard therefore relevant. The manufacturer has also practice. The patient population was also failed fully to consider uncertainty when justifying representative of those UK patients who were the use of CMA. considered it enough for standard chemotherapy, 15

TABLE 2 Estimated overall NHS incremental costs reported in the manufacturer’s (MS) base-case and worst-case scenario proile for capecitabine overall. There was also no analysis, and results from the ERG’s additional analysis evidence of any difference in QoL between the two luoropyrimidines. Cost (£) Although some uncertainty remains over the issues ECX vs EOX vs CX vs ECF EOF CF identiied above, the ERG deems CMA to be an appropriate framework with which to analyse the Base case current decision problem. Overall, cost estimates for the CMA were generated appropriately and MS –1620 –1572 –4210 were robust to uncertainties regarding assumptions ERG –1585 –1538 –4060 and sources. Worst-case scenario MS –74 –41 –1175 Summary of NICE guidance ERG –213 –180 –965 issued as a result of the STA CF, cisplatin + 5-FU; CX, cisplatin + capecitabine; ECF, epirubicin + cisplatin + 5-FU; ECX, epirubicin + cisplatin At the time of writing, the guidance document + capecitabine; EOF, epirubicin + oxaliplatin + 5-FU; EOX, issued by NICE on 28 July 2010 states that: epirubicin + oxaliplatin + capecitabine; ERG, evidence review group; MS, manufacturer’s submission. Capecitabine in combination with a platinum- based regimen is recommended for the irst-line treatment of inoperable advanced gastric cancer. Overall, cost estimates for the CMA were generated appropriately. The ERG identiied a number of shortcomings and potential uncertainties related Acknowledgements to resource utilisation, unit costs, utilities and sensitivity analysis in the MS. However, these were Matthew Seymour, Professor of Gastrointestinal considered minor, and additional analysis provided Cancer Medicine, Cancer Research UK Clinical by the manufacturer, and further evaluations by the Centre, University of Leeds, Leeds, UK. ERG, showed no impact on the overall conclusions. Results from the MS and ERG’s additional analysis Daniel Swinson, Medical Oncologist, St James’s are compared in Table 2. Institute of Oncology, St James’s University Hospital, Leeds, UK. A full probabilistic analysis was not performed, so the probabilities that capecitabine is less and more Stephen Kelly, Advanced Clinical Pharmacist costly than its comparators have not been formally for Oncology & Oncology/Haematology Clinical quantiied. However, the mean estimates, sensitivity Trials, St James’s Institute for Oncology, St James’s analyses and worst-case scenario are consistent University Hospital, Leeds, UK. in suggesting that capecitabine has a lower mean cost than 5-FU-based regimens. Further analyses exploring the additional costs incurred by the NHS Key references resulting from extending survival duration show 1. National Institute for Health and Clinical that these are unlikely to have a material effect on Excellence (NICE). Guide to the single technology decision-making regarding capecitabine. (STA) process. London: NICE; 2006. URL: www.nice. org.uk/page.aspx?o=STAprocessguide.

Conclusions 2. Centre for Reviews & Dissemination and Centre for Health Economics Technology Assessment Group. The submission was considered to contain Capecitabine for the treatment of advanced gastric cancer: a single technology appraisal. York: University of York, convincing evidence of the non-inferiority of CRD; 2010. capecitabine to 5-FU on the outcomes of OS and PFS; this evidence was considered to be 3. Cunningham D, Starling N, Rao S, Iveson T, applicable to UK practice. There was evidence Nicolson M, Coxon F, et al. Capecitabine and of some differences in adverse event proiles, oxaliplatin for advanced esophagogastric cancer. but there was no evidence of a poorer safety N Engl J Med 2008;358:36–46.

16 Health Technology Assessment 2010; Vol. 14: Suppl. 2

4. Kang YK, Kang WK, Shin DB, Chen J, Xiong based combination chemotherapy and infused J, Wang J, et al. Capecitabine/cisplatin versus 5-luorouracil-based combination chemotherapy 5-luorouracil/cisplatin as irst-line therapy for the treatment of advanced oesophago-gastric in patients with advanced gastric cancer: a cancer. Ann Oncol 2009;20:1529–34. randomised phase III noninferiority trial. Ann Oncol 2009;20:666–73. 8. Aaronson N, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez N, et al. The European Organization 5. National Institute for Health and Clinical for Research and Treatment of Cancer QLQ-C30: Excellence (NICE). Guide to the methods of technology a quality-of-life instrument for use in international appraisal. London: NICE; 2008. clinical trials in oncology. J Natl Cancer Inst 1993;85:365–76. 6. Drummond M, Sculpher M, Torrance G, O’Brien BJ, Stoddart G. Methods for the economic evaluation 9. Chau I, Norman AR, Cunningham D, Oates of health care programmes. 3rd edn. Oxford: Oxford J, Hawkins R, Iveson T, et al. The impact of University Press; 2005. primary tumour origins in patients with advanced oesophageal, oesophago-gastric junction and gastric 7. Okines AFC, Norman AR, McCloud P, Kang YK, adenocarcinoma: individual patient data from Cunningham D. Meta-analysis of the REAL-2 1775 patients in four randomised controlled trials. and ML17032 trials: evaluating capecitabine- Ann Oncol 2009;20:885–91.

DOI: 10.3310/hta14suppl2/03 Health Technology Assessment 2010; Vol. 14: Suppl. 2

Rituximab for the treatment of relapsed/ refractory chronic lymphocytic leukaemia

J Dretzke,1* P Barton,2 B Kaambwa,2 M Connock,1 O Uthman,1 S Bayliss1 and C Meads1

1Unit of Public Health, Epidemiology and Biostatistics, University of Birmingham, Birmingham, UK 2Unit of Health Economics, University of Birmingham, Birmingham, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 08/94/01

This paper presents a summary of the evidence Date of ERG submission: review group (ERG) report on the clinical 14 September 2009 effectiveness and cost-effectiveness of rituximab TAR Centre(s): with chemotherapy compared to chemotherapy West Midlands Health Technology Assessment only for the treatment of relapsed/refractory Collaboration chronic lymphocytic leukaemia (CLL) based on List of authors: the manufacturer’s submission to the National J Dretzke, P Barton, B Kaambwa, M Connock, O Uthman, Institute for Health and Clinical Excellence (NICE) S Bayliss and C Meads as part of the single technology appraisal (STA) Contact details: process. Evidence was available in the form of one Janine Dretzke, Unit of Public Health, Epidemiology open-label, ongoing, unpublished randomised and Biostatistics, University of Birmingham, Edgbaston, controlled trial (RCT), REACH (Rituximab in Birmingham B15 2TT, UK the Study of Relapsed Chronic Lymphocytic E-mail: [email protected] Leukemia), conducted by the manufacturer, which compared rituximab with a ludarabine The research reported in this article of the journal and cyclophosphamide combination (R-FC) to supplement was commissioned and funded by the HTA programme on behalf of NICE as project number 08/94/01. ludarabine and cyclophosphamide (FC) only. The assessment report began editorial review in October REACH was scheduled to run for 8 years; however, 2009 and was accepted for publication in November 2009. the data provided were immature, with a median See the HTA programme website for further project observation time at the time of data analysis of information (www.hta.ac.uk). This summary of the ERG 2.1 years. REACH provided evidence of prolonged report was compiled after the Appraisal Committee’s progression free survival with R-FC compared to FC review. (10 months, investigators’ data), but no evidence The views and opinions expressed therein are those of of an overall survival beneit with R-FC. Patients the authors and do not necessarily relect those of the refractory to ludarabine and with prior rituximab Department of Health. exposure were excluded from REACH and no Discussion of ERG reports is invited. Visit the HTA website controlled studies were identiied by the ERG correspondence forum (www.hta.ac.uk/correspond). for these patient groups. The ERG had concerns about the structure of the economic model submitted by the manufacturer, which did not allow

improvement in quality of life from treatment while Description of the underlying in a progressed state. The manufacturer’s model health problem further assumed a divergence in cumulative deaths The underlying health problem is relapsed/ between the R-FC and FC treatment arms from the progressed and refractory chronic lymphocytic outset, which did not accord with observed data leukaemia (CLL). CLL is deined as relapsed in a from REACH. When the survival advantage was patient who has previously achieved the criteria removed, the manufacturer’s base-case incremental for a complete or partial response, but after a cost-effectiveness ratio (ICER) changed from period of 6 or more months demonstrates evidence £15,593 to between £40,000 and £42,000 per of disease progression. Refractory disease is quality-adjusted life-year (QALY). With no survival deined as treatment failure (stable disease or non- advantage, the ICER became sensitive to changes response) or disease progression within 6 months in utility. There was no good empirical evidence of the last therapy.3 Median age at diagnosis on the utility of CLL patients in different states. lies between 65 and 70 years, so will be higher Allowing for the possibility of a survival advantage for relapse, and the incidence rate at diagnosis with rituximab (although not supported by current is 3/100,000. The proportion of patients that evidence), the ERG performed further modelling, progress in a 1-year period is estimated at 30–40% which found that rituximab would be cost-effective (Dr Jim Murray, University Hospitals Birmingham, at £20,000/QALY (£30,000/QALY) if a reduction in personal communication). Prognosis can vary survival advantage relative to the manufacturer’s depending on the presence or absence of various base case of 40% (80%) was assumed. The guidance cytogenetic abnormalities. Loss or mutation in the issued by NICE in July 2010 as a result of the p-arm of chromosome 17 (del 17) is associated with STA recommends rituximab with FC for people decreased survival. with relapsed or refractory chronic lymphocytic leukaemia, except when the condition is refractory Treatment of CLL is with cytotoxic drugs/drug to ludarabine or where there has been previous combinations (chemotherapy) including alkylating treatment with rituximab. agents (chlorambucil, cyclophosphamide, bendamustine) or antimetabolites/purine analogues (ludarabine, cladripine). Drug combinations Introduction are also used, such as FC (ludarabine and cyclophosphamide), CHOP [cyclophosphamide, The National Institute for Health and Clinical doxorubicin hydrochloride, vincristine (also Excellence (NICE) is an independent organisation called oncovin), prednisolone] and CVP within the NHS that is responsible for providing [cyclophosphamide, vincristine (also called national guidance on the treatment and care of oncovin), prednisolone]. Monoclonal antibodies people using the NHS in England and Wales. (biological therapy, immunotherapy) such as One of the responsibilities of NICE is to provide rituximab or alemtuzumab are also used, with guidance to the NHS on the use of selected new rituximab (+FC) recently approved for irst-line and established health technologies, based on an treatment by NICE [technology appraisal (TA) appraisal of those technologies. 1744].

NICE’s single technology appraisal (STA) process1 In UK practice, most patients receive ludarabine is speciically designed for the appraisal of a or FC as irst-line treatment then on progression single product, device or other technology, with may receive F(C) again, CVP, CHOP or CVP/ a single indication, where most of the relevant CHOP with (off-licence) rituximab. Chlorambucil evidence lies with one manufacturer or sponsor is predominantly reserved for patients unable (here, Roche Products Ltd). Typically, it is used to tolerate ludarabine or FC. Testing for for new pharmaceutical products close to launch. genetic markers for tailoring treatment is not The principal evidence for an STA is derived from routinely undertaken but is being investigated a submission by the manufacturer/sponsor of the in clinical trials. The choice of irst and second- technology. In addition, a report reviewing the line treatment, and the decision about the stage evidence submission is submitted by the evidence of disease at which to (re-)initiate treatment is review group (ERG), an external organisation made on a patient-by-patient basis and varies independent of NICE. This paper presents a according to regional treatment policies, previous summary of the ERG report for the STA entitled treatment(s) and itness of the patient. The British ‘Rituximab for relapsed/refractory chronic lymphocytic Committee for Standards in Haematology 2004 leukaemia’.2 20 Health Technology Assessment 2010; Vol. 14: Suppl. 2

guidelines5 are in the process of being updated to (non-preference based) utility values were obtained relect indings of recent trials. from the literature.7

Scope of the evidence review group report Methods

The key research question was the clinical The ERG report comprised a critical review of the effectiveness and cost-effectiveness of rituximab evidence for the clinical effectiveness and cost- plus chemotherapy compared to chemotherapy effectiveness of the technology based upon the only in the treatment of patients with relapsed/ manufacturer’s/sponsor’s submission to NICE as refractory CLL, including patients with a del part of the STA process. 17p mutation. Rituximab (MabThera®; Roche Products Ltd, Welwyn Garden City, UK) in The ERG reran the searches for RCTs using slightly combination with chemotherapy has been licensed modiied versions of the search strategies employed for use in relapsed/refractory chronic lymphocytic by the manufacturer and independently assessed leukaemia.6 the validity of the REACH trial. The ERG also looked at commercial-in-conidence (CIC) results The bulk of the clinical effectiveness data based on an independent (blinded) assessment submitted by the manufacturer was based on one of progression (as well as the investigators’ ongoing, open-label, 8-year randomised controlled assessment); summary data (rather than individual trial (RCT) [REACH (Rituximab in the Study patient data) on the independent analysis were of Relapsed Chronic Lymphocytic Leukemia), supplied by the manufacturer in a separate n = 552], which compared rituximab with a document. ludarabine and cyclophosphamide combination (R-FC) versus FC alone. At the time of data analysis The main results on PFS and OS in the submission (on which this report is based) median observation were presented in Kaplan–Meier plots. These time was 2.1 years. Refractory patients included plots were modelled using a variety of parametric in the trial were those refractory to alkylators distributions (exponential, lognormal, log logistic, (CHOP, CVP, chlorambucil). The trial was not Weibull, Gompertz and gamma) to identify the best representative of all UK rituximab eligible patients itting function according to Akaike’s information as it excluded those refractory to ludarabine and criteria. For economic modelling, the its were those with prior rituximab exposure. Outcome extrapolated beyond observed data to a time measures in REACH were progression-free survival horizon of 25 years. The ERG would have liked (PFS), overall survival (OS), event-free survival and to independently obtain their own parametric its response rates. Quality of life (QoL) measurements in order to (a) test the biological plausibility of all were based on the Functional Assessment of Cancer the PFS extrapolations used in the manufacturer’s Therapy-General and measured for 1 year only and economic modelling, (b) make a comparison of the only up to the time of a patient experiencing an relative advantage of R-FC versus FC delivered by event. the various parametric models and (c) effectively compare the investigator and independent Further (unpublished) evidence was submitted assessments of PFS. This was not possible as by the manufacturer in the form of uncontrolled individual patient data were not made available, studies to support evidence of effectiveness of and furthermore not all the requested parameters rituximab in ludarabine refractory patients and for were supplied by the manufacturer. rituximab in combination with other chemotherapy regimens. The model structure and internal model validity were analysed by the ERG, and model parameters The manufacturer submitted an economic model to were assessed for their appropriateness. A number assess the cost per quality-adjusted life-year (QALY) of additional sensitivity analyses were run based of R-FC compared to FC. Clinical effectiveness on varying assumptions set out in the submission, parameters were based mainly on the REACH trial. and the effect on the incremental cost-effectiveness QoL in REACH was not measured in a way that ratio (ICER) was assessed. allowed conversion into utility values. Estimated

Results Non-randomised studies Summary of submitted The manufacturer provided data from one clinical evidence uncontrolled study on salvage therapy with R-FC in sub-groups of patients with and without prior Progression-free survival ludarabine exposure, and with and without prior Investigators’ assessment The curves for the rituximab exposure. These conidential results were FC and R-FC arm were similar in slope for provided ahead of publication, and the ERG were most of the time represented but separated unable to identify data in the public domain. from each other especially during a 3-month period between 15 and 18 months. There was a Summary of submitted cost- statistically signiicant difference in median time to effectiveness evidence progression of 10.2 months in favour of R-FC. At the time of this analysis, an event had occurred in The cost per QALY for the base case 53% of patients, the remainder were censored. (manufacturer’s calculation) was £15,593. This was based on utility values of 0.8 for PFS and 0.6 for Independent assessment An independent, blinded progression, and on a difference in mean life-years assessment of progression, which is less likely to between the R-FC arm and FC arm of 0.671, and be susceptible to bias, was performed as part of a difference in mean QALYs of 0.585. The results REACH. The results are CIC. for a number of one-way sensitivity analyses varied between £13,017 and £23,790. Parameters that Overall survival were varied in the submission include the utility At the time of data analysis, 75% (FC arm) and values, type of curve it, rituximab costs, adverse 78% (R-FC arm) of patients were still alive. Median event costs and supportive care costs. survival could not be estimated for the R-FC arm. The curves were the same for both arms up to A number of alternative analyses were carried out 2.5 years, after which they separated (Figure 1). by the ERG in order to test the effect of changes There was no statistically signiicant difference to various assumptions within the manufacturer’s between the curves (hazard ratio 0.83; 95% submission. The effects on the ICER can be found conidence interval 0.59 to 1.17). in Table 1.

1.0 Log-rank test 0.9 p = 0.2874

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0 0 91 182 273 364 455 546 637 728 819 910 1001 1092 1183 1274 1365 1456 1547 1638 1729 No. left FC 276 259 248 238 231 206 182 164 141 121 101 75 61 48 38 23 10 6 1 0 Days R–FC 276 266 259 249 236 207 185 167 154 141 125 106 85 66 45 30 16 11 3 0

FIGURE 1 Kaplan–Meier plot of overall survival (intention to treat) (from manufacturer’s submission). FC, ludarabine and cyclophosphamide; R-FC, rituximab, ludarabine and cyclophosphamide. 22 Health Technology Assessment 2010; Vol. 14: Suppl. 2

TABLE 1 Sensitivity analyses around ICER (performed by the ERG)

General issue Details for this submission Effect on ICER (£) (Roche base case following clariication questions) 15,593 Model structure Alternative choice of curves for PFS 13,140–17,317 Correction of minor errors of logic 15,584 Measurement of Removal of overall survival beneit from rituximab 31,009–47,963 effectiveness Use of PFS curves based on independent assessment of progression 16,911–17,467 Measurement of utility Halving and doubling difference between utilities for PFS and 13,017–17,306 progressed states Adverse events Doubling costs for rituximab arm only 16,455 Rituximab costs One fewer or one more 100-mg vial per cycle 13,803–17,383 Retiming of rituximab costs 15,277–20,110 Assessment of Independent (blinded) assessment rather than investigators’ 17,507 progression assessment (Weibull) Survival No OS beneit 40,568–42,444 Combination Independent assessment of progression combined with no OS beneit 44,669–48,385 Combination No OS beneit and utilities: PFS = 0.9; progressed = 0.5 20,284–21,222 Combination No OS beneit and utilities: PFS = 0.75; progressed = 0.65 81,135–84,889

ICER, incremental cost-effectiveness ratio; OS, overall survival; PFS, progression-free survival.

Removing the survival effect had the most makes it possible to consider any desired fraction substantial impact on the ICER and results were of the modelled advantage in overall survival from subsequently more sensitive to changes in utilities. rituximab. Table 2 shows the effect of such changes, using a Weibull curve for PFS. Similar patterns Intermediate results can be obtained by taking a could be expected for other curve options. weighted average of the two survival curves. This

TABLE 2 Effect of reducing overall survival advantage (modelled by ERG)

Case considered ICER (£)

Percentage reduction in OS advantage for rituximab Amended 1a Amended 2b 0 (as base case) 15,593 15,593 10 16,457 16,478 20 17,453 17,508 30 18,615 18,721 40 19,991 20,169 50 21,647 21,925 60 23,681 24,098 70 26,242 26,852 80 29,573 30,455 90 34,088 35,365 100 (no OS advantage) 40,568 42,444

ICER, incremental cost-effectiveness ratio; OS, overall survival. a The cumulative probability of death calculated in the comparator arm of the model was applied also to the rituximab arm. b The cumulative probability of death calculated for the rituximab arm was applied also to the comparator arm.

Commentary on the robustness relapsed patients were at Binet stage A, which of submitted evidence appears high. Younger and/or healthier patients The analysis relies on the results of a single open- are less likely to drop out due to side effects. label, unpublished, ongoing RCT with immature data (median observation time of only 2.1 years at In REACH, ludarabine and cyclophosphamide the time of analysis). were given as an infusion. These drugs are usually given orally in the UK. It is unclear whether this There was evidence that treatment with R-FC would have an impact on the effectiveness of the compared to FC alone results in a statistically drugs. signiicantly longer period of progression-free survival (10 months investigators’ assessment; There was no evidence on the effectiveness of R-FC independent assessment results CIC) in both compared to another treatment in ludarabine patients with and without the del 17 mutation. It is refractory patients or patients with prior rituximab likely that this delay was associated with QoL gains, exposure. although there was a lack of suitable empirical evidence. The model submitted by Roche follows the same structure as that used in the assessment of For OS, the median had not yet been reached in rituximab for irst line treatment of CLL. There the R-FC arm and 75% and 78% of patients were are three states in the model: PFS, progressed and still alive in the FC and R-FC arms respectively. death. No transition from progressed to PFS is There was no convincing evidence that there was possible. We share the concerns of the Peninsula a survival beneit in the R-FC arm. The Kaplan– Technology Assessment Group (PenTAG) about Meier curves separate out after 2.5 years (see this structure. In summary, this has the effect of Figure 1), and the ERG was unsure whether there combining all patients post-progression into a was a biologically plausible reason for why this single state. It is therefore not possible to improve might happen. Because of crossover from the FC QoL from treatment while in the progressed state. to the R-FC arm over time, the curves are likely to become increasingly susceptible to bias. There was considerable uncertainty associated with estimates of OS in the economic model. OS has The patients in REACH do not appear been modelled by applying death rates to the PFS representative of a general relapsed CLL and progressed states in each arm of the model population, but may be representative of those separately. The cumulative deaths modelled show eligible for treatment with FC. The median age a divergence between the two arms of the model in REACH was 63 years at relapse compared to from the start (Figure 2): this is not in accord with a median age of 65–70 years at diagnosis in the the observed pattern of deaths in the trial (see general population. Ten per cent of included Figure 1). When the survival advantage is removed,

1.00

0.86

0.73 R-FC cumulative progression FC cumulative progression 0.59 R-FC cumulative deaths 0.45 FC cumulative deaths Events (%) Events 0.31

0.18

0.04

8 16 24 32 40 48 56 64 72 80 88 96 104 112120 128 136 144 152 160 168 176 184 192 200 208 216 224 232 240 248 256 264 272 280 288 296 –0.10 Time (months)

24 FIGURE 2 Cumulative time to progression and death (from manufacturer’s submission). FC, ludarabine and cyclophosphamide; R-FC, rituximab, ludarabine and cyclophosphamide. Health Technology Assessment 2010; Vol. 14: Suppl. 2

the base-case ICER changes from £15,593 to survival beneit relative to the manufacturer’s base between £40,000 and £42,000/QALY. case was assumed. Further evidence is needed on whether there is a survival beneit, the extent of With no OS advantage for the rituximab arm, the this beneit and the associated utilities. Robust economic model output becomes sensitive to the evidence is lacking on (a) the effectiveness of R-FC differential in utility between the non-progressed in patients who have previously received FC, R-FC and the progressed state. There is a lack of or R-chemotherapy (other) as irst-line therapy and empirical evidence about the utility of patients in (b) the effectiveness of R-chemotherapy (other) as these states. treatment for relapsed CLL.

While a range of different parametric curves have been applied to the data for PFS, none of them is Summary of NICE guidance a particularly good it to the data, and there are issued as a result of the STA doubts about the long term extrapolation of these curves. NICE guidance from July 2010 recommends rituximab in combination with ludarabine and The model assumes that the costs of rituximab cyclophosphamide for people with relapsed or are incurred throughout a cycle, so a patient refractory chronic lymphocytic leukaemia, but progressing after half a cycle incurs only half of not when there has been previous treatment with that cycle’s cost. As rituximab is given as a one-off rituximab. Exceptions to the previous treatment infusion at the start of each cycle, this assumption with rituximab rule apply where this was in the does not seem appropriate. context of a clinical trial (with any chemotherapy), or at a dose lower than the dose currently licensed The model uses the investigators’ assessment of for chronic lymphocytic leukaemia. progression rather than the independent (blinded) assessments, which are likely to give less biased People who are currently receiving rituximab results. However, when parametric its were made in combination with ludarabine and to the independent analysis results, only small cyclophosphamide should have the option to differences in the resulting ICERs were observed continue treatment until they and their clinicians and the direction of change was not consistent. consider it appropriate to stop. The guidance is due to be reviewed in December 2010. An area of uncertainty is the difference in the cost of relapse therapy with rituximab (£9128) compared to the cost of irst line therapy (£11,617) Key references as given in the recent submission on rituximab in 1. NICE. Guide to single technology (STA) process. URL: CLL.8 www.nice.org.uk/media/42D/B3/STAguideLrFinal. pdf (accessed 24 September 2010).

Conclusions 2. Dretzke J, Barton P, Kaambwa B, Connock M, Uthman O, Bayliss S, Meads C. Rituximab for the The ERG found evidence that R-FC delays treatment of relapsed/refractory chronic lymphocytic progression by 10 months (investigators’ leukaemia. Birmingham, West Midlands Health Technology Assessment Collaboration, University assessment) compared to treatment with FC alone of Birmingham, September 2009. URL: http://www. in patients who have previously received alkylator- nice.org.uk/nicemedia/live/12042/46063/46063.pdf. containing chemotherapy or ludarabine alone, are ludarabine sensitive and are considered suitable 3. Hallek M, Cheson BD, Catovsky D, Caligaris- for treatment with FC. There was no evidence from Cappio F, Dighiero G, Dohner H, et al. current data to show that R-FC prolongs survival Guidelines for the diagnosis and treatment of compared to FC. With no survival beneit assumed chronic lymphocytic leukemia: a report from the in the economic model, the base-case ICER International Workshop on Chronic Lymphocytic changes from £15,593 to between £40,000 and Leukemia (IWCLL) updating the National Cancer £42,000/QALY and becomes sensitive to changes Institute-Working Group (NCI-WG) 1996 guidelines. in utility. Further modelling around a hypothetical Blood 2008;111:5446–56. survival beneit found that rituximab would be cost- 4. Technology Appraisal 174. Rituximab for ﬁrst line effective at a threshold of around £20,000/QALY treatment of chronic lymphocytic leukaemia. URL: www. (£30,000/QALY) when a 40% (80%) reduction in nice.org.uk/TA174 (accessed October 2010). 25

5. Oscier D, Fegan C, Hillmen P, Illidge T, Johnson 7. Hancock S, Wake B, Hyde C, Doordujin A. S, Maguire P, et al. Guidelines on the diagnosis and Fludaribine as ﬁrst line therapy for chronic lymphocytic management of chronic lymphocytic leukaemia. Br leukaemia. 2009. A West Midlands Health J Haematol 2004;125:294–317. Technology Assessment Collaboration Report 2002. Birmingham, University of Birmingham. 6. European Medicines Agency. Summary of product characteristics. 2010. URL: www.emea.europa.eu/ 8. Roche Products Limited. Rituximab for the 1st docs/en_GB/document_library/EPAR_Product_ line treatment of Chronic Lymphocytic Leukaemia. Information/human/000165/WC500025821.pdf./ 2009. URL: www.nice.org.uk/nicemedia/pdf/ RituximabSubmissionFinalCICAIC.pdf.

26 DOI: 10.3310/hta14suppl2/04 Health Technology Assessment 2010; Vol. 14: Suppl. 2

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

C Main,* M Pitt, T Moxham and K Stein

Peninsula Technology Assessment Group (PenTAG), Exeter, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 08/95/01

This paper presents a summary of the evidence Date of ERG submission: review group (ERG) report into the clinical 30 January 2009 effectiveness and cost-effectiveness of rituximab TAR Centre(s): for the irst-line treatment of chronic lymphocytic Peninsula Technology Assessment Group (PenTAG) leukaemia (CLL) based upon a review of the List of authors: manufacturer’s submission to the National C Main, M Pitt, T Moxham and K Stein Institute for Health and Clinical Excellence Contact details: (NICE) as part of the single technology appraisal Caroline Main, Peninsula Technology Assessment Group (STA) process. The manufacturer’s searches (PenTAG), Noy Scott House, Barrack Road, Exeter, UK for clinical effectiveness and cost-effectiveness data were appropriate and included all relevant E-mail: [email protected] studies. The submission’s evidence came The research reported in this article of the journal from a single, unpublished, well-conducted supplement was commissioned and funded by the HTA randomised controlled trial (RCT) comparing programme on behalf of NICE as project number 08/95/01. rituximab in combination with ludarabine and The assessment report began editorial review in April 2009 cyclophosphamide (R-FC) with ludarabine and was accepted for publication in May 2009. See the HTA programme website for further project information (www. and cyclophosphamide (FC) alone for the irst- hta.ac.uk). This summary of the ERG report was compiled line treatment of CLL. There was a statistically after the Appraisal Committee’s review. signiicant increase in progression-free survival (PFS) with R-FC compared with FC alone {median The views and opinions expressed therein are those of 39.8 months vs 32.2 months; hazard ratio [HR] the authors and do not necessarily relect those of the Department of Health. 0.56 [95% conidence interval (CI) 0.43 to 0.72]}. However, the initial signiicant treatment beneit Discussion of ERG reports is invited. Visit the HTA website for R-FC compared with FC for overall survival was correspondence forum (www.hta.ac.uk/correspond). 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 signiicantly superior to chlorambucil alone for both PFS and overall

and complete response rates. The incidence of product, device or other technology, for a single grade 3 or 4 adverse events was higher in the indication, for which most of the relevant evidence R-FC arm (77%) than in the FC arm (62%). Dose lies with one manufacturer or sponsor.1 Typically, modiications were also more frequent in this arm, it is used for new pharmaceutical products close but this did not lead to differences in treatment to launch. The principal evidence for an STA is discontinuation. Roche used a three-state Markov derived from a submission by the manufacturer/ model (PFS, progressed and death) to model sponsor of the technology. In addition, a report the cost-effectiveness of R-FC compared with FC reviewing the evidence submission is submitted and chlorambucil alone. The model used a cycle by the evidence review group (ERG), an external length of 1 month and a lifetime time horizon. organisation independent of NICE. This paper The approach taken to modelling was reasonable presents a summary of the ERG report for the STA and the sources and justiication of estimates of the clinical effectiveness and cost-effectiveness were generally sound. The base-case analysis of rituximab for the irst-line treatment of chronic produced an incremental cost-effectiveness ratio lymphocytic leukaemia.2 (ICER) of £13,189 per quality-adjusted life-year (QALY) for R-FC versus FC, and £6422 per QALY for the comparison of R-FC versus chlorambucil, Description of the suggesting that R-FC is cost-effective at normal underlying health problem willingness-to-pay thresholds. One-way sensitivity analyses produced a range of ICERs from £10,249 Chronic lymphocytic leukaemia (CLL) is the to £22,661 per QALY for R-FC versus FC, and most common type of leukaemia, comprising £5612 and £6921 per QALY for R-FC versus approximately 30% of all adult leukaemias. The chlorambucil. Probabilistic sensitivity analysis incidence is about 3 per 100,000, but this varies results matched the deterministic results very with age and sex. The median age of diagnosis closely. However, the sensitivity analysis did not is between 65 and 70 years, and men are twice as fully investigate the uncertainty associated with likely to be affected as women. Incidence increases differential values across arms or with the structural signiicantly with age, with a rate of almost 50 per assumptions of the model, and utility values were 100,000 in patients over 70 years. not drawn from an empirical study. The NICE guidance issued as a result of the STA states that: The exact causes of CLL remain unknown; Rituximab in combination with ludarabine and however, a combination of genetic and cyclophosphamide (R-FC) is recommended as environmental factors is thought to be involved. an option for the irst-line treatment of chronic The presentation of patients with CLL to health- lymphocytic leukaemia in people for whom care providers is typically heterogeneous, with ludarabine in combination with cyclophosphamide about 70–80% of patients diagnosed as an (FC) is considered appropriate. Rituximab in incidental inding following a full blood count test combination with chemotherapy agents other for some other reason. A deinitive diagnosis of than ludarabine and cyclophosphamide is not CLL has a characteristic lymphocyte morphology recommended for the irst-line treatment of on blood ilm, with a speciic immunophenotype chronic lymphocytic leukaemia. (as shown by low cytometry), and requires an absolute B-cell lymphocytosis of at least 5 × 109/l.

Introduction Two methods have been devised to stage CLL: the Binet and Rai systems. The Binet system is more The National Institute for Health and Clinical commonly used in Europe and comprises three Excellence (NICE) is an independent organisation stages: stage A, less than three lymphoid areas within the NHS that is responsible for providing involved; stage B, more than three lymphoid areas national guidance on the treatment and care of involved; and stage C, haemoglobin < 10 g/dl people using the NHS in England and Wales. or platelets 100 × 109/l. The course of CLL is One of the responsibilities of NICE is to provide heterogeneous and it is generally anticipated guidance to the NHS on the use of selected new that approximately one-third of patients (usually and established health technologies, based on an with Binet stage A disease) will never need any appraisal of those technologies. form of treatment and will die with, rather than of, their disease.3 For the remaining majority of NICE’s single technology appraisal (STA) process patients (usually with Binet stage B or C disease) is speciically designed for the appraisal of a single CLL is incurable and has a median life expectancy 28 Health Technology Assessment 2010; Vol. 14: Suppl. 2

of between 5 and 10 years. Standard criteria and cyclophosphamide (R-FC) versus ludarabine from the International Workshop on Chronic and cyclophosphamide (FC) alone the model Lymphocytic Leukaemia are used to guide whether was parameterised by effectiveness data from the patients should start treatment with a irst-line German Chronic Lymphocytic Leukaemia trial chemotherapeutic regimen.4 (CLL-8).5 For the comparison of R-FC versus chlorambucil monotherapy, HRs for PFS were As CLL is characterised by periods of active derived using a mixed-treatment comparison disease, during which patients are symptomatic, (MTC) model. Health-state utility values were taken separated by chemotherapy-induced remissions, from a report by Hancock and colleagues6 on the once patients have started treatment the main aim use of ludarabine as irst-line treatment for CLL; of therapy is to induce durable remissions during these values were estimated by the report authors. which patients are free of disease symptoms, the Costs were based on an NHS and Personal Social psychological burden of active life-threatening Services perspective. illness and the toxicity of chemotherapy. Stated potential health effects

Scope of the ERG report Rituximab is a chimeric murine/human monoclonal Research question antibody that binds selectively to the CD20 cell antigen expressed on the surface of mature B What is the clinical effectiveness and cost- lymphocytes and any tumour cell that expresses effectiveness of rituximab in combination with CD20, including B-cell CLL. It causes depletion ludarabine therapies versus ludarabine therapies of normal and malignant B cells. Although its alone or chlorambucil for the irst-line treatment of mechanism of action is not precisely deined, CLL? antibody-directed cytotoxicity, complement- dependent cytotoxicity, induction of apoptosis and Intervention sensitisation of cells to conventional cytotoxic drugs are all likely to be important.7–9 • Brand name: MabThera®. • Approved name: rituximab. Stated costs • Therapeutic class: antineoplastic agents. • Product licence holder: Roche Products. Rituximab is available in two vials sizes: 10-ml vial (minus VAT) = £174.63; 50-ml vial (minus Outcomes VAT) = £873.15.

Clinical effectiveness outcomes were progression- free survival (PFS), overall survival (OS), event- Methods free survival, disease-free survival, response rates, duration of response, time to new CLL treatment, The ERG report comprised a critical review of the health-related quality of life and adverse effects evidence for the clinical effectiveness and cost- of treatment. Cost-effectiveness outcomes were effectiveness of the technology based upon the incremental cost per quality-adjusted life-year manufacturer’s/sponsor’s submission to NICE as (QALY), resource utilisation and the cost of treating part of the STA process. adverse events (blood transfusions and bone marrow transplants). The manufacturer’s search strategy was reviewed by an information scientist and the searches were Type of clinical effectiveness/ rerun with text words and a full clinical trials ilter cost-effectiveness data used to see if any relevant trials had been omitted. The methods used by the manufacturer to report For clinical effectiveness, ‘time to event’ data were clinical effectiveness were critiqued using the used, reported as median time in either days or principles advocated in the Centre for Reviews and months with the point estimates expressed as Dissemination’s (CRD) guidance for undertaking hazard ratios (HRs) and 95% conidence intervals reviews in health care.10 Roche’s economic (CIs). For cost-effectiveness, Roche built a three- evaluation was assessed against the following state Markov model. For the comparison of study quality checklists: NICE reference case,11 rituximab (R) in combination with ludarabine Drummond and colleagues12 and Philips and

colleagues13 for decision model-based economic The incidence of grade 3 or 4 adverse events was evaluations. The model was extensively checked higher in the R-FC arm (77%) than in the FC and rerun to check for wiring and parameterisation arm (62%), mostly because of a higher incidence errors. of blood and lymphatic system disorders (57% versus 41%). Dose modiications were also more frequent in this arm. However, this did not lead Results to differences in treatment discontinuation. There Summary of submitted were also no difference between arms in the rate of clinical evidence deaths considered related to therapy (2%).

The evidence for the submission was based Mixed-treatment comparison model on one phase III randomised controlled trial Based on results of the ive trials included in the (RCT) comparing R-FC with FC for the irst-line MTC5,14–17 (with chlorambucil used as the reference treatment of people with CLL (the CLL-8 trial;5 treatment), R-FC signiicantly increased PFS n = 810). Additional evidence was provided in the compared with chlorambucil alone [mean HR 0.24 form of an MTC model based on PFS hazards (lower bound 0.17, upper bound 0.34)]. from ive trials allowing for an indirect comparison of R-FC with chlorambucil monotherapy.5,14–17 Summary of submitted cost- Chlorambucil had been included as a comparator effectiveness evidence in two of the ive trials.15,16 Roche used a Markov model with a three-state The CLL-8 trial was a randomised, parallel-group, structure (PFS, progressed and death) to model the multicentre trial; however, blinding of both patients cost-effectiveness of R-FC compared with FC and and outcome assessors to treatment allocation was chlorambucil alone. The model used a cycle length not attained, which may have introduced bias into of 1 month and a lifetime time horizon (equating the results. The trial was stopped early (median to 15 years). follow-up 20.7 months) at the time of the planned interim analysis because of signiicant differences Roche’s base-case analysis produced an incremental in PFS between treatment arms. Data from four cost-effectiveness ratio (ICER) of £13,189 per different sets of analyses of the trial are presented: QALY for R-FC versus FC, and an ICER of (1) interim analysis (median follow-up 20.7 months; £6422 per QALY for the comparison of R-FC (2) snapshot analysis 1 (median follow-up versus chlorambucil. One-way sensitivity analyses 25.4 months); (3) snapshot analysis 2 (median produced a range of ICERs from £10,249 per follow-up 25.5 months); and (4) economic analyses QALY to £22,661 per QALY for the comparison of snapshot (median follow-up 26.4 months). R-FC versus FC, and £5612 per QALY and £6921 per QALY for R-FC versus chlorambucil. Results At 20.7 months follow-up there was a statistically from further probabilistic sensitivity analysis signiicant increase in PFS with R-FC compared matched the deterministic results very closely. with FC alone [median 39.8 months vs 32.2 months; HR 0.56 (95% CI 0.43 to 0.72)]. However, for OS, the initial treatment beneit for the R-FC Commentary on the robustness regimen noted at the time of the interim analysis of submitted evidence was no longer maintained at slightly longer follow- Strengths up (snapshot analysis 1) [HR 0.72 (95% CI 0.48 to 1.09)]. Patients in the R-FC arm remained event The searches for clinical effectiveness and cost- free (disease progression, relapse, death or start effectiveness data were appropriate and included of new CLL treatment) signiicantly longer than all relevant studies. The identiied RCT was well those in the FC-arm [39.8 months vs 31.1 months; conducted and the indings were likely to be HR 0.55 (95% CI 0.43 to 0.70)]. Response rates reasonably robust. also signiicantly favoured treatment with R-FC, with 36.0% of patients in this arm achieving The approach taken to modelling was reasonable complete response compared with 17.2% in the FC and the sources and justiication of estimates were arm. Partial response rates were not signiicantly generally sound. different between trial arms at 50.1% for R-FC and 55.5% for FC respectively.

30 Health Technology Assessment 2010; Vol. 14: Suppl. 2

Weaknesses felt that this was likely to be clinically unrealistic The evidence was based on only one completed as patients will receive further treatment at and unpublished RCT. progression that may then result in further periods of PFS. The relapsing nature of CLL means that The sensitivity analysis was limited and did not subsequent periods of progression are less likely to fully investigate the uncertainty associated with respond to further treatment, implying that later differential values across arms or with the structural periods of progression in the course of disease are assumptions of the model. Utility values were not likely to be associated with higher disease-related drawn from an empirical study. mortality. This casts doubts over the simplifying assumption of a constant hazard of death after progression as modelled by Roche. Conclusions Additionally, it should be noted that once any There was a statistically signiicant increase in PFS assumed beneit for OS is removed, model outputs with R-FC compared with FC alone [median 39.8 become highly sensitive to the utility parameters months vs 32.2 months; HR 0.56 (95% CI 0.43 to assumed for the PFS and progressed states, and 0.72)]. However, the initial signiicant treatment these values are not currently available from an beneit for R-FC compared with FC for OS was appropriate source. 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 Summary of NICE guidance with event-free survival and duration of response issued as a result of the STA all favoured treatment with R-FC. At the time of writing, the Appraisal Consultation The MTC model indicated R-FC to be signiicantly Document issued by NICE on 26 March 2009 states superior to chlorambucil alone for both PFS and that: overall and complete response rates. Rituximab in combination with ludarabine and With an ICER of £13,189 per QALY for R-FC cyclophosphamide (R-FC) is recommended as versus FC, and £6422 for R-FC versus chlorambucil an option for the irst-line treatment of chronic alone, there is a strong probability that R-FC lymphocytic leukaemia in people for whom is cost-effective at normal willingness-to-pay ludarabine in combination with cyclophosphamide thresholds. (FC) is considered appropriate. Rituximab in combination with chemotherapy agents other Areas of uncertainty than ludarabine and cyclophosphamide is not recommended for the irst-line treatment of It was unclear whether the observed treatment chronic lymphocytic leukaemia. beneit for use of rituximab combination therapy for PFS was associated with longer-term gains in OS and how plausible it was to extrapolate any PFS References beneits in the longer term. 1. National Institute for Health and Clinical Excellence. Guide to the single technology (STA) process. Key issues 19 September 2006. URL: www.nice.org.uk/page. aspx?o=STAprocessguide. Almost all data parameters for effectiveness were drawn from the CLL-8 trial. Although this trial was 2. Main C, Pitt M, Moxham T, Stein K. The clinical and of reasonable quality, there are inherent limitations cost-effectiveness of rituximab for the ﬁrst-line treatment of in an analysis that relies on data from a single chronic lymphocytic leukaemia: an evidence review of the submission from Roche. London: NICE; 2009. URL: clinical trial. www.nice.org.uk.

The issue of structural uncertainty in the model 3. Dighiero G. Unsolved issues in CLL biology and relating to the treatment of OS rates between the management. Leukemia 2003;17:2385–91. trial arms was not adequately explored in sensitivity analyses. This relates speciically to the assumption 4. Hallek M, Cheson BD, Catovsky D, Caligaris- of aggregation in the post-relapse state. The ERG Cappio F, Dighiero G, Dohner H, et al.

Guidelines for the diagnosis and treatment of devnicetech/technologyappraisalprocessguides/ chronic lymphocytic leukemia: a report from the guidetothemethodsoftechnologyappraisal. International Workshop on Chronic Lymphocytic jsp?domedia=1&mid=B52851A3–19B9-E0B5- Leukemia updating the National Cancer D48284D172BD8459. Institute-Working Group 1996 guidelines. Blood 2008;111:5446–56. 12. Drummond M, O’Brien B, Stoddart G, Torrance G. Methods for the economic evaluation of health care 5. Roche. CLL8 ﬁnal clinical study report ML17102. programmes 47. Oxford, UK: Oxford University 2008. Press; 1997.

6. Hancock S, Wake B, Hyde C. Fludarabine as 13. Philips Z, Bojke L, Sculpher M, Claxton K, Golder ﬁrst-line therapy for chronic lymphocytic leukaemia. S. Good practice guidelines for decision-analytic West Midlands Health Technology Assessment modelling in health technology assessment: a Collaboration Report 42. Birmingham: University review and consolidation of quality assessment. of Birmingham, Department of Public Health and Pharmacoeconomics 2006;24:355–71. Epidemiology; 2002. 14. Eichhorst BF, Busch R, Hopinger G, Pasold R, 7. Reff ME, Carner K, Chambers KS, Chinn PC, Hensel M, Steinbrecher C, et al. Fludarabine plus Leonard JE, Raab R, et al. Depletion of B cells cyclophosphamide versus ludarabine alone in in vivo by a chimeric mouse human monoclonal irst-line therapy of younger patients with chronic antibody to CD20. Blood 1994;83:435–45. lymphocytic leukemia. Blood 2006;107:885–91.

8. Demidem A, Lam T, Alas S, Hariharan K, Hanna 15. Catovsky D, Richards S, Matutes E, Oscier D, Dyer N, Bonavida B. Chimeric anti-CD20 (IDEC-C2B8) MJ, Bezares RF, et al. Assessment of ludarabine monoclonal antibody sensitizes a B cell lymphoma plus cyclophosphamide for patients with chronic cell line to cell killing by cytotoxic drugs. Cancer lymphocytic leukaemia (the LRF CLL4 Trial): a Biother Radiopharm 1997;12:177–86. randomised controlled trial. Lancet 2007;370:230–9.

9. Anderson DR, Grillo-Lopez A, Varns CEA. 16. Hillmen P, Skotnicki AB, Robak T, Jaksic B, Targeting cytotoxic immunotherapy. Biochem Soc Dmoszynska A, Wu J, et al. Alemtuzumab Trans 1997;25:705–8. compared with chlorambucil as irst-line therapy for chronic lymphocytic leukemia. J Clin Oncol 10. NHS Centre for Reviews and Dissemination. 2007;25:5616–23. Systematic reviews: CRD’s guidance for undertaking reviews in health care. Report No. 4 update. York: 17. Flinn IW, Neuberg DS, Grever MR, Dewald GW, CRD, University of York; 2009. Bennett JM, Paietta EM, et al. Phase III trial of ludarabine plus cyclophosphamide compared with 11. National Institute for Health and Clinical ludarabine for patients with previously untreated Excellence. Guide to the methods of technology appraisal. chronic lymphocytic leukemia: US Intergroup Trial 2008. URL: www.nice.org.uk/aboutnice/howwework/ E2997. J Clin Oncol 2007;25:793–8.

32 DOI: 10.3310/hta14suppl2/05 Health Technology Assessment 2010; Vol. 14: Suppl. 2

Pemetrexed for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer

J Greenhalgh,* C McLeod, A Bagust, A Boland, N Fleeman, Y Dundar, J Oyee, R Dickson, H Davis, J Green, E McKenna and M Pearson

Liverpool Reviews and Implementation Group, University of Liverpool, Whelan Building, The Quadrangle, Brownlow Hill, Liverpool, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 08/207/01

This paper presents a summary of the evidence Date of ERG submission: review group (ERG) report into the clinical 12 October 2009 effectiveness and cost-effectiveness of pemetrexed TAR Centre(s): for the maintenance treatment of locally advanced Liverpool Reviews and Implementation Group or metastatic non-small cell lung cancer (NSCLC), List of authors: in accordance with the licensed indication, J Greenhalgh, C McLeod, A Bagust, A Boland, N Fleeman, based upon the evidence submission from the Y Dundar, J Oyee, R Dickson, H Davis, J Green, E McKenna manufacturer (Eli Lilly) to the National Institute for and M Pearson Health and Clinical Excellence (NICE) as part of Contact details: the single technology appraisal (STA) process. The Janette Greenhalgh, Liverpool Reviews and Implementation primary clinical outcome measure was progression Group, University of Liverpool, Room 2.21, Whelan free survival (PFS). Secondary outcomes included Building, The Quadrangle, Brownlow Hill, Liverpool L69 overall survival (OS), time to worsening of 3GB, UK symptoms, objective tumour response rate, adverse E-mail: [email protected] events and changes in lung cancer symptom scale. Data for two populations were presented: The research reported in this article of the journal supplement was commissioned and funded by the patients with non-squamous NSCLC histology HTA programme on behalf of NICE as project number and patients with adenocarcinoma histology. The 08/207/01. The assessment report began editorial review clinical evidence was derived from a double-blind, in November 2009 and was accepted for publication in placebo-controlled randomised controlled trial February 2010. See the HTA programme website for (RCT), the JMEN trial. The trial compared the further project information (www.hta.ac.uk). This summary use of pemetrexed + best supportive care (BSC ) of the ERG report was compiled after the Appraisal as maintenance therapy, with placebo + BSC in Committee’s review. patients with NSCLC (n = 663) who had received The views and opinions expressed therein are those of four cycles of platinum-based chemotherapy the authors and do not necessarily relect those of the (CTX) and whose disease had not progressed. Department of Health. In the licensed population (patients with non- Discussion of ERG reports is invited. Visit the HTA website squamous histology), the trial demonstrated correspondence forum (www.hta.ac.uk/correspond). greater median PFS for patients treated with

pemetrexed than for patients in the placebo arm NICE’s single technology appraisal (STA) process [4.5 vs 2.6 months; hazard ratio (HR) 0.44; 95% is speciically designed for the appraisal of a single conidence interval (CI) 0.36 to 0.55, p < 0.00001]. product, device or other technology, with a single Median OS was also greater for the pemetrexed- indication, where most of the relevant evidence treated patients (15.5 vs 10.3 months; HR 0.70; lies with one manufacturer or sponsor.1 Typically, 95% CI 0.56 to 0.88, p = 0.002). In addition, it is used for new pharmaceutical products close tumour response and disease control rates were to launch. The principal evidence for an STA is statistically signiicantly greater for patients who derived from a submission by the manufacturer/ received pemetrexed. Patient survival rates at 1 sponsor of the technology. In addition, a report year and 2 years were higher in the pemetrexed reviewing the evidence submission is submitted arm. The incremental cost-effectiveness ratios by the evidence review group (ERG), an external (ICERs) estimated by the manufacturer’s model organisation independent of NICE. This paper were £33,732 per quality adjusted life-year (QALY) presents a summary of the ERG report for the STA for the licensed nonsquamous population, and entitled ‘Pemetrexed for the maintenance treatment of £39,364 per QALY for the adenocarcinoma locally advanced or metastatic non-small cell lung cancer subgroup. Both of these ICERs were above the (NSCLC)’. standard NICE willingness-to-pay range (£20,000– £30,000 per QALY). The manufacturer also Description of the underlying presented a case for pemetrexed to be considered health problem as an end of life treatment. The ERG identiied a number of problems in the economic model Lung cancer is the second most common cancer presented by the manufacturer; after correction, diagnosed in the UK, with over 33,000 new cases the base case ICER was re-estimated as £51,192 diagnosed in England and Wales in 2006, and the per QALY gained and likely to exceed NICE’s leading cause of cancer death.2 Lung cancer is the willingness-to-pay thresholds. Following a revised second most common cancer in men after prostate economic analysis submitted by the manufacturer, cancer, and the third most common cancer in the AC accepted that an ICER of £47,000 per women after breast and bowel cancer. QALY gained was most plausible. The AC also considered that maintenance treatment with Non-small cell lung cancer (NSCLC) accounts for pemetrexed fulilled the end of life criteria.The approximately 80% of all lung cancers diagnosed. guidance issued by NICE, on 20 June 20 2010, The main subtypes of NSCLC are squamous in TA190 as a result of the STA states that: People cell carcinoma (33%), adenocarcinoma (25%), who have received pemetrexed in combination large cell carcinoma (4%), and NSCLC ‘not- with cisplatin as irst-line chemotherapy cannot otherwise speciied’ (NOS; 36%).3 A further 1% are receive pemetrexed maintenance treatment. ‘carcinoma in situ’ and 1% are broncho-alveolar 1.1 Pemetrexed is recommended as an option for cell carcinoma. While cigarette smoking has been the maintenance treatment of people with locally linked to all four types of lung cancer, the incidence advanced or metastatic non-small-cell lung cancer of adenocarcinoma has been steadily increasing other than predominantly squamous cell histology worldwide, and modiications to cigarette design if disease has not progressed immediately following are thought to be responsible for this shift in platinum-based chemotherapy in combination with pathologic diagnosis pattern.4 gemcitabine, paclitaxel or docetaxel. Survival in patients with lung cancer is poor. It was responsible for approximately 29,600 deaths Introduction in England and Wales in 2007.2 For patients with stage IIIB, only 7–9% may live for 5 years and for The National Institute for Health and Clinical patients with stage IV (metastatic) cancer, only Excellence (NICE) is an independent organisation about 2–13% survive for 5 years.2 within the NHS that is responsible for providing national guidance on the treatment and care of One reason for this poor prognosis is the late people using the NHS in England and Wales. identiication of the disease. Lung cancer is One of the responsibilities of NICE is to provide asymptomatic in the early stages and advanced guidance to the NHS on the use of selected new disease is not amenable to curative treatment. and established health technologies, based on an Another reason, which explains the UK’s relatively appraisal of those technologies. poor performance in comparison with other

34 Health Technology Assessment 2010; Vol. 14: Suppl. 2

developed countries, is low active anti-cancer Methods treatment rates. The National Lung Cancer Audit states that only 23.2% of NSCLC patients The ERG report comprised a critical review of the in England and Wales received irst-line CTX in evidence for the clinical effectiveness and cost- 2006.5 effectiveness of the technology based upon the manufacturer’s/sponsor’s submission to NICE as Maintenance treatment is a new treatment part of the STA process. paradigm and is proposed as an alternative for the ‘watch and wait’ phase of the current treatment The ERG evaluated the quality of the pathway, for patients with complete or partial manufacturer’s clinical effectiveness review. response/stable disease after four cycles of irst-line Searches conducted by the manufacturer were treatment. assessed for completeness, and the single trial put forward as evidence of effectiveness was critically The goal of maintenance treatment is to maintain appraised using the manufacturer’s responses the clinical beneit achieved with irst-line CTX. to speciic questions in the submission template. Maintenance treatment is continued until disease With regard to cost-effectiveness evidence, the progression. ERG assessed the manufacturer’s searches for completeness, critically appraised the submitted Scope of the evidence economic model using a standard assessment review group report tool,7 and conducted a detailed evaluation of the model. The ERG recalculated the base-case Pemetrexed is licensed in Europe as monotherapy cost-effectiveness results, correcting a number for the maintenance treatment of patients with of methodological errors and reanalysed the NSCLC, other than predominantly squamous cell survival estimates. The ERG also undertook a basic histology. First-line treatment should be a platinum probabilistic sensitivity analysis as this was not doublet with gemcitabine, paclitaxel or docetaxel.6 provided by the manufacturer.

The ERG report presents the results of the evaluation of the manufacturer (Eli Lilly) evidence Results submission regarding the use of pemetrexed as a Summary of submitted maintenance therapy in the patient group outlined clinical evidence above. The report includes an assessment of both the clinical effectiveness and cost-effectiveness The evidence described in the MS is derived from evidence submitted by the manufacturer. The a double-blind, placebo-controlled randomised manufacturer submission (MS) described the use controlled trial (RCT), the JMEN trial.8 The of pemetrexed + best supportive care (BSC) with trial compared the use of pemetrexed + BSC BSC + placebo. as maintenance therapy, with placebo + BSC in patients with NSCLC (n = 663) who had received The primary clinical outcome measure was four cycles of platinum-based CTX and whose progression-free survival (PFS). Secondary disease had not progressed. The MS focused on outcomes included overall survival (OS), time to the clinical outcomes of the subgroup of patients worsening of symptoms, objective tumour response with non-squamous histology (n = 481), which is rate, adverse events and changes in lung cancer the population for which pemetrexed is licensed symptom scale. in this indication; the MS also focused on a subgroup of the licensed population, patients with Cost-effectiveness was measured in terms of adenocarcinoma. incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY). The results for the licensed non-squamous population are summarised in Table 1. In the Data for two populations were presented: patients licensed population the trial demonstrated greater with non-squamous NSCLC histology and patients median PFS for patients treated with pemetrexed with adenocarcinoma histology. than for patients in the placebo arm [4.5 vs 2.6

TABLE 1 Key results of the JMEN trial (non-squamous population)

Pemetrexed Placebo End point (n = 325) (n = 156) HR (95% CI) p-value

Primary PFS (months) median 4.5 2.6 0.44 (0.36 to 0.55) < 0.00001

Secondary OS (months) median 15.5 10.3 0.70 (0.56 to 0.88) 0.002 Tumour response (%) (CR + PR) 7.4 1.9 0.018 Disease control rate (%) (CR+PR+SD) 57.7 32.7 < 0.001 Survival rate at 1 year (%) 60 42 Survival rate at 2 year (%) 28 22

CI, conidence interval; CR, complete response; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease.

months; hazard ratio (HR) 0.44; 95% conidence perspective is that of the UK NHS and Personal interval (CI) 0.36 to 0.55, p < 0.00001]. Median Social Services. OS was also greater for the pemetrexed-treated patients (15.5 versus 10.3 months; HR 0.70; 95% The ICERs estimated by the manufacturer’s model CI 0.56 to 0.88, p = 0.002). In addition, tumour are £33,732 per QALY for the licensed non- response and disease control rates were statistically squamous population, and £39,364 per QALY signiicantly greater for patients who received for the adenocarcinoma subgroup. Both of these pemetrexed. Patient survival rates at 1 year and ICERs are above the standard NICE willingness-to- 2 years were higher in the pemetrexed arm. pay range (£20,000–£30,000 per QALY). The health-related quality of life (HRQoL) data presented were limited owing to high levels of The manufacturer also presented a case for censoring/missing data. Safety data demonstrated pemetrexed to be considered as an end-of-life that patients treated with pemetrexed had treatment. statistically signiicantly higher rates of grade 3 or 4 neutropenia, and experienced higher rates Commentary on the robustness of transfusions and hospitalisation due to drug of submitted evidence toxicity. The manufacturer cited evidence from a well- Summary of submitted cost- designed trial (JMEN)8 of the clinical beneit of effectiveness evidence pemetrexed + BSC as maintenance treatment compared with placebo + BSC. The trial recruited a The manufacturer did not identify any published substantial number of patients in a dificult disease cost-effectiveness analyses of pemetrexed for area. It is noteworthy that patients and assessors the maintenance treatment of patients with in the JMEN8 trial were blinded to treatment NSCLC, and therefore developed a de novo group allocation and that investigators’ outcome economic model to support their economic assessments were independently veriied. case. The model compares pemetrexed + BSC with ‘watch and wait’ + BSC. The clinical data The ERG noted that there was only one relevant used in the economic model were primarily RCT (JMEN)8 that compared pemetrexed + BSC generated from the JMEN trial.8 Although the as maintenance treatment with placebo + BSC. model was trial-based, there was also a modelling Despite designing the trial to include a component to allow the extrapolation of health comprehensive analysis of HRQoL, very limited effects beyond the 29 month trial period up to data was collected and reported in the MS. This 6 years. The manufacturer’s economic evaluation means it was very dificult to determine how adopts a lifetime horizon (taken as 6 years) for patients’ HRQoL would be affected by pemetrexed the consideration of costs and beneits, and the in a maintenance setting.

36 Health Technology Assessment 2010; Vol. 14: Suppl. 2 , quality-adjusted life-years. , rer’s model for the non-squamous population the non-squamous for model rer’s PemetrexedCosts£20,638 QALYs Placebo 0.9841 Costs £8323 QALYs Costs Incremental 0.6989£20,925 QALYs £12,315£20,902 0.9539 (£/QALY) 0.2852 ICER Costs 0.9851 £8370 £43,179 Changes QALYs £8382 0.6881 +£3178 ICER 0.7405 £12,555 +0.0143 £12,520 0.2658 +£9447 0.2446 £47,239 £51,192 +£3418 +£3383 –0.0051 –0.0263 +£13,507 +£17,460 Effect of corrections and amendments made by ERG to the manufactu by made amendments and corrections of Effect Model amendment Submitted Submitted base case and cycles ofAll pemetrexed CTX costs revised values utility Revised £17,455 correctionContinuity double discountingCorrect 0.9697Discounting assumptions £17,455 £17,522 £17,405 Include monitoring costs £8318 0.9540 £17,421 arithmeticCorrect 1.0006 0.9467 of above £17,838Combined effect changes 0.9617 0.6988 £8318 £8352 of all Combined effect £8288 0.9697 IPDincluding changes survival £17,398 £8312 signiicant(excluding analysis 0.7057 £9137 0.7149 violations) protocol £8452 0.6851 0.9658 QALYs patient individual data; IPD, ratio; cost-effectiveness incremental ICER, chemotherapy; CTX, 0.6909 0.2709 £9137 £9169 0.6988 £8248 £9117 £33,732 0.2483 £9109 0.2857 0.2615 0.6953 £9386 0.2708 £36,798 £32,091 £34,860 0.2709 – £9149 £33,640 +£32 £34,651 0.2706 –£20 – –£60 – +0.0148 +£249 –0.0094 £33,817 –0.0226 –0.0001 –£1641 +£1128 +£3066 +£12 – – –£88 –0.0003 +£919 +£85

TABLE 2 TABLE 37

The primary end point of the key trial was changed times compared with patients of other by the manufacturer from OS to PFS during the ethnicities.9 course of the trial. No information was provided • Patients in the trial were able to receive that fully justiied the change of clinical end point. unlimited cycles of maintenance therapy. This is unlikely to be the case in clinical practice in The statistical analysis plan described by the England and Wales and it is unclear how this manufacturer also included a test for treatment difference would impact on survival in a clinical by histology interaction and corresponding setting. subgroup analyses. The results for the subgroup • Paclitaxel was used in the JMEN trial as a of patients with non-squamous histology provided irst-line treatment for a greater proportion the clinical evidence in the MS. However, the trial of patients in the trial than might be the case randomisation process did not include stratiication in clinical practice in England and Wales. The by histology status. Moreover, the restriction of impact of this when generalising the results is the licensed population to only the non-squamous unknown. subgroup effectively reduced the statistical power • A number of patients in the trial received of the trial, with consequences of increased second-line therapies that are not available uncertainty in the cost-effectiveness analysis. to patients in clinical practice in England and Wales, which may have affected the OS The projection of survival from the end of the observed in the trial. trial period, the costing of CTX treatment and the • Conirmed histological diagnosis of non- utility values used in the manufacturer’s model squamous NSCLC is required before patients were not ideal and underestimate the size of the can be offered maintenance treatment with ICER. pemetrexed. While histological testing is routinely carried out in many centres in The manufacturer implemented a capping rule England and Wales, this will not be available in its economic model to limit the maximum to all patients. Therefore, it is unclear if number of cycles of maintenance treatment that pemetrexed for maintenance therapy will be patients could receive. However, the cycle capping available in all centres in the UK, which may rule affected only costs; it did not take account give rise to equity concerns. of any reduction in outcomes caused by capping the maximum number of cycles at 17 rather than ‘End-of-life’ criteria allowing the JMEN trial8 maximum of 55. Again, this capping rule underestimated the size of the Analysis of the JMEN trial8 individual patient data ICER. and revised projection modelling conirmed that the mean life extension from use of pemetrexed Making all of the necessary ERG corrections/ as maintenance therapy was likely to exceed adjustments to the manufacturer’s model, the 3 months. However, the number of patients ERG’s base-case ICER for the non-squamous who would be eligible to receive pemetrexed is population was estimated at £51,192 per QALY uncertain. The manufacturer’s estimates (used (Table 2). to present its end of life case) were based on amalgamation of information from different sources with differing deinitions. The methods of Conclusions calculation are not well reported and a number of assumptions were made which may not be valid. The generalisability of the JMEN trial8 to UK clinical practice is uncertain for a number of Several factors serve to limit the generalisability reasons: of the trial to UK clinical practice, and the ERG could not be conident that the clinical results • None of the patients in the trial were recruited presented in the MS give a true relection of the from the UK. A sizeable proportion (35%) beneits that could be expected with pemetrexed of patients were from Asian countries; these for the maintenance treatment of patients with patients are documented in the literature as non-squamous NSCLC in UK clinical practice. having a better prognosis for NSCLC than Furthermore, in the economic analysis there were a other ethnic groups, and the Asian patients number of problems identiied with the model (in in the trial appear to have improved survival addition to the JMEN trial8 data) which indicate

38 Health Technology Assessment 2010; Vol. 14: Suppl. 2

that the ICER (re-estimated as £51,192 per QALY 2. Cancer Research UK. Cancer stats. 2009. URL: www. cancerresearchuk.org/. gained) could well exceed NICE’s willingness-to- pay thresholds. 3. National lung cancer audit. Key ﬁndings about the quality of care for people with lung cancer in England and Wales incorporating headline and completeness data Summary of NICE guidance from Scotland. Report for the audit period 2006. issued as a result of the STA 4. Gabrielson E. Worldwide trends in lung cancer Following a revised economic analysis submitted by pathology. Respirology 2006;11:533–8. the manufacturer, the AC accepted that an ICER of £47,000 per QALY gained was most plausible. 5. National lung cancer audit. Key ﬁndings about the The AC also considered that maintenance quality of care for people with lung cancer in England and Wales incorporating headline and completeness data treatment with pemetrexed fulilled the end of life from Scotland. Report for the audit period 2007. criteria. The guidance issued by NICE, on 20 June 2010, in TA190 as a result of the STA states that: 6. EMEA. Committee for medicinal products for human use post authorisation summary of positive opinion for Alimta. People who have received pemetrexed in 2009. URL: www.emea.europa.eu. combination with cisplatin as irst-line chemotherapy cannot receive pemetrexed 7. Drummond M, Jefferson T. Guidelines for authors maintenance treatment. and peer reviewers of economic submissions to the BMJ. The BMJ Economic Evaluation Working. 1.1 Pemetrexed is recommended as an option for BMJ 1996;313:275–83. the maintenance treatment of people with locally 8. Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, advanced or metastatic non-small-cell lung cancer Krzakowski M, Laack E, et al. Maintenance other than predominantly squamous cell histology pemetrexed plus best supportive care versus placebo if disease has not progressed immediately following plus best supportive care for non-small-cell lung platinum-based chemotherapy in combination with cancer: a randomised, double-blind, phase 3 study. gemcitabine, paclitaxel or docetaxel. Lancet 2009;374:1432–40.

9. Ou S-H, Ziogas AP, Zell JA. Asian ethnicity is a Key references favorable prognostic factor for overall survival in non-small cell lung cancer (NSCLC) and is 1. NICE. Guide to the single technology (STA) process. independent of smoking status. J Thorac Oncol 2006. URL: www.nice.org.uk/media/913/06/Guide_ 2009;4:1083–93. to_the_STA_proof_6-26-10-09.pdf

DOI: 10.3310/hta14suppl2/06 Health Technology Assessment 2010; Vol. 14: Suppl. 2

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

M Pitt, L Crathorne,* T Moxham, M Bond and C Hyde

PenTAG, Peninsula Medical School, University of Exeter, Exeter, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 08/208/01

This paper represents a summary of the evidence Date of ERG submission: review group (ERG) report into the clinical eficacy, 30 November 2009 safety and cost-effectiveness of everolimus plus TAR Centre(s): best supportive care (BSC) for the treatment of Peninsula Technology Assessment Group (PenTAG) advanced renal cell carcinoma (RCC) which has List of authors: progressed following or on vascular endothelial M Pitt, L Crathorne, T Moxham, M Bond and C Hyde growth factor-targeted therapy (sunitinib, Contact details: sorafenib, bevacizumab), compared to BSC alone. Louise Crathorne, PenTAG, Peninsula Medical School, The submitting manufacturer’s case for clinical University of Exeter, Veysey Building, Salmon Pool Lane, effectiveness and cost-effectiveness was mainly Exeter EX2 4SG, UK based on a well-conducted randomised controlled E-mail: [email protected] trial (RCT), Renal Cell Cancer Treatment with Oral RAD001 Given Daily-1 (RECORD-1), The research reported in this article of the journal comparing BSC plus everolimus with BSC plus supplement was commissioned and funded by the placebo and a de novo economic model. The HTA programme on behalf of NICE as project number RCT indicated a marked statistically signiicant 08/208/01. The assessment report began editorial review in February 2010 and was accepted for publication in effect on progression-free survival. The base-case March 2010. See the HTA programme website for further incremental cost-effectiveness ratio (ICER) estimate project information (www.hta.ac.uk). This summary of the was £52,000 per quality-adjusted life-year (this ERG report was compiled after the Appraisal Committee’s included a reduction in drug cost associated with review. an approved patient access scheme). The ERG The views and opinions expressed therein are those of undertook a critical appraisal of the submission. the authors and do not necessarily relect those of the The ERG was generally in agreement with the Department of Health. submitting manufacturer concerning its estimates of effectiveness; however, there was greater concern Discussion of ERG reports is invited. Visit the HTA website surrounding the estimates of cost-effectiveness. correspondence forum (www.hta.ac.uk/correspond). 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 Early, small RCC tumours are usually cost-effectiveness in RCC, the observations in the asymptomatic; the diagnosis of early RCC is ERG report provide strong further support for usually incidental after abdominal scans for research collecting rigorous estimates of utilities other indications. The most common presenting associated with the main health states likely to symptoms of advanced RCC are blood in the urine be experienced by patients with renal cell cancer. (haematuria), a palpable mass in the lank or At the time of writing, NICE was yet to issue abdomen, and abdominal pain. Other non-speciic the Appraisal Consultation Document for this symptoms include fever, night sweats, malaise and appraisal. weight loss.

Kidney cancer accounts for around 2% of all Introduction cancers in the UK. In 2004, 6180 new kidney cancers were diagnosed in England and Wales, of The National Institute for Health and Clinical which an estimated 85–90% were RCC. RCC is Excellence (NICE) is an independent organisation nearly twice as common in men as in women, and within the NHS that is responsible for providing most commonly affects adults aged 50–80 years national guidance on the treatment and care of old. In 2005, there were 3134 registered deaths people using the NHS in England and Wales. from kidney cancer in England and Wales. One of the responsibilities of NICE is to provide guidance to the NHS on the use of selected new Approximately 25% of RCC patients present with and established health technologies, based on an advanced and/or metastatic disease (stage III appraisal of those technologies. or IV). An estimated 50% of patients who have curative resection for earlier stages will develop NICE’s single technology appraisal (STA) process recurrent and/or metastatic disease. Without is speciically designed for the appraisal of a single treatment, these patients have a median survival product, device or other technology, with a single rate of only 6–12 months and a 2-year survival rate indication, where most of the relevant evidence of 10–20%. lies with one manufacturer or sponsor.1 Typically, it is used for new pharmaceutical products close Surgical resection to remove the entire kidney to launch. The principal evidence for an STA is (radical nephrectomy) or part of the kidney derived from a submission by the manufacturer/ (partial nephrectomy) is the only accepted curative sponsor of the technology. In addition, a report treatment for patients with non-metastatic RCC reviewing the evidence submission is submitted (TNM stage I–III), and the success of surgery by the evidence review group (ERG), an external depends on the stage of disease. Current organisation independent of the Institute. This standard treatment of metastatic RCC (stage IV) paper presents a summary of the ERG report is immunotherapy with interleukin-2 (sometimes for the STA entitled ‘Everolimus for the second-line called aldesleukin) or interferon-alpha (IFN-α) treatment of advanced and/or metastatic renal cell which may lead to tumour shrinkage. Palliative cancer’.2 surgery, arterial embolism or radiotherapy may also be considered in these patients. Bevacizumab Description of the underlying plus IFN-α, sorafenib, sunitinib and temsirolimus health problem all have UK marketing authorisations for use in the treatment of those with advanced and/or metastatic Renal cell carcinoma (RCC), also called renal RCC who are suitable for immunotherapy and adenocarcinoma or hypernephroma, is a cancer have an Eastern Cooperative Oncology Group usually originating in the lining of the tubules of performance status of 0 or 1. the kidney. The stage of RCC is usually reported using the tumour, node and metastasis (TNM) Everolimus (Ainitor, Novartis Pharmaceuticals, classiication. This is based on the extent of the Camberley, Surrey, UK) is an oral, once-daily primary tumour (T), whether lymph nodes are selective inhibitor of the mammalian target of affected (N) and whether metastases are present rapamycin protein, that controls tumour cell (M). Advanced and metastatic RCC falls within division, growth and angiogenesis. It does not stages III and IV, stage III denotes disease that have a UK marketing authorisation for use in is locally advanced and/or has spread to regional advanced/metastatic RCC. However, in May lymph nodes and stage IV denotes that distant 2009, the European Medicines Agency adopted metastasis has occurred. 42 Health Technology Assessment 2010; Vol. 14: Suppl. 2

a positive opinion, recommending everolimus • discussion of the nature of the problem with a for the treatment of patients with advanced RCC clinical expert whose disease has progressed on, or after treatment • rerunning searches indicated to have been with vascular endothelial growth factor targeted performed to inform the manufacturer’s therapy.3 Everolimus has a marketing authorisation submission for other indications in the European Union. • extending searches • formal critical appraisal of systematic review Scope of the evidence underpinning the manufacturer’s submission, review group report using the principles found in the Centre for Reviews and Dissemination’s guidance for The purpose of the ERG report was to comment undertaking reviews in health care4 on the validity of the manufacturer’s submission • checking and appraising the economic model on the technology of interest. The scope for this submitted submission and hence the scope for the ERG report • rerunning the model to correct for potential is shown in Table 1. problems as best as possible within the limited time available • commenting on further analyses provided Methods by the company immediately prior to the appraisal committee The ERG report comprised a critical review of the • the work was carried out between 30 evidence for the clinical effectiveness and cost- September 2009 and 30 November 2009. effectiveness of the technology based upon the manufacturer’s/sponsor’s submission to NICE as Members of the ERG team attended and advised part of the STA process. the meeting of the NICE appraisal committee where this guidance was discussed on 13 January Speciic steps undertaken by the ERG included: 2010.

TABLE 1 Submission scope

Appraisal objective To appraise the clinical eficacy, safety and cost-effectiveness of everolimus plus BSC for the treatment of advanced RCC which has progressed after or during VEGF-targeted therapy (sunitinib, sorafenib, bevacizumab), compared to BSC alone Intervention(s) Everolimus plus BSC Population(s) Adults aged ≥ 18 years with advanced RCC who had progressed on or within 6 months of stopping treatment with sunitinib, sorafenib or both drugs Standard comparators The standard comparator to be considered was placebo plus BSC Outcomes The outcome measures to be considered included: overall survival progression-free survival objective tumour response rate health-related quality of life adverse effects of treatment Economic analysis The reference case stipulates that the cost-effectiveness of treatments should be expressed in terms of incremental cost per quality-adjusted life-year The time horizon should be suficiently long enough to relect any differences in costs or outcomes between the technologies being compared Costs were considered from an NHS and Personal Social Services perspective Other considerations If the evidence allows, the following subgroups will be considered: resected vs unresected primary tumour; clear cell vs non-clear cell; prognostic risk group; and prior therapy Guidance will only be issued in accordance with the marketing authorisation

BSC, best supportive care; RCC, renal cell carcinoma; VEGF, vascular endothelial growth factor.

Results with BSC alone, mirroring the question addressed Summary of submitted in the RECORD-1 RCT. The four states were: clinical evidence stable disease, stable disease with adverse events, progressive disease and death. Outputs The evidence for this submission is based on one were expressed as cost per quality-adjusted life- randomised controlled trial (RCT), the RECORD-1 year (QALY). The base-case incremental cost- (Renal Cell Cancer Treatment with Oral RAD001 effectiveness ratio (ICER) was £61,330; this Given Daily-1) study.5 This was a randomised, estimate was somewhat reduced when a patient double-blind, placebo-controlled, phase III clinical access scheme (PAS) was applied. The base- trial of 416 participants. Eligible patients were case ICER when PAS was applied (leading to a adults aged ≥ 18 years with RCC whose disease reduction in the cost of the drug) was £51,613. had progressed on or within 6 months of stopping PAS was formally approved by the Department of treatment with sunitinib, sorafenib or both drugs, Health during the course of the appraisal, which a directly relevant population consistent with the led to cost-effectiveness estimates in the original scope of the appraisal. Of 416 patients, 277 were submission no longer being commercially-in- randomised to 10-mg everolimus once daily plus conidence. The components of the base-case best supportive care (BSC), and 139 to an identical ICER (with PAS) were an incremental cost of placebo tablet plus BSC. The blinded phase £15,704, mostly attributable to the acquisition became open-label upon disease progression when cost of everolimus, and 0.304 additional QALYs patients were allowed to cross over from placebo (a mean of 0.607 QALYs for BSC plus everolimus, to treatment group. Of 139 participants in the compared to 0.302 QALYs for BSC plus placebo). BSC plus placebo arm, 112 received everolimus following disease progression. The Inverse Probability of Censoring Weight (IPCW) statistical approach was used to adjust for The primary outcome was progression-free survival crossover bias in the trial data. This meant that the (PFS). RECORD-1 (inal analysis) showed an estimate of OS being used in the model was an HR improvement in this outcome which was unlikely of 0.55. In response to a request for clariication, to have occurred by chance alone [hazard ratio the submitting manufacturer indicated that the (HR) 0.33; 95% conidence interval (CI) 0.25 to ICER, using the unadjusted OS estimate from 0.43; p < 0.001].5 This equated to a mean PFS of RECORD-1, was £91,000 (this incorporates the 4.9 months in the BSC plus everolimus arm and reduction in drug price consequent on the PAS). 1.9 months for BSC plus placebo. No important variation in relative PFS estimates by subgroups In a supplementary analysis, the submitting were observed. In addition, a non-statistically manufacturer also used an alternative statistical signiicant treatment-related difference in overall approach, the Rank Preserving Structural survival (OS) was detected (HR 0.82; 95% CI Favouring Time (RPSFT) method, to adjust 0.57 to 1.17; p = 0.137).5 This result was highly for crossover. This produced a very similar likely to have been inluenced by the very high HR estimate to the IPCW of 0.52, and when level of patients in the BSC plus placebo arm incorporated into the economic model also switching to everolimus treatment. Partial or stable produced an ICER of £53,128. However, on tumour response was seen in 69% of patients examination, the ERG found a signiicant error in with everolimus against 32% in the placebo arm, the supplementary analysis which, when corrected, and stable quality of life (QoL)/patient-reported raised this ICER value considerably. This error outcomes in the everolimus arm compared with was in addition to those uncovered in the original placebo. submission (as outlined below).

Summary of submitted cost- effectiveness evidence Commentary on the robustness of No published economic evaluations of everolimus submitted evidence in acute and/or metastatic RCC were identiied and so the cost-effectiveness work focused on a new Clinical effectiveness model and economic evaluation undertaken by the The searches were appropriate and included all manufacturer. relevant studies. The main RCT, RECORD-1, was of high quality. No directly relevant ongoing trials A Markov state transition cost–utility model were identiied, but there did appear to be studies 44 compared treatment with everolimus plus BSC Health Technology Assessment 2010; Vol. 14: Suppl. 2

in progress investigating the role of everolimus the result that that the observed HR in the earlier in the management of advanced RCC. model in most cycles was substantially less than the HR intended, 0.55. This had the effect Cost-effectiveness of seriously biasing the result in favour of everolimus. The overall approach taken to modelling was 3. Not introducing discounting into the model reasonable and the sources and justiication of from the irst cycle onwards (as opposed to estimates were also generally reasonable. introducing discounting from the irst year onwards). Weaknesses Of these potential errors, the second was the most The evidence was based on only one completed serious. The ERG attempted to recalibrate the and published RCT, albeit a well-conducted and model to correct for the potential errors, and the adequately powered study. The interpretation was result was an increase in the base-case model ICER reasonable, although the ERG would have more to £65,231 (with PAS). clearly presented the trial results on the higher frequency of adverse events, of a severity likely to A further concern was that QoL data were not have an impact on patient QoL, in the everolimus based on European Quality of Life-5 Dimensions arm of the trial relative to the placebo arm. For sources. The resulting lack of conidence in the example, 40.1% of participants experienced utility parameters in models dealing with advanced adverse events and serious adverse events in the and metastatic RCC has been commented on in BSC plus everolimus arm, compared to 22.6% NICE appraisals before. A speciic concern was that in BSC plus placebo. Further data illustrating the small modelled difference in utility between the same point were identiied in the Clinical stable disease and progressive disease (0.76 vs 0.68) Study Report. The trial data available indicated does not seem consistent with the improvement in that patient health-related QoL was identical in well-being likely to be present in practice. the early stage of the trial, despite there being a response to treatment in the everolimus arm. Conclusions Although the OS results from the RECORD-1 RCT are clear and uncontroversial, indicating a survival The ERG was generally in agreement with the improvement that could have resulted from chance submitting manufacturer concerning its estimates alone, the adjustment of the results for switching of effectiveness. placebo patients to everolimus following disease progression is an area of genuine academic debate, There was greater concern about the estimates particularly concerning the most appropriate of cost-effectiveness. The ERG judged that if the analytical method. The ERG took expert potential errors were corrected, the ICERs offered statistical advice on this (but could not replicate by the submitting manufacturer overstate the cost- the calculation of OS estimates correcting for effectiveness of everolimus for the second-line crossover). There is an alternative, possibly slightly treatment of metastatic RCC (this ICER would be preferred, approach to the IPCW method used in higher). the original submission, RPSFT. The submitting manufacturer provided an additional analysis offering an estimate of OS and ICER based on this Areas of uncertainty method, which actually led to little change from its original submission (see Summary of submitted The areas of uncertainty mirrored the areas of cost-effectiveness evidence, page 44). weakness indicated in the section Weaknesses (page 45). More seriously, however, a number of potential errors were identiied in the model: Key issues

1. Transition probabilities were not converted The key issues were: to rates before multiplying by the HRs in the model. • The existence of errors in the model and the 2. Introduction of a structural error in effects of correcting for them. implementation of the mortality HR, with 45

• The validity of adjusting for crossover bias in Further investigation of the role of everolimus RCTs and the appropriate statistical technique earlier in the management of RCC appears to be required to adjust for it. in progress and would not currently seem to be a • The effect of concerns about utilities (as priority for further research. outlined above).

Implications for research Summary of NICE guidance issued as a result of the STA Concerning the estimates of cost-effectiveness in RCC, the observations in the ERG report provide At the time of writing, NICE was yet to issue strong further support for research collecting the Appraisal Consultation Document for this rigorous estimates of utilities associated with appraisal. the main health states likely to be experienced by patients with renal cell cancer. This speciic appraisal highlights the possibility that the utility Key references values associated with stable disease/progressive 1. National Institute for Health and Clinical disease may vary depending on the number of Excellence. Guide to the single technology (STA) process. additional potentially effective lines of further URL: www.nice.org.uk/nicemedia/pdf/STA_Process_ treatment available. Guide.pdf (accessed 26 January 2010).

Switching in clinical trials for new cancer 2. Pitt M, Crathorne L, Moxham T, Bond M, Hyde C. treatments as last line is a common and recurring Everolimus for the second-line treatment of advanced and/ problem in trial analysis. This STA considered a or metastatic renal cell cancer: a critique of the submission from Novartis. London: NICE; 2010. number of statistical approaches to adjustment. However, the issues highlighted have general 3. European Medicines Agency. European Public applicability to other topics where switching Assessment Report (EPAR) Aﬁnitor. 2009. from placebo to active treatment occurs when the primary end point has been reached, and this may 4. NHS Centre for Reviews and Dissemination. be further enhanced by methodological research. Systematic reviews: CRD’s guidance for undertaking Such research could, for example, focus on the reviews in health care. Report No. 4 update. York: CRD appropriateness of alternative approaches in this University of York; 2009. context and towards the development of coherent guidelines for both the application of these 5. Motzer RJ, Escudier B, Oudard S, Hutson TE, statistical methods in health technology appraisals Porta C, Bracarda S, et al. Eficacy of everolimus in advanced renal cell carcinoma: a double-blind, more generally as well as their integration in cost- randomised, placebo-controlled phase III trial. effectiveness modelling. Lancet 2008;372:449-56.

46 DOI: 10.3310/hta14suppl2/07 Health Technology Assessment 2010; Vol. 14: Suppl. 2

Bevacizumab in combination with luoropyrimidine-based chemotherapy for the irst-line treatment of metastatic colorectal cancer

S Whyte,* A Pandor, M Stevenson and A Rees

ScHARR Technology Assessment Group, The University of Shefield, Shefield, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 08/211/01

This paper presents a summary of the evidence Date of ERG submission: review group (ERG) report into the clinical 25 September 2009 effectiveness and cost-effectiveness of bevacizumab TAR Centre(s): in combination with luoropyrimidine-based ScHARR Technology Assessment Group chemotherapy for the irst-line treatment List of authors: of metastatic colorectal cancer based on the S Whyte, A Pandor, M Stevenson and A Rees manufacturer’s submission to the National Institute Contact details: for Health and Clinical Excellence (NICE) as part Sophie Whyte, Research Associate, ScHARR, University of of the single technology appraisal (STA) process. Shefield, Regent Court, 30 Regent Street, Shefield S1 4DA, Evidence was available in the form of one phase UK III, multicentre, multinational, randomised, open- E-mail: [email protected] label study (NO16966 trial). This two-arm study was originally designed to demonstrate the non- The research reported in this article of the journal inferiority of oral capecitabine plus oxaliplatin supplement was commissioned and funded by the (XELOX) compared with 5-luorouracil plus folinic HTA programme on behalf of NICE as project number acid plus oxaliplatin (FOLFOX)-4 in adult patients 08/211/01. The assessment report began editorial review in November 2009 and was accepted for publication in with histologically conirmed metastatic colorectal March 2010. See the HTA programme website for further cancer who had not previously been treated. project information (www.hta.ac.uk). This summary of the Following randomisation of 634 patients, the open- ERG report was compiled after the Appraisal Committee’s label study was amended to include a 2 × 2 factorial review. randomised (partially blinded for bevacizumab) The views and opinions expressed therein are those of phase III trial with the coprimary objective of the authors and do not necessarily relect those of the demonstrating superiority of bevacizumab in Department of Health. combination with chemotherapy compared with chemotherapy alone. Measured outcomes included Discussion of ERG reports is invited. Visit the HTA website overall survival, progression-free survival, response correspondence forum (www.hta.ac.uk/correspond). rate, adverse effects of treatment and health-related quality of life. The manufacturer’s primary pooled analysis of superiority (using the intention-to-treat population) showed that after a median follow- up of 28 months, the addition of bevacizumab to chemotherapy signiicantly improved progression- free survival and overall survival compared 47

with chemotherapy alone in adult patients with in the majority of cases, incurable and treatment histologically conirmed metastatic colorectal is palliative in nature. Although local radiotherapy cancer who were not previously treated [median and, less commonly, surgery both have a role, progression-free survival 9.4 vs 7.7 months metastatic disease is essentially a systemic disease (absolute difference 1.7 months); hazard ratio (HR) requiring systemic treatment. Traditionally this 0.79, 97.5% conidence interval (CI) 0.72 to 0.87; has meant cytotoxic chemotherapy although, in p = 0.0001; median overall survival 21.2 vs 18.9 recent years, passive immunotherapy in the form months (absolute difference 2.3 months); HR 0.83, of monoclonal antibody treatment has been added 97.5% CI 0.74 to 0.93; p = 0.0019]. The NO16966 to chemotherapy regimens. Commonly used trial was of reasonable methodological quality and regimens include oral capecitabine monotherapy, demonstrated a signiicant improvement in both oral capecitabine + intravenous (IV) oxaliplatin progression-free survival and overall survival when (XELOX), IV 5-luorouracil + folinic acid + bevacizumab was added to XELOX or FOLFOX. oxaliplatin (FOLFOX), IV 5-luorouracil + folinic However, the size of the actual treatment effect of acid + irinotecan (FOLFIRI), IV 5-luorouracil bevacizumab is uncertain. The ERG believed that ± folinic acid, and oral capecitabine + IV the modelling structure employed was appropriate, irinotecan (XELIRI). With current standard irst- but highlighted several key issues and areas of line chemotherapy, median survival is around uncertainty. At the time of writing, NICE was yet to 15–20 months.3–5 issue the guidance for this appraisal. Scope of the evidence review group report Introduction The objective of the appraisal was to evaluate The National Institute for Health and Clinical the clinical effectiveness and cost-effectiveness Excellence (NICE) is an independent organisation of bevacizumab, within its licensed indications, within the NHS that is responsible for providing in combination with oxaliplatin and either national guidance on the treatment and care of 5-luorouracil or capecitabine for the treatment of people using the NHS in England and Wales. metastatic colorectal cancer. The comparator was One of the responsibilities of NICE is to provide oxaliplatin or irinotecan, including chemotherapy guidance to the NHS on the use of selected new regimens without bevacizumab. Measured and established health technologies, based on an outcomes included overall survival, progression- appraisal of those technologies. free survival, response rate, adverse effects of treatment and health-related quality of life. NICE’s single technology appraisal (STA) process is speciically designed for the appraisal of a single The licensed indication permits the use product, device or other technology, with a single of bevacizumab in combination with indication, where most of the relevant evidence luoropyrimidine-based chemotherapy for the lies with one manufacturer or sponsor.1 Typically, treatment of patients with metastatic colorectal it is used for new pharmaceutical products close cancer but does not specify a line of treatment. The to launch. The principal evidence for an STA is NICE scope included the use of bevacizumab in derived from a submission by the manufacturer/ combination with oxaliplatin-based chemotherapy sponsor of the technology. In addition, a report in individuals with histologically conirmed reviewing the evidence submission is submitted metastatic colorectal cancer as irst-line therapy by the evidence review group (ERG), an external (for patients not previously treated for metastatic organisation independent of the Institute. This disease), and as second-line therapy. The paper presents a summary of the ERG report for manufacturer’s submission (MS), however, focuses the STA entitled ‘Bevacizumab in combination with on irst-line use only. ﬂuoropyrimidine-based chemotherapy for the ﬁrst-line treatment of metastatic colorectal cancer’. The main evidence presented in support of the clinical effectiveness of bevacizumab was based Description of the underlying on one phase III, multicentre, multinational, health problem randomised, open-label study (NO16966 trial).6 This two-arm study was originally designed Colorectal cancer is the third most common cancer to demonstrate the non-inferiority of XELOX in the UK, with 36,766 new cases diagnosed in compared with FOLFOX-4 in adult patients with England and Wales in 2005.2 Metastatic disease is, histologically conirmed metastatic colorectal 48 Health Technology Assessment 2010; Vol. 14: Suppl. 2

cancer who had not previously been treated. the NO16966 trial and compared the addition of Following randomisation of 634 patients, the bevacizumab to chemotherapy with chemotherapy open-label study was amended (additional phase II alone. The manufacturer’s primary pooled and III studies that were published demonstrated analysis of superiority (using the intention-to-treat the beneit of adding bevacizumab to irinotecan, population) showed that after a median follow- 5-luorouracil and folinic acid)7,8 to include a up of 28 months, the addition of bevacizumab to 2 × 2 factorial randomised (partially blinded for chemotherapy (B-XELOX/B-FOLFOX-4 combined) bevacizumab) phase III trial (n = 1401) with the signiicantly improved progression-free survival coprimary objective of demonstrating superiority and overall survival compared with chemotherapy of bevacizumab in combination with chemotherapy alone (P-XELOX/P-FOLFOX-4/XELOX/FOLFOX-4 (B-XELOX or B-FOLFOX-4) compared with combined) in adult patients with histologically chemotherapy alone (P-XELOX or P-FOLFOX-4). conirmed metastatic colorectal cancer who were The dose of bevacizumab was 5 mg/kg every not previously treated [median progression-free 2 weeks (B-FOLFOX-4) or 7.5 mg/kg every 3 weeks survival 9.4 vs 7.7 months (absolute difference (B-XELOX). 1.7 months); hazard ratio (HR) 0.79, 97.5% conidence interval (CI) 0.72 to 0.87; p = 0.0001; The scope of the manufacturer’s cost-effectiveness median overall survival 21.2 vs 18.9 months submission focused on a comparison with regimens (absolute difference 2.3 months); HR 0.83, 97.5% containing oxaliplatin which was considered to CI 0.74 to 0.93; p = 0.0019]. be the most relevant comparator. A comparison with irinotecan-based chemotherapy was also A secondary pooled analysis of superiority included for completeness. The manufacturer (requested by the ERG as it was believed to submitted additional analyses in response to the be more appropriate) restricted to patients in ERG clariication questions. Further data and the second 2 × 2 factorial part of the NO16966 analyses were also submitted following the irst study as per the original statistical trial plan committee meeting. These included further data (B-XELOX/B-FOLFOX-4 combined vs P-XELOX/P- on the patient access scheme’s (PAS’s) operating FOLFOX-4 combined) found similar results costs as well as pharmacy and preparation costs for [median progression-free survival 9.4 vs 8.0 months bevacizumab. (absolute difference 1.4 months); HR 0.83, 97.5% CI 0.72 to 0.95; p = 0.0023; median overall survival 21.3 versus 19.9 months (absolute difference Methods 1.4 months); HR 0.89, 97.5% CI 0.76 to 1.03; p = 0.0769]. The ERG report comprised a critical review of the evidence for the clinical evidence and cost- The manufacturer’s pooled analysis of non- effectiveness of the technology based upon the inferiority (using the eligible patient population manufacturer’s/sponsor’s submission to NICE as and the intention-to-treat population) showed part of the STA process. that the XELOX (XELOX/P-XELOX/B- XELOX combined) and FOLFOX-4 (FOLFOX- The manufacturer’s literature searches were 4/P-FOLFOX-4/B-FOLFOX-4 combined) based repeated and a narrative critique of the submitted regimens were equivalent for both progression-free evidence was undertaken. The economic model survival and overall survival (p-values were stated as submitted by the manufacturer was considered not signiicant, but these values were not reported). structurally adequate to assess the decision No analysis was undertaken for the factorial design problem, but not all of the model inputs were (P-XELOX/B-XELOX combined versus P-FOLFOX- considered satisfactory. Additional work carried 4/B-FOLFOX-4 combined). out by the ERG focused on conducting sensitivity analyses relating to areas of uncertainty. A pre-deined subgroup analysis on progression- free survival found that the statistical superiority of bevacizumab plus chemotherapy was evident in Results the XELOX subgroups (B-XELOX vs P-XELOX; Summary of submitted HR 0.80, 97.5% CI 0.66 to 0.96; p-value not clinical evidence reported) but did not reach the signiicance level in the FOLFOX-4 subgroups (B-FOLFOX-4 The manufacturer’s main analysis pooled data from vs P-FOLFOX-4; HR 0.89, 97.5% CI 0.74 to the initial two arms and the 2 × 2 factorial part of 1.06; p-value not reported). Additional post hoc 49

exploratory analyses, following the results from FOLFOX-4/XELOX/FOLFOX-4 combined, 25.3%), the Adjuvant Colon Cancer End Points (ACCENT) Corresponding data, restricted to the 2 × 2 factorial study,9 found that there was a signiicant and analyses, yielded similar results (B-XELOX/B- direct correlation between time to recurrence FOLFOX-4 combined, 30.8% vs P-XELOX/P- after surgery and survival after recurrence in FOLFOX-4 combined, 20.8%). The statistical patients whose disease recurred after surgery and analysis comparing the rates of discontinuation adjuvant treatment. Removing the subgroup of between treatment groups was not reported in patients that may have slower tumour progression the MS or in the manufacturer’s supplementary after adjuvant treatment (an imbalance between evidence. treatment groups with regard to an important prognostic factor that was not recognised at the Summary of submitted cost- start of the NO16966 trial) signiicantly improved effectiveness evidence (i.e. lowered) the HRs for adding bevacizumab to chemotherapy compared with chemotherapy Cost-effectiveness was estimated using a Microsoft alone for both overall survival and progression-free EXCEL model with four states: pre-progression on survival. Depending on the analyses conducted treatment, pre-progression and post treatment, (e.g. exclusion of patients with prior adjuvant progressive disease and dead. An area under the chemotherapy from all four treatment arms of the curve approach was used to estimate the disease factorial study, from FOLFOX groups only or from progression of metastatic colorectal cancer patients. P-FOLFOX group only) the HRs for overall survival The distribution of patients between health states ranged from 0.83 to 0.85 (p < 0.03) and the HRs was used to calculate total direct costs and quality- for progression-free survival ranged from 0.74 to adjusted life-years (QALYs) for each intervention. 0.77 (p < 0.0001). Although this may be plausible, Costs were considered from an NHS and Personal the ERG notes that caution should be exercised as Social Services perspective. Cost-effectiveness was this is a post hoc exploratory analysis. expressed in terms of incremental cost per QALY with a time horizon of 8 years, which is equivalent The majority of adverse events were generally to a lifetime horizon in the population of interest. associated with cytotoxic chemotherapy. FOLFOX- The analysis focused on the interventions 4-based regimens were generally associated B-XELOX and B-FOLFOX. The model was with increased neutropenia/granulocytopenia, populated with eficacy data from the N016966 and XELOX-based regimens were generally trial but as discussed in the clinical effectiveness associated with increased diarrhoea and hand section these trial data have been analysed in and foot syndrome. Adverse events that could several different ways. Data on treatment duration be potentially related to bevacizumab included and dose intensity were also based on the N016966 increased frequencies of high blood pressure, trial. Survival data were modelled using Kaplan– proteinuria, bleeding, gastrointestinal perforation, Meier data up to median survival of 28 months thromboembolic events and wound healing and a Weibull distribution after this point. The complications. Serious (grade 3) or life threatening ERG requested several changes to the model inputs (grade 4) adverse events that occurred more and modelling assumptions (including additional commonly in patients receiving bevacizumab analyses). plus chemotherapy (B-XELOX/B-FOLFOX-4 combined) than those receiving chemotherapy A summary of the key incremental cost- alone (P-XELOX/P-FOLFOX-4/XELOX/FOLFOX-4 effectiveness ratios (ICERs) included in the combined) were thromboembolic events (7.8% submission are presented in Table 1. Of the vs 5.1%, respectively), hypertension (4.0% vs several analyses presented by the manufacturer, 0.8%, respectively), proteinuria (3.5% vs 0.9%, the ERG considered the analysis using the 2 × 2 respectively) and bleeding problems (1.9% vs part of the N016966 trial, with the XELOX 1.5%, respectively). Grade 3 and 4 gastrointestinal and FOLFOX arms pooled, with patients with perforations and wound healing complications prior adjuvant treatment excluded to be the were rare (< 1%). Similar results were observed most appropriate. This analysis produced ICERs when data were restricted to the factorial analyses. of £36,006 and £31,174 for B-XELOX versus XELOX and B-FOLFOX versus FOLFOX, The rates of discontinuation were higher in the respectively. The inclusion of patients with bevacizumab containing groups (B-XELOX/B- prior adjuvant chemotherapy resulted in higher FOLFOX-4 combined, 30.8%) than in the no ICERs. Unpooling the XELOX and FOLFOX bevacizumab containing groups (P-XELOX/P- arms affected the individual XELOX and 50 Health Technology Assessment 2010; Vol. 14: Suppl. 2

TABLE 1 A summary of ICERs included in the manufacturer’s submission (MS)

ICERs (£ per QALY saved)

B-XELOX vs B-FOLFOX vs Scenario XELOX FOLFOX

MS original analysis Without PAS Analysis using data from all six arms of N016966, XELOX £82,098 £94,989 and FOLFOX–4 arms pooled With PAS Analysis using data from all six arms of N016966, XELOX £34,170 £41,388 and FOLFOX–4 arms pooled

MS supplementary data, requested by ERG With PAS Analysis using data from all six arms of N016966, XELOX £35,912 £36,569 and FOLFOX–4 arms pooled With PAS Analysis using the 2 × 2 part of N016966, XELOX and £48,111 £39,771 FOLFOX–4 arms pooled With PAS Analysis using 2 × 2 part of N016966, XELOX and £35,662 £62,714 FOLFOX–4 arms unpooled With PAS Analysis using the 2 × 2 part of N016966, XELOX and £36,006 £31,174 FOLFOX–4 arms pooled, without prior adjuvant treatment Without PAS Analysis using data from all six arms of N016966, XELOX £90,945 £98,436 and FOLFOX–4 arms pooled, including bevacizumab wastage Without PAS Analysis using the 2 × 2 part of N016966, XELOX and £92,698 £96,687 FOLFOX–4 arms pooled, without prior adjuvant treatment Without PAS Analysis using 2 × 2 part of N016966, XELOX and £90,779 £240,324 FOLFOX–4 arms unpooled Without PAS Analysis using the 2 × 2 part of N016966, XELOX and £129,911 £134,309 FOLFOX–4 arms pooled

MS additional submission (post irst committee meeting) With PAS Analysis using the 2 × 2 part of N016966, XELOX and £36,494 £31,122 FOLFOX–4 arms pooled, without prior adjuvant treatment

ERG, evidence review group; B-FOLFOX–4, bevacizumab in combination with FOLFOX–4; B-XELOX, bevacizumab in combination with XELOX; FOLFOX–4, intravenous 5-luorouracil plus folinic acid plus oxaliplatin; ICERs, incremental cost- effectiveness ratios; MS, manufacturer’s submission; PAS, patient access scheme; QALY, quality-adjusted life-year; XELOX, oral capecitabine plus intravenous oxaliplatin.

FOLFOX ICERs in different directions. While no The ERG believed that the modelling structure systematic review was undertaken with irinotecan employed was appropriate. as a comparator, a cost-effectiveness analysis was undertaken (data not presented here). Weaknesses

Despite no evidence to suggest that the Commentary on statistical validity of the factorial approach was the robustness of methodologically inappropriate, the validity of submitted evidence simply pooling data from essentially two different study designs (i.e. a two-arm design and a 2 × 2 Strengths factorial design) without accounting for between- The NO16966 trial was of reasonable study variability is inappropriate. Unweighted methodological quality (with some limitations) (for uncertainty) pooling of results from different and measured a range of outcomes that were as studies is not advisable as there are almost certainly appropriate and clinically relevant as possible. differences between trials that, if not accounted

for, are likely to lead to biased estimates of effect. three times the incremental cost of adding The appropriateness of combining data from bevacizumab to oxaliplatin. Hence the impact of the two parts of the study was also questioned by continuing bevacizumab treatment on the ICERs the European Medicines Agency.10 The resulting could be considerable. pooled data (manufacturer’s primary pooled analysis of superiority and non-inferiority) should Under the PAS, bevacizumab has a ixed price therefore be treated with caution. Additionally it per cycle, but for calculations without the PAS it is is unclear whether patients with prior adjuvant important that drug wastage should be included chemotherapy should be excluded from the for both oxaliplatin and bevacizumab. The MS analysis. ‘without PAS’ ICERs did not include drug wastage within the base case although bevacizumab wastage The restriction to the trial data from the 2 × 2 part was included within one analysis as stated in Table of the NO16966 study, the pooling of the XELOX 1. The inclusion of drug wastage resulted in higher and FOLFOX arms, and the restriction to the data ICERs. of patients without prior adjuvant chemotherapy all had a large impact on the resulting ICERs. Conclusions The MS did not make use of the range of utility values identiied from the literature review and The NO16966 trial was of reasonable did not explain why these values were not used. methodological quality and demonstrated a The sources of the utility values used in the MS signiicant improvement in both progression-free were poorly referenced, resulting in the ERG being survival and overall survival when bevacizumab was unable to verify them. The distributions used for added to XELOX or FOLFOX. However, the size the utility values in the probabilistic sensitivity of the actual treatment effect of bevacizumab is analyses (PSA) relected the uncertainty relating uncertain due to the following: to the speciic values used but underestimated the uncertainty relating to the selection of • trial design limitations (two-part study, open- utility values. The ERG noted that using wider label design) distributions for utility values would signiicantly • imbalance of known prognostic factor (time increase the CIs around the mean ICERs from between primary treatment and recurrence) the PSA, and reducing the utility values by 20% • relatively short duration of chemotherapy markedly increased the ICERs. treatment (approximately 6 months) despite the fact that the trial protocol allowed Chemotherapy can be administered intermittently continuation of the study therapy until or continuously, but the difference in cost and progressive disease or unacceptable toxicity effectiveness between intermittent and continuous • interpretation of the statistical analyses (pooled treatment is unclear. Current care in England is analysis of all patients versus analysis by often intermittent treatment with chemotherapy, factorial design). but the trial and the model both represent continuous treatment chemotherapy. It is unclear In addition, there was uncertainty around whether how this difference may impact the ICERs but, as bevacizumab treatment should be continued until an example, if intermittent treatment was cheaper progression of the underlying disease. than continuous treatment whilst having a similar eficacy, then the ICER for continuous treatment The ERG believed that the modelling structure with bevacizumab versus intermittent treatment employed was appropriate, but highlighted several would be greater than the ICER for continuous key issues and areas of uncertainty and included treatment with bevacizumab versus continuous the following: treatment. • It is unclear which approach to data analysis In clinical practice, treatment with non-oxaliplatin (pooling, excluding adjuvant therapy patients, chemotherapy components may continue beyond etc.) is most appropriate and the choice of oxaliplatin cessation although in the N016966 approach has a signiicant impact on the trial this was rarely seen. Because of the structure resulting ICERs. of the PAS (in which oxaliplatin is received free • Unlike the N016966 trial, in clinical of charge), the incremental cost of continuing practice chemotherapy may be administered bevacizumab after oxaliplatin cessation is almost intermittently rather than continuously. 52 Health Technology Assessment 2010; Vol. 14: Suppl. 2

This introduces considerable uncertainty as 2. Cancer Research UK. Number of new cases of cancer diagnosed by site, UK, 2005. URL: http://publications. the differences in cost and eficacy between cancerresearchuk.org/WebRoot/crukstoredb/CRUK_ intermittent and continuous use are not known. PDFs/incidence/cs_inc_t8.3.pdf (accessed 10 July • At the time of writing the decision on whether 2009). the proposed PAS scheme would be accepted was unknown. The majority of the analysis 3. Douillard JY, Cunningham D, Roth AD, Navarro presented by the manufacturer included the M, James RD, Karasek P, et al. Irinotecan combined PAS. Running the model without the PAS with luorouracil compared with luorouracil alone resulted in much higher ICERs. as irst-line treatment for metastatic colorectal • The eficacy associated with the continuation of cancer: a multicentre randomised trial. Lancet treatment with bevacizumab after cessation of 2000;355:1041–7. oxaliplatin is unknown. However, with the PAS 4. de Gramont A, Figer A, Seymour MT, Homerin the incremental cost of continuing bevacizumab M, Hmissi A, Cassidy J, et al. Leucovorin and after oxaliplatin cessation is almost three times luorouracil with or without oxaliplatin as irst-line the incremental cost of adding bevacizumab to treatment in advanced colorectal cancer. J Clin Oncol oxaliplatin. Hence bevacizumab treatment post 2000;18:2938–47. oxaliplatin cessation has the potential to have a signiicant impact on the resulting ICERs. 5. Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced Research recommendations colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22:229–37. The ERG makes three recommendations for areas 6. Saltz LBC. Bevacizumab in combination with requiring further research: oxaliplatin-based chemotherapy as irst-line therapy in metastatic colorectal cancer: A randomized phase • research into the likely duration of III study. J Clin Oncol 2008;26:2013–19 (Erratum bevacizumab treatment in clinical practice and published in: J Clin Oncol 2008;26:3110; J Clin Oncol the survival associated with longer treatment 2009;27:653). duration • research into the cost-effectiveness of 7. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright bevacizumab for patients currently receiving T, Hainsworth J, Heim W, et al. Bevacizumab intermittent XELOX or FOLFOX plus irinotecan, luorouracil, and leucovorin • inding ways to select patients who will beneit for metastatic colorectal cancer. N Engl J Med from bevacizumab. 2004;350:2335–42. 8. Kabbinavar FFS. Addition of bevacizumab to bolus Summary of NICE guidance luorouracil and leucovorin in irst-line metastatic colorectal cancer: Results of a randomized phase II issued as a result of the STA trial. J Clin Oncol 2005;23:3697–705.

At the time of writing, NICE was yet to issue the 9. O’Connell MJ, Campbell ME, Goldberg RM, guidance for this appraisal. Grothey A, Seitz JF, Benedetti JK, et al. Survival following recurrence in stage II and III colon cancer: indings from the ACCENT data set. J Clin Key references Oncol 2008;10:2336–41.

1. National Institute for Health and Clinical 10. European Medicines Agency. Assessment Report Excellence. 2006. Guide to the single technology for Avastin. Procedure Number. EMEA/H/C/000582/ appraisal (STA) process. URL: www.nice.org.uk/ II/0014. 2009. URL: www.emea.europa.eu/ nicemedia/pdf/STA_Process_Guide.pdf. humandocs/PDFs/EPAR/avastin/Avastin-H-582-II- 14-AR.pdf (accessed 6 September 2009).

DOI: 10.3310/hta14suppl2/08 Health Technology Assessment 2010; Vol. 14: Suppl. 2

Dronedarone for the treatment of atrial ibrillation and atrial lutter

E Maund,* C McKenna, M Sarowar, D Fox, M Stevenson, C Pepper, S Palmer and N Woolacott

Centre for Reviews and Dissemination/Centre for Health Economics, University of York, York, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 08/214/01

This paper presents a summary of the evidence Date of ERG submission: 28 October 2009 review group (ERG) report on the clinical effectiveness and cost-effectiveness of dronedarone TAR Centre(s): for the treatment of atrial ibrillation (AF) or atrial Centre for Reviews and Dissemination/Centre for Health lutter based upon a review of the manufacturer’s Economics submission to the National Institute for Health and List of authors: Clinical Excellence (NICE) as part of the single E Maund, C McKenna, M Sarowar, D Fox, M Stevenson, technology appraisal process. The population C Pepper, S Palmer and N Woolacott considered in the submission were adult clinically Contact details: stable patients with a recent history of or current Emma Maund, Research Fellow, Centre for Reviews and non-permanent AF. Comparators were the Dissemination, University of York, Heslington, York YO10 current available anti-arrhythmic drugs: class 1c 5DD, UK agents (lecainide and propafenone), sotalol and E-mail: [email protected] amiodarone. Outcomes were AF recurrence, all- cause mortality, stroke, treatment discontinuations The research reported in this article of the journal supplement was commissioned and funded by the (due to any cause or due to adverse events) and HTA programme on behalf of NICE as project number serious adverse events. The main evidence came 08/214/01. The assessment report began editorial review from four phase III randomised controlled trials, in January 2010 and was accepted for publication in March direct and indirect meta-analyses from a systematic 2010. See the HTA programme website for further project review, and a synthesis of the direct and indirect information (www.hta.ac.uk). This summary of the ERG evidence using a mixed-treatment comparison. report was compiled after the Appraisal Committee’s Overall, the results from the different synthesis review. approaches showed that the odds of AF recurrence The views and opinions expressed therein are those of appeared statistically signiicantly lower with the authors and do not necessarily relect those of the dronedarone and other anti-arrhythmic drugs Department of Health. than with non-active control, and that the odds Discussion of ERG reports is invited. Visit the HTA website of AF recurrence are statistically signiicantly correspondence forum (www.hta.ac.uk/correspond). higher for dronedarone than for amiodarone. However, the results for outcomes of all-cause mortality, stroke and treatment discontinuations and serious adverse events were all uncertain. A discrete event simulation model was used to evaluate dronedarone versus antiarrhythmic drugs

and standard therapy alone. The incremental cost- NICE’s single technology appraisal (STA) process effectiveness ratio of dronedarone was relatively is speciically designed for the appraisal of a single robust and less than £20,000 per quality-adjusted product, device or other technology, with a single life-year. Exploratory work undertaken by the ERG indication, where most of the relevant evidence identiied that the main drivers of cost-effectiveness lies with one manufacturer or sponsor.1 Typically, were the beneits assigned to dronedarone for it is used for new pharmaceutical products close all-cause mortality and stroke. Dronedarone is to launch. The principal evidence for an STA is not cost-effective relative to its comparators when derived from a submission by the manufacturer/ the only effect of treatment is a reduction in AF sponsor of the technology. In addition, a report recurrences. In conclusion, uncertainties remain reviewing the evidence submission is submitted in the clinical effectiveness and cost-effectiveness by the evidence review group (ERG), an external of dronedarone. In particular, the clinical evidence organisation independent of the Institute. This for the major drivers of cost-effectiveness (all- paper presents a summary of the ERG report for cause mortality and stroke), and consequently the the STA.2 additional beneits attributed in the economic model to dronedarone compared to other anti- Description of the underlying arrhythmic drugs are highly uncertain. The inal health problem guidance, issued by NICE on 25 August 2010, states that: Dronedarone is recommended as an Atrial ibrillation (AF) is the most common cardiac option for the treatment of non-permanent atrial arrhythmia with a prevalence that increases ibrillation only in people: whose atrial ibrillation with age. Symptoms of AF include dificulty is not controlled by irst-line therapy (usually breathing, palpitations, chest pain, dizziness and including beta-blockers), that is, as a second-line loss of consciousness. AF is also associated with treatment option, and who have at least one of the an increased risk of thrombus formation and following cardiovascular risk factors: - hypertension consequently a ivefold increased risk of stroke requiring drugs of at least two different classes, compared to people without AF.3 AF and its diabetes mellitus, previous transient ischaemic symptoms can be treated using pharmacological or attack, stroke or systemic embolism, left atrial electrophysiological/surgical interventions to either diameter of 50 mm or greater, left ventricular control ventricular rate, which does not eliminate ejection fraction less than 40% (noting that the AF but improves AF symptoms, or restore normal summary of product characteristics [SPC] does sinus rhythm. There are three different types of not recommend dronedarone for people with left AF: paroxysmal, which spontaneously terminates ventricular ejection fraction less than 35% because within 7 days; persistent, which requires treatment of limited experience of using it in this group) (cardioversion) to terminate; and permanent, in or age 70 years or older, and who do not have which normal heart rhythm can not be restored by unstable New York Heart Association (NYHA) class treatment. III or IV heart failure. Furthermore, ‘People who do not meet the criteria above who are currently Scope of the evidence receiving dronedarone should have the option to review group report continue treatment until they and their clinicians consider it appropriate to stop’. Dronedarone, Multaq® (Sanoi–Aventis), is an antiarrhythmic drug (AAD) that has properties belonging to all four Vaughan–Williams’ classes Introduction of AAD. It is indicated in adult clinically stable patients with history of, or current, non-permanent The National Institute for Health and Clinical AF to prevent recurrence of AF or to lower Excellence (NICE) is an independent organisation ventricular rate. The recommended dose is 400 mg within the NHS that is responsible for providing twice daily, with patients expected to remain national guidance on the treatment and care of indeinitely on dronedarone unless there is lack of people using the NHS in England and Wales. eficacy, or intolerability. One of the responsibilities of NICE is to provide guidance to the NHS on the use of selected new The manufacturer (Sanoi Aventis Ltd) presented and established health technologies, based on an a submission to NICE on the use of dronedarone, appraisal of those technologies. (within the context of its licensed indication) for

56 Health Technology Assessment 2010; Vol. 14: Suppl. 2

the treatment of AF and atrial lutter (AFL), both with left ventricular dysfunction; (iv) persistent AF as a irst-line adjunctive treatment to standard with no SHD; and (v) persistent AF with SHD. baseline therapy (with or without beta-blockers and anticoagulation therapy) and as a second-line treatment compared to other AADs: (i) class 1c Methods agents (lecainide and propafenone); (ii) sotalol; and (iii) amiodarone. The ERG report comprised a critical review of the evidence for the clinical effectiveness and cost- Evidence for the eficacy and safety of dronedarone effectiveness of the technology based upon the and other AADs came from randomised controlled manufacturer’s/sponsor’s submission to NICE as trials (RCTs), meta-analysis (presenting direct and part of the STA process. indirect comparisons) and a synthesis of the direct and indirect evidence using a mixed-treatment The ERG critiqued the search strategy, comparison (MTC). A total of 39 studies, including study selection, validity assessment, outcome four studies of dronedarone [EURIDIS (European selection and the statistical methods used in the Trial in Atrial Fibrillation or Flutter Patients manufacturer’s submission of clinical effectiveness. Receiving Dronedarone for the Maintenance of It also explored the inconsistency of inclusion Sinus Rhythm) ADONIS (American–Australian– and exclusion of studies and use of continuity African Trial with Dronedarone in Atrial corrected data both within and between different Fibrillation or Flutter Patients for the Maintenance types of statistical analyses. In addition, the ERG of Sinus Rhythm), ATHENA (A placebo- also checked the validity of the MTC analysis controlled, double-blind parallel arm Trial to by running it using WINBUGS software. The ERG assess the eficacy of dronedarone 400mg bid for critiqued the methods used in the manufacturer’s the prevention of cardiovascular Hospitalisation economic evaluation. It corrected the cost- or death from any cause in patiENts with Atrial effectiveness results presented by the manufacturer, ibrillation/atrial lutter) and DIONYSOS (Eficacy undertook additional exploratory work to identify and Safety of Dronedarone Versus Amiodarone for the main drivers of cost-effectiveness and key the Maintenance of Sinus Rhythm in Patients with assumptions for the different comparisons, and Atrial Fibrillation)] conducted by the manufacturer, explored the robustness of the cost-effectiveness to were considered eligible for inclusion in the direct speciic assumptions and additional uncertainties and indirect meta-analyses and the MTC; however, identiied by itself. the studies included in the direct meta-analysis and the MTC were subject to different inclusion criteria. Outcomes of interest were: AF recurrence, all-cause Results mortality, stroke, treatment discontinuation (due Summary of submitted to any cause or adverse events) and serious adverse clinical evidence events of treatment (SAEs). The EURIDIS/ADONIS trials (see Table 1 for The manufacturer’s submission included a study details) demonstrated that dronedarone discrete event simulation model which was used was statistically signiicantly more effective than to estimate the cost-effectiveness of dronedarone placebo for maintenance of sinus rhythm [hazard with other licensed AADs and standard therapy ratio (HR) 0.75; 95% conidence interval (CI) 0.65 alone for AF. The comparison with standard to 0.87, p < 0.001] and in reducing the ventricular therapy alone was restricted to high-risk elderly rate during recurrence of AF/AFL [103.4 ± 25.9

AF patients with a CHADS2 score ≥ 4 (CHADS2 is beats per minute (b.p.m) vs 117.1 ± 30.4 b.p.m, a stroke risk stratiication scheme which is based p < 0.001].4 on speciic risk factors including congestive heart failure, hypertension, age > 75 years, diabetes The ATHENA study (see Table 1), which recruited mellitus, and prior stroke or transient ischaemic only moderate- to high-risk elderly AF patients, attack). This model was used to evaluate the cost- 75% of whom were in sinus rhythm, showed that effectiveness of ive main patient groups according dronedarone resulted in a signiicant reduction in to their clinical AF type and baseline risk factors the primary composite end point of time to irst in line with UK guidelines: (i) paroxysmal AF with cardiovascular hospitalisation or death from any no structural heart disease (SHD); (ii) paroxysmal cause (HR 0.76; 95% CI 0.69 to 0.84, p < 0.001). AF with coronary heart disease; (iii) paroxysmal AF The primary end point appeared to be mainly

TABLE 1 Summary of dronedarone trials included in the manufacturer’s submission

ADONIS/EURIDISa ATHENA DIONYSOS

Population characteristics n 1237 4628 504 Dose 400 mg BD 400 mg BD 400 mg BD Age range Dronedarone: mean 63.5 Mean: 71.6 (SD 9.0) years Mean 64 years (10.7) years < 65 years: 18.9% Range 28–90 years Placebo: mean 62.2 (11.1) 65 to < 75 years: 39.5% < 65 years: 52% years ≥ 75 years: 41.6% > 75 years: 19% Type of AF Paroxysmal and persistent Paroxysmal and persistent Persistent (cardioversion AF AF indicated); (although At least one risk factor excluded, some were for cardiovascular classed as having paroxysmal hospitalisation or permanent AF) Anticoagulation used? Majority of patients were 44% receiving aspirin Yes receiving anticoagulants Hypertension Dronedarone: 60% 86.3% 67% Placebo: 50.1% SHD Dronedarone: 42.4% 59.6% 28% Placebo: 39.7% CHF Dronedarone: 17.3% 21.2% 22% (not III or IV at time of Placebo: 17.87% randomisation) Treatment duration 12 months Minimum 12 months > 6 months

Outcome measure Primary outcome measure Recurrence of First hospitalisation due to AF recurrence or AF (measured by CV events or death premature discontinuation transtelephonic ECG when due to intolerance or lack symptomatic) of eficacy (AF recurrence measured by unscheduled ECG) Secondary outcomes Symptoms related to AF Death from any cause Occurrence of major safety Mean ventricular rate during Death from CV causes end point irst recurrence of AF First hospitalisation due to Occurrence of drug speciic CV event AEs Post hoc analyses AF recurrence (measured by scheduled ECGs, hospitalisation for AF/AFL, electrical cardioversion) Stroke

AEs, adverse events; AF, atrial ibrillation; AFL, atrial lutter; BD, twice a day ; CHF, congestive heart failure; CV, cardiovascular; ECGs, electrocardiograms; SHD, structural heart disease; SD, standard deviation. a These two trials have identical protocols and are often considered as a single trial.

driven by a reduction in time to irst cardiovascular stroke in patients receiving dronedarone compared hospitalisation due to a signiicant reduction in to those receiving placebo (HR 0.66; 95% CI 0.46 hospitalisation for AF (HR 0.63; 95% CI 0.55 to 0.96, p = 0.027).5 to 0.72, p < 0.001). There was no statistically signiicant difference in all-cause mortality The DIONYSOS trial (see Table 1), which directly between patients receiving dronedarone and those compared dronedarone with amiodarone, receiving placebo (HR 0.84; 95% CI 0.66 to 1.08, showed that the incidence of recurrence of AF p = 0.18). A post hoc analysis showed that there or premature study drug discontinuation was 58 was a statistically signiicant reduction in the risk of statistically signiicantly greater for dronedarone Health Technology Assessment 2010; Vol. 14: Suppl. 2

TABLE 2 Incremental cost per QALY results for the base-case analysis, a sensitivity analysis exploring the assumption that sotalol and amiodarone have the same effect on mortality as dronedarone; and a sensitivity analysis exploring the assumption of a treatment effect on AF recurrence alone

Summary of incremental cost per QALY results for each of the base case populations Paroxysmal AF Persistent AF No SHD CAD LVD No SHD SHD Dronedarone vs standard therapy £3620 £4014 £3577 £3358 £3520 Dronedarone vs sotalol £1692 £1,988 NA £1848 NA Dronedarone vs class 1c £18,206 NA NA £18,955 NA Dronedarone vs amiodarone NA NA £1895 NA £2349

Incremental cost per QALY results for each base case population when amiodarone and sotalol are assumed to have the same effect on mortality as dronedarone Paroxysmal AF Persistent AF No SHD CAD LVD No SHD SHD Dronedarone vs sotalol £119,704 £102,668 NA £92,009 NA Dronedarone vs amiodarone NA NA £55,063 NA £71,306

ERG’s incremental cost per QALY results for each of the base case populations when the model assumes a treatment effect on AF recurrences alone Paroxysmal AF Persistent AF No SHD CAD LVD No SHD SHD Dronedarone vs standard therapy £7,486,908 £70,323,846 £1,355,984 £1,630,715 £2,254,522 Dronedarone vs sotalol £5,232,678 D NA D NA Dronedarone vs class 1c D NA NA D NA Dronedarone vs amiodarone NA NA £5,694,862 NA D

AF, atrial ibrillation; CAD, coronary artery disease; D, dominated; LVD, left ventricular dysfunction; NA, not applicable; SHD, structural heart disease. than for amiodarone (73.9% vs 55.3%, p- signiicant reduction in stroke compared to control. value < 0.0001). No signiicant difference was reported between dronedarone and either amiodarone or sotalol Overall, the results from the direct and indirect based on the results from the MTC. meta-analyses and the MTC showed that the odds of AF recurrence appeared statistically signiicantly With regard to treatment discontinuations, the lower with all AADs than with non-active control, results reported from the direct and indirect but that the odds of AF recurrence are statistically meta-analyses were inconsistent with the MTC, signiicantly higher for dronedarone than for other suggesting considerable uncertainty. Results from AADs. the different synthesis approaches showed that compared with other AADs, dronedarone had the There were no statistically signiicant differences lowest odds of SAEs. However, the omission of data between AADs for all-cause mortality based on from the EURIDIS/ADONIS trial for this outcome the head-to-head RCT (DIONYSOS) or the means that the results are unreliable. results from the indirect comparison. However, in the MTC, dronedarone was reported to have Summary of submitted cost- a statistically signiicant reduction in the odds of effectiveness evidence all-cause mortality compared to both sotalol and amiodarone. No previous published cost-effectiveness studies of dronedarone in patients with AF/AFL were For stroke, results from the MTC analysis only identiied by the manufacturer. The results from were reported in the manufacturer’s submission. the manufacturer’s submission demonstrated that Dronedarone was associated with a statistically dronedarone appeared highly cost-effective in each 59

of the populations compared to using standard economic model structure was considered baseline therapy alone as irst-line treatment, appropriate for the decision problem, and the or compared to sotalol or amiodarone as a irst- detailed sensitivity analyses were thorough and line antiarrhythmic (Table 2). The results for informative in exploring the robustness of the dronedarone, relative to class 1c agents, showed results. that dronedarone was borderline in terms of cost- effectiveness, with an incremental cost-effectiveness Weaknesses ratio (ICER) just above £20,000 per quality- Potential weaknesses that the ERG identiied in adjusted life-year (QALY) and a 50% probability of relation to the clinical effectiveness evidence were: being cost-effective at this threshold. The indings were reported to be robust across a wide range of 1. The inclusion/exclusion criteria applied to alternative assumptions. The results appeared most studies to be included in the direct and indirect sensitive to assumptions regarding the beneits analyses were not explicitly stated. from AADs on mortality. 2. Different inclusion/exclusion criteria were applied to studies for the direct meta-analysis The main driver of cost-effectiveness for the and the MTC, with a substantial reduction comparisons of dronedarone versus standard in the number of studies entering the MTC therapy as irst-line treatment, and sotalol or compared to the direct meta-analysis. amiodarone as irst line antiarrhythmics, is 3. Issues of clinical and statistical heterogeneity the additional mortality beneit attributed to between the different studies were insuficiently dronedarone. If sotalol and amiodarone are reported or were not explored. assumed to have the same effect on mortality as 4. Neither the exchangeability of the ATHENA dronedarone, dronedarone is no longer considered study with lower risk and younger AF to be cost-effective (see Table 2). Stroke beneits populations nor the generalisability of and differences in treatment-related adverse the ATHENA population to the overall events have only a very limited impact on cost- AF population managed in the NHS were effectiveness for these comparisons. In contrast, considered. the main drivers of cost-effectiveness for the comparison of dronedarone versus class 1c agents The ERG identiied a number of potential are a combination of the beneits assumed from weaknesses related to the economic submission and stroke and a reduction in adverse events. The electronic model which were considered to impact ERG noted that if only the potential beneits of on the validity of the cost-effectiveness results. AF recurrence are included in the model then These included: dronedarone does not appear cost-effective for any of the populations considered (see Table 2). 1. The treatment pathways evaluated by the manufacturer may not represent the full range Commentary on the robustness of relevant strategies or sequences. of submitted evidence 2. The use of baseline data from the ATHENA trial may not be generalisable to the UK AF Strengths population. The manufacturer conducted a comprehensive 3. The use of a restricted set of studies to inform systematic review that identiied not only all the relative effectiveness estimates applied in relevant trials of dronedarone but also additional the model. RCTs for other relevant comparator AADs, 4. The assumptions used for class 1c agents, that including class 1c agents, sotalol and amiodarone. for all-cause mortality there is no difference A range of alternative synthesis approaches was between dronedarone and class 1c agents, employed by the manufacturer in order to assess whilst for stroke, class 1c agents have no effect the relative effectiveness of dronedarone compared compared to standard care alone. to other AADs that are currently used in the NHS. 5. The estimates of the mortality effects of The results of these separate comparisons were amiodarone and dronedarone. reported for each of the main clinical outcomes. 6. Uncertainty surrounding the health-related quality of life (HRQoL) data used in the model. In general, the ERG considered the economic 7. Uncertainty in relation to the acquisition submission to be of high quality, meeting the costs, initiation and monitoring costs of requirements of the NICE reference case. The dronedarone.

60 Health Technology Assessment 2010; Vol. 14: Suppl. 2

The ERG explored the robustness to a number Conclusions of these uncertainties. The ICER of dronedarone remained relatively robust throughout (< £20,000 The effectiveness of dronedarone as an adjunctive per QALY) except for the following assumptions: treatment to standard care is highly uncertain, the (i) amiodarone and sotalol have the same effect on key issue being the generalisability of the ATHENA all-cause mortality as dronedarone; and (ii) class 1c study which relects a moderate- to high-risk has the same effect on stroke as dronedarone. In elderly AF population relative to the general AF these situations, the ICER of dronedarone was well population. above £30,000 per QALY (see Table 2). In terms of the broader comparison of Finally, the submission does not explicitly consider dronedarone with AADs, the ERG considers that the potential clinical effectiveness or cost- the clinical evidence is highly uncertain for the key effectiveness of dronedarone for patients with AFL. drivers of the cost-effectiveness of dronedarone: all-cause mortality and stroke. The uncertainty Areas of uncertainty arises because the potential clinical and statistical The relative effectiveness and cost-effectiveness heterogeneity of the included RCTs has not been of dronedarone versus other AADs remains adequately considered, and the exchangeability subject to a number of areas of uncertainty in of the ATHENA study with the other studies is terms of informing current NHS practice. These questionable. Also, the additional restrictions uncertainties include: (i) the generalisability of imposed on the inclusion of RCTs in the MTC are evidence from the ATHENA study to inform likely to increase the overall decision uncertainty the management of a lower risk and younger compared to a fuller use of this evidence. AF population; (ii) the relative eficacy of Furthermore, the question of how the reduction in dronedarone compared to other AADs; (iii) all-cause mortality or stroke is mediated, given that the validity of pooling the individual studies dronedarone is the least effective AAD in terms of in the different synthesis approaches given the AF recurrence, remains to be elucidated. lack of consideration of clinical and statistical heterogeneity across the different studies; (iv) the Key issues speciically relevant to the economic clinical evidence for the major drivers of cost- evaluation include: establishing the most effectiveness (e.g. all-cause mortality and stroke) appropriate source of data to inform the baseline and consequently, the additional beneits attributed event rates applied in the model; the potential in the economic model to dronedarone compared cost-effectiveness of dronedarone in a range of to other AADs; (v) the clinical evidence for the alternative and feasible treatment sequences; the eficacy of dronedarone and other AADs to lower potential HRQoL beneits of dronedarone and the ventricular rate as rate control was not included maintenance of beneits over the longer term; and as an outcome measure in the submission; and the absence of a inal conirmed acquisition price (vi) the presence and potential magnitude of any at the time of the submission of the ERG report. quality of life beneits attributed to dronedarone as Finally, the lower initiation and monitoring costs HRQoL have not been directly assessed in any of assumed for dronedarone are uncertain, although the existing dronedarone RCTs. these do not appear to have a signiicant impact on the inal ICER results. There remains a number of additional sources of uncertainty related to the cost-effectiveness of Implications for research dronedarone that the ERG has been unable to adequately address. This includes establishing Further and longer term trials or the the most appropriate source of data to inform implementation of registries would be helpful the baseline event rates applied in the model; to further establish the eficacy and safety of the position for dronedarone in the pathway dronedarone relative to other AAD treatments that of treatment sequences; HRQoL beneits of are regularly used in this indication within UK dronedarone; and the maintenance of beneits over clinical practice. This is of particular importance the longer term. in regard to outcomes of all-cause mortality and stroke, as these appear to be the key drivers of the cost-effectiveness results. Given the lack of existing HRQoL data, future RCTs of dronedarone and other AADs should also consider using a relevant

HRQoL measure. Additional evidence related to should have the option to continue treatment until the effectiveness of AADs for patients with AFL they and their clinicians consider it appropriate to would also be valuable. stop’.

Summary of NICE guidance Key references issued as a result of the STA 1. NICE. Guide to the single technology appraisal (STA) process. URL: www.nice.org.uk/nicemedia/pdf/STA_ The inal guidance, issued by NICE on 25 August Process_Guide.pdf. 2010, states that: 2. McKenna C, Maund E, Sarowar M, Fox D, Dronedarone is recommended as an option for Stevenson M, Pepper C, et al. Dronedarone the treatment of non-permanent atrial ibrillation for atrial ﬁbrillation and atrial ﬂutter. A single only in people: whose atrial ibrillation is not technology appraisal. York: Centre for Reviews and Dissemination and Centre for Health Economics; controlled by irst-line therapy (usually including 2009. beta-blockers), that is, as a second-line treatment option, and who have at least one of the following 3. Kannel WB, Wolf PA, Benjamin EJ, Levy D. cardiovascular risk factors: - hypertension requiring Prevalence, incidence, prognosis, and predisposing drugs of at least two different classes, diabetes conditions for atrial ibrillation: population-based mellitus, previous transient ischaemic attack, estimates. Am J Cardiol 1998;82:2N–9N. stroke or systemic embolism, left atrial diameter of 50 mm or greater, left ventricular ejection 4. Singh BN, Connolly SJ, Crijns HJ, Roy D, Kowey fraction less than 40% (noting that the summary of PR, Capucci A, et al. Dronedarone for maintenance product characteristics [SPC] does not recommend of sinus rhythm in atrial ibrillation or lutter. N dronedarone for people with left ventricular Engl J Med 2007;357:987–99. ejection fraction less than 35% because of limited 5. Connolly SJ, Crijns HJGM, Torp-Pedersen C, van experience of using it in this group) or age 70 years Eickels M, Gaudin C, Page RL, et al. Analysis of or older, and who do not have unstable New York stroke in ATHENA: a placebo-controlled, double- Heart Association (NYHA) class III or IV heart blind, parallel-arm trial to assess the eficacy of failure. dronedarone 400 mg BID for the prevention of cardiovascular hospitalization or death from any Furthermore, ‘People who do not meet the criteria cause in patients with atrial ibrillation/atrial lutter. above who are currently receiving dronedarone Circulation 2009;120:1174–80.

62 DOI: 10.3310/hta14suppl2/09 Health Technology Assessment 2010; Vol. 14: Suppl. 2

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

J Dretzke,1* J Round,2 M Connock,1 S Tubeuf,2 M Pennant,1 A Fry-Smith,1 C Hulme,2 C McCabe2 and C Meads1

1Unit of Public Health, Epidemiology & Biostatistics, University of Birmingham, Birmingham, UK 2Academic Unit of Health Economics, Leeds Institute of Health Sciences, University of Leeds, Leeds, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 08/239/01

This is a summary of the evidence review group Date of ERG submission: (ERG) report on the clinical effectiveness and cost- 1 November 2009 effectiveness of adjuvant imatinib post resection TAR Centre(s): of KIT-positive gastrointestinal stromal tumours West Midlands Health Technology Assessment (GISTs) compared with resection only in patients at Collaboration (WMHTAC) signiicant risk of relapse. The ERG report is based List of authors: on the manufacturer’s submission to the National J Dretzke, J Round, M Connock, S Tubeuf, Institute for Health and Clinical Excellence (NICE) M Pennant, A Fry-Smith, C Hulme, C McCabe and as part of the single technology appraisal (STA) C Meads process. The bulk of the clinical evidence submitted Contact details: was in the form of one randomised controlled Janine Dretzke, Unit of Public Health, Epidemiology trial (RCT), the Z9001 trial, funded by the & Biostatistics, University of Birmingham, Edgbaston, manufacturer, which compared resection + adjuvant Birmingham B15 2TT, UK imatinib for 1 year to resection only. Results were E-mail: [email protected] immature, with median recurrence-free survival (RFS) not yet having been reached at the time of The research reported in this article of the journal supplement was commissioned and funded by the analysis. The trial did provide evidence of a delay HTA programme on behalf of NICE as project number in disease recurrence [1-year RFS rate of 98% 08/239/01. The assessment report began editorial review in the imatinib arm vs 83% in the placebo arm March 2010 and was accepted for publication in May 2010. [hazard ratio (HR) 0.35, 95% conidence interval See the HTA programme website for further project (CI) 0.22 to 0.53, p < 0.0001)] but no evidence of information (www.hta.ac.uk). This summary of the ERG an overall survival beneit. There was no long-term report was compiled after the Appraisal Committee’s evidence around the rate of imatinib resistance review. over time with different treatment strategies The views and opinions expressed therein are those of (± adjuvant treatment). The relevant patient the authors and do not necessarily relect those of the group for this appraisal is those at signiicant risk Department of Health. of relapse. These form a subgroup of the Z9001 Discussion of ERG reports is invited. Visit the HTA website trial, and all information regarding this group was correspondence forum (www.hta.ac.uk/correspond). designated ‘Commercial-in-Conidence’ (CIC).

Median observation time for RFS was also CIC. Pharmaceuticals UK Ltd). Typically, it is used The manufacturer constructed a Markov model for new pharmaceutical products that are close comprising 10 health states designed to estimate to launch. The principal evidence for an STA is costs and effects of treatment over a lifetime time derived from a submission by the manufacturer/ horizon. The manufacturer’s estimate of the base- sponsor of the technology. In addition, a report case incremental cost-effectiveness ratio (ICER) was reviewing the evidence submission is submitted £22,937/quality-adjusted life-year (subsequently by the evidence review group (ERG), an external amended by the manufacturer to £23,601). While organisation independent of the Institute. This the structure of the model reasonably relected paper presents a summary of the ERG report for the natural history of the disease, the ERG had the STA entitled ‘Imatinib as adjuvant treatment numerous concerns regarding the selection of, and following resection of KIT-positive gastrointestinal assumptions around, input parameters (utilities, stromal tumours (GISTs)’.2 monthly probabilities of recurrence and death). Furthermore, the model was set up in such a way Description of the underlying that any delay in recurrence translated directly health problem into a survival beneit, an assumption that has no evidence base. A further assumption not supported Patients eligible for adjuvant imatinib according by evidence was that any treatment beneit gained to the UK licence are those who have had a in the irst year is carried on for a further 2 resection of KIT (CD117)-positive GIST and years at the same rate. Appropriate probabilistic are deemed to be at signiicant risk of relapse. sensitivity analysis was undertaken on the base ‘Signiicant’ risk is not deined in the licence. In case only, but not on scenario analyses, or choice the industry submission it includes those patients of model used to estimate long-term survival data. in the moderate- and high-risk groups as deined The model was not amenable to changes in input by the Miettinen and Lasota criteria,3 which take values, thus limiting any additional analyses by into account tumour size, location and mitotic the ERG to test assumptions. Due to the large count. Risk of relapse and choice of treatment number of uncertainties and assumptions, the also depend on the speciic type of KIT exon gene estimated ICERs should be regarded as highly mutations. uncertain. The guidance issued by NICE in June 2010 as a result of the STA does not recommend Based on the indings of studies in different imatinib as adjuvant treatment after resection countries, GIST has an annual incidence of of gastrointestinal stromal tumours, although between 6.8 and 14.5 per million; around two- individuals currently receiving adjuvant imatinib thirds of patients with GIST are thought to be should have the option to continue treatment until resectable. Of the resected patients, around one- they and their clinician consider it appropriate to half may have a signiicant risk of relapse.4 stop. Survival after resection ranged from 48% to 80% at 5 years for low-risk GIST before the introduction Introduction of imatinib; the 5-year survival rate (approximately 95%) is similar to that of the general population, The National Institute for Health and Clinical while for high-risk GISTs the 5-year survival rate Excellence (NICE) is an independent organisation ranged from 0% to 30% before the introduction within the UK NHS that is responsible for of imatinib.5 As imatinib is a relatively recent providing national guidance on the treatment and treatment for GIST, there are fewer long-term care of people using the NHS in England and survival estimates. In a trial of imatinib for Wales. One of the responsibilities of NICE is to advanced GIST, with a reported follow-up of up to provide guidance to the NHS on the use of selected 71 months, median overall survival increased from new and established health technologies, based on 18 months to 60 months.6 an appraisal of those technologies. Most patients eventually show resistance to imatinib NICE’s single technology appraisal (STA) process1 due to secondary mutations in the KIT and/or is speciically designed for the appraisal of a single PDGFRA (alpha-type platelet-derived growth factor product, device or other technology, with a single receptor) kinase domains. One study found that indication, where most of the relevant evidence lies secondary or acquired resistance develops after a with one manufacturer or sponsor (here, Novartis median of about 2 years of treatment.7

64 Health Technology Assessment 2010; Vol. 14: Suppl. 2

Current guidelines state that imatinib increases (QALY) of resection with 3 years’ adjuvant imatinib recurrence-free survival (RFS) and suggest that it (note: this differs from the trial where imatinib is may be an effective treatment to prevent recurrence given for 1 year) compared with resection only. following primary surgery in those patients with Recurrence results were taken from the trial and a high risk of recurrence; these patients should extrapolated for longer time periods. Mortality be considered for inclusion in clinical trials of results for patients in various health states were neoadjuvant and adjuvant therapy with imatinib.8 obtained from a variety of literature sources. Utility Optimal treatment duration with adjuvant imatinib estimates were not available from the trial and were is not yet established, nor whether adjuvant therefore taken from other literature sources or treatment was a clinically effective or cost-effective estimated by the manufacturer. option. Methods Scope of the ERG report The ERG report comprised a critical review of The research question was the clinical effectiveness the evidence for the clinical evidence and cost- and cost-effectiveness of adjuvant imatinib effectiveness of the technology based on the following resection compared with resection only manufacturer’s/sponsor’s submission to NICE as in patients with KIT-positive GISTs who are at part of the STA process. signiicant risk of relapse. This is consistent with the licence indication. Additional searches to conirm the completeness of published data on effectiveness and cost- The clinical effectiveness data was primarily based effectiveness were undertaken. The ERG on one ongoing randomised controlled trial independently assessed the validity of the Z9001 (RCT), the Z9001 trial4 (n = 713), which compared trial and analysed CIC results for the signiicant- resection + adjuvant imatinib for 1 year with risk subgroup, which were provided separately by resection alone. the manufacturer.

Data on those patients who were at signiicant The model provided by the manufacturer risk of relapse and who formed a subgroup of the was complex and not amenable to changes in trial (n = 302) were supplied as ‘Commercial in parameter values, particularly with regard to Conidence’ (CIC) data. Classiication of patients running alternative probabilistic sensitivity analyses according to risk was retrospective and was (PSAs). This limited the scope for the ERG to fully performed for only 78% of patients, making the validate the model, and thus reduced the ERG’s results susceptible to bias. It is likely that patients conidence in the results of the model. There was in this trial are similar to patients in the UK who also a lack of information around uncertainty would be eligible for treatment with adjuvant estimates for certain parameters, particularly utility imatinib, although there is a possibility of differing values, again restricting any additional sensitivity thresholds for what constitutes ‘signiicant’ risk. analyses.

Outcome measures in the Z9001 trial were RFS, overall survival (OS) and adverse events. Quality- Results of-life outcomes were not collected. Median follow- Summary of submitted up time for OS was 19.7 months (data is CIC for clinical evidence RFS and for both RFS and OS in the signiicant- risk subgroup). It should be noted that on disease All information relating to the relevant subgroup progression, all patients received treatment with of patients (those at signiicant risk of relapse) was imatinib or other treatment options (e.g. sunitinib) CIC and therefore cannot be reported here. The as appropriate, regardless of the treatment arm to total trial population included patients at low risk which they were allocated; it is, in effect, different of relapse, who would not be eligible for adjuvant treatment strategies (one commencing with treatment in the UK. For this total population, the adjuvant imatinib) that are being compared long estimated 1-year RFS rate was 98% in the imatinib term. arm and 83% in the placebo arm (HR 0.35, 95% CI 0.22 to 0.53, p < 0.0001), therefore a delay in The manufacturer submitted an economic model recurrence was evident (Figure 1). Median RFS had to assess the cost per quality-adjusted life-year not yet been reached at the time of analysis and

Total Events Imatinib 359 30 100 Placebo 354 70 90 80 70 60 50 40 30

Recurrence-free and alive (%) and alive Recurrence-free 20

10 HR 0.35 (95% CI 0.22 to 0.53); p < 0.0001 0 0 6 12 18 24 30 36 42 48 Time (months) Number at risk Placebo 354 188 89 34 8 Imatinib 359 207 105 33 6

FIGURE 1 Recurrence-free survival in total population (from manufacturer’s submission).

Total Events Imatinib 359 5 Placebo 354 8

100 90 80 70 60 50 Alive (%) Alive 40 30 20

10 HR 0.66 (95% CI 0.22 to 2.03); p = 0.47 0 0 6 12 18 24 30 36 42 48 Time (months) Number at risk Placebo 354 241 151 58 15 Imatinib 359 226 137 51 15

FIGURE 2 Overall survival in total population (from manufacturer’s submission). 66 Health Technology Assessment 2010; Vol. 14: Suppl. 2

few patients were evaluable at later time points. treatment arm (total trial population). There is The OS rates for the total population were similar no good long-term evidence on recurrence rates and most patients were still alive at the time of (resistance) when imatinib is given repeatedly. data analysis (Figure 2). Results from the Z9001 Quality of life was not measured as part of the trial on subsequent use of imatinib in patients who Z9001 trial. have previously had adjuvant imatinib were also CIC. The ERG identiied no additional results on Cost-effectiveness imatinib resistance rates with subsequent use in the The model provided by the manufacturer long term. contained no programming errors and the structure of the model reasonably relected the Summary of submitted cost- natural history of the disease. However, the ERG effectiveness evidence was unable to conduct more than a limited range of alternative analyses to test assumptions made by The manufacturer’s estimate of the base-case the manufacturers, as the model was not amenable incremental cost-effectiveness ratio (ICER) was to changes in input values. Furthermore, the ERG £22,937/QALY (subsequently amended by the had a number of concerns relating to the monthly manufacturer to £23,601). This estimate relies on probabilities of death in various health states and patients receiving adjuvant imatinib for 3 years, their application in the model. The manufacturer for which there is no evidence from the Z9001 assumed that all monthly probabilities post health trial, which used 1 year of adjuvant treatment. states A, B and D (Figure 3) were the same in both The manufacturer’s base-case analysis suggested treatment arms, i.e. the probability of recurrence that there was an approximately 60% chance that or death did not depend on whether a patient imatinib was cost-effective at willingness-to-pay received adjuvant treatment or resection only. This thresholds of between £20,000 and £30,000 per seems implausible to the ERG. The result of this QALY. Four additional analyses were submitted: is that any differences in a delay in progression (1) signiicant-risk patients, receiving imatinib translate directly into a survival gain of the same for 1 year; (2) the overall at-risk population (no length. treatment time speciied); (3) the high-risk only population, receiving 1 year of imatinib; and (4) The manufacturer also provided no justiication the high-risk only population, receiving 3 years of for the selection of studies from which the input imatinib. ICERs were £13,550, £32,981, £6109 and parameters were derived, no details on how £19,813, respectively. the death and recurrence rates were calculated, and there appeared to be some errors and Commentary on the robustness inconsistencies. The impact on the ICER is unlikely of submitted evidence to be large – because of the model structure, patients in both treatment arms received the same Clinical effectiveness inputs post health states A, B and D – but this does The population relevant to this appraisal was not impart conidence in the modelling process. a subgroup of patients with signiicant risk of recurrence. Assignment of risk level was The assumption of sustained beneit from retrospective, and only 78% of patients were treatment for 2 years beyond the evidence base is a categorised according to risk. There is therefore generous one and systematically favours imatinib, a possibility of imbalances at baseline and risk of resulting in a reduced ICER. Because of this way of bias. Baseline characteristics of the signiicant risk extrapolating the treatment beneit, and because of population in the two trial arms are CIC. the model structure, the logic of the model is that it is not sensible to stop adjuvant imatinib at any There was some uncertainty around the handling time point but to continue indeinitely. The ERG of missing data and which deinition of ‘recurrence’ suggests that there is no proven beneit for this was used for the analyses in the submission; the treatment strategy. ERG was unable to gauge the potential impact on results. The results from the trial were immature, as A further concern is that appropriate PSA was follow-up times were short, and results at later time undertaken on the base case only, and not on the points were based on few patients at risk. There is other scenario analyses. In particular, PSA was not no evidence to show that adjuvant imatinib given undertaken on the subgroup analyses. One-way for 1 year prolongs overall survival. Median overall sensitivity analyses were conducted as part of the survival estimates were not reached in either clariication process, but no scenario analyses were 67

A B

No recurrence No recurrence and no and imatinib treatment adjuvant therapy

E Death GIST Post recurrence D and 800 mg No recurrence imatinib C and completed imatinib adjuvant Post recurrence therapy and 400 mg imatinib

Sunitinib second-line G treatment Death other

Dose escalation Best supportive F to 800 mg care H imatinib

FIGURE 3 Transition pathways in manufacturer’s model.

undertaken on choice of model used to estimate Conclusions long-term survival data. The absence of PSA for the subgroup analyses provided further exacerbates the A survival beneit with adjuvant imatinib has to paucity of the evidence on the uncertainty around date not been shown. There is a lack of good the cost-effectiveness estimates provided in the long-term evidence around the rate of imatinib submission. resistance over time with different treatment strategies (± adjuvant imatinib, for 1 year or 3 The utility values used relied heavily on one study years), and the effect on overall survival. There (Chabot et al.9) based on treatment with sunitinib are serious concerns around the validity and (after imatinib failure). The authors of this study application in the manufacturer’s model of a advised caution in the interpretation of their results number of input parameters, such as utilities and due to large uncertainty. The ERG also identiied monthly probabilities of death. The model also laws in how health-state utilities were modelled, makes a basic assumption that any beneit in delay for example relating to age adjustment, and the use of recurrence translates directly into an increase in of a mean utility value only (rather than a range). survival over the long term; this assumption is not supported by any evidence and does not take into Table 1 shows ERG estimates of the likely impact on account the possibility of differing rates of imatinib the ICER of a number of parameter assumptions/ resistance between the two treatment arms. Due to changes. the large number of uncertainties and assumptions,

68 Health Technology Assessment 2010; Vol. 14: Suppl. 2

TABLE 1 Effect of parameter changes on ICER (ERG estimates)

Effect on ICER Parameter (↑ = increase, ↓ = decrease) Decrease in utility value for RFS to 0.95 and 0.9 (manufacturer assumed a utility value of 1) ↑ (small) No estimate of uncertainty associated with recurrence-free health state in model (beneit ↑ for patients likely to have been overestimated) No utilities < 0 included (should have been included as within range of possible utilities) ↑ No disutility associated with adverse events of adjuvant treatment ↑ Gradual increase in recurrence rates after year 1 with adjuvant treatment (rather than ↑ sustained beneit over 3 years, which seems implausible) Correction of potential double-counting of utility loss (for health state and age) ↑ Error identiied by manufacturer relating to recurrence rates ↑ (also wider 95% CI) Increased resistance to imatinib over time (manufacturer’s sensitivity analysis found a ↑ reduced ICER – this seems implausible to the ERG and no adequate explanation was given) Reduction in survival beneit with adjuvant treatment (manufacturer’s sensitivity analysis ↑ found a reduced ICER – this seems implausible as this means a net beneit from patients dying earlier) Reduction in length of time of imatinib use (1 year only) ↓ Use of adjuvant imatinib in high-risk population only ↓

CI, conidence interval; ERG, evidence review group; ICER, incremental cost-effectiveness ratio; RFS, recurrence-free survival.

the estimated ICERs should be regarded as highly Key references uncertain. It is possible that results from ongoing 1. National Institute for Health and Clinical trials will inform this issue. The EORTEC 62024 Excellence (NICE). Guide to single technology (STA) trial10 in particular has as an end point time to process. URL: www.nice.org.uk/media/42D/B3/ imatinib resistance, which may be a more useful STAGuideLrFinal.pdf (accessed 24 September proxy for overall survival. Should adjuvant imatinib 2010). treatment be shown to be beneicial in the future, further research would also be required into the 2. Dretzke J, Round J, Connock M, Tubeuf S, Pennant type of patient most likely to beneit from adjuvant M, Fry-Smith A, et al. Imatinib as adjuvant treatment following resection of KIT-positive gastrointestinal stromal treatment based on mutational analysis. tumours; 2009. 25 March 2010. URL: http:www.nice. org.uk/nicemedia/live/12178/48128/48128.pdf. Summary of NICE guidance 3. Miettinen M, Lasota J. Gastrointestinal stromal issued as a result of the STA tumours: pathology and prognosis at different sites. Semin Diagn Pathol 2006;23:70–83. NICE guidance issued in June 2010 does not recommend imatinib as adjuvant treatment after 4. DeMatteo RP, Ballman KV, Antonescu CR, Maki RG, resection of gastrointestinal stromal tumours, Pisters PWT, Demetri GD, et al. Adjuvant imatinib although individuals currently receiving adjuvant mesylate after resection of localised, primary imatinib should have the option to continue gastrointestinal stromal tumour: a randomised, treatment until they and their clinician consider it appropriate to stop.

double-blind, placebo-controlled trial. Lancet imatinib: a randomised controlled trial. Lancet 2009;373:1097–104. 2006;368:1329–38.

5. Park CK, Lee EJ, Kim M, Lim HY, Choi DI, Noh 8. Reid R, Bulusu R, Buckels JEA. Guidelines for JH, et al. Prognostic stratiication of high-risk the management of gastrointestinal stromal tumours gastrointestinal tumours in the era of targeted (GISTs); 2009. URL: www.mccn.nhs.uk/useriles/ therapy. Ann Surg 2008;247:1011–18. documents/04%20GIST_Mngmnt_Gdlns.pdf.

6. Blanke CD, Demetri GD, von Mehren M, Heinrich 9. Chabot I, LeLorier J, Blackstein ME. The challenge MC, Eisenberg B, Fletcher JA, et al. Long-term of conducting pharmacoeconomic evaluations results from a randomised phase II trial of in oncology using crossover trials: the example standard versus higher-dose imatinib mesylate of sunitinib for gastrointestinal stromal tumours. for patients with unresectable or metastatic Eur J Cancer 2008;44:972–7. gastrointestinal stromal tumours expressing KIT. J Clin Oncol 2008;26:620–5. 10. US National Institutes of Health. Imatinib mesylate or observation only in treating patients who have 7. Demetri GD, van Oosterom AT, Garrett CR. Eficacy undergone surgery for localised gastrointestinal stromal and safety of sunitinib in patients with advanced tumor; 2010. URL: www.clinicaltrials.gov/ct2/show/ gastrointestinal stromal tumour after failure of NCT00103168?term=62024&rank=1.

70 DOI: 10.3310/hta14suppl2/10 Health Technology Assessment 2010; Vol. 14: Suppl. 2

Geitinib for the irst-line treatment of locally advanced or metastatic non-small cell lung cancer

T Brown,* A Boland, A Bagust, J Oyee, J Hockenhull, Y Dundar, R Dickson, VS Ramani and C Proudlove

Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 09/59/01

This paper presents a summary of the evidence Date of ERG submission: review group (ERG) report into the clinical 16 February 2010 effectiveness and cost-effectiveness of geitinib TAR Centre(s): for the irst-line treatment of locally advanced or Liverpool metastatic non-small cell lung cancer, in accordance List of authors: with the licensed indication, based upon the T Brown, A Boland, A Bagust, J Oyee, J Hockenhull, manufacturer’s submission to the National Institute Y Dundar, R Dickson, VS Ramani and C Proudlove for Health and Clinical Excellence (NICE) as Contact details: part of the single technology appraisal process. Tamara Brown, Research Fellow (Clinical Reviews), The submitted clinical evidence consisted of the Liverpool Reviews and Implementation Group, University IRESSA Pan-ASian Study (IPASS); a phase III of Liverpool, Room 2.07, Whelan Building, The Quadrangle, open-label randomised controlled trial conducted Brownlow Hill, Liverpool L69 3GB, UK in 87 centres in East Asia which compared the E-mail: [email protected] use of geitinib with paclitaxel/carboplatin in 1217 chemotherapy (CTX)-naive patients with The research reported in this article of the journal stage IIIB/IV pulmonary adenocarcinoma. The supplement was commissioned and funded by the HTA programme on behalf of NICE as project number 09/59/01. manufacturer’s submission focused on a subgroup The assessment report began editorial review in June 2010 of patients in IPASS who were epidermal growth and was accepted for publication in July 2010. See the HTA factor receptor (EGFR) gene mutation-positive programme website for further project information (www. (M+) (n = 261; 21% of the total IPASS population). hta.ac.uk). This summary of the ERG report was compiled The primary clinical outcome was progression- after the Appraisal Committee’s review. free survival (PFS). Secondary outcomes included The views and opinions expressed therein are those of overall survival, clinically relevant improvement the authors and do not necessarily relect those of the in quality of life and adverse events (AEs). Cost- Department of Health. effectiveness was measured in terms of incremental cost per quality-adjusted life-year (QALY). In the Discussion of ERG reports is invited. Visit the HTA website correspondence forum (www.hta.ac.uk/correspond). overall population, PFS was signiicantly longer in patients treated with geitinib than in those treated with paclitaxel/carboplatin (hazard ratio 0.74, 95% conidence interval 0.65 to 0.85; p < 0.0001). The manufacturer reported an incremental cost- effectiveness ratio (ICER) of £20,744 per QALY gained for the target population. The probabilistic sensitivity analysis illustrated that for patients who are EGFR M+, geitinib compared with 71

doublet CTX was not likely to be cost-effective Description of the underlying at what would usually be considered standard health problem levels of willingness to pay for an additional Lung cancer is the leading cause of cancer death QALY; the mean ICER for geitinib EGFR M+ worldwide and is responsible for over 33,000 versus doublet CTX EGFR M+ was reported as deaths a year in England and Wales.2 NSCLC is £35,700 per QALY. Additional analysis by the ERG the most common subtype, accounting for 80% included amendments to the base-case analysis, of all lung cancer cases. Despite advances in early including an alternative approach to projecting detection, most patients still present with late-stage survival, inclusion of two important additional disease. comparators, sensitivity to EGFR M+ prevalence, and AE costs and disutilities. The manufacturer’s Survival rates for lung cancer are very poor. In submission provides clinical evidence to support England, for patients diagnosed between 1993 the use of geitinib in EGFR M+ patients with and 1995 and followed up to 2000, 21.4% of men adenocarcinoma histology only. Before patients can and 21.8% of women with lung cancer were alive be offered irst-line treatment with geitinib they 1 year after diagnosis and less than 1% of advanced must undergo EGFR mutation status testing which NSCLC lung cancer patients were alive after is currently not routinely available in the NHS. At 5 years.3,4 the time of writing, the guidance document issued by NICE on 28 July 2010 states that ‘Geitinib The majority of patients with lung cancer are is recommended as an option for the irst-line diagnosed, or relapse, with incurable disease and treatment of people with locally advanced or receive palliative treatment only. For otherwise metastatic non-small-cell lung cancer (NSCLC) if it patients with stage III/IV NSCLC, irst-line they test positive for the epidermal growth factor treatment consists of platinum-based combination receptor tyrosine kinase (EGFR-TK) mutation and chemotherapy (CTX) followed by docetaxel CTX the manufacturer provides geitinib at the ixed or erlotinib, as currently recommended in NICE price agreed under the patient access scheme’. clinical guidelines.3

Scope of the evidence Introduction review group report

The National Institute for Health and Clinical Geitinib is an orally active, selective epidermal Excellence (NICE) is an independent organisation growth factor receptor (EGFR) gene tyrosine within the NHS that is responsible for providing kinase inhibitor which helps to slow the growth and national guidance on the treatment and care of spread of the cancer. people using the NHS in England and Wales. One of responsibilities of NICE is to provide Geitinib is indicated for the treatment of adult guidance to the NHS on the use of selected new patients with locally advanced or metastatic NSCLC and established health technologies, based on an with activating mutations of EGFR;5 the scope appraisal of those technologies. issued by NICE is for irst-line treatment only.

NICE’s single technology appraisal (STA) process Before patients can be offered irst-line treatment is speciically designed for the appraisal of a single with geitinib they must undergo EGFR mutation product, device or other technology, with a single status testing which is currently not routinely indication, where most of the relevant evidence available in the NHS. lies with one manufacturer or sponsor.1 Typically, it is used for new pharmaceutical products close The ERG report includes an assessment of both the to launch. The principal evidence for an STA is clinical effectiveness and cost-effectiveness evidence derived from a submission by the manufacturer/ submitted by the manufacturer (AstraZeneca) for sponsor of the technology. In addition, a report the use of geitinib compared with doublet CTX reviewing the evidence submission is submitted for the treatment of CTX-naive patients with by the evidence review group (ERG), an external stage IIIB/IV pulmonary adenocarcinoma who organisation independent of the Institute. This tested positive (M+) for the EGFR mutation. Data paper presents a summary of the ERG report for were presented for all patients and a subgroup of the STA entitled ‘Geﬁtinib for the ﬁrst-line treatment of patients who were EGFR M+. locally advanced or metastatic non-small cell lung cancer (NSCLC)’. 72 Health Technology Assessment 2010; Vol. 14: Suppl. 2

The primary clinical outcome was progression- of geitinib with paclitaxel/carboplatin in 1217 free survival (PFS). Secondary outcomes CTX-naive patients with stage IIIB/IV pulmonary included overall survival (OS), clinically relevant adenocarcinoma.8 The manufacturer’s submission improvement in quality of life (QoL) and adverse focused on a subgroup of patients in IPASS8 who events (AEs). Cost-effectiveness was measured in were EGFR M+ (n = 261; 21% of the total IPASS terms of incremental cost per quality-adjusted life- population). year (QALY). In the overall population, PFS was signiicantly longer in patients treated with geitinib than in Methods those treated with paclitaxel/carboplatin [hazard ratio (HR) 0.74, 95% conidence interval (CI) 0.65 The ERG report comprised a critical review of to 0.85; p < 0.0001]. In a subgroup analysis of 261 the evidence for the clinical evidence and cost- patients who were EGFR M+, PFS was signiicantly effectiveness of the technology based upon the longer among those who received geitinib than manufacturer’s/sponsor’s submission to NICE as among those who received paclitaxel/carboplatin part of the STA process. (HR 0.48, 95% CI 0.36 to 0.64; p < 0.0001). In the subgroup of patients who were EGFR mutation- The ERG evaluated the quality of the negative (M–) (n = 176), PFS was signiicantly manufacturer’s clinical effectiveness review which longer among those who received paclitaxel/ comprised of a systematic review, meta-analysis carboplatin (HR with geitinib 2.85, 95% CI 2.05 to and mixed-treatment comparison (MTC). Searches 3.98; p < 0.001). conducted by the manufacturer were assessed for completeness and the single trial put forward as Overall survival estimates were based on an evidence of effectiveness was critically appraised interim analysis (37% maturity) and were similar using the manufacturer’s responses to speciic for geitinib and paclitaxel/carboplatin patients questions in the submission template. in the overall trial population [18.6 months for geitinib vs 17.3 months for paclitaxel/carboplatin Cost-effectiveness evidence submitted by the (HR 0.91, 95% CI 0.76 to 1.10)]. There was no manufacturer consisted of a systematic review and signiicant difference in OS between geitinib and a de novo economic evaluation. The ERG assessed paclitaxel/carboplatin in EGFR M+ patients groups the manufacturer’s searches for completeness, (HR 0.78, 95% CI 0.50 to 1.20). Median OS was critically appraised the submitted economic model 12.1 months in the geitinib EGFR M– subgroup using the NICE reference case checklist6 and the and was 12.6 months in the paclitaxel/carboplatin Drummond 10-point checklist,7 and conducted a EGFR M– subgroup. detailed evaluation of the model and the validity of the MTC results for economic analysis of non-trial Signiicantly more patients in the geitinib group comparators. than in the paclitaxel/carboplatin group had a clinically relevant improvement in QoL, as assessed Additional analysis by the ERG included by scores on the Functional Assessment of Cancer amendments to the base-case analysis, including Therapy – Lung questionnaire,9 [odds ratio (OR) an alternative approach to projecting survival, 1.34, 95% CI 1.06 to 1.69; p = 0.01] and by scores inclusion of two important additional comparators, on the Trial Outcome Index (OR 1.78, 95% CI 1.40 sensitivity to EGFR M+ prevalence, and AE costs to 2.26; p < 0.001). Geitinib was associated with and disutilities. fewer grade 3 or 4 AEs.

After late identiication of interim analysis Results data from an ongoing RCT, the manufacturer Summary of submitted performed a meta-analysis using data from 8 clinical evidence IPASS and the North East Japan Geitinib Study Group (NEJGSG).10 Meta-analysis demonstrated Only one relevant randomised controlled trial signiicant improvement in PFS for EGFR M+ (RCT) was identiied by the manufacturer; the patients in the geitinib arm compared with EGFR IRESSA Pan-ASian Study (IPASS).8 IPASS8 is M+ patients in the paclitaxel/carboplatin arm (HR a phase III open-label RCT conducted in 87 0.43, 95% CI 0.34 to 0.53; p < 0.00001). centres in East Asia which compared the use

The manufacturer conducted an MTC comparing status testing. Currently, EGFR mutation testing is doublet CTX in CTX-naive patients with NSCLC, not routinely available in the NHS. It is uncertain using paclitaxel/carboplatin evidence from IPASS8 how future testing of newly diagnosed patients as a baseline and including 29 RCTS. The MTC with NSCLC will be orchestrated within the NHS did not identify any individual doublet CTX in England and Wales. In addition, patients with as offering both signiicant clinical beneit and adenocarcinoma histology would need to be signiicantly improved tolerability over the other identiied prior to EGFR mutation testing. This doublet CTX regimens. diagnostic service is not routinely available to patients in the NHS. Summary of submitted cost- effectiveness evidence The ERG highlighted that the clinical validity characteristics of EGFR tests could impact on The manufacturer conducted a de novo economic treatment outcomes with geitinib. In particular, evaluation. A Markov model was developed a positive result for EGFR mutation status does to evaluate the cost-effectiveness of geitinib not guarantee a good outcome, as a proportion compared to four different doublet CTX regimens. (clinical false-positives) of such patients receiving The clinical data used in the economic evaluation geitinib will not experience any beneit (shorter were generated from a variety of sources. The PFS) compared with current treatment with doublet HR for PFS for geitinib EGFR M+ patients was CTX and may in fact be worse off by not receiving derived from a meta-analysis conducted by the doublet CTX (Figure 1). The implications of using manufacturer and the HR for OS for geitinib EGFR mutation tests must be carefully considered EGFR M+ patients was extrapolated from IPASS.8 for both EGFR M+ and EGFR M– patients. Estimates of the HRs for PFS and OS for the doublet CTX regimens were sourced indirectly The number of patients requiring irst-line from the MTC. Although the economic evaluation treatment for NSCLC who are EGFR M+ in is primarily trial-based, there is a modelling England and Wales is currently uncertain. A recent component with regard to the extrapolation of publication has estimated this igure to be between health effects because IPASS8 is ongoing. The 5% and 10% in the Western population.11 economic evaluation adopts a lifetime horizon for consideration of costs and beneits and the The clinical evidence was derived from a high perspective is that of the UK NHS and Personal quality trial in patients with NSCLC; convincing Social Services. eficacy and QoL evidence were presented by the manufacturer for a speciic group of patients. The manufacturer reported an incremental cost- effectiveness ratio (ICER) of £20,744 per QALY The main evidence cited by the manufacturer gained for the target population. In addition to the was derived from the IPASS8 trial; this study has main cost-effectiveness results, ICERs for selected reached only 37% maturity for the determination subgroups were presented. Univariate sensitivity of OS. The inal OS estimates for patients in analysis, scenario analyses and probabilistic IPASS8 will be available in 2010. However, it may sensitivity analysis (PSA) were undertaken by the be dificult for the investigators to interpret the manufacturer. inal OS data from IPASS8 owing to the substantial number of patients in both groups who went on to The PSA illustrated that for patients who are EGFR receive a variety of second-line CTX regimens. M+, geitinib compared with doublet CTX was not likely to be cost-effective at what would usually be Clinical data from two other smaller trials [the considered standard levels of willingness to pay for NEJGSG10 trial and the First-SIGNAL (First- an additional QALY; the mean ICER for geitinib line Single agent Iressa versus Gemcitabine EGFR M+ versus doublet CTX EGFR M+ was and cisplatin trial in Never-smokers with reported as £35,700 per QALY. Adenocarcinoma of the Lung)12 trial] comparing geitinib with doublet CTX are also available. Commentary on the robustness of submitted evidence The main focus of the manufacturer’s submission was on patients who were EGFR M+; this subgroup Clinical evidence of patients cannot be considered to have been Before patients can be offered irst-line treatment truly randomised in the trial as the randomisation with geitinib they must undergo EGFR mutation process did not include stratiication by biomarker 74 Health Technology Assessment 2010; Vol. 14: Suppl. 2

Strategy Conventional Testing for EGFR M+ CTX (no testing) (for gefitinib Tx)

Histology Adenocarcinoma Adenocarcinoma

EGFR testing No testing EGFR M+ testing

Test results Negative Positive for mutations

Treatment CTX CTX Gefitinib prescribed

‘True’ gefitinib Non Respondera Non Responder response respondera responder

Patient Current Current Current ‘Placebo’ Gefitinib M+ outcome outcomes outcomes outcomes outcomes + AEs outcomes

Consequences No change No change Missed Worse Better opportunity PFS/OS PFS/OS

FIGURE 1 Effects of diagnostic test on treatment pathways and patient outcome. AEs, adverse events; CTX, chemotherapy; EGFR, epidermal growth factor receptor gene; M+, mutation-positive; PFS, progression-free survival; OS, overall survival; Tx, treatment.

type. In addition, the trial was not powered to In the UK, the most common irst-line CTX perform this subgroup analysis. regimen for patients with NSCLC is gemcitabine with either carboplatin or cisplatin. In IPASS,8 The generalisability of the IPASS8 study to patients geitinib is compared with paclitaxel/carboplatin; in England and Wales is limited. None of the it has been estimated by the manufacturer IPASS8 centres were based in the UK; all of the that approximately only 5% of patients receive patients were from East Asia. All of the IPASS8 paclitaxel/carboplatin as a irst-line treatment for patients had adenocarcinoma histology; in the NSCLC in England and Wales. UK patients with adenocarcinoma are estimated to make up approximately 25% of the population The MTC methods used by the manufacturer to with NSCLC.13 IPASS8 includes patients with compare paclitaxel/carboplatin with a range of performance status (PS) 2; in England and Wales, doublet CTX regimens in unselected populations CTX is not recommended by NICE for patients are appropriate. However, the ERG considered with metastatic disease with PS 2 unless as part of that the MTC was weak as it was reliant on the a clinical trial.3 The demographic characteristics assumption that EGFR mutation status does not of patients in IPASS8 do not match those of the affect treatment outcomes if patients are receiving relevant population in England and Wales; IPASS8 doublet CTX. The ERG believes this assumption patients are predominantly female and never is too strong as it is wholly reliant on the results of smokers. a subgroup analysis from a single RCT of patients with adenocarcinoma histology. The evidence base

for the studies used in the comparison of geitinib these analyses. The manufacturer responded that with doublet CTX may not be generalisable to the it would not able to provide the results of the EGFR M+ population. requested analyses within the timeframe of the STA process. Economic evidence

The manufacturer’s economic evaluation did not Conclusions compare geitinib with docetaxel or pemetrexed; both of these CTX regimens are listed as relevant The manufacturer’s submission provides clinical comparators in the inal NICE scope. In response evidence to support the use of geitinib in EGFR to the ERG’s clariication letter, the manufacturer M+ patients with adenocarcinoma histology only. provided an updated version of the MTC and Before patients can be offered irst-line treatment included pemetrexed. The ERG considered with geitinib they must undergo EGFR mutation that not including pemetrexed or docetaxel as status testing which is currently not routinely comparators in the economic evaluation was a available in the NHS. major weakness of the manufacturer’s submission. Major weaknesses in the clinical section of the The ERG identiied key areas where corrections manufacturer’s submission identiied by the ERG and/or adjustments to the economic model are include: (i) the clinical results of IPASS8 are not required: CTX costs, cycles, and exposure; OS generalisable to the majority of patients with and PFS modelling; and use of discounting and NSCLC in clinical practice in England and Wales; continuity correction methods. Taken together, and (ii) to date, there are no direct clinical trial the ERG’s corrections and/or adjustments to the data to demonstrate that use of geitinib as a irst- submitted model increased the size of the ICER line treatment by EGFR M+ patients leads to for the base-case population from £20,010 to over improved OS compared with the use of paclitaxel/ £70,000 per QALY (Tables 1 and 2). This suggests carboplatin. that the cost-effectiveness of geitinib compared to doublet CTX for CTX-naive EGFR M+ patients The ERG’s corrections and/or adjustments to the may be less favourable than presented by the submitted economic model have increased the manufacturer in the manufacturer’s submission. size of the ICER for the base-case population; the cost-effectiveness of geitinib compared to doublet The ERG highlighted that the results of the CTX for CTX-naive EGFR M+ patients may be less manufacturer’s economic evaluation were favourable than presented by the manufacturer in predicated on the use of the EGFR mutation test the manufacturer’s submission. (or similar) described in IPASS.8 This means that if a different EGFR mutation test is used and/ or does not demonstrate similar analytic validity, Summary of NICE guidance the manufacturer’s cost-effectiveness results may issued as a result of the STA no longer be valid. This assessment does not relate solely to use of geitinib, but to the speciic The guidance document issued by NICE on 28 July combination of mutation testing and geitinib 2010 states that: treatment studied in IPASS.8 Geitinib is recommended as an option for the irst- Finally, during the clariication process the line treatment of people with locally advanced or manufacturer was asked to provide individual metastatic non-small-cell lung cancer (NSCLC) if: patient data (IPD) from IPASS8 that would allow the ERG to explore a number of weaknesses identiied they test positive for the epidermal growth factor in the economic model. The manufacturer replied receptor tyrosine kinase (EGFR-TK) mutation and that it could not share IPD, but would be willing to conduct speciic analyses on behalf of the ERG. A the manufacturer provides geitinib at the ixed request was made to the manufacturer to conduct price agreed under the patient access scheme.

76 Health Technology Assessment 2010; Vol. 14: Suppl. 2 ICER ICER (£/QALY) ICER ICER (£/QALY) Costs Inc. QALYs Inc. emental cost-effectiveness ratio; Inc., incremental; IPASS, IRESSA Pan-ASian Study; MA, MA, IRESSA Pan-ASian Study; IPASS, incremental; Inc., ratio; emental cost-effectiveness ression-free survival; QALY, quality-adjusted life-year. QALY, survival; ression-free rer’s model for the base-case analysis (other modelled comparators) over 6 years comparators) modelled (other over analysis the base-case for model rer’s ICER ICER (£/QALY) Costs Inc. QALYs Inc. £4057 0.1767 £22,956 £8447 0.2229 £37,890 £4077 0.1445 £28,215 Gemcitabine/carboplatin CostsInc. QALYs Inc. Vinorelbine/cisplatin Gemcitabine/cisplatin Effect of corrections and amendments made by ERG to the manufactu by made amendments and corrections of Effect CTX, chemotherapy; GCSF, granulocyte colony stimulating factor; HR, hazard ratio; ICER, incr ICER, ratio; hazard HR, factor; stimulating colony granulocyte GCSF, chemotherapy; CTX, prog PFS, survival; overall OS, comparison; mixed-treatment MTC, meta-analysis; Combined effect of changesall Combined effect £7554 0.1253 £60,273 £8842 0.1256 £70,390 £7322 0.1241 £59,016 CTX treatment exposureCTX treatment £4543 0.1767 £25,706 £8737 0.2229 £39,189 £5067 0.1445 £35,062 Common CTX outcomes £5114 0.1892 £27,028 £7043 0.1896 £37,148 £5149 0.1880 £27,394 Correct second-line CTX costsCorrect £4380 0.1767 £24,785 £8085 0.2229 £36,264 £4657 0.1445 £32,228 Correct misaligned cyclesCorrect £3762 0.1767 £21,290 £8152 0.2229 £36,567 £4223 0.1445 £29,223 Continuity correctionContinuity £3362 0.1767 £19,024 £7891 0.2229 £35,398 £3895 0.1445 £26,956 Omit GCSF prophylaxis GCSF Omit £4039 0.1767 £22,855 £8429 0.2229 £37,809 £4500 0.1445 £31,141 Revise discounting methodRevise £3674 0.1796 £20,453 £8123 0.2266 £35,839 £4146 0.1469 £28,229 IPASS PFS HR (not MA)IPASS £4450 0.1678 £26,520 £8840 0.2140 £41,304 £4911 0.1356 £36,219 Revise PFS modelsRevise £5019 0.1630 £30,788 £9299 0.2097 £44,356 £5409 0.1313 £41,209 Revise OS modelsOS Revise £1985 0.1174 £16,907 £7175 0.1893 £37,905 £2245 0.0788 £28,509 Reduced cycles of CTX £5599 0.1735 £32,278 £9547 0.2194 £43,512 £6244 0.1409 £44,308 Amend irst-line AmendCTX costsirst-line Revised MTCRevised £3858 0.1824 £21,151 £8149 0.2229 £36,557 £4218 0.1445 £29,181 Base case with 6-year horizonBase case 6-year with £3761 0.1767 £21,284 £8151 0.2229 £36,562 £4222 0.1445 £29,217 Submitted Submitted model £3666 0.1767 £20,744 £8024 0.2229 £35,992 £4138 0.1445 £28,633 Model amendment

TABLE 1 TABLE 77

TABLE 2 Effect of corrections and amendments made by ERG to the manufacturer’s model for the base-case analysis (other modelled comparators) over 6 years (continuation of Table 1)

Docetaxel/cisplatin Pemetrexed/cisplatin

ICER ICER Model amendment Inc. costs Inc. QALYs (£/QALY) Inc. costs Inc. QALYs (£/QALY) Submitted modela -– – – – – – With revised MTC £4434 0.1627 £27,252 –£134 0.0601 –£2223 Reduced cycles of CTXb £6254 0.1593 £39,263 £2484 0.0565 £43,984 Revise OS models £2591 0.1013 £25,590 –£3115 –0.0379 £82,125 Revise PFS models £5636 0.1494 £37,735 £1091 0.0469 £23,271 IPASS PFS HR (not MA) £5123 0.1538 £33,311 £555 0.0512 £10,838 Revise discounting method £4356 0.1654 £26,340 –£264 0.0610 –£4323 Omit GCSF prophylaxis £4712 0.1627 £28,961 £144 0.0601 £2402 Continuity correction £4024 0.1627 £24,728 –£600 0.0601 –£9984 Correct misaligned cycles £4435 0.1627 £27,257 –£134 0.0601 –£2223 Correct second-line CTX £4944 0.1627 £30,385 £842 0.0601 £14,004 costs CTX treatment exposure £5200 0.1627 £31,961 £958 0.0601 £15,931 Combined effect of all changes £6285 0.0862 £72,908 £1574 –0.0560 –£28,080 (geitinib dominated)

CTX, chemotherapy; GCSF, granulocyte colony stimulating factor; HR, hazard ratio; ICER, incremental cost-effectiveness ratio; Inc., incremental; IPASS, IRESSA Pan-ASian Study; MA, meta-analysis; MTC, mixed-treatment comparison; OS, overall survival; PFS, progression-free survival; QALY, quality-adjusted life-year. a Submitted model did not include these comparators. b Submitted model did not include costs for these comparators.

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Health Technology Assessment reports published to date

Volume 1, 1997 No. 11 No. 6 Newborn screening for inborn errors of Effectiveness of hip prostheses in metabolism: a systematic review. primary total hip replacement: a critical No. 1 By Seymour CA, Thomason MJ, review of evidence and an economic Home parenteral nutrition: a systematic Chalmers RA, Addison GM, Bain MD, model. review. Cockburn F, et al. By Faulkner A, Kennedy LG, Baxter By Richards DM, Deeks JJ, Sheldon K, Donovan J, Wilkinson M, Bevan G. TA, Shaffer JL. No. 12 Routine preoperative testing: a No. 7 No. 2 systematic review of the evidence. Antimicrobial prophylaxis in colorectal Diagnosis, management and screening By Munro J, Booth A, Nicholl J. surgery: a systematic review of of early localised prostate cancer. randomised controlled trials. A review by Selley S, Donovan J, No. 13 By Song F, Glenny AM. Faulkner A, Coast J, Gillatt D. Systematic review of the effectiveness of laxatives in the elderly. No. 8 No. 3 By Petticrew M, Watt I, Sheldon T. The diagnosis, management, treatment Bone marrow and peripheral and costs of prostate cancer in England blood stem cell transplantation for and Wales. No. 14 malignancy. A review by Chamberlain J, Melia J, When and how to assess fast-changing A review by Johnson PWM, Moss S, Brown J. technologies: a comparative study of Simnett SJ, Sweetenham JW, Morgan GJ, medical applications of four generic Stewart LA. No. 4 technologies. Screening for fragile X syndrome. A review by Mowatt G, Bower DJ, No. 9 A review by Murray J, Cuckle H, Brebner JA, Cairns JA, Grant AM, McKee Screening for speech and language Taylor G, Hewison J. L. delay: a systematic review of the literature. No. 5 By Law J, Boyle J, Harris F, A review of near patient testing in Volume 2, 1998 Harkness A, Nye C. primary care. By Hobbs FDR, Delaney BC, No. 10 Fitzmaurice DA, Wilson S, Hyde CJ, Resource allocation for chronic Thorpe GH, et al. No. 1 Antenatal screening for Down’s stable angina: a systematic review of syndrome. effectiveness, costs and cost-effectiveness No. 6 of alternative interventions. Systematic review of outpatient services A review by Wald NJ, Kennard A, By Sculpher MJ, Petticrew M, for chronic pain control. Hackshaw A, McGuire A. Kelland JL, Elliott RA, Holdright DR, By McQuay HJ, Moore RA, Eccleston Buxton MJ. C, Morley S, de C Williams AC. No. 2 Screening for ovarian cancer: a No. 7 systematic review. No. 11 Neonatal screening for inborn errors of By Bell R, Petticrew M, Luengo S, Detection, adherence and control of metabolism: cost, yield and outcome. Sheldon TA. hypertension for the prevention of A review by Pollitt RJ, Green A, stroke: a systematic review. McCabe CJ, Booth A, Cooper NJ, No. 3 By Ebrahim S. Leonard JV, et al. Consensus development methods, and their use in clinical guideline No. 12 No. 8 development. Postoperative analgesia and vomiting, Preschool vision screening. A review by Murphy MK, Black NA, with special reference to day-case A review by Snowdon SK, Lamping DL, McKee CM, Sanderson surgery: a systematic review. Stewart-Brown SL. CFB, Askham J, et al. By McQuay HJ, Moore RA. No. 9 No. 4 No. 13 Implications of socio-cultural contexts Choosing between randomised and for the ethics of clinical trials. A cost–utility analysis of interferon beta nonrandomised studies: a systematic A review by Ashcroft RE, Chadwick for multiple sclerosis. review. DW, Clark SRL, Edwards RHT, Frith L, By Parkin D, McNamee P, Jacoby A, Hutton JL. Miller P, Thomas S, Bates D. By Britton A, McKee M, Black N, McPherson K, Sanderson C, Bain C. No. 10 No. 5 A critical review of the role of neonatal Effectiveness and eficiency of methods No. 14 hearing screening in the detection of of dialysis therapy for end-stage renal Evaluating patient-based outcome congenital hearing impairment. disease: systematic reviews. measures for use in clinical trials. By Davis A, Bamford J, Wilson I, By MacLeod A, Grant A, Donaldson A review by Fitzpatrick R, Davey C, Ramkalawan T, Forshaw M, Wright S. C, Khan I, Campbell M, Daly C, et al. Buxton MJ, Jones DR. 81

No. 15 No. 4 No. 15 Ethical issues in the design and conduct A randomised controlled trial of Near patient testing in diabetes clinics: of randomised controlled trials. different approaches to universal appraising the costs and outcomes. antenatal HIV testing: uptake and By Grieve R, Beech R, Vincent J, A review by Edwards SJL, Lilford RJ, acceptability. Annex: Antenatal HIV Braunholtz DA, Jackson JC, Hewison J, testing – assessment of a routine Mazurkiewicz J. Thornton J. voluntary approach. By Simpson WM, Johnstone FD, No. 16 No. 16 Boyd FM, Goldberg DJ, Hart GJ, Positron emission tomography: Qualitative research methods in health Gormley SM, et al. establishing priorities for health technology assessment: a review of the technology assessment. No. 5 literature. A review by Robert G, Milne R. By Murphy E, Dingwall R, Methods for evaluating area-wide and Greatbatch D, Parker S, Watson P. organisation-based interventions in health and health care: a systematic No. 17 (Pt 1) review. The debridement of chronic wounds: a No. 17 By Ukoumunne OC, Gulliford MC, systematic review. The costs and beneits of paramedic Chinn S, Sterne JAC, Burney PGJ. By Bradley M, Cullum N, Sheldon T. skills in pre-hospital trauma care. No. 6 By Nicholl J, Hughes S, Dixon S, No. 17 (Pt 2) Turner J, Yates D. Assessing the costs of healthcare technologies in clinical trials. Systematic reviews of wound care A review by Johnston K, Buxton MJ, management: (2) Dressings and topical No. 18 Jones DR, Fitzpatrick R. agents used in the healing of chronic Systematic review of endoscopic wounds. ultrasound in gastro-oesophageal No. 7 By Bradley M, Cullum N, Nelson EA, cancer. Cooperatives and their primary care Petticrew M, Sheldon T, Torgerson D. By Harris KM, Kelly S, Berry E, emergency centres: organisation and Hutton J, Roderick P, Cullingworth J, impact. No. 18 By Hallam L, Henthorne K. et al. A systematic literature review of spiral and electron beam computed No. 19 No. 8 tomography: with particular reference Screening for cystic ibrosis. to clinical applications in hepatic Systematic reviews of trials and other A review by Murray J, Cuckle H, studies. lesions, pulmonary embolus and Taylor G, Littlewood J, Hewison J. coronary artery disease. By Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F. No. 9 By Berry E, Kelly S, Hutton J, Harris KM, Roderick P, Boyce JC, et al. A review of the use of health status No. 20 measures in economic evaluation. No. 19 Primary total hip replacement surgery: By Brazier J, Deverill M, Green C, a systematic review of outcomes Harper R, Booth A. What role for statins? A review and and modelling of cost-effectiveness economic model. associated with different prostheses. No. 10 By Ebrahim S, Davey Smith Methods for the analysis of quality- A review by Fitzpatrick R, Shortall G, McCabe C, Payne N, Pickin M, of-life and survival data in health Sheldon TA, et al. E, Sculpher M, Murray D, Morris R, technology assessment. Lodge M, et al. A review by Billingham LJ, No. 20 Abrams KR, Jones DR. Factors that limit the quality, number Volume 3, 1999 No. 11 and progress of randomised controlled Antenatal and neonatal trials. haemoglobinopathy screening in the A review by Prescott RJ, Counsell CE, UK: review and economic analysis. Gillespie WJ, Grant AM, Russell IT, No. 1 By Zeuner D, Ades AE, Karnon J, Kiauka S, et al. Informed decision making: an Brown J, Dezateux C, Anionwu EN. annotated bibliography and systematic No. 21 review. No. 12 Antimicrobial prophylaxis in total hip By Bekker H, Thornton JG, Assessing the quality of reports of replacement: a systematic review. randomised trials: implications for the Airey CM, Connelly JB, Hewison J, By Glenny AM, Song F. Robinson MB, et al. conduct of meta-analyses. A review by Moher D, Cook DJ, Jadad AR, Tugwell P, Moher M, No. 22 No. 2 Jones A, et al. Health promoting schools and health Handling uncertainty when performing promotion in schools: two systematic economic evaluation of healthcare No. 13 reviews. interventions. ‘Early warning systems’ for identifying By Lister-Sharp D, Chapman S, A review by Briggs AH, Gray AM. new healthcare technologies. Stewart-Brown S, Sowden A. By Robert G, Stevens A, Gabbay J. No. 3 No. 23 No. 14 The role of expectancies in the placebo A systematic review of the role of Economic evaluation of a primary effect and their use in the delivery of human papillomavirus testing within a care-based education programme for health care: a systematic review. cervical screening programme. patients with osteoarthritis of the knee. By Crow R, Gage H, Hampson S, By Cuzick J, Sasieni P, Davies P, A review by Lord J, Victor C, 82 Hart J, Kimber A, Thomas H. Adams J, Normand C, Frater A, et al. Littlejohns P, Ross FM, Axford JS. Health Technology Assessment 2010; Vol. 14: Suppl. 2

Volume 4, 2000 No. 11 No. 21 Cost and outcome implications of the Systematic reviews of wound care organisation of vascular services. management: (3) antimicrobial agents No. 1 By Michaels J, Brazier J, for chronic wounds; (4) diabetic foot ulceration. The estimation of marginal time Palfreyman S, Shackley P, Slack R. preference in a UK-wide sample By O’Meara S, Cullum N, Majid M, (TEMPUS) project. No. 12 Sheldon T. A review by Cairns JA, Monitoring blood glucose control in No. 22 van der Pol MM. diabetes mellitus: a systematic review. By Coster S, Gulliford MC, Seed PT, Using routine data to complement and enhance the results of randomised No. 2 Powrie JK, Swaminathan R. controlled trials. Geriatric rehabilitation following No. 13 By Lewsey JD, Leyland AH, Murray fractures in older people: a systematic GD, Boddy FA. review. The effectiveness of domiciliary By Cameron I, Crotty M, Currie C, health visiting: a systematic review of international studies and a selective No. 23 Finnegan T, Gillespie L, Gillespie W, Coronary artery stents in the treatment et al. review of the British literature. By Elkan R, Kendrick D, Hewitt M, of ischaemic heart disease: a rapid and Robinson JJA, Tolley K, Blair M, et al. systematic review. No. 3 By Meads C, Cummins C, Jolly K, Screening for sickle cell disease and Stevens A, Burls A, Hyde C. thalassaemia: a systematic review with No. 14 The determinants of screening uptake supplementary research. No. 24 By Davies SC, Cronin E, Gill M, and interventions for increasing uptake: a systematic review. Outcome measures for adult critical Greengross P, Hickman M, Normand C. care: a systematic review. By Jepson R, Clegg A, Forbes C, Lewis R, Sowden A, Kleijnen J. By Hayes JA, Black NA, Jenkinson C, No. 4 Young JD, Rowan KM, Daly K, et al. Community provision of hearing aids No. 15 and related audiology services. No. 25 The effectiveness and cost-effectiveness A review by Reeves DJ, Alborz A, A systematic review to evaluate the Hickson FS, Bamford JM. of prophylactic removal of wisdom teeth. effectiveness of interventions to promote the initiation of breastfeeding. A rapid review by Song F, O’Meara S, No. 5 By Fairbank L, O’Meara S, Wilson P, Golder S, Kleijnen J. False-negative results in screening Renfrew MJ, Woolridge M, Sowden AJ, programmes: systematic review of Lister-Sharp D. No. 16 impact and implications. Ultrasound screening in pregnancy: By Petticrew MP, Sowden AJ, No. 26 a systematic review of the clinical Lister-Sharp D, Wright K. Implantable cardioverter deibrillators: effectiveness, cost-effectiveness and arrhythmias. A rapid and systematic women’s views. No. 6 review. By Bricker L, Garcia J, Henderson J, By Parkes J, Bryant J, Milne R. Costs and beneits of community Mugford M, Neilson J, Roberts T, et al. postnatal support workers: a randomised controlled trial. No. 27 No. 17 By Morrell CJ, Spiby H, Stewart P, Treatments for fatigue in multiple A rapid and systematic review of the Walters S, Morgan A. sclerosis: a rapid and systematic review. effectiveness and cost-effectiveness of By Brañas P, Jordan R, Fry-Smith A, the taxanes used in the treatment of Burls A, Hyde C. No. 7 advanced breast and ovarian cancer. Implantable contraceptives (subdermal By Lister-Sharp D, McDonagh MS, No. 28 implants and hormonally impregnated Khan KS, Kleijnen J. intrauterine systems) versus other Early asthma prophylaxis, natural history, skeletal development and forms of reversible contraceptives: two No. 18 systematic reviews to assess relative economy (EASE): a pilot randomised Liquid-based cytology in cervical effectiveness, acceptability, tolerability controlled trial. screening: a rapid and systematic and cost-effectiveness. By Baxter-Jones ADG, Helms PJ, review. By French RS, Cowan FM, Russell G, Grant A, Ross S, Cairns JA, By Payne N, Chilcott J, McGoogan E. Mansour DJA, Morris S, Procter T, et al. Hughes D, et al. No. 19 No. 29 No. 8 Randomised controlled trial of non- Screening for hypercholesterolaemia directive counselling, cognitive– An introduction to statistical methods versus case inding for familial behaviour therapy and usual general for health technology assessment. hypercholesterolaemia: a systematic practitioner care in the management of review and cost-effectiveness analysis. A review by White SJ, Ashby D, depression as well as mixed anxiety and Brown PJ. By Marks D, Wonderling depression in primary care. D, Thorogood M, Lambert H, By King M, Sibbald B, Ward E, Humphries SE, Neil HAW. No. 9 Bower P, Lloyd M, Gabbay M, et al. Disease-modifying drugs for multiple No. 30 sclerosis: a rapid and systematic review. No. 20 A rapid and systematic review of By Clegg A, Bryant J, Milne R. Routine referral for radiography of the clinical effectiveness and cost- patients presenting with low back pain: effectiveness of glycoprotein IIb/ No. 10 is patients’ outcome inluenced by GPs’ IIIa antagonists in the medical Publication and related biases. referral for plain radiography? management of unstable angina. A review by Song F, Eastwood AJ, By Kerry S, Hilton S, Patel S, By McDonagh MS, Bachmann LM, Gilbody S, Duley L, Sutton AJ. Dundas D, Rink E, Lord J. Golder S, Kleijnen J, ter Riet G. 83

No. 31 Volume 5, 2001 No. 11 A randomised controlled trial Effectiveness of autologous chondrocyte of prehospital intravenous luid transplantation for hyaline cartilage replacement therapy in serious trauma. No. 1 defects in knees: a rapid and systematic review. By Turner J, Nicholl J, Webber L, Clinical and cost-effectiveness Cox H, Dixon S, Yates D. of donepezil, rivastigmine and By Jobanputra P, Parry D, Fry-Smith galantamine for Alzheimer’s disease: a A, Burls A. No. 32 rapid and systematic review. No. 12 Intrathecal pumps for giving opioids in By Clegg A, Bryant J, Nicholson T, McIntyre L, De Broe S, Gerard K, et al. Statistical assessment of the learning chronic pain: a systematic review. curves of health technologies. By Williams JE, Louw G, By Ramsay CR, Grant AM, Wallace No. 2 Towlerton G. SA, Garthwaite PH, Monk AF, Russell IT. The clinical effectiveness and cost- effectiveness of riluzole for motor No. 33 No. 13 neurone disease: a rapid and systematic Combination therapy (interferon review. The effectiveness and cost-effectiveness alfa and ribavirin) in the treatment of temozolomide for the treatment of By Stewart A, Sandercock J, Bryan S, of chronic hepatitis C: a rapid and recurrent malignant glioma: a rapid Hyde C, Barton PM, Fry-Smith A, et al. systematic review. and systematic review. By Shepherd J, Waugh N, By Dinnes J, Cave C, Huang S, No. 3 Hewitson P. Major K, Milne R. Equity and the economic evaluation of healthcare. No. 34 No. 14 By Sassi F, Archard L, Le Grand J. A systematic review of comparisons of A rapid and systematic review of the clinical effectiveness and cost- effect sizes derived from randomised No. 4 and non-randomised studies. effectiveness of debriding agents in Quality-of-life measures in chronic treating surgical wounds healing by By MacLehose RR, Reeves BC, diseases of childhood. secondary intention. Harvey IM, Sheldon TA, Russell IT, By Eiser C, Morse R. By Lewis R, Whiting P, ter Riet G, Black AMS. O’Meara S, Glanville J. No. 5 No. 35 Eliciting public preferences for No. 15 Intravascular ultrasound-guided healthcare: a systematic review of Home treatment for mental health interventions in coronary artery techniques. problems: a systematic review. disease: a systematic literature review, By Ryan M, Scott DA, Reeves C, Bate By Burns T, Knapp M, Catty J, with decision-analytic modelling, of A, van Teijlingen ER, Russell EM, et al. Healey A, Henderson J, Watt H, et al. outcomes and cost-effectiveness. By Berry E, Kelly S, Hutton J, No. 6 No. 16 Lindsay HSJ, Blaxill JM, Evans JA, et al. General health status measures for How to develop cost-conscious people with cognitive impairment: guidelines. No. 36 learning disability and acquired brain By Eccles M, Mason J. A randomised controlled trial to injury. evaluate the effectiveness and cost- By Riemsma RP, Forbes CA, No. 17 effectiveness of counselling patients Glanville JM, Eastwood AJ, Kleijnen J. The role of specialist nurses in multiple with chronic depression. sclerosis: a rapid and systematic review. By Simpson S, Corney R, No. 7 By De Broe S, Christopher F, Fitzgerald P, Beecham J. An assessment of screening strategies Waugh N. for fragile X syndrome in the UK. No. 18 No. 37 By Pembrey ME, Barnicoat AJ, Systematic review of treatments for Carmichael B, Bobrow M, Turner G. A rapid and systematic review atopic eczema. of the clinical effectiveness and cost-effectiveness of orlistat in the No. 8 By Hoare C, Li Wan Po A, management of obesity. Williams H. Issues in methodological research: By O’Meara S, Riemsma R, perspectives from researchers and Shirran L, Mather L, ter Riet G. No. 38 commissioners. Bayesian methods in health technology By Lilford RJ, Richardson A, Stevens No. 19 A, Fitzpatrick R, Edwards S, Rock F, et al. assessment: a review. The clinical effectiveness and cost- By Spiegelhalter DJ, Myles JP, effectiveness of pioglitazone for Jones DR, Abrams KR. No. 9 type 2 diabetes mellitus: a rapid and Systematic reviews of wound systematic review. No. 39 care management: (5) beds; By Chilcott J, Wight J, Lloyd Jones (6) compression; (7) laser therapy, M, Tappenden P. The management of dyspepsia: a therapeutic ultrasound, electrotherapy systematic review. and electromagnetic therapy. No. 20 By Delaney B, Moayyedi P, Deeks J, By Cullum N, Nelson EA, Innes M, Soo S, Barton P, et al. Extended scope of nursing practice: Flemming K, Sheldon T. a multicentre randomised controlled trial of appropriately trained nurses No. 40 No. 10 and preregistration house oficers in A systematic review of treatments for Effects of educational and psychosocial preoperative assessment in elective severe psoriasis. interventions for adolescents with general surgery. By Grifiths CEM, Clark CM, diabetes mellitus: a systematic review. By Kinley H, Czoski-Murray C, Chalmers RJG, Li Wan Po A, By Hampson SE, Skinner TC, Hart J, George S, McCabe C, Primrose J, 84 Williams HC. Storey L, Gage H, Foxcroft D, et al. Reilly C, et al. Health Technology Assessment 2010; Vol. 14: Suppl. 2

No. 21 No. 31 No. 4 Systematic reviews of the effectiveness Design and use of questionnaires: a A systematic review of discharge of day care for people with severe review of best practice applicable to arrangements for older people. mental disorders: (1) Acute day hospital surveys of health service staff and By Parker SG, Peet SM, McPherson versus admission; (2) Vocational patients. A, Cannaby AM, Baker R, Wilson A, et al. rehabilitation; (3) Day hospital versus By McColl E, Jacoby A, Thomas L, outpatient care. Soutter J, Bamford C, Steen N, et al. No. 5 By Marshall M, Crowther R, The clinical effectiveness and cost- Almaraz-Serrano A, Creed F, Sledge W, No. 32 effectiveness of inhaler devices used Kluiter H, et al. in the routine management of chronic A rapid and systematic review of asthma in older children: a systematic the clinical effectiveness and cost- No. 22 review and economic evaluation. effectiveness of paclitaxel, docetaxel, The measurement and monitoring of By Peters J, Stevenson M, Beverley C, surgical adverse events. gemcitabine and vinorelbine in non- small-cell lung cancer. Lim J, Smith S. By Bruce J, Russell EM, Mollison J, By Clegg A, Scott DA, Sidhu M, Krukowski ZH. No. 6 Hewitson P, Waugh N. The clinical effectiveness and cost- No. 23 effectiveness of sibutramine in the Action research: a systematic review and No. 33 management of obesity: a technology guidance for assessment. Subgroup analyses in randomised assessment. By Waterman H, Tillen D, Dickson R, controlled trials: quantifying the risks By O’Meara S, Riemsma R, Shirran de Koning K. of false-positives and false-negatives. L, Mather L, ter Riet G. By Brookes ST, Whitley E, Peters TJ, No. 24 Mulheran PA, Egger M, Davey Smith G. No. 7 A rapid and systematic review of The cost-effectiveness of magnetic the clinical effectiveness and cost- No. 34 resonance angiography for carotid effectiveness of gemcitabine for the artery stenosis and peripheral vascular treatment of pancreatic cancer. Depot antipsychotic medication in the treatment of patients with disease: a systematic review. By Ward S, Morris E, Bansback N, schizophrenia: (1) Meta-review; (2) By Berry E, Kelly S, Westwood ME, Calvert N, Crellin A, Forman D, et al. Patient and nurse attitudes. Davies LM, Gough MJ, Bamford JM, et al. No. 25 By David AS, Adams C. A rapid and systematic review of the No. 8 No. 35 evidence for the clinical effectiveness Promoting physical activity in South and cost-effectiveness of irinotecan, A systematic review of controlled Asian Muslim women through ‘exercise oxaliplatin and raltitrexed for the trials of the effectiveness and cost- on prescription’. treatment of advanced colorectal effectiveness of brief psychological By Carroll B, Ali N, Azam N. cancer. treatments for depression. By Lloyd Jones M, Hummel S, By Churchill R, Hunot V, Corney R, No. 9 Bansback N, Orr B, Seymour M. Knapp M, McGuire H, Tylee A, et al. Zanamivir for the treatment of No. 26 inluenza in adults: a systematic review No. 36 and economic evaluation. Comparison of the effectiveness of Cost analysis of child health inhaler devices in asthma and chronic By Burls A, Clark W, Stewart T, surveillance. obstructive airways disease: a systematic Preston C, Bryan S, Jefferson T, et al. review of the literature. By Sanderson D, Wright D, Acton C, By Brocklebank D, Ram F, Wright J, Duree D. No. 10 Barry P, Cates C, Davies L, et al. A review of the natural history and epidemiology of multiple sclerosis: No. 27 Volume 6, 2002 implications for resource allocation and The cost-effectiveness of magnetic health economic models. resonance imaging for investigation of By Richards RG, Sampson FC, the knee joint. Beard SM, Tappenden P. By Bryan S, Weatherburn G, Bungay No. 1 H, Hatrick C, Salas C, Parry D, et al. A study of the methods used to select No. 11 review criteria for clinical audit. Screening for gestational diabetes: No. 28 By Hearnshaw H, Harker R, a systematic review and economic A rapid and systematic review of Cheater F, Baker R, Grimshaw G. evaluation. the clinical effectiveness and cost- By Scott DA, Loveman E, McIntyre effectiveness of topotecan for ovarian No. 2 L, Waugh N. cancer. Fludarabine as second-line therapy for No. 12 By Forbes C, Shirran L, Bagnall A-M, B cell chronic lymphocytic leukaemia: a Duffy S, ter Riet G. technology assessment. The clinical effectiveness and cost- effectiveness of surgery for people with By Hyde C, Wake B, Bryan S, Barton No. 29 morbid obesity: a systematic review and P, Fry-Smith A, Davenport C, et al. Superseded by a report published in a economic evaluation. later volume. By Clegg AJ, Colquitt J, Sidhu MK, No. 3 Royle P, Loveman E, Walker A. No. 30 Rituximab as third-line treatment for The role of radiography in primary refractory or recurrent Stage III or IV No. 13 care patients with low back pain of at follicular non-Hodgkin’s lymphoma: The clinical effectiveness of least 6 weeks duration: a randomised a systematic review and economic trastuzumab for breast cancer: a (unblinded) controlled trial. evaluation. systematic review. 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No. 14 No. 23 No. 32 The clinical effectiveness and cost- A systematic review and economic The measurement of satisfaction with effectiveness of vinorelbine for breast evaluation of pegylated liposomal healthcare: implications for practice cancer: a systematic review and doxorubicin hydrochloride for ovarian from a systematic review of the economic evaluation. cancer. literature. By Lewis R, Bagnall A-M, King S, By Forbes C, Wilby J, Richardson G, By Crow R, Gage H, Hampson S, Woolacott N, Forbes C, Shirran L, et al. Sculpher M, Mather L, Riemsma R. Hart J, Kimber A, Storey L, et al.

No. 15 No. 24 No. 33 A systematic review of the effectiveness A systematic review of the effectiveness The effectiveness and cost-effectiveness and cost-effectiveness of metal-on- of interventions based on a stages-of- of imatinib in chronic myeloid metal hip resurfacing arthroplasty for change approach to promote individual leukaemia: a systematic review. treatment of hip disease. behaviour change. By Garside R, Round A, Dalziel K, By Vale L, Wyness L, McCormack K, By Riemsma RP, Pattenden J, Bridle Stein K, Royle R. McKenzie L, Brazzelli M, Stearns SC. C, Sowden AJ, Mather L, Watt IS, et al. No. 34 No. 16 No. 25 A comparative study of hypertonic saline, daily and alternate-day rhDNase The clinical effectiveness and cost- A systematic review update of the in children with cystic ibrosis. effectiveness of bupropion and nicotine clinical effectiveness and cost- replacement therapy for smoking effectiveness of glycoprotein IIb/IIIa By Suri R, Wallis C, Bush A, cessation: a systematic review and antagonists. Thompson S, Normand C, Flather M, economic evaluation. By Robinson M, Ginnelly L, Sculpher et al. By Woolacott NF, Jones L, Forbes CA, M, Jones L, Riemsma R, Palmer S, et al. No. 35 Mather LC, Sowden AJ, Song FJ, et al. No. 26 A systematic review of the costs and effectiveness of different models of No. 17 A systematic review of the effectiveness, paediatric home care. A systematic review of effectiveness cost-effectiveness and barriers to implementation of thrombolytic and By Parker G, Bhakta P, Lovett CA, and economic evaluation of new drug Paisley S, Olsen R, Turner D, et al. treatments for juvenile idiopathic neuroprotective therapy for acute arthritis: etanercept. ischaemic stroke in the NHS. By Cummins C, Connock M, By Sandercock P, Berge E, Dennis M, Fry-Smith A, Burls A. Forbes J, Hand P, Kwan J, et al. Volume 7, 2003 No. 27 No. 18 A randomised controlled crossover trial Clinical effectiveness and cost- No. 1 of nurse practitioner versus doctor- effectiveness of growth hormone in How important are comprehensive led outpatient care in a bronchiectasis children: a systematic review and literature searches and the assessment clinic. economic evaluation. of trial quality in systematic reviews? By Caine N, Sharples LD, By Bryant J, Cave C, Mihaylova B, Empirical study. Hollingworth W, French J, Keogan M, Chase D, McIntyre L, Gerard K, et al. By Egger M, J̈ni P, Bartlett C, Exley A, et al. Holenstein F, Sterne J. No. 19 No. 28 Clinical effectiveness and cost- No. 2 Clinical effectiveness and cost – Systematic review of the effectiveness effectiveness of growth hormone consequences of selective serotonin in adults in relation to impact on and cost-effectiveness, and economic reuptake inhibitors in the treatment of evaluation, of home versus hospital or quality of life: a systematic review and sex offenders. economic evaluation. satellite unit haemodialysis for people By Adi Y, Ashcroft D, Browne K, with end-stage renal failure. By Bryant J, Loveman E, Chase D, Beech A, Fry-Smith A, Hyde C. Mihaylova B, Cave C, Gerard K, et al. By Mowatt G, Vale L, Perez J, Wyness L, Fraser C, MacLeod A, et al. No. 29 No. 20 Treatment of established osteoporosis: No. 3 Clinical medication review by a a systematic review and cost–utility Systematic review and economic pharmacist of patients on repeat analysis. evaluation of the effectiveness of prescriptions in general practice: a By Kanis JA, Brazier JE, Stevenson inliximab for the treatment of Crohn’s randomised controlled trial. M, Calvert NW, Lloyd Jones M. disease. By Zermansky AG, Petty DR, Raynor By Clark W, Raftery J, Barton P, DK, Lowe CJ, Freementle N, Vail A. No. 30 Song F, Fry-Smith A, Burls A. Which anaesthetic agents are cost- No. 21 effective in day surgery? Literature No. 4 The effectiveness of inliximab and review, national survey of practice and A review of the clinical effectiveness etanercept for the treatment of randomised controlled trial. and cost-effectiveness of routine anti-D rheumatoid arthritis: a systematic By Elliott RA, Payne K, Moore JK, prophylaxis for pregnant women who review and economic evaluation. Davies LM, Harper NJN, St Leger AS, are rhesus negative. By Jobanputra P, Barton P, Bryan S, et al. By Chilcott J, Lloyd Jones M, Wight Burls A. J, Forman K, Wray J, Beverley C, et al. No. 31 No. 22 Screening for hepatitis C among No. 5 A systematic review and economic injecting drug users and in Systematic review and evaluation of the evaluation of computerised cognitive genitourinary medicine clinics: use of tumour markers in paediatric behaviour therapy for depression and systematic reviews of effectiveness, oncology: Ewing’s sarcoma and anxiety. modelling study and national survey of neuroblastoma. By Kaltenthaler E, Shackley P, current practice. By Riley RD, Burchill SA, Stevens K, Beverley C, Parry G, By Stein K, Dalziel K, Walker A, Abrams KR, Heney D, Lambert PC, 86 Chilcott J. McIntyre L, Jenkins B, Horne J, et al. Jones DR, et al. Health Technology Assessment 2010; Vol. 14: Suppl. 2

No. 6 No. 15 No. 25 The cost-effectiveness of screening for Early thrombolysis for the treatment The clinical and cost-effectiveness of Helicobacter pylori to reduce mortality of acute myocardial infarction: a pulsatile machine perfusion versus cold and morbidity from gastric cancer and systematic review and economic storage of kidneys for transplantation peptic ulcer disease: a discrete-event evaluation. retrieved from heart-beating and non- simulation model. heart-beating donors. By Boland A, Dundar Y, Bagust A, By Roderick P, Davies R, Raftery J, Haycox A, Hill R, Mujica Mota R, et al. By Wight J, Chilcott J, Holmes M, Crabbe D, Pearce R, Bhandari P, et al. Brewer N. No. 16 No. 7 No. 26 The clinical effectiveness and cost- Screening for fragile X syndrome: a Can randomised trials rely on existing effectiveness of routine dental checks: literature review and modelling. electronic data? A feasibility study to a systematic review and economic By Song FJ, Barton P, Sleightholme explore the value of routine data in evaluation. V, Yao GL, Fry-Smith A. health technology assessment. By Davenport C, Elley K, Salas By Williams JG, Cheung WY, C, Taylor-Weetman CL, Fry-Smith A, No. 17 Cohen DR, Hutchings HA, Longo MF, Bryan S, et al. Systematic review of endoscopic sinus Russell IT. surgery for nasal polyps. No. 8 No. 27 A multicentre randomised controlled By Dalziel K, Stein K, Round A, Garside R, Royle P. Evaluating non-randomised trial assessing the costs and beneits intervention studies. of using structured information and By Deeks JJ, Dinnes J, D’Amico R, analysis of women’s preferences in the No. 18 Sowden AJ, Sakarovitch C, Song F, et al. management of menorrhagia. Towards eficient guidelines: how to By Kennedy ADM, Sculpher MJ, monitor guideline use in primary care. No. 28 Coulter A, Dwyer N, Rees M, Horsley S, By Hutchinson A, McIntosh A, et al. A randomised controlled trial to assess Cox S, Gilbert C. the impact of a package comprising a patient-orientated, evidence-based self- No. 9 No. 19 help guidebook and patient-centred Clinical effectiveness and cost–utility consultations on disease management Effectiveness and cost-effectiveness of photodynamic therapy for wet and satisfaction in inlammatory bowel of acute hospital-based spinal cord age-related macular degeneration: disease. a systematic review and economic injuries services: systematic review. By Kennedy A, Nelson E, Reeves D, evaluation. By Bagnall A-M, Jones L, Richardson Richardson G, Roberts C, Robinson A, By Meads C, Salas C, Roberts T, G, Duffy S, Riemsma R. et al. Moore D, Fry-Smith A, Hyde C. No. 20 No. 29 No. 10 Prioritisation of health technology The effectiveness of diagnostic tests for Evaluation of molecular tests for assessment. The PATHS model: the assessment of shoulder pain due prenatal diagnosis of chromosome methods and case studies. to soft tissue disorders: a systematic abnormalities. review. By Grimshaw GM, Szczepura A, By Townsend J, Buxton M, Hultén M, MacDonald F, Nevin NC, Harper G. By Dinnes J, Loveman E, McIntyre L, Sutton F, et al. Waugh N. No. 21 No. 30 No. 11 Systematic review of the clinical First and second trimester antenatal effectiveness and cost-effectiveness of The value of digital imaging in diabetic screening for Down’s syndrome: tension-free vaginal tape for treatment retinopathy. the results of the Serum, Urine and of urinary stress incontinence. By Sharp PF, Olson J, Strachan F, Ultrasound Screening Study (SURUSS). Hipwell J, Ludbrook A, O’Donnell M, By Cody J, Wyness L, Wallace S, et al. By Wald NJ, Rodeck C, Hackshaw Glazener C, Kilonzo M, Stearns S, et al. AK, Walters J, Chitty L, Mackinson AM. No. 31 No. 22 No. 12 Lowering blood pressure to prevent The effectiveness and cost-effectiveness The clinical and cost-effectiveness of myocardial infarction and stroke: a new of ultrasound locating devices for patient education models for diabetes: preventive strategy. central venous access: a systematic a systematic review and economic By Law M, Wald N, Morris J. review and economic evaluation. evaluation. By Calvert N, Hind D, McWilliams By Loveman E, Cave C, Green C, No. 32 RG, Thomas SM, Beverley C, Royle P, Dunn N, Waugh N. Clinical and cost-effectiveness of Davidson A. capecitabine and tegafur with uracil for No. 23 the treatment of metastatic colorectal No. 13 The role of modelling in prioritising cancer: systematic review and economic A systematic review of atypical and planning clinical trials. evaluation. antipsychotics in schizophrenia. By Ward S, Kaltenthaler E, Cowan J, By Chilcott J, Brennan A, Booth A, By Bagnall A-M, Jones L, Lewis R, Brewer N. Karnon J, Tappenden P. Ginnelly L, Glanville J, Torgerson D, et al. No. 33 No. 24 Clinical and cost-effectiveness of new No. 14 Cost–beneit evaluation of routine and emerging technologies for early Prostate Testing for Cancer and inluenza immunisation in people localised prostate cancer: a systematic Treatment (ProtecT) feasibility study. 65–74 years of age. review. By Donovan J, Hamdy F, Neal D, By Allsup S, Gosney M, Haycox A, By Hummel S, Paisley S, Morgan A, Peters T, Oliver S, Brindle L, et al. Regan M. Currie E, Brewer N. 87

No. 34 Volume 8, 2004 No. 10 Literature searching for clinical and A systematic review and economic cost-effectiveness studies used in health evaluation of magnetic resonance cholangiopancreatography compared technology assessment reports carried No. 1 with diagnostic endoscopic retrograde out for the National Institute for What is the best imaging strategy for Clinical Excellence appraisal system. cholangiopancreatography. acute stroke? By Kaltenthaler E, Bravo Vergel Y, By Royle P, Waugh N. By Wardlaw JM, Keir SL, Seymour J, Chilcott J, Thomas S, Blakeborough T, Lewis S, Sandercock PAG, Dennis MS, Walters SJ, et al. No. 35 et al. Systematic review and economic No. 11 decision modelling for the prevention No. 2 The use of modelling to evaluate and treatment of inluenza A and B. Systematic review and modelling of the new drugs for patients with a chronic By Turner D, Wailoo A, Nicholson K, investigation of acute and chronic chest condition: the case of antibodies Cooper N, Sutton A, Abrams K. pain presenting in primary care. against tumour necrosis factor in By Mant J, McManus RJ, Oakes RAL, rheumatoid arthritis. Delaney BC, Barton PM, Deeks JJ, et al. By Barton P, Jobanputra P, Wilson J, No. 36 Bryan S, Burls A. A randomised controlled trial No. 3 to evaluate the clinical and cost- No. 12 effectiveness of Hickman line insertions The effectiveness and cost-effectiveness Clinical effectiveness and cost- in adult cancer patients by nurses. of microwave and thermal balloon effectiveness of neonatal screening By Boland A, Haycox A, Bagust A, endometrial ablation for heavy for inborn errors of metabolism using Fitzsimmons L. menstrual bleeding: a systematic review tandem mass spectrometry: a systematic and economic modelling. review. By Garside R, Stein K, Wyatt K, No. 37 By Pandor A, Eastham J, Beverley C, Round A, Price A. Chilcott J, Paisley S. Redesigning postnatal care: a randomised controlled trial of protocol- No. 4 No. 13 based midwifery-led care focused A systematic review of the role of Clinical effectiveness and cost- on individual women’s physical and bisphosphonates in metastatic disease. effectiveness of pioglitazone and psychological health needs. By Ross JR, Saunders Y, rosiglitazone in the treatment of type By MacArthur C, Winter HR, Edmonds PM, Patel S, Wonderling D, 2 diabetes: a systematic review and Bick DE, Lilford RJ, Lancashire RJ, Normand C, et al. economic evaluation. Knowles H, et al. By Czoski-Murray C, Warren E, Chilcott J, Beverley C, Psyllaki MA, No. 5 No. 38 Cowan J. Systematic review of the clinical Estimating implied rates of discount in effectiveness and cost-effectiveness No. 14 healthcare decision-making. ® of capecitabine (Xeloda ) for locally Routine examination of the newborn: By West RR, McNabb R, Thompson advanced and/or metastatic breast the EMREN study. Evaluation of an AGH, Sheldon TA, Grimley Evans J. cancer. extension of the midwife role including By Jones L, Hawkins N, Westwood M, a randomised controlled trial of No. 39 Wright K, Richardson G, Riemsma R. appropriately trained midwives and Systematic review of isolation policies paediatric senior house oficers. in the hospital management of No. 6 By Townsend J, Wolke D, Hayes J, methicillin-resistant Staphylococcus Effectiveness and eficiency of guideline Davé S, Rogers C, Bloomield L, et al. aureus: a review of the literature dissemination and implementation with epidemiological and economic strategies. No. 15 modelling. By Grimshaw JM, Thomas RE, Involving consumers in research and development agenda setting for the By Cooper BS, Stone SP, Kibbler CC, MacLennan G, Fraser C, Ramsay CR, Vale L, et al. NHS: developing an evidence-based Cookson BD, Roberts JA, Medley GF, approach. et al. By Oliver S, Clarke-Jones L, Rees R, No. 7 Milne R, Buchanan P, Gabbay J, et al. No. 40 Clinical effectiveness and costs of the Treatments for spasticity and pain in Sugarbaker procedure for the treatment No. 16 multiple sclerosis: a systematic review. of pseudomyxoma peritonei. A multi-centre randomised controlled By Beard S, Hunn A, Wight J. By Bryant J, Clegg AJ, Sidhu MK, trial of minimally invasive direct Brodin H, Royle P, Davidson P. coronary bypass grafting versus percutaneous transluminal coronary No. 41 No. 8 angioplasty with stenting for proximal The inclusion of reports of randomised Psychological treatment for insomnia stenosis of the left anterior descending trials published in languages other than in the regulation of long-term hypnotic coronary artery. English in systematic reviews. drug use. By Reeves BC, Angelini GD, Bryan AJ, Taylor FC, Cripps T, Spyt TJ, et al. By Moher D, Pham B, Lawson ML, By Morgan K, Dixon S, Mathers N, Klassen TP. Thompson J, Tomeny M. No. 17 Does early magnetic resonance imaging No. 42 No. 9 inluence management or improve The impact of screening on future Improving the evaluation of outcome in patients referred to health-promoting behaviours and therapeutic interventions in multiple secondary care with low back pain? A health beliefs: a systematic review. sclerosis: development of a patient- pragmatic randomised controlled trial. By Bankhead CR, Brett J, Bukach C, based measure of outcome. By Gilbert FJ, Grant AM, Gillan Webster P, Stewart-Brown S, Munafo M, By Hobart JC, Riazi A, Lamping DL, MGC, Vale L, Scott NW, Campbell MK, 88 et al. Fitzpatrick R, Thompson AJ. et al. Health Technology Assessment 2010; Vol. 14: Suppl. 2

No. 18 No. 27 No. 36 The clinical and cost-effectiveness Methods for expected value of Review of guidelines for good practice of anakinra for the treatment of information analysis in complex health in decision-analytic modelling in health rheumatoid arthritis in adults: a economic models: developments on technology assessment. systematic review and economic the health economics of interferon-β By Philips Z, Ginnelly L, Sculpher M, analysis. and glatiramer acetate for multiple Claxton K, Golder S, Riemsma R, et al. By Clark W, Jobanputra P, Barton P, sclerosis. Burls A. By Tappenden P, Chilcott JB, No. 37 Eggington S, Oakley J, McCabe C. Rituximab (MabThera®) for aggressive non-Hodgkin’s lymphoma: systematic No. 19 No. 28 review and economic evaluation. A rapid and systematic review and Effectiveness and cost-effectiveness By Knight C, Hind D, Brewer N, economic evaluation of the clinical of imatinib for irst-line treatment Abbott V. and cost-effectiveness of newer drugs of chronic myeloid leukaemia in for treatment of mania associated with chronic phase: a systematic review and No. 38 bipolar affective disorder. economic analysis. Clinical effectiveness and cost- By Bridle C, Palmer S, Bagnall A-M, By Dalziel K, Round A, Stein K, effectiveness of clopidogrel and Darba J, Duffy S, Sculpher M, et al. Garside R, Price A. modiied-release dipyridamole in the secondary prevention of occlusive No. 20 No. 29 vascular events: a systematic review and Liquid-based cytology in cervical VenUS I: a randomised controlled trial economic evaluation. screening: an updated rapid and of two types of bandage for treating By Jones L, Grifin S, Palmer S, Main systematic review and economic venous leg ulcers. C, Orton V, Sculpher M, et al. analysis. By Iglesias C, Nelson EA, Cullum NA, Torgerson DJ, on behalf of the No. 39 By Karnon J, Peters J, Platt J, VenUS Team. Pegylated interferon α-2a and -2b Chilcott J, McGoogan E, Brewer N. in combination with ribavirin in the No. 30 treatment of chronic hepatitis C: No. 21 Systematic review of the effectiveness a systematic review and economic Systematic review of the long-term and cost-effectiveness, and economic evaluation. effects and economic consequences of evaluation, of myocardial perfusion By Shepherd J, Brodin H, Cave C, treatments for obesity and implications scintigraphy for the diagnosis and Waugh N, Price A, Gabbay J. for health improvement. management of angina and myocardial By Avenell A, Broom J, Brown TJ, infarction. No. 40 Poobalan A, Aucott L, Stearns SC, et al. By Mowatt G, Vale L, Brazzelli M, Clopidogrel used in combination with Hernandez R, Murray A, Scott N, et al. aspirin compared with aspirin alone No. 22 in the treatment of non-ST-segment- No. 31 elevation acute coronary syndromes: Autoantibody testing in children A pilot study on the use of decision a systematic review and economic with newly diagnosed type 1 diabetes theory and value of information evaluation. mellitus. analysis as part of the NHS Health By Main C, Palmer S, Grifin S, Jones By Dretzke J, Cummins C, Technology Assessment programme. L, Orton V, Sculpher M, et al. Sandercock J, Fry-Smith A, Barrett T, By Claxton K, Ginnelly L, Sculpher Burls A. M, Philips Z, Palmer S. No. 41 Provision, uptake and cost of cardiac No. 23 No. 32 rehabilitation programmes: improving Clinical effectiveness and cost- The Social Support and Family Health services to under-represented groups. effectiveness of prehospital intravenous Study: a randomised controlled trial By Beswick AD, Rees K, Griebsch I, luids in trauma patients. and economic evaluation of two Taylor FC, Burke M, West RR, et al. By Dretzke J, Sandercock J, Bayliss alternative forms of postnatal support S, Burls A. for mothers living in disadvantaged No. 42 inner-city areas. Involving South Asian patients in By Wiggins M, Oakley A, Roberts I, clinical trials. No. 24 Turner H, Rajan L, Austerberry H, et al. By Hussain-Gambles M, Leese B, Newer hypnotic drugs for the short- Atkin K, Brown J, Mason S, Tovey P. term management of insomnia: a No. 33 systematic review and economic Psychosocial aspects of genetic No. 43 evaluation. screening of pregnant women and Clinical and cost-effectiveness of By D̈ndar Y, Boland A, Strobl J, newborns: a systematic review. continuous subcutaneous insulin Dodd S, Haycox A, Bagust A, et al. By Green JM, Hewison J, Bekker HL, infusion for diabetes. Bryant LD, Cuckle HS. By Colquitt JL, Green C, Sidhu MK, No. 25 Hartwell D, Waugh N. Development and validation of No. 34 methods for assessing the quality of Evaluation of abnormal uterine No. 44 diagnostic accuracy studies. bleeding: comparison of three Identiication and assessment of By Whiting P, Rutjes AWS, Dinnes J, outpatient procedures within cohorts ongoing trials in health technology Reitsma JB, Bossuyt PMM, Kleijnen J. deined by age and menopausal status. assessment reviews. By Critchley HOD, Warner P, Lee AJ, By Song FJ, Fry-Smith A, Davenport Brechin S, Guise J, Graham B. C, Bayliss S, Adi Y, Wilson JS, et al. No. 26 EVALUATE hysterectomy trial: No. 35 No. 45 a multicentre randomised trial Coronary artery stents: a rapid Systematic review and economic comparing abdominal, vaginal and systematic review and economic evaluation of a long-acting insulin laparoscopic methods of hysterectomy. evaluation. analogue, insulin glargine By Garry R, Fountain J, Brown J, By Hill R, Bagust A, Bakhai A, By Warren E, Weatherley-Jones E, Manca A, Mason S, Sculpher M, et al. Dickson R, D̈ndar Y, Haycox A, et al. Chilcott J, Beverley C. 89

No. 46 No. 4 No. 13 Supplementation of a home-based Randomised evaluation of alternative Cervical screening programmes: can exercise programme with a class- electrosurgical modalities to treat automation help? Evidence from based programme for people bladder outlow obstruction in men systematic reviews, an economic with osteoarthritis of the knees: a with benign prostatic hyperplasia. analysis and a simulation modelling randomised controlled trial and health By Fowler C, McAllister W, Plail R, exercise applied to the UK. economic analysis. Karim O, Yang Q. By Willis BH, Barton P, Pearmain P, By McCarthy CJ, Mills PM, Pullen R, Bryan S, Hyde C. Richardson G, Hawkins N, Roberts CR, No. 5 et al. No. 14 A pragmatic randomised controlled Laparoscopic surgery for inguinal trial of the cost-effectiveness of No. 47 hernia repair: systematic review of palliative therapies for patients with effectiveness and economic evaluation. Clinical and cost-effectiveness of once- inoperable oesophageal cancer. By McCormack K, Wake B, Perez J, daily versus more frequent use of same By Shenine J, McNamee P, Steen N, Fraser C, Cook J, McIntosh E, et al. potency topical corticosteroids for Bond J, Grifin SM. atopic eczema: a systematic review and No. 15 economic evaluation. No. 6 Clinical effectiveness, tolerability and By Green C, Colquitt JL, Kirby J, Impact of computer-aided detection cost-effectiveness of newer drugs for Davidson P, Payne E. prompts on the sensitivity and epilepsy in adults: a systematic review speciicity of screening mammography. and economic evaluation. No. 48 By Taylor P, Champness J, Given- By Wilby J, Kainth A, Hawkins N, Acupuncture of chronic headache Wilson R, Johnston K, Potts H. Epstein D, McIntosh H, McDaid C, et al. disorders in primary care: randomised controlled trial and economic analysis. No. 7 No. 16 By Vickers AJ, Rees RW, Zollman CE, A randomised controlled trial to Issues in data monitoring and interim McCarney R, Smith CM, Ellis N, et al. compare the cost-effectiveness of analysis of trials. tricyclic antidepressants, selective By Grant AM, Altman DG, Babiker No. 49 serotonin reuptake inhibitors and AB, Campbell MK, Clemens FJ, lofepramine. Generalisability in economic evaluation Darbyshire JH, et al. studies in healthcare: a review and case By Peveler R, Kendrick T, Buxton M, studies. Longworth L, Baldwin D, Moore M, et al. No. 8 By Sculpher MJ, Pang FS, Manca A, Lay public’s understanding of equipoise No. 17 Drummond MF, Golder S, Urdahl H, and randomisation in randomised Clinical effectiveness and cost- et al. controlled trials. effectiveness of immediate angioplasty By Robinson EJ, Kerr CEP, for acute myocardial infarction: No. 50 Stevens AJ, Lilford RJ, Braunholtz DA, systematic review and economic Virtual outreach: a randomised Edwards SJ, et al. evaluation. controlled trial and economic By Hartwell D, Colquitt J, Loveman evaluation of joint teleconferenced No. 9 E, Clegg AJ, Brodin H, Waugh N, et al. medical consultations. Clinical and cost-effectiveness of By Wallace P, Barber J, Clayton W, No. 18 electroconvulsive therapy for depressive Currell R, Fleming K, Garner P, et al. A randomised controlled comparison of illness, schizophrenia, catatonia alternative strategies in stroke care. and mania: systematic reviews and By Kalra L, Evans A, Perez I, economic modelling studies. Knapp M, Swift C, Donaldson N. Volume 9, 2005 By Greenhalgh J, Knight C, Hind D, Beverley C, Walters S. No. 19 The investigation and analysis of No. 1 No. 10 critical incidents and adverse events in Randomised controlled multiple Measurement of health-related quality healthcare. treatment comparison to provide a cost- of life for people with dementia: By Woloshynowych M, Rogers S, effectiveness rationale for the selection development of a new instrument Taylor-Adams S, Vincent C. of antimicrobial therapy in acne. (DEMQOL) and an evaluation of By Ozolins M, Eady EA, Avery A, current methodology. No. 20 Cunliffe WJ, O’Neill C, Simpson NB, By Smith SC, Lamping DL, Banerjee Potential use of routine databases in et al. S, Harwood R, Foley B, Smith P, et al. health technology assessment. By Raftery J, Roderick P, Stevens A. No. 2 No. 11 No. 21 Do the indings of case series studies Clinical effectiveness and cost- vary signiicantly according to effectiveness of drotrecogin alfa Clinical and cost-effectiveness of newer immunosuppressive regimens in renal methodological characteristics? (activated) (Xigris®) for the treatment transplantation: a systematic review and By Dalziel K, Round A, Stein K, of severe sepsis in adults: a systematic review and economic evaluation. modelling study. Garside R, Castelnuovo E, Payne L. By Woodroffe R, Yao GL, Meads C, By Green C, Dinnes J, Takeda A, Bayliss S, Ready A, Raftery J, et al. No. 3 Shepherd J, Hartwell D, Cave C, et al. Improving the referral process No. 22 for familial breast cancer genetic No. 12 A systematic review and economic counselling: indings of three A methodological review of how evaluation of alendronate, etidronate, randomised controlled trials of two heterogeneity has been examined in risedronate, raloxifene and teriparatide interventions. systematic reviews of diagnostic test for the prevention and treatment of By Wilson BJ, Torrance N, accuracy. postmenopausal osteoporosis. Mollison J, Wordsworth S, Gray JR, By Dinnes J, Deeks J, Kirby J, By Stevenson M, Lloyd Jones M, De 90 Haites NE, et al. Roderick P. Nigris E, Brewer N, Davis S, Oakley J. Health Technology Assessment 2010; Vol. 14: Suppl. 2

No. 23 No. 32 No. 40 A systematic review to examine Longer term clinical and economic A randomised controlled trial and the impact of psycho-educational beneits of offering acupuncture care to cost-effectiveness study of systematic interventions on health outcomes patients with chronic low back pain. screening (targeted and total and costs in adults and children with population screening) versus routine By Thomas KJ, MacPherson dificult asthma. practice for the detection of atrial H, Ratcliffe J, Thorpe L, Brazier J, ibrillation in people aged 65 and over. By Smith JR, Mugford M, Holland Campbell M, et al. R, Candy B, Noble MJ, Harrison BDW, The SAFE study. et al. By Hobbs FDR, Fitzmaurice DA, No. 33 Mant J, Murray E, Jowett S, Bryan S, No. 24 Cost-effectiveness and safety of et al. An evaluation of the costs, effectiveness epidural steroids in the management and quality of renal replacement of sciatica. No. 41 therapy provision in renal satellite units By Price C, Arden N, Coglan L, Displaced intracapsular hip fractures in England and Wales. Rogers P. in it, older people: a randomised By Roderick P, Nicholson T, Armitage comparison of reduction and ixation, A, Mehta R, Mullee M, Gerard K, et al. No. 34 bipolar hemiarthroplasty and total hip arthroplasty. The British Rheumatoid Outcome By Keating JF, Grant A, Masson M, No. 25 Study Group (BROSG) randomised Scott NW, Forbes JF. Imatinib for the treatment of patients controlled trial to compare the with unresectable and/or metastatic effectiveness and cost-effectiveness of gastrointestinal stromal tumours: aggressive versus symptomatic therapy No. 42 systematic review and economic in established rheumatoid arthritis. Long-term outcome of cognitive evaluation. By Symmons D, Tricker K, Roberts C, behaviour therapy clinical trials in By Wilson J, Connock M, Song F, Davies L, Dawes P, Scott DL. central Scotland. Yao G, Fry-Smith A, Raftery J, et al. By Durham RC, Chambers JA, Power KG, Sharp DM, Macdonald RR, No. 35 No. 26 Major KA, et al. Indirect comparisons of competing Conceptual framework and systematic interventions. review of the effects of participants’ No. 43 and professionals’ preferences in By Glenny AM, Altman DG, Song F, randomised controlled trials. The effectiveness and cost-effectiveness Sakarovitch C, Deeks JJ, D’Amico R, of dual-chamber pacemakers compared et al. By King M, Nazareth I, Lampe F, with single-chamber pacemakers for Bower P, Chandler M, Morou M, et al. bradycardia due to atrioventricular No. 27 block or sick sinus syndrome: systematic Cost-effectiveness of alternative No. 36 review and economic evaluation. strategies for the initial medical The clinical and cost-effectiveness of By Castelnuovo E, Stein K, Pitt M, management of non-ST elevation acute implantable cardioverter deibrillators: Garside R, Payne E. coronary syndrome: systematic review a systematic review. and decision-analytical modelling. By Bryant J, Brodin H, Loveman E, No. 44 By Robinson M, Palmer S, Sculpher Payne E, Clegg A. Newborn screening for congenital heart M, Philips Z, Ginnelly L, Bowens A, et al. defects: a systematic review and cost- effectiveness analysis. No. 37 No. 28 By Knowles R, Griebsch I, Outcomes of electrically stimulated A trial of problem-solving by Dezateux C, Brown J, Bull C, Wren C. gracilis neosphincter surgery. community mental health nurses for anxiety, depression and life dificulties By Tillin T, Chambers M, Feldman R. among general practice patients. The No. 45 CPN-GP study. The clinical and cost-effectiveness of No. 29 left ventricular assist devices for end- By Kendrick T, Simons L, stage heart failure: a systematic review The effectiveness and cost-effectiveness Mynors-Wallis L, Gray A, Lathlean J, and economic evaluation. of pimecrolimus and tacrolimus for Pickering R, et al. atopic eczema: a systematic review and By Clegg AJ, Scott DA, Loveman E, economic evaluation. Colquitt J, Hutchinson J, Royle P, et al. No. 38 By Garside R, Stein K, Castelnuovo E, Pitt M, Ashcroft D, Dimmock P, et al. The causes and effects of socio- No. 46 demographic exclusions from clinical The effectiveness of the Heidelberg trials. No. 30 Retina Tomograph and laser diagnostic Systematic review on urine albumin By Bartlett C, Doyal L, Ebrahim S, glaucoma scanning system (GDx) in testing for early detection of diabetic Davey P, Bachmann M, Egger M, et al. detecting and monitoring glaucoma. complications. By Kwartz AJ, Henson DB, Harper By Newman DJ, Mattock MB, No. 39 RA, Spencer AF, McLeod D. Dawnay ABS, Kerry S, McGuire A, Is hydrotherapy cost-effective? Yaqoob M, et al. A randomised controlled trial of No. 47 combined hydrotherapy programmes Clinical and cost-effectiveness of No. 31 compared with physiotherapy land autologous chondrocyte implantation Randomised controlled trial of the cost- techniques in children with juvenile for cartilage defects in knee joints: effectiveness of water-based therapy for idiopathic arthritis. systematic review and economic lower limb osteoarthritis. By Epps H, Ginnelly L, Utley M, evaluation. By Cochrane T, Davey RC, Southwood T, Gallivan S, Sculpher M, By Clar C, Cummins E, McIntyre L, Matthes Edwards SM. et al. Thomas S, Lamb J, Bain L, et al. 91

No. 48 No. 6 No. 15 Systematic review of effectiveness of Systematic review and evaluation Measurement of the clinical and cost- different treatments for childhood of methods of assessing urinary effectiveness of non-invasive diagnostic retinoblastoma. incontinence. testing strategies for deep vein By McDaid C, Hartley S, Bagnall By Martin JL, Williams KS, Abrams thrombosis. KR, Turner DA, Sutton AJ, Chapple C, A-M, Ritchie G, Light K, Riemsma R. By Goodacre S, Sampson F, et al. Stevenson M, Wailoo A, Sutton A, No. 49 Thomas S, et al. Towards evidence-based guidelines No. 7 for the prevention of venous The clinical effectiveness and cost- No. 16 thromboembolism: systematic effectiveness of newer drugs for reviews of mechanical methods, oral children with epilepsy. A systematic Systematic review of the effectiveness anticoagulation, dextran and regional review. and cost-effectiveness of HealOzone® anaesthesia as thromboprophylaxis. By Connock M, Frew E, Evans B-W, for the treatment of occlusal pit/issure By Roderick P, Ferris G, Wilson K, Bryan S, Cummins C, Fry-Smith A, et al. caries and root caries. Halls H, Jackson D, Collins R, et al. By Brazzelli M, McKenzie L, Fielding No. 8 S, Fraser C, Clarkson J, Kilonzo M, et al. No. 50 Surveillance of Barrett’s oesophagus: The effectiveness and cost-effectiveness exploring the uncertainty through No. 17 of parent training/education systematic review, expert workshop and Randomised controlled trials of programmes for the treatment economic modelling. conventional antipsychotic versus of conduct disorder, including By Garside R, Pitt M, Somerville M, new atypical drugs, and new atypical oppositional deiant disorder, in Stein K, Price A, Gilbert N. drugs versus clozapine, in people with children. schizophrenia responding poorly to, or By Dretzke J, Frew E, Davenport C, No. 9 intolerant of, current drug treatment. Barlow J, Stewart-Brown S, Sandercock J, Topotecan, pegylated liposomal et al. doxorubicin hydrochloride and By Lewis SW, Davies L, Jones PB, paclitaxel for second-line or subsequent Barnes TRE, Murray RM, Kerwin R, treatment of advanced ovarian cancer: et al. Volume 10, 2006 a systematic review and economic evaluation. No. 18 By Main C, Bojke L, Grifin S, Diagnostic tests and algorithms used Norman G, Barbieri M, Mather L, et al. in the investigation of haematuria: No. 1 systematic reviews and economic The clinical and cost-effectiveness of No. 10 evaluation. donepezil, rivastigmine, galantamine Evaluation of molecular techniques and memantine for Alzheimer’s By Rodgers M, Nixon J, Hempel S, in prediction and diagnosis Aho T, Kelly J, Neal D, et al. disease. of cytomegalovirus disease in By Loveman E, Green C, Kirby J, immunocompromised patients. Takeda A, Picot J, Payne E, et al. By Szczepura A, Westmoreland D, No. 19 Vinogradova Y, Fox J, Clark M. Cognitive behavioural therapy in No. 2 addition to antispasmodic therapy for FOOD: a multicentre randomised trial No. 11 irritable bowel syndrome in primary evaluating feeding policies in patients Screening for thrombophilia in high- care: randomised controlled trial. admitted to hospital with a recent risk situations: systematic review By Kennedy TM, Chalder T, stroke. and cost-effectiveness analysis. The McCrone P, Darnley S, Knapp M, By Dennis M, Lewis S, Cranswick G, Thrombosis: Risk and Economic Jones RH, et al. Forbes J. Assessment of Thrombophilia Screening (TREATS) study. No. 20 No. 3 By Wu O, Robertson L, Twaddle S, A systematic review of the The clinical effectiveness and cost- Lowe GDO, Clark P, Greaves M, et al. clinical effectiveness and cost- effectiveness of computed tomography effectiveness of enzyme replacement screening for lung cancer: systematic No. 12 therapies for Fabry’s disease and reviews. A series of systematic reviews to inform mucopolysaccharidosis type 1. By Black C, Bagust A, Boland A, a decision analysis for sampling and Walker S, McLeod C, De Verteuil R, et al. treating infected diabetic foot ulcers. By Connock M, Juarez-Garcia A, By Nelson EA, O’Meara S, Craig D, Frew E, Mans A, Dretzke J, Fry-Smith A, No. 4 Iglesias C, Golder S, Dalton J, et al. et al. A systematic review of the effectiveness and cost-effectiveness of neuroimaging No. 13 No. 21 assessments used to visualise the seizure Randomised clinical trial, observational Health beneits of antiviral therapy for focus in people with refractory epilepsy study and assessment of cost- mild chronic hepatitis C: randomised being considered for surgery. effectiveness of the treatment of controlled trial and economic By Whiting P, Gupta R, Burch J, varicose veins (REACTIV trial). evaluation. Mujica Mota RE, Wright K, Marson A, By Michaels JA, Campbell WB, By Wright M, Grieve R, Roberts J, et al. Brazier JE, MacIntyre JB, Palfreyman SJ, Main J, Thomas HC, on behalf of the Ratcliffe J, et al. UK Mild Hepatitis C Trial Investigators. No. 5 Comparison of conference abstracts No. 14 No. 22 and presentations with full-text articles The cost-effectiveness of screening for in the health technology assessments of oral cancer in primary care. Pressure relieving support surfaces: a rapidly evolving technologies. By Speight PM, Palmer S, Moles DR, randomised evaluation. By Dundar Y, Dodd S, Dickson R, Downer MC, Smith DH, Henriksson M, By Nixon J, Nelson EA, Cranny G, 92 Walley T, Haycox A, Williamson PR. et al. Iglesias CP, Hawkins K, Cullum NA, et al. Health Technology Assessment 2010; Vol. 14: Suppl. 2

No. 23 No. 31 No. 40 A systematic review and economic Etanercept and inliximab for the What are the clinical outcome and cost- model of the effectiveness and cost- treatment of psoriatic arthritis: a effectiveness of endoscopy undertaken effectiveness of methylphenidate, systematic review and economic by nurses when compared with doctors? dexamfetamine and atomoxetine evaluation. A Multi-Institution Nurse Endoscopy for the treatment of attention deicit By Woolacott N, Bravo Vergel Y, Trial (MINuET). hyperactivity disorder in children and Hawkins N, Kainth A, Khadjesari Z, By Williams J, Russell I, Durai D, adolescents. Misso K, et al. Cheung W-Y, Farrin A, Bloor K, et al. By King S, Grifin S, Hodges Z, No. 32 Weatherly H, Asseburg C, Richardson G, No. 41 et al. The cost-effectiveness of testing for hepatitis C in former injecting drug The clinical and cost-effectiveness of oxaliplatin and capecitabine for the No. 24 users. adjuvant treatment of colon cancer: The clinical effectiveness and cost- By Castelnuovo E, Thompson-Coon J, Pitt M, Cramp M, Siebert U, Price A, systematic review and economic effectiveness of enzyme replacement evaluation. therapy for Gaucher’s disease: a et al. systematic review. By Pandor A, Eggington S, Paisley S, Tappenden P, Sutcliffe P. By Connock M, Burls A, Frew E, No. 33 Fry-Smith A, Juarez-Garcia A, McCabe C, Computerised cognitive behaviour et al. therapy for depression and anxiety No. 42 update: a systematic review and A systematic review of the effectiveness economic evaluation. No. 25 of adalimumab, etanercept and By Kaltenthaler E, Brazier J, Effectiveness and cost-effectiveness inliximab for the treatment of De Nigris E, Tumur I, Ferriter M, rheumatoid arthritis in adults and of salicylic acid and cryotherapy for Beverley C, et al. cutaneous warts. An economic decision an economic evaluation of their cost- effectiveness. model. No. 34 By Chen Y-F, Jobanputra P, Barton P, By Thomas KS, Keogh-Brown MR, Cost-effectiveness of using prognostic Jowett S, Bryan S, Clark W, et al. Chalmers JR, Fordham RJ, Holland RC, information to select women with breast Armstrong SJ, et al. cancer for adjuvant systemic therapy. By Williams C, Brunskill S, Altman D, No. 43 No. 26 Briggs A, Campbell H, Clarke M, et al. Telemedicine in dermatology: a A systematic literature review of the randomised controlled trial. effectiveness of non-pharmacological No. 35 By Bowns IR, Collins K, Walters SJ, interventions to prevent wandering in Psychological therapies including McDonagh AJG. dementia and evaluation of the ethical dialectical behaviour therapy for implications and acceptability of their borderline personality disorder: a No. 44 use. systematic review and preliminary Cost-effectiveness of cell salvage and By Robinson L, Hutchings D, Corner economic evaluation. alternative methods of minimising L, Beyer F, Dickinson H, Vanoli A, et al. By Brazier J, Tumur I, Holmes M, perioperative allogeneic blood Ferriter M, Parry G, Dent-Brown K, et al. transfusion: a systematic review and No. 27 economic model. A review of the evidence on the effects No. 36 and costs of implantable cardioverter Clinical effectiveness and cost- By Davies L, Brown TJ, Haynes S, deibrillator therapy in different effectiveness of tests for the diagnosis Payne K, Elliott RA, McCollum C. patient groups, and modelling of cost- and investigation of urinary tract effectiveness and cost–utility for these infection in children: a systematic No. 45 groups in a UK context. review and economic model. Clinical effectiveness and cost- By Buxton M, Caine N, Chase D, By Whiting P, Westwood M, Bojke L, effectiveness of laparoscopic surgery Connelly D, Grace A, Jackson C, et al. Palmer S, Richardson G, Cooper J, et al. for colorectal cancer: systematic reviews and economic evaluation. No. 28 No. 37 By Murray A, Lourenco T, de Verteuil Adefovir dipivoxil and pegylated Cognitive behavioural therapy R, Hernandez R, Fraser C, McKinley A, interferon alfa-2a for the treatment of in chronic fatigue syndrome: a et al. chronic hepatitis B: a systematic review randomised controlled trial of an outpatient group programme. and economic evaluation. No. 46 By O’Dowd H, Gladwell P, Rogers By Shepherd J, Jones J, Takeda A, CA, Hollinghurst S, Gregory A. Etanercept and efalizumab for the Davidson P, Price A. treatment of psoriasis: a systematic No. 38 review. No. 29 A comparison of the cost-effectiveness By Woolacott N, Hawkins N, An evaluation of the clinical and cost- of ive strategies for the prevention Mason A, Kainth A, Khadjesari Z, Bravo effectiveness of pulmonary artery of nonsteroidal anti-inlammatory Vergel Y, et al. catheters in patient management in drug-induced gastrointestinal toxicity: intensive care: a systematic review and a a systematic review with economic No. 47 randomised controlled trial. modelling. Systematic reviews of clinical decision By Harvey S, Stevens K, Harrison D, By Brown TJ, Hooper L, Elliott RA, tools for acute abdominal pain. Young D, Brampton W, McCabe C, et al. Payne K, Webb R, Roberts C, et al. By Liu JLY, Wyatt JC, Deeks JJ, Clamp S, Keen J, Verde P, et al. No. 30 No. 39 Accurate, practical and cost-effective The effectiveness and cost-effectiveness assessment of carotid stenosis in the of computed tomography screening No. 48 UK. for coronary artery disease: systematic Evaluation of the ventricular assist By Wardlaw JM, Chappell FM, review. device programme in the UK. Stevenson M, De Nigris E, Thomas S, By Waugh N, Black C, Walker S, By Sharples L, Buxton M, Caine N, Gillard J, et al. McIntyre L, Cummins E, Hillis G. Cafferty F, Demiris N, Dyer M, et al. 93

No. 49 No. 7 No. 16 A systematic review and economic Glucocorticoid-induced osteoporosis: Additional therapy for young model of the clinical and cost- a systematic review and cost–utility children with spastic cerebral palsy: a effectiveness of immunosuppressive analysis. randomised controlled trial. therapy for renal transplantation in By Kanis JA, Stevenson M, children. McCloskey EV, Davis S, Lloyd-Jones M. By Weindling AM, Cunningham CC, Glenn SM, Edwards RT, Reeves DJ. By Yao G, Albon E, Adi Y, Milford D, Bayliss S, Ready A, et al. No. 8 Epidemiological, social, diagnostic and No. 17 economic evaluation of population No. 50 screening for genital chlamydial Screening for type 2 diabetes: literature Amniocentesis results: investigation of infection. review and economic modelling. anxiety. The ARIA trial. By Low N, McCarthy A, Macleod J, By Waugh N, Scotland G, McNamee By Hewison J, Nixon J, Fountain J, Salisbury C, Campbell R, Roberts TE, P, Gillett M, Brennan A, Goyder E, et al. Cocks K, Jones C, Mason G, et al. et al. No. 18 No. 9 Methadone and buprenorphine for the The effectiveness and cost-effectiveness Volume 11, 2007 management of opioid dependence: of cinacalcet for secondary a systematic review and economic hyperparathyroidism in end-stage renal evaluation. disease patients on dialysis: a systematic review and economic evaluation. No. 1 By Connock M, Juarez-Garcia A, Jowett S, Frew E, Liu Z, Taylor RJ, et al. Pemetrexed disodium for the treatment By Garside R, Pitt M, Anderson R, of malignant pleural mesothelioma: Mealing S, Roome C, Snaith A, et al. a systematic review and economic No. 10 Exercise Evaluation Randomised evaluation. No. 19 Trial (EXERT): a randomised trial By Dundar Y, Bagust A, Dickson R, comparing GP referral for leisure The clinical effectiveness and cost- Dodd S, Green J, Haycox A, et al. centre-based exercise, community-based effectiveness of gemcitabine for walking and advice only. metastatic breast cancer: a systematic No. 2 By Isaacs AJ, Critchley JA, See Tai review and economic evaluation. A systematic review and economic S, Buckingham K, Westley D, Harridge By Takeda AL, Jones J, Loveman E, model of the clinical effectiveness SDR, et al. Tan SC, Clegg AJ. and cost-effectiveness of docetaxel in combination with prednisone or No. 11 prednisolone for the treatment of Interferon alfa (pegylated and non- No. 20 hormone-refractory metastatic prostate pegylated) and ribavirin for the A systematic review of duplex cancer. treatment of mild chronic hepatitis ultrasound, magnetic resonance By Collins R, Fenwick E, Trowman R, C: a systematic review and economic angiography and computed Perard R, Norman G, Light K, et al. evaluation. tomography angiography for By Shepherd J, Jones J, Hartwell D, the diagnosis and assessment of Davidson P, Price A, Waugh N. symptomatic, lower limb peripheral No. 3 arterial disease. A systematic review of rapid diagnostic No. 12 By Collins R, Cranny G, Burch J, tests for the detection of tuberculosis Systematic review and economic Aguiar-Ibáñez R, Craig D, Wright K, infection. evaluation of bevacizumab and et al. By Dinnes J, Deeks J, Kunst H, cetuximab for the treatment of Gibson A, Cummins E, Waugh N, et al. metastatic colorectal cancer. By Tappenden P, Jones R, Paisley S, No. 21 No. 4 Carroll C. The clinical effectiveness and cost- The clinical effectiveness and cost- effectiveness of treatments for children effectiveness of strontium ranelate for No. 13 with idiopathic steroid-resistant the prevention of osteoporotic fragility A systematic review and economic nephrotic syndrome: a systematic fractures in postmenopausal women. evaluation of epoetin alfa, epoetin review. beta and darbepoetin alfa in anaemia By Stevenson M, Davis S, Lloyd-Jones associated with cancer, especially that By Colquitt JL, Kirby J, Green C, M, Beverley C. attributable to cancer treatment. Cooper K, Trompeter RS. By Wilson J, Yao GL, Raftery J, No. 5 Bohlius J, Brunskill S, Sandercock J, No. 22 et al. A systematic review of quantitative and A systematic review of the routine qualitative research on the role and monitoring of growth in children of effectiveness of written information No. 14 primary school age to identify growth- available to patients about individual A systematic review and economic related conditions. medicines. evaluation of statins for the prevention By Fayter D, Nixon J, Hartley S, By Raynor DK, Blenkinsopp of coronary events. Rithalia A, Butler G, Rudolf M, et al. A, Knapp P, Grime J, Nicolson DJ, By Ward S, Lloyd Jones M, Pandor A, Pollock K, et al. Holmes M, Ara R, Ryan A, et al. No. 23 No. 15 No. 6 A systematic review of the effectiveness Systematic review of the effectiveness of Oral naltrexone as a treatment for and cost-effectiveness of different preventing and treating Staphylococcus relapse prevention in formerly opioid- models of community-based respite aureus carriage in reducing peritoneal dependent drug users: a systematic care for frail older people and their catheter-related infections. review and economic evaluation. carers. By McCormack K, Rabindranath K, By Adi Y, Juarez-Garcia A, Wang D, By Mason A, Weatherly H, Spilsbury Kilonzo M, Vale L, Fraser C, McIntyre L, 94 Jowett S, Frew E, Day E, et al. K, Arksey H, Golder S, Adamson J, et al. et al. Health Technology Assessment 2010; Vol. 14: Suppl. 2

No. 24 No. 33 No. 41 The clinical effectiveness and cost The clinical effectiveness and cost- The clinical effectiveness and cost- of repetitive transcranial magnetic effectiveness of inhaled insulin in effectiveness of screening for open stimulation versus electroconvulsive diabetes mellitus: a systematic review angle glaucoma: a systematic review therapy in severe depression: a and economic evaluation. and economic evaluation. multicentre pragmatic randomised By Black C, Cummins E, Royle P, By Burr JM, Mowatt G, Hernández controlled trial and economic analysis. Philip S, Waugh N. R, Siddiqui MAR, Cook J, Lourenco T, By McLoughlin DM, Mogg A, Eranti et al. S, Pluck G, Purvis R, Edwards D, et al. No. 34 No. 42 No. 25 Surveillance of cirrhosis for A randomised controlled trial and hepatocellular carcinoma: systematic Acceptability, beneit and costs of early economic evaluation of direct versus review and economic analysis. screening for hearing disability: a study of potential screening tests and models. indirect and individual versus group By Thompson Coon J, Rogers G, modes of speech and language therapy Hewson P, Wright D, Anderson R, By Davis A, Smith P, Ferguson M, for children with primary language Cramp M, et al. Stephens D, Gianopoulos I. impairment. By Boyle J, McCartney E, Forbes J, No. 35 No. 43 O’Hare A. Contamination in trials of educational The Birmingham Rehabilitation interventions. No. 26 Uptake Maximisation Study (BRUM). Hormonal therapies for early breast Homebased compared with hospital- By Keogh-Brown MR, Bachmann cancer: systematic review and economic based cardiac rehabilitation in a multi- MO, Shepstone L, Hewitt C, Howe A, evaluation. ethnic population: cost-effectiveness Ramsay CR, et al. By Hind D, Ward S, De Nigris E, and patient adherence. Simpson E, Carroll C, Wyld L. By Jolly K, Taylor R, Lip GYH, No. 44 Greenield S, Raftery J, Mant J, et al. Overview of the clinical effectiveness of No. 27 positron emission tomography imaging Cardioprotection against the toxic No. 36 in selected cancers. effects of anthracyclines given to By Facey K, Bradbury I, Laking G, A systematic review of the clinical, children with cancer: a systematic Payne E. review. public health and cost-effectiveness of rapid diagnostic tests for the detection By Bryant J, Picot J, Levitt G, No. 45 Sullivan I, Baxter L, Clegg A. and identiication of bacterial intestinal pathogens in faeces and food. The effectiveness and cost-effectiveness of carmustine implants and No. 28 By Abubakar I, Irvine L, Aldus CF, temozolomide for the treatment of Adalimumab, etanercept and inliximab Wyatt GM, Fordham R, Schelenz S, et al. newly diagnosed high-grade glioma: for the treatment of ankylosing a systematic review and economic spondylitis: a systematic review and No. 37 evaluation. economic evaluation. A randomised controlled trial By McLeod C, Bagust A, Boland A, By Garside R, Pitt M, Anderson R, examining the longer-term outcomes Rogers G, Dyer M, Mealing S, et al. Dagenais P, Dickson R, Dundar Y, et al. of standard versus new antiepileptic drugs. The SANAD trial. No. 29 No. 46 Prenatal screening and treatment By Marson AG, Appleton R, Baker Drug-eluting stents: a systematic review strategies to prevent group B GA, Chadwick DW, Doughty J, Eaton B, and economic evaluation. et al. streptococcal and other bacterial By Hill RA, Boland A, Dickson R, infections in early infancy: cost- D̈ndar Y, Haycox A, McLeod C, et al. effectiveness and expected value of No. 38 information analyses. Clinical effectiveness and cost- No. 47 By Colbourn T, Asseburg C, Bojke L, effectiveness of different models The clinical effectiveness and Philips Z, Claxton K, Ades AE, et al. of managing long-term oral anti- cost-effectiveness of cardiac coagulation therapy: a systematic resynchronisation (biventricular pacing) No. 30 review and economic modelling. for heart failure: systematic review and Clinical effectiveness and cost- By Connock M, Stevens C, Fry-Smith effectiveness of bone morphogenetic economic model. A, Jowett S, Fitzmaurice D, Moore D, By Fox M, Mealing S, Anderson R, proteins in the non-healing of fractures et al. and spinal fusion: a systematic review. Dean J, Stein K, Price A, et al. By Garrison KR, Donell S, Ryder J, Shemilt I, Mugford M, Harvey I, et al. No. 39 No. 48 A systematic review and economic Recruitment to randomised trials: No. 31 model of the clinical effectiveness strategies for trial enrolment and A randomised controlled trial of and cost-effectiveness of interventions participation study. The STEPS study. for preventing relapse in people with postoperative radiotherapy following By Campbell MK, Snowdon C, bipolar disorder. breast-conserving surgery in a Francis D, Elbourne D, McDonald AM, minimum-risk older population. The By Soares-Weiser K, Bravo Vergel Y, Knight R, et al. PRIME trial. Beynon S, Dunn G, Barbieri M, Duffy S, By Prescott RJ, Kunkler IH, Williams et al. LJ, King CC, Jack W, van der Pol M, et al. No. 49 Cost-effectiveness of functional No. 40 No. 32 cardiac testing in the diagnosis and Current practice, accuracy, effectiveness Taxanes for the adjuvant treatment of management of coronary artery and cost-effectiveness of the school early breast cancer: systematic review disease: a randomised controlled trial. entry hearing screen. and economic evaluation. The CECaT trial. By Bamford J, Fortnum H, Bristow K, By Ward S, Simpson E, Davis S, Hind By Sharples L, Hughes V, Crean A, Smith J, Vamvakas G, Davies L, et al. D, Rees A, Wilkinson A. Dyer M, Buxton M, Goldsmith K, et al. 95

No. 50 No. 5 No. 14 Evaluation of diagnostic tests when A multi-centre retrospective cohort A randomised controlled trial of there is no gold standard. A review of study comparing the eficacy, safety cognitive behaviour therapy in methods. and cost-effectiveness of hysterectomy adolescents with major depression By Rutjes AWS, Reitsma and uterine artery embolisation for treated by selective serotonin reuptake JB, Coomarasamy A, Khan KS, the treatment of symptomatic uterine inhibitors. The ADAPT trial. Bossuyt PMM. ibroids. The HOPEFUL study. By Goodyer IM, Dubicka B, Wilkinson By Hirst A, Dutton S, Wu O, Briggs A, P, Kelvin R, Roberts C, Byford S, et al. Edwards C, Waldenmaier L, et al. No. 51 No. 15 Systematic reviews of the clinical No. 6 effectiveness and cost-effectiveness of The use of irinotecan, oxaliplatin proton pump inhibitors in acute upper Methods of prediction and prevention and raltitrexed for the treatment of gastrointestinal bleeding. of pre-eclampsia: systematic reviews of advanced colorectal cancer: systematic accuracy and effectiveness literature review and economic evaluation. By Leontiadis GI, Sreedharan A, with economic modelling. Dorward S, Barton P, Delaney B, Howden By Hind D, Tappenden P, Tumur I, By Meads CA, Cnossen JS, Meher S, CW, et al. Eggington E, Sutcliffe P, Ryan A. Juarez-Garcia A, ter Riet G, Duley L, et al. No. 16 No. 52 No. 7 A review and critique of modelling in Ranibizumab and pegaptanib for The use of economic evaluations in the treatment of age-related macular prioritising and designing screening NHS decision-making: a review and programmes. degeneration: a systematic review and empirical investigation. economic evaluation. By Karnon J, Goyder E, Tappenden P, By Williams I, McIver S, Moore D, By Colquitt JL, Jones J, Tan SC, McPhie S, Towers I, Brazier J, et al. Bryan S. Takeda A, Clegg AJ, Price A. No. 53 No. 8 No. 17 An assessment of the impact of the Stapled haemorrhoidectomy Systematic review of the clinical NHS Health Technology Assessment (haemorrhoidopexy) for the treatment effectiveness and cost-effectiveness Programme. of haemorrhoids: a systematic review and economic evaluation. of 64-slice or higher computed By Hanney S, Buxton M, Green C, tomography angiography as an By Burch J, Epstein D, Baba-Akbari Coulson D, Raftery J. alternative to invasive coronary A, Weatherly H, Fox D, Golder S, et al. angiography in the investigation of coronary artery disease. No. 9 Volume 12, 2008 By Mowatt G, Cummins E, Waugh N, The clinical effectiveness of diabetes Walker S, Cook J, Jia X, et al. education models for Type 2 diabetes: a systematic review. No. 18 No. 1 By Loveman E, Frampton GK, Structural neuroimaging in psychosis: A systematic review and economic Clegg AJ. a systematic review and economic model of switching from evaluation. nonglycopeptide to glycopeptide No. 10 antibiotic prophylaxis for surgery. Payment to healthcare professionals for By Albon E, Tsourapas A, Frew E, Davenport C, Oyebode F, Bayliss S, et al. By Cranny G, Elliott R, Weatherly H, patient recruitment to trials: systematic Chambers D, Hawkins N, Myers L, et al. review and qualitative study. By Raftery J, Bryant J, Powell J, No. 19 No. 2 Kerr C, Hawker S. Systematic review and economic analysis of the comparative effectiveness of ‘Cut down to quit’ with nicotine No. 11 different inhaled corticosteroids and replacement therapies in smoking their usage with long-acting beta Cyclooxygenase-2 selective non- 2 cessation: a systematic review of agonists for the treatment of chronic effectiveness and economic analysis. steroidal anti-inlammatory drugs (etodolac, meloxicam, celecoxib, asthma in adults and children aged By Wang D, Connock M, Barton P, rofecoxib, etoricoxib, valdecoxib and 12 years and over. Fry-Smith A, Aveyard P, Moore D. lumiracoxib) for osteoarthritis and By Shepherd J, Rogers G, Anderson rheumatoid arthritis: a systematic review R, Main C, Thompson-Coon J, No. 3 and economic evaluation. Hartwell D, et al. A systematic review of the effectiveness By Chen Y-F, Jobanputra P, Barton P, of strategies for reducing fracture risk Bryan S, Fry-Smith A, Harris G, et al. No. 20 in children with juvenile idiopathic Systematic review and economic analysis arthritis with additional data on long- No. 12 of the comparative effectiveness of term risk of fracture and cost of disease The clinical effectiveness and cost- different inhaled corticosteroids and management. effectiveness of central venous catheters their usage with long-acting beta2 By Thornton J, Ashcroft D, O’Neill T, treated with anti-infective agents in agonists for the treatment of chronic Elliott R, Adams J, Roberts C, et al. preventing bloodstream infections: asthma in children under the age of a systematic review and economic 12 years. No. 4 evaluation. By Main C, Shepherd J, Anderson R, Does befriending by trained lay workers By Hockenhull JC, Dwan K, Boland Rogers G, Thompson-Coon J, Liu Z, et al. improve psychological well-being and A, Smith G, Bagust A, Dundar Y, et al. quality of life for carers of people No. 21 with dementia, and at what cost? A No. 13 Ezetimibe for the treatment of randomised controlled trial. Stepped treatment of older adults on hypercholesterolaemia: a systematic By Charlesworth G, Shepstone L, laxatives. The STOOL trial. review and economic evaluation. Wilson E, Thalanany M, Mugford M, By Mihaylov S, Stark C, McColl E, By Ara R, Tumur I, Pandor A, Duenas 96 Poland F. Steen N, Vanoli A, Rubin G, et al. A, Williams R, Wilkinson A, et al. Health Technology Assessment 2010; Vol. 14: Suppl. 2

No. 22 No. 31 No. 3 Topical or oral ibuprofen for chronic The effectiveness and cost-effectivness Surgical procedures and non-surgical knee pain in older people. The TOIB of minimal access surgery amongst devices for the management of non- study. people with gastro-oesophageal relux apnoeic snoring: a systematic review of By Underwood M, Ashby D, Carnes disease – a UK collaborative study. The clinical effects and associated treatment D, Castelnuovo E, Cross P, Harding G, REFLUX trial. costs. et al. By Grant A, Wileman S, Ramsay C, By Main C, Liu Z, Welch K, Weiner G, Bojke L, Epstein D, Sculpher M, et al. Quentin Jones S, Stein K. No. 23 A prospective randomised comparison No. 4 of minor surgery in primary and No. 32 Continuous positive airway pressure secondary care. The MiSTIC trial. Time to full publication of studies of devices for the treatment of obstructive anti-cancer medicines for breast cancer By George S, Pockney P, Primrose J, sleep apnoea–hypopnoea syndrome: a and the potential for publication bias: a Smith H, Little P, Kinley H, et al. systematic review and economic analysis. short systematic review. By McDaid C, Grifin S, Weatherly H, No. 24 By Takeda A, Loveman E, Harris P, Durée K, van der Burgt M, van Hout S, A review and critical appraisal Hartwell D, Welch K. Akers J, et al. of measures of therapist–patient interactions in mental health settings. No. 33 No. 5 By Cahill J, Barkham M, Hardy G, Performance of screening tests for Gilbody S, Richards D, Bower P, et al. Use of classical and novel biomarkers child physical abuse in accident and as prognostic risk factors for localised emergency departments. No. 25 prostate cancer: a systematic review. The clinical effectiveness and cost- By Woodman J, Pitt M, Wentz R, By Sutcliffe P, Hummel S, Simpson E, effectiveness of screening programmes Taylor B, Hodes D, Gilbert RE. Young T, Rees A, Wilkinson A, et al. for amblyopia and strabismus in children up to the age of 4–5 years: No. 34 No. 6 a systematic review and economic Curative catheter ablation in atrial The harmful health effects of recreational evaluation. ibrillation and typical atrial lutter: ecstasy: a systematic review of By Carlton J, Karnon J, Czoski- systematic review and economic observational evidence. Murray C, Smith KJ, Marr J. evaluation. By Rogers G, Elston J, Garside R, By Rodgers M, McKenna C, Palmer S, Roome C, Taylor R, Younger P, et al. No. 26 Chambers D, Van Hout S, Golder S, et al. A systematic review of the clinical No. 7 effectiveness and cost-effectiveness and Systematic review of the clinical economic modelling of minimal incision No. 35 effectiveness and cost-effectiveness total hip replacement approaches in Systematic review and economic of oesophageal Doppler monitoring the management of arthritic disease of modelling of effectiveness and cost in critically ill and high-risk surgical the hip. utility of surgical treatments for men patients. By de Verteuil R, Imamura M, Zhu S, with benign prostatic enlargement. Glazener C, Fraser C, Munro N, et al. By Mowatt G, Houston G, Hernández By Lourenco T, Armstrong N, N’Dow R, de Verteuil R, Fraser C, Cuthbertson J, Nabi G, Deverill M, Pickard R, et al. B, et al. No. 27 A preliminary model-based assessment No. 36 of the cost–utility of a screening No. 8 programme for early age-related Immunoprophylaxis against respiratory The use of surrogate outcomes in model- macular degeneration. syncytial virus (RSV) with palivizumab based cost-effectiveness analyses: a survey By Karnon J, Czoski-Murray C, Smith in children: a systematic review and of UK Health Technology Assessment K, Brand C, Chakravarthy U, Davis S, economic evaluation. reports. et al. By Wang D, Cummins C, Bayliss S, By Taylor RS, Elston J. Sandercock J, Burls A. No. 28 No. 9 Intravenous magnesium sulphate Controlling Hypertension and and sotalol for prevention of atrial Volume 13, 2009 Hypotension Immediately Post Stroke ibrillation after coronary artery (CHHIPS) – a randomised controlled bypass surgery: a systematic review and trial. economic evaluation. By Potter J, Mistri A, Brodie F, By Shepherd J, Jones J, Frampton No. 1 Chernova J, Wilson E, Jagger C, et al. GK, Tanajewski L, Turner D, Price A. Deferasirox for the treatment of iron overload associated with regular No. 10 No. 29 blood transfusions (transfusional Routine antenatal anti-D prophylaxis Absorbent products for urinary/faecal haemosiderosis) in patients suffering for RhD-negative women: a systematic incontinence: a comparative evaluation with chronic anaemia: a systematic review and economic evaluation. of key product categories. review and economic evaluation. By Pilgrim H, Lloyd-Jones M, Rees A. By Fader M, Cottenden A, Getliffe K, By McLeod C, Fleeman N, Kirkham Gage H, Clarke-O’Neill S, Jamieson K, J, Bagust A, Boland A, Chu P, et al. et al. No. 11 Amantadine, oseltamivir and zanamivir No. 2 No. 30 for the prophylaxis of inluenza A systematic review of repetitive Thrombophilia testing in people with (including a review of existing guidance functional task practice with modelling venous thromboembolism: systematic no. 67): a systematic review and of resource use, costs and effectiveness. review and cost-effectiveness analysis. economic evaluation. By French B, Leathley M, Sutton C, By Simpson EL, Stevenson MD, By Tappenden P, Jackson R, Cooper McAdam J, Thomas L, Forster A, et al. Rawdin A, Papaioannou D. K, Rees A, Simpson E, Read R, et al. 97

No. 12 No. 21 No. 29 Improving the evaluation of therapeutic Neuroleptics in the treatment of Sensitivity analysis in economic interventions in multiple sclerosis: the aggressive challenging behaviour for evaluation: an audit of NICE current role of new psychometric methods. people with intellectual disabilities: practice and a review of its use and By Hobart J, Cano S. a randomised controlled trial value in decision-making. (NACHBID). By Andronis L, Barton P, Bryan S. No. 13 By Tyrer P, Oliver-Africano P, Romeo R, Knapp M, Dickens S, Bouras N, et al. Treatment of severe ankle sprain: a Suppl. 1 pragmatic randomised controlled trial Trastuzumab for the treatment of comparing the clinical effectiveness No. 22 primary breast cancer in HER2-positive and cost-effectiveness of three types of Randomised controlled trial to women: a single technology appraisal. mechanical ankle support with tubular determine the clinical effectiveness By Ward S, Pilgrim H, Hind D. bandage. The CAST trial. and cost-effectiveness of selective Docetaxel for the adjuvant treatment By Cooke MW, Marsh JL, Clark M, serotonin reuptake inhibitors plus of early node-positive breast cancer: a Nakash R, Jarvis RM, Hutton JL, et al., supportive care, versus supportive care single technology appraisal. on behalf of the CAST trial group. alone, for mild to moderate depression with somatic symptoms in primary By Chilcott J, Lloyd Jones M, care: the THREAD (THREshold for Wilkinson A. No. 14 AntiDepressant response) study. Non-occupational postexposure By Kendrick T, Chatwin J, Dowrick C, The use of paclitaxel in the prophylaxis for HIV: a systematic review. Tylee A, Morriss R, Peveler R, et al. management of early stage breast By Bryant J, Baxter L, Hird S. cancer. No. 23 By Grifin S, Dunn G, Palmer S, No. 15 Diagnostic strategies using DNA testing Macfarlane K, Brent S, Dyker A, et al. for hereditary haemochromatosis in Blood glucose self-monitoring in type 2 Rituximab for the irst-line treatment at-risk populations: a systematic review diabetes: a randomised controlled trial. of stage III/IV follicular non-Hodgkin’s and economic evaluation. By Farmer AJ, Wade AN, French DP, lymphoma. By Bryant J, Cooper K, Picot J, Clegg Simon J, Yudkin P, Gray A, et al. By Dundar Y, Bagust A, Hounsome J, A, Roderick P, Rosenberg W, et al. McLeod C, Boland A, Davis H, et al. No. 16 How far does screening women for No. 24 Bortezomib for the treatment of domestic (partner) violence in different Enhanced external counterpulsation multiple myeloma patients. health-care settings meet criteria for for the treatment of stable angina and By Green C, Bryant J, Takeda A, a screening programme? Systematic heart failure: a systematic review and Cooper K, Clegg A, Smith A, et al. reviews of nine UK National Screening economic analysis. Committee criteria. By McKenna C, McDaid C, Suekarran Fludarabine phosphate for the irst- line treatment of chronic lymphocytic By Feder G, Ramsay J, Dunne D, Rose S, Hawkins N, Claxton K, Light K, et al. leukaemia. M, Arsene C, Norman R, et al. No. 25 By Walker S, Palmer S, Erhorn S, Brent S, Dyker A, Ferrie L, et al. No. 17 Development of a decision support tool for primary care management of Spinal cord stimulation for chronic Erlotinib for the treatment of relapsed patients with abnormal liver function pain of neuropathic or ischaemic non-small cell lung cancer. tests without clinically apparent liver origin: systematic review and economic By McLeod C, Bagust A, Boland A, evaluation. disease: a record-linkage population cohort study and decision analysis Hockenhull J, Dundar Y, Proudlove C, By Simpson EL, Duenas A, Holmes (ALFIE). et al. MW, Papaioannou D, Chilcott J. By Donnan PT, McLernon D, Dillon Cetuximab plus radiotherapy for the JF, Ryder S, Roderick P, Sullivan F, et al. No. 18 treatment of locally advanced squamous cell carcinoma of the head and neck. The role of magnetic resonance imaging No. 26 in the identiication of suspected By Grifin S, Walker S, Sculpher M, A systematic review of presumed White S, Erhorn S, Brent S, et al. acoustic neuroma: a systematic review consent systems for deceased organ of clinical and cost-effectiveness and donation. Inliximab for the treatment of adults natural history. By Rithalia A, McDaid C, Suekarran with psoriasis. By Fortnum H, O’Neill C, Taylor R, S, Norman G, Myers L, Sowden A. By Loveman E, Turner D, Hartwell D, Lenthall R, Nikolopoulos T, Lightfoot Cooper K, Clegg A. G, et al. No. 27 Paracetamol and ibuprofen for the No. 30 No. 19 treatment of fever in children: the Psychological interventions for postnatal Dipsticks and diagnostic algorithms in PITCH randomised controlled trial. depression: cluster randomised trial urinary tract infection: development By Hay AD, Redmond NM, Costelloe and economic evaluation. The PoNDER and validation, randomised trial, C, Montgomery AA, Fletcher M, trial. economic analysis, observational cohort Hollinghurst S, et al. By Morrell CJ, Warner R, Slade P, and qualitative study. Dixon S, Walters S, Paley G, et al. By Little P, Turner S, Rumsby K, No. 28 Warner G, Moore M, Lowes JA, et al. A randomised controlled trial to No. 31 compare minimally invasive glucose The effect of different treatment No. 20 monitoring devices with conventional durations of clopidogrel in patients Systematic review of respite care in the monitoring in the management of with non-ST-segment elevation acute frail elderly. insulin-treated diabetes mellitus coronary syndromes: a systematic review By Shaw C, McNamara R, Abrams K, (MITRE). and value of information analysis. Cannings-John R, Hood K, Longo M, By Newman SP, Cooke D, Casbard A, By Rogowski R, Burch J, Palmer S, 98 et al. Walker S, Meredith S, Nunn A, et al. Craigs C, Golder S, Woolacott N. Health Technology Assessment 2010; Vol. 14: Suppl. 2

No. 32 No. 40 Adalimumab for the treatment of Systematic review and individual patient Breastfeeding promotion for infants in psoriasis. data meta-analysis of diagnosis of heart neonatal units: a systematic review and By Turner D, Picot J, Cooper K, failure, with modelling of implications economic analysis. Loveman E. of different diagnostic strategies in By Renfrew MJ, Craig D, Dyson L, Dabigatran etexilate for the prevention primary care. McCormick F, Rice S, King SE, et al. of venous thromboembolism in patients By Mant J, Doust J, Roalfe A, Barton undergoing elective hip and knee P, Cowie MR, Glasziou P, et al. No. 41 surgery: a single technology appraisal. The clinical effectiveness and cost- By Holmes M, Carroll C, No. 33 effectiveness of bariatric (weight loss) Papaioannou D. surgery for obesity: a systematic review and A multicentre randomised controlled economic evaluation. Romiplostim for the treatment trial of the use of continuous positive of chronic immune or idiopathic airway pressure and non-invasive By Picot J, Jones J, Colquitt JL, thrombocytopenic purpura: a single positive pressure ventilation in the early Gospodarevskaya E, Loveman E, Baxter technology appraisal. treatment of patients presenting to the L, et al. emergency department with severe By Mowatt G, Boachie C, Crowther acute cardiogenic pulmonary oedema: No. 42 M, Fraser C, Hernández R, Jia X, et al. the 3CPO trial. Rapid testing for group B streptococcus Sunitinib for the treatment of By Gray AJ, Goodacre S, Newby during labour: a test accuracy study with gastrointestinal stromal tumours: a DE, Masson MA, Sampson F, Dixon evaluation of acceptability and cost- critique of the submission from Pizer. S, et al., on behalf of the 3CPO study effectiveness. By Bond M, Hoyle M, Moxham T, investigators. By Daniels J, Gray J, Pattison H, Napier M, Anderson R. Roberts T, Edwards E, Milner P, et al. No. 34 No. 45 Early high-dose lipid-lowering therapy No. 43 Vitamin K to prevent fractures in older to avoid cardiac events: a systematic Screening to prevent spontaneous women: systematic review and economic review and economic evaluation. preterm birth: systematic reviews of evaluation. accuracy and effectiveness literature By Stevenson M, Lloyd-Jones M, By Ara R, Pandor A, Stevens J, Rees with economic modelling. Papaioannou D. A, Raia R. By Honest H, Forbes CA, Durée KH, Norman G, Duffy SB, Tsourapas A, et al. No. 46 No. 35 The effects of biofeedback for the Adefovir dipivoxil and pegylated No. 44 treatment of essential hypertension: a interferon alpha for the treatment The effectiveness and cost-effectiveness systematic review. of chronic hepatitis B: an updated of cochlear implants for severe to By Greenhalgh J, Dickson R, systematic review and economic profound deafness in children and Dundar Y. evaluation. adults: a systematic review and By Jones J, Shepherd J, Baxter L, economic model. No. 47 A randomised controlled trial of the Gospodarevskaya E, Hartwell D, Harris By Bond M, Mealing S, Anderson R, use of aciclovir and/or prednisolone for P, et al. Elston J, Weiner G, Taylor RS, et al. the early treatment of Bell’s palsy: the No. 36 BELLS study. Suppl. 2 By Sullivan FM, Swan IRC, Donnan Methods to identify postnatal Gemcitabine for the treatment of PT, Morrison JM, Smith BH, McKinstry depression in primary care: an metastatic breast cancer. B, et al. integrated evidence synthesis and value By Jones J, Takeda A, Tan SC, Cooper of information analysis. K, Loveman E, Clegg A. Suppl. 3 By Hewitt CE, Gilbody SM, Brealey S, Lapatinib for the treatment of HER2- Paulden M, Palmer S, Mann R, et al. Varenicline in the management of overexpressing breast cancer. smoking cessation: a single technology By Jones J, Takeda A, Picot J, von No. 37 appraisal. Keyserlingk C, Clegg A. A double-blind randomised placebo- By Hind D, Tappenden P, Peters J, controlled trial of topical intranasal Kenjegalieva K. Inliximab for the treatment of corticosteroids in 4- to 11-year-old ulcerative colitis. Alteplase for the treatment of acute children with persistent bilateral otitis By Hyde C, Bryan S, Juarez-Garcia A, ischaemic stroke: a single technology media with effusion in primary care. Andronis L, Fry-Smith A. appraisal. By Williamson I, Benge S, Barton S, By Lloyd Jones M, Holmes M. Rimonabant for the treatment of Petrou S, Letley L, Fasey N, et al. overweight and obese people. Rituximab for the treatment of By Burch J, McKenna C, Palmer S, No. 38 rheumatoid arthritis. Norman G, Glanville J, Sculpher M, et al. By Bagust A, Boland A, Hockenhull The effectiveness and cost-effectiveness Telbivudine for the treatment of chronic J, Fleeman N, Greenhalgh J, Dundar Y, of methods of storing donated kidneys hepatitis B infection. from deceased donors: a systematic et al. By Hartwell D, Jones J, Harris P, review and economic model. Cooper K. By Bond M, Pitt M, Akoh J, Moxham Omalizumab for the treatment of severe T, Hoyle M, Anderson R. persistent allergic asthma. Entecavir for the treatment of chronic By Jones J, Shepherd J, Hartwell D, hepatitis B infection. Harris P, Cooper K, Takeda A, et al. No. 39 By Shepherd J, Gospodarevskaya E, Frampton G, Cooper K. Rehabilitation of older patients: day Rituximab for the treatment of relapsed hospital compared with rehabilitation at or refractory stage III or IV follicular Febuxostat for the treatment of home. A randomised controlled trial. non-Hodgkin’s lymphoma. hyperuricaemia in people with gout: a By Parker SG, Oliver P, Pennington By Boland A, Bagust A, Hockenhull J, single technology appraisal. M, Bond J, Jagger C, Enderby PM, et al. Davis H, Chu P, Dickson R. By Stevenson M, Pandor A. 99

Rivaroxaban for the prevention of No. 54 Volume 14, 2010 venous thromboembolism: a single Randomised controlled trial of the use technology appraisal. of three dressing preparations in the By Stevenson M, Scope A, Holmes M, management of chronic ulceration of No. 1 Rees A, Kaltenthaler E. the foot in diabetes. Multicentre randomised controlled By Jeffcoate WJ, Price PE, Phillips CJ, trial examining the cost-effectiveness of Cetuximab for the treatment of Game FL, Mudge E, Davies S, et al. recurrent and/or metastatic squamous contrast-enhanced high ield magnetic cell carcinoma of the head and neck. resonance imaging in women with No. 55 primary breast cancer scheduled for By Greenhalgh J, Bagust A, Boland A, VenUS II: a randomised controlled trial wide local excision (COMICE). Fleeman N, McLeod C, Dundar Y, et al. of larval therapy in the management of By Turnbull LW, Brown SR, Olivier C, leg ulcers. Mifamurtide for the treatment of Harvey I, Brown J, Drew P, et al. osteosarcoma: a single technology By Dumville JC, Worthy G, Soares MO, Bland JM, Cullum N, Dowson C, appraisal. No. 2 et al. By Pandor A, Fitzgerald P, Stevenson Bevacizumab, sorafenib tosylate, M, Papaioannou D. sunitinib and temsirolimus for renal No. 56 cell carcinoma: a systematic review and Ustekinumab for the treatment of A prospective randomised controlled economic evaluation. moderate to severe psoriasis. trial and economic modelling of antimicrobial silver dressings versus By Thompson Coon J, Hoyle M, By Gospodarevskaya E, Picot J, Green C, Liu Z, Welch K, Moxham T, Cooper K, Loveman E, Takeda A. non-adherent control dressings for venous leg ulcers: the VULCAN trial. et al. No. 48 By Michaels JA, Campbell WB, King BM, MacIntyre J, Palfreyman SJ, No. 3 Endovascular stents for abdominal Shackley P, et al. The clinical effectiveness and cost- aortic aneurysms: a systematic review effectiveness of testing for cytochrome and economic model. No. 57 P450 polymorphisms in patients By Chambers D, Epstein D, Walker S, Communication of carrier status with schizophrenia treated with Fayter D, Paton F, Wright K, et al. information following universal antipsychotics: a systematic review and newborn screening for sickle cell economic evaluation. No. 49 disorders and cystic ibrosis: qualitative By Fleeman N, McLeod C, Bagust A, Clinical and cost-effectiveness of study of experience and practice. Beale S, Boland A, Dundar Y, et al. epoprostenol, iloprost, bosentan, By Kai J, Ulph F, Cullinan T, sitaxentan and sildenail for pulmonary Qureshi N. No. 4 arterial hypertension within their Systematic review of the clinical licensed indications: a systematic review No. 58 effectiveness and cost-effectiveness of and economic evaluation. Antiviral drugs for the treatment of photodynamic diagnosis and urine By Chen Y-F, Jowett S, Barton P, inluenza: a systematic review and biomarkers (FISH, ImmunoCyt, Malottki K, Hyde C, Gibbs JSR, et al. economic evaluation. NMP22) and cytology for the detection By Burch J, Paulden M, Conti S, Stock and follow-up of bladder cancer. No. 50 C, Corbett M, Welton NJ, et al. By Mowatt G, Zhu S, Kilonzo M, Cessation of attention deicit Boachie C, Fraser C, Grifiths TRL, et al. hyperactivity disorder drugs No. 59 in the young (CADDY) – a Development of a toolkit and glossary No. 5 pharmacoepidemiological and to aid in the adaptation of health Effectiveness and cost-effectiveness of qualitative study. technology assessment (HTA) reports arthroscopic lavage in the treatment By Wong ICK, Asherson P, Bilbow A, for use in different contexts. of osteoarthritis of the knee: a mixed Clifford S, Coghill D, DeSoysa R, et al. By Chase D, Rosten C, Turner S, methods study of the feasibility of Hicks N, Milne R. conducting a surgical placebo-controlled No. 51 trial (the KORAL study). ARTISTIC: a randomised trial of No. 60 By Campbell MK, Skea ZC, human papillomavirus (HPV) testing in Colour vision testing for diabetic Sutherland AG, Cuthbertson BH, primary cervical screening. retinopathy: a systematic review of Entwistle VA, McDonald AM, et al. By Kitchener HC, Almonte M, diagnostic accuracy and economic Gilham C, Dowie R, Stoykova B, Sargent evaluation. No. 6 A, et al. By Rodgers M, Hodges R, Hawkins A randomised 2 × 2 trial of community J, Hollingworth W, Duffy S, McKibbin versus hospital pulmonary rehabilitation No. 52 M, et al. for chronic obstructive pulmonary The clinical effectiveness of glucosamine disease followed by telephone or and chondroitin supplements in slowing No. 61 conventional follow-up. or arresting progression of osteoarthritis Systematic review of the effectiveness By Waterhouse JC, Walters SJ, of the knee: a systematic review and and cost-effectiveness of weight Oluboyede Y, Lawson RA. economic evaluation. management schemes for the under By Black C, Clar C, Henderson R, ives: a short report. No. 7 MacEachern C, McNamee P, Quayyum By Bond M, Wyatt K, Lloyd J, Welch The effectiveness and cost-effectiveness Z, et al. K, Taylor R. of behavioural interventions for the prevention of sexually transmitted No. 53 No. 62 infections in young people aged 13–19: Randomised preference trial of medical Are adverse effects incorporated in a systematic review and economic versus surgical termination of pregnancy economic models? An initial review of evaluation. less than 14 weeks’ gestation (TOPS). current practice. By Shepherd J, Kavanagh J, Picot J, By Robson SC, Kelly T, Howel D, By Craig D, McDaid C, Fonseca T, Cooper K, Harden A, Barnett-Page E, 100 Deverill M, Hewison J, Lie MLS, et al. Stock C, Duffy S, Woolacott N. et al. Health Technology Assessment 2010; Vol. 14: Suppl. 2

No. 8 No. 16 No. 24 Dissemination and publication of Randomised controlled trials for policy A systematic review and economic research indings: an updated review of interventions: a review of reviews and evaluation of the clinical effectiveness related biases. meta-regression. and cost-effectiveness of aldosterone By Song F, Parekh S, Hooper L, Loke By Oliver S, Bagnall AM, Thomas J, antagonists for postmyocardial YK, Ryder J, Sutton AJ, et al. Shepherd J, Sowden A, White I, et al. infarction heart failure. By McKenna C, Burch J, Suekarran S, Walker S, Bakhai A, Witte K, et al. No. 9 No. 17 Paracetamol and selective and The effectiveness and cost-effectiveness non-selective non-steroidal anti- No. 25 of biomarkers for the prioritisation inlammatory drugs (NSAIDs) for the Avoiding and identifying errors in of patients awaiting coronary reduction of morphine-related side health technology assessment models: revascularisation: a systematic review effects after major surgery: a systematic qualitative study and methodological and decision model. review. review. By Hemingway H, Henriksson By McDaid C, Maund E, Rice S, By Chilcott JB, Tappenden P, Rawdin M, Chen R, Damant J, Fitzpatrick N, Wright K, Jenkins B, Woolacott N. A, Johnson M, Kaltenthaler E, Paisley S, Abrams K, et al. et al. No. 18 No. 10 A systematic review of outcome No. 26 Comparison of case note review measures used in forensic mental health BoTULS: a multicentre randomised methods for evaluating quality and research with consensus panel opinion. controlled trial to evaluate the clinical safety in health care. By Fitzpatrick R, Chambers J, Burns effectiveness and cost-effectiveness of By Hutchinson A, Coster JE, Cooper T, Doll H, Fazel S, Jenkinson C, et al. treating upper limb spasticity due to KL, McIntosh A, Walters SJ, Bath PA, stroke with botulinum toxin type A. et al. No. 19 By Shaw L, Rodgers H, Price C, van The clinical effectiveness and cost- Wijck F, Shackley P, Steen N, et al., on behalf of the BoTULS investigators. No. 11 effectiveness of topotecan for small cell lung cancer: a systematic review and Clinical effectiveness and cost- No. 27 effectiveness of continuous economic evaluation. Weighting and valuing quality-adjusted subcutaneous insulin infusion for By Loveman E, Jones J, Hartwell D, life-years using stated preference diabetes: systematic review and Bird A, Harris P, Welch K, et al. methods: preliminary results from the economic evaluation. Social Value of a QALY Project. No. 20 By Cummins E, Royle P, Snaith A, By Baker R, Bateman I, Donaldson C, Antenatal screening for Greene A, Robertson L, McIntyre L, et al. Jones-Lee M, Lancsar E, Loomes G, et al. haemoglobinopathies in primary care: No. 12 a cohort study and cluster randomised trial to inform a simulation model. The Suppl. 1 Self-monitoring of blood glucose in type Screening for Haemoglobinopathies in Cetuximab for the irst-line treatment of 2 diabetes: systematic review. First Trimester (SHIFT) trial. metastatic colorectal cancer. By Clar C, Barnard K, Cummins E, By Dormandy E, Bryan S, Gulliford By Meads C, Round J, Tubeuf S, Royle P, Waugh N. MC, Roberts T, Ades T, Calnan M, et al. Moore D, Pennant M, Bayliss S. Inliximab for the treatment of acute No. 13 No. 21 exacerbations of ulcerative colitis. North of England and Scotland Study of Early referral strategies for By Bryan S, Andronis L, Hyde C, Tonsillectomy and Adeno-tonsillectomy management of people with markers of Connock M, Fry-Smith A, Wang D. in Children (NESSTAC): a pragmatic renal disease: a systematic review of the randomised controlled trial with a evidence of clinical effectiveness, cost- Sorafenib for the treatment of advanced parallel non-randomised preference effectiveness and economic analysis. hepatocellular carcinoma. study. By Black C, Sharma P, Scotland G, By Connock M, Round J, Bayliss S, By Lock C, Wilson J, Steen N, Eccles McCullough K, McGurn D, Robertson Tubeuf S, Greenheld W, Moore D. M, Mason H, Carrie S, et al. L, et al. Tenofovir disoproxil fumarate for the treatment of chronic hepatitis B No. 14 No. 22 A randomised controlled trial of infection. Multicentre randomised controlled trial cognitive behaviour therapy and By Jones J, Colquitt J, Shepherd J, of the clinical and cost-effectiveness of motivational interviewing for people Harris P, Cooper K. a bypass-surgery-irst versus a balloon- with Type 1 diabetes mellitus with angioplasty-irst revascularisation persistent sub-optimal glycaemic Prasugrel for the treatment of acute strategy for severe limb ischaemia due control: A Diabetes and Psychological coronary artery syndromes with to infrainguinal disease. The Bypass Therapies (ADaPT) study. percutaneous coronary intervention. versus Angioplasty in Severe Ischaemia By Greenhalgh J, Bagust A, Boland of the Leg (BASIL) trial. By Ismail K, Maissi E, Thomas S, Chalder T, Schmidt U, Bartlett J, et al. A, Saborido CM, Fleeman N, McLeod By Bradbury AW, Adam DJ, Bell J, C, et al. Forbes JF, Fowkes FGR, Gillespie I, et al. No. 23 Alitretinoin for the treatment of severe A randomised controlled equivalence chronic hand eczema. No. 15 trial to determine the effectiveness By Paulden M, Rodgers M, Grifin S, A randomised controlled multicentre and cost–utility of manual chest Slack R, Duffy S, Ingram JR, et al. trial of treatments for adolescent physiotherapy techniques in the anorexia nervosa including assessment management of exacerbations of Pemetrexed for the irst-line treatment of cost-effectiveness and patient chronic obstructive pulmonary disease of locally advanced or metastatic non- acceptability – the TOuCAN trial. (MATREX). small cell lung cancer. By Gowers SG, Clark AF, Roberts C, By Cross J, Elender F, Barton G, By Fleeman N, Bagust A, McLeod C, Byford S, Barrett B, Grifiths A, et al. Clark A, Shepstone L, Blyth A, et al. Greenhalgh J, Boland A, Dundar Y, et al. 101

Topotecan for the treatment of No. 34 No. 38 recurrent and stage IVB carcinoma of Exploring the needs, concerns and Towards single embryo transfer? the cervix. behaviours of people with existing Modelling clinical outcomes of potential By Paton F, Paulden M, Saramago P, respiratory conditions in relation to the treatment choices using multiple data Manca A, Misso K, Palmer S, et al. H1N1 ‘swine inluenza’ pandemic: a sources: predictive models and patient multicentre survey and qualitative study. perspectives. Trabectedin for the treatment of By Caress A-L, Duxbury P, Woodcock By Roberts SA, McGowan L, Hirst advanced metastatic soft tissue sarcoma. A, Luker KA, Ward D, Campbell M, et al. WM, Brison DR, Vail A, Lieberman BA. By Simpson EL, Raia R, Stevenson MD, Papaioannou D. Inluenza A/H1N1v in pregnancy: an No. 39 Sugammadex for the reversal of muscle investigation of the characteristics and Azacitidine for the treatment of relaxation in general anaesthesia: management of affected women and the myelodysplastic syndrome, chronic a systematic review and economic relationship to pregnancy outcomes for myelomonocytic leukaemia and acute assessment. mother and infant. myeloid leukaemia. By Chambers D, Paulden M, Paton F, By Yates L, Pierce M, Stephens S, Mill By Edlin R, Connock M, Tubeuf S, Heirs M, Duffy S, Craig D, et al. AC, Spark P, Kurinczuk JJ, et al. Round J, Fry-Smith A, Hyde C, et al. No. 40 The impact of communications about No. 28 Systematic review and economic swine lu (inluenza A H1N1v) on public The safety and effectiveness of modelling of the effectiveness and cost- responses to the outbreak: results from different methods of earwax removal: effectiveness of non-surgical treatments 36 national telephone surveys in the a systematic review and economic for women with stress urinary UK. incontinence. evaluation. By Rubin GJ, Potts HWW, Michie S. By Imamura M, Abrams P, Bain C, By Clegg AJ, Loveman E, Buckley B, Cardozo L, Cody J, et al. Gospodarevskaya E, Harris P, Bird A, The impact of illness and the impact Bryant J, et al. of school closure on social contact No. 41 patterns. A multicentred randomised controlled No. 29 By Eames KTD, Tilston NL, White PJ, trial of a primary care-based cognitive Systematic review of the clinical Adams E, Edmunds WJ. behavioural programme for low back effectiveness and cost-effectiveness pain. The Back Skills Training (BeST) of rapid point-of-care tests for the Vaccine effectiveness in pandemic trial. detection of genital chlamydia infection inluenza – primary care reporting By Lamb SE, Lall R, Hansen Z, in women and men. (VIPER): an observational study to Castelnuovo E, Withers EJ, Nichols V, et al. By Hislop J, Quayyum Z, Flett G, assess the effectiveness of the pandemic Boachie C, Fraser C, Mowatt G. inluenza A (H1N1)v vaccine. No. 42 By Simpson CR, Ritchie LD, No. 30 Recombinant human growth hormone Robertson C, Sheikh A, McMenamin J. School-linked sexual health services for for the treatment of growth disorders in children: a systematic review and young people (SSHYP): a survey and Physical interventions to interrupt or systematic review concerning current economic evaluation. reduce the spread of respiratory viruses: By Takeda A, Cooper K, models, effectiveness, cost-effectiveness a Cochrane review. Bird A, Baxter L, Frampton GK, and research opportunities. By Jefferson T, Del Mar C, Dooley L, Gospodarevskaya E, et al. By Owen J, Carroll C, Cooke J, Ferroni E, Al-Ansary LA, Bawazeer GA, Formby E, Hayter M, Hirst J, et al. et al. No. 43 A pragmatic randomised controlled No. 31 No. 35 trial to compare antidepressants with Systematic review and cost-effectiveness Randomised controlled trial and a community-based psychosocial evaluation of ‘pill-in-the-pocket’ strategy parallel economic evaluation of intervention for the treatment of for paroxysmal atrial ibrillation conventional ventilatory support versus women with postnatal depression: the compared to episodic in-hospital extracorporeal membrane oxygenation RESPOND trial. treatment or continuous antiarrhythmic for severe adult respiratory failure By Sharp DJ, Chew-Graham C, Tylee drug therapy. (CESAR). A, Lewis G, Howard L, Anderson I, et al. By Martin Saborido C, Hockenhull J, By Peek GJ, Elbourne D, Mugford M, No. 44 Bagust A, Boland A, Dickson R, Todd D. Tiruvoipati R, Wilson A, Allen E, et al. Group cognitive behavioural therapy for postnatal depression: a systematic No. 32 No. 36 review of clinical effectiveness, cost- Chemoprevention of colorectal cancer: Newer agents for blood glucose control effectiveness and value of information systematic review and economic in type 2 diabetes: systematic review and analyses. evaluation. economic evaluation. By Stevenson MD, Scope A, Sutcliffe By Cooper K, Squires H, Carroll C, By Waugh N, Cummins E, Royle P, PA, Booth A, Slade P, Parry G, et al. Papaioannou D, Booth A, Logan RF, et al. Clar C, Marien M, Richter B, et al. No. 45 No. 33 No. 37 Screening for hyperglycaemia in Cross-trimester repeated measures Barrett’s oesophagus and cancers of the pregnancy: a rapid update for the testing for Down’s syndrome screening: biliary tract, brain, head and neck, lung, National Screening Committee. an assessment. oesophagus and skin. By Waugh N, Royle P, Clar C, By Wright D, Bradbury I, Malone F, By Fayter D, Corbett M, Heirs M, Fox Henderson R, Cummins E, Hadden D, 102 D’Alton M, Summers A, Huang T, et al. D, Eastwood A. et al. Health Technology Assessment 2010; Vol. 14: Suppl. 2

No. 46 Virus shedding and environmental No. 49 Open-label, randomised, parallel- deposition of novel A (H1N1) pandemic Relapse prevention in UK Stop group, multicentre study to evaluate the inluenza virus: interim indings. Smoking Services: current practice, safety, tolerability and immunogenicity By Killingley B, Greatorex J, systematic reviews of effectiveness and of an AS03B/oil-in-water emulsion- Cauchemez S, Enstone JE, Curran M, cost-effectiveness analysis. adjuvanted (AS03B) split-virion versus Read R, et al. By Coleman T, Agboola S, Leonardi- non-adjuvanted wholevirion H1N1 Bee J, Taylor M, McEwen A, McNeill A. inluenza vaccine in UK children Neuraminidase inhibitors for 6 months to 12 years of age. preventing and treating inluenza in No. 50 By Waddington CS, Andrews N, healthy adults: a Cochrane review. A systematic review of positron emission Hoschler K, Walker WT, Oeser C, Reiner By Jefferson T, Jones M, Doshi P, Del tomography (PET) and positron A, et al. Mar C, Dooley L, Foxlee R. emission tomography/computed tomography (PET/CT) for the diagnosis Evaluation of droplet dispersion during No. 47 of breast cancer recurrence. non-invasive ventilation, oxygen Intensity-modulated radiotherapy By Pennant M, Takwoingi Y, Pennant therapy, nebuliser treatment and chest for the treatment of prostate cancer: L, Davenport C, Fry-Smith A, Eisinga A, physiotherapy in clinical practice: a systematic review and economic et al. implications for management of evaluation. pandemic inluenza and other airborne By Hummel S, Simpson EL, infections. Hemingway P, Stevenson MD, Rees A. By Simonds AK, Hanak A, Chatwin M, Morrell MJ, Hall A, Parker KH, et al. No. 48 Computerised decision support systems Evaluation of triage methods used to in order communication for diagnostic, select patients with suspected pandemic screening or monitoring test ordering: inluenza for hospital admission: cohort systematic reviews of the effects and study. cost-effectiveness of systems. By Goodacre S, Challen, K, Wilson R, By Main C, Moxham T, Wyatt JC, Kay Campbell M. J, Anderson R, Stein K.

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Health Technology Assessment 2010; Vol. 14: Suppl. 2

Health Technology Assessment programme

Director, Deputy Director, Professor Tom Walley, Professor Jon Nicholl, Director, NIHR HTA Director, Medical Care Research programme, Professor of Unit, University of Shefield Clinical Pharmacology, University of Liverpool

Prioritisation Strategy Group Members Chair, Dr Andrew Cook, Professor Paul Glasziou, Ms Lynn Kerridge, Professor Tom Walley, Consultant Advisor, NETSCC, Professor of Evidence-Based Chief Executive Oficer, Director, NIHR HTA HTA Medicine, University of Oxford NETSCC and NETSCC, HTA programme, Professor of Clinical Pharmacology, Dr Peter Davidson, Dr Nick Hicks, Professor Ruairidh Milne, University of Liverpool Director of NETSCC, Health Consultant Adviser, NETSCC, Director of NETSCC External Technology Assessment HTA Relations Deputy Chair, Professor Jon Nicholl, Professor Robin E Ferner, Dr Edmund Jessop, Ms Kay Pattison, Director, Medical Care Research Consultant Physician and Medical Adviser, National Senior NIHR Programme Unit, University of Shefield Director, West Midlands Centre Specialist, National Manager, Department of for Adverse Drug Reactions, Commissioning Group (NCG), Health Dr Bob Coates, City Hospital NHS Trust, Department of Health, London Consultant Advisor, NETSCC, Birmingham Ms Pamela Young, HTA Specialist Programme Manager, NETSCC, HTA

HTA Commissioning Board Members Programme Director, Professor Deborah Ashby, Professor Freddie Hamdy, Professor Ian Roberts, Professor Tom Walley, Professor of Medical Statistics, Professor of Urology, Professor of Epidemiology & Director, NIHR HTA Queen Mary, University of University of Shefield Public Health, London School programme, Professor of London of Hygiene and Tropical Clinical Pharmacology, Professor Allan House, Medicine University of Liverpool Professor John Cairns, Professor of Liaison Psychiatry, Professor of Health Economics, University of Leeds Professor Mark Sculpher, Chairs, London School of Hygiene and Professor of Health Economics, Professor Sallie Lamb, Tropical Medicine Dr Martin J Landray, University of York Director, Warwick Clinical Trials Reader in Epidemiology, Unit Professor Peter Croft, Honorary Consultant Physician, Professor Helen Smith, Director of Primary Care Clinical Trial Service Unit, Professor of Primary Care, Professor Hywel Williams, Sciences Research Centre, Keele University of Oxford University of Brighton Director, Nottingham Clinical University Trials Unit Professor Stuart Logan, Professor Kate Thomas, Professor Nicky Cullum, Director of Health & Social Professor of Complementary & Deputy Chair, Director of Centre for Evidence- Care Research, The Peninsula Alternative Medicine Research, Dr Andrew Farmer, Based Nursing, University of Medical School, Universities of University of Leeds Senior Lecturer in General York Exeter and Plymouth Practice, Department of Professor David John Primary Health Care, Professor Jenny Donovan, Dr Rafael Perera, Torgerson, University of Oxford Professor of Social Medicine, Lecturer in Medical Statisitics, Director of York Trials Unit, University of Bristol Department of Primary Health University of York Professor Ann Ashburn, Care, University of Oxford Professor of Rehabilitation Professor Steve Halligan, and Head of Research, Professor of Gastrointestinal Southampton General Hospital Radiology, University College Hospital, London

Observers Ms Kay Pattison, Dr Morven Roberts, Section Head, NHS R&D Clinical Trials Manager, Programme, Department of Medical Research Council Health 105

Diagnostic Technologies and Screening Panel Members Chair, Dr Dianne Baralle, Professor Anthony Robert Mrs Una Rennard, Professor Paul Glasziou, Consultant & Senior Lecturer Kendrick, Service User Representative Professor of Evidence-Based in Clinical Genetics, Human Professor of Primary Medicine, University of Oxford Genetics Division & Wessex Medical Care, University of Ms Jane Smith, Clinical Genetics Service, Southampton Consultant Ultrasound Deputy Chair, Southampton, University of Practitioner, Ultrasound Dr David Elliman, Southampton Dr Susanne M Ludgate, Department, Leeds Teaching Consultant Paediatrician and Director, Medical Devices Hospital NHS Trust, Leeds Honorary Senior Lecturer, Dr Stephanie Dancer, Agency, London Great Ormond Street Hospital, Consultant Microbiologist, Dr W Stuart A Smellie, London Hairmyres Hospital, East Dr Anne Mackie, Consultant, Bishop Auckland Kilbride Director of Programmes, UK General Hospital Professor Judith E Adams, National Screening Committee Consultant Radiologist, Dr Ron Gray, Professor Lindsay Wilson Manchester Royal Inirmary, Consultant, National Perinatal Dr David Mathew Turnbull, Central Manchester & Epidemiology Unit, Institute of Service User Representative Scientiic Director of the Centre for Magnetic Resonance Manchester Children’s Health Sciences, University of Dr Michael Millar, Lead University Hospitals NHS Oxford Investigations and YCR Consultant in Microbiology, Professor of Radiology, Hull Trust, and Professor of Department of Pathology & Diagnostic Radiology, Imaging Professor Paul D Grifiths, Royal Inirmary Professor of Radiology, Microbiology, Barts and The Science and Biomedical London NHS Trust, Royal Dr Alan J Williams, Engineering, Cancer & Academic Unit of Radiology, University of Shefield London Hospital Consultant in General Imaging Sciences, University of Medicine, Department of Manchester Mr Martin Hooper, Mr Stephen Pilling, Thoracic Medicine, The Royal Service User Representative Director, Centre for Outcomes, Bournemouth Hospital Mr A S Arunkalaivanan, Research & Effectiveness, Honorary Senior Lecturer, University College London University of Birmingham and Consultant Urogynaecologist and Obstetrician, City Hospital

Observers Dr Tim Elliott, Dr Catherine Moody, Dr Ursula Wells, Team Leader, Cancer Programme Manager, Principal Research Oficer, Screening, Department of Neuroscience and Mental Department of Health Health Health Board

Disease Prevention Panel Members Chair, Dr Elizabeth Fellow-Smith, Dr Chris McCall, Professor Ian Roberts, Dr Edmund Jessop, Medical Director, West London General Practitioner, The Professor of Epidemiology and Medical Adviser, National Mental Health Trust, Middlesex Hadleigh Practice, Corfe Public Health, London School Specialist Commissioning Mullen, Dorset of Hygiene & Tropical Medicine Advisory Group (NSCAG), Dr Colin Greaves Department of Health Senior Research Fellow, Miss Nicky Mullany, Professor Carol Tannahill, Peninsular Medical School Service User Representative Glasgow Centre for Population Deputy Chair, (Primary Care) Health Professor Margaret Dr Julie Mytton, Thorogood, Dr John Jackson, Locum Consultant in Public Mrs Jean Thurston, Professor of Epidemiology, General Practitioner, Parkway Health Medicine, Bristol Service User Representative University of Warwick Medical Medical Centre, Newcastle Primary Care Trust upon Tyne Professor David Weller, School, Coventry Professor Irwin Nazareth, Head, School of Clinical Dr Robert Cook Dr Russell Jago, Professor of Primary Care Science and Community Clinical Programmes Director, Senior Lecturer in Exercise, and Director, Department of Health, University of Bazian Ltd, London Nutrition and Health, Centre Primary Care and Population Edinburgh for Sport, Exercise and Health, Sciences, University College University of Bristol London

Observers Ms Christine McGuire, Ms Kay Pattison Dr Caroline Stone, Research & Development, Senior NIHR Programme Programme Manager, Medical Department of Health Manager, Department of Research Council Health

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Current and past membership details of all HTA programme ‘committees’ are available from the HTA website (www.hta.ac.uk) Health Technology Assessment 2010; Vol. 14: Suppl. 2

External Devices and Physical Therapies Panel Members

Chair, Dr Dawn Carnes, Dr Peter Martin, Dr Pippa Tyrrell, Dr John Pounsford, Senior Research Fellow, Barts Consultant Neurologist, Stroke Medicine, Senior Consultant Physician North and the London School of Addenbrooke’s Hospital, Lecturer/Consultant Stroke Bristol NHS Trust, Bristol Medicine and Dentistry, Cambridge Physician, Salford Royal London Foundation Hospitals’ Trust, Deputy Chair, Dr Lorraine Pinnigton, Salford Professor E Andrea Nelson, Dr Emma Clark, Associate Professor in Reader in Wound Healing and Clinician Scientist Fellow Rehabilitation, University of Dr Sarah Tyson, Director of Research, University & Cons. Rheumatologist, Nottingham, Nottingham Senior Research Fellow & of Leeds, Leeds University of Bristol, Bristol Associate Head of School, Dr Kate Radford, University of Salford, Salford Professor Bipin Bhakta Mrs Anthea De Barton-Watson, Division of Rehabilitation and Charterhouse Professor in Service User Representative Ageing, School of Community Dr Nefyn Williams, Rehabilitation Medicine, Health Sciences. University of Clinical Senior Lecturer, Cardiff University of Leeds, Leeds Professor Christopher Grifiths, Nottingham, Nottingham University, Cardiff Professor of Primary Care, Mrs Penny Calder Barts and the London School Mr Jim Reece, Service User Representative of Medicine and Dentistry, Service User Representative London Professor Paul Carding, Professor Maria Stokes, Professor of Voice Pathology, Dr Shaheen Hamdy, Professor of Newcastle Hospital NHS Trust, Clinical Senior Lecturer Neuromusculoskeletal Newcastle and Consultant Physician, Rehabilitation, University of University of Manchester, Southampton, Southampton Manchester

Observers Dr Phillip Leech, Ms Kay Pattison Dr Morven Roberts, Dr Ursula Wells Principal Medical Oficer for Senior NIHR Programme Clinical Trials Manager, MRC, PRP, DH, London Primary Care, Department of Manager, Department of London Health , London Health

Interventional Procedures Panel Members Chair, Mr Seamus Eckford, Dr Nadim Malik, Dr Ashish Paul, Professor Jonathan Michaels, Consultant in Obstetrics & Consultant Cardiologist/ Medical Director, Bedfordshire Consultant Surgeon & Gynaecology, North Devon Honorary Lecturer, University PCT Honorary Clinical Lecturer, District Hospital of Manchester University of Shefield Dr Sarah Purdy, Professor David Taggart, Mr Hisham Mehanna, Consultant Senior Lecturer, Mr David P Britt, Consultant Cardiothoracic Consultant & Honorary University of Bristol Service User Representative, Surgeon, John Radcliffe Associate Professor, University Cheshire Hospital Hospitals Coventry & Mr Michael Thomas, Warwickshire NHS Trust Consultant Colorectal Surgeon, Mr Sankaran Dr Matthew Hatton, Bristol Royal Inirmary ChandraSekharan, Consultant in Clinical Dr Jane Montgomery, Consultant Surgeon, Colchester Oncology, Shefield Teaching Consultant in Anaesthetics and Professor Yit Chiun Yang, Hospital University NHS Hospital Foundation Trust Critical Care, South Devon Consultant Ophthalmologist, Foundation Trust Healthcare NHS Foundation Royal Wolverhampton Hospitals Dr John Holden, Trust NHS Trust Professor Nicholas Clarke, General Practitioner, Garswood Consultant Orthopaedic Surgery, Wigan Dr Simon Padley, Mrs Isabel Boyer, Surgeon, Southampton Consultant Radiologist, Chelsea Service User Representative, University Hospitals NHS Trust & Westminster Hospital London

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Pharmaceuticals Panel Members Chair, Dr Peter Elton, Dr Dyfrig Hughes, Dr Martin Shelly, Professor Imti Choonara, Director of Public Health, Reader in Pharmacoeconomics General Practitioner, Leeds, Professor in Child Health, Bury Primary Care Trust and Deputy Director, Centre and Associate Director, NHS University of Nottingham for Economics and Policy in Clinical Governance Support Professor Robin Ferner, Health, IMSCaR, Bangor Team, Leicester Deputy Chair, Consultant Physician and University Dr Lesley Wise, Director, West Midlands Centre Dr Gillian Shepherd, Unit Manager, for Adverse Drug Reactions, Dr Yoon K Loke, Director, Health and Clinical Pharmacoepidemiology City Hospital NHS Trust, Senior Lecturer in Clinical Excellence, Merck Serono Ltd Research Unit, VRMM, Birmingham Pharmacology, University of Medicines & Healthcare East Anglia Mrs Katrina Simister, Products Regulatory Agency Dr Ben Goldacre, Assistant Director New Research Fellow, Division of Professor Femi Oyebode, Medicines, National Prescribing Mrs Nicola Carey, Psychological Medicine and Consultant Psychiatrist Centre, Liverpool Senior Research Fellow, Psychiatry, King’s College and Head of Department, School of Health and Social London University of Birmingham Mr David Symes, Care, The University of Service User Representative Reading Dr Bill Gutteridge, Dr Andrew Prentice, Medical Adviser, London Senior Lecturer and Consultant Mr John Chapman, Strategic Health Authority Obstetrician and Gynaecologist, Service User Representative The Rosie Hospital, University of Cambridge

Observers Ms Kay Pattison Mr Simon Reeve, Dr Heike Weber, Dr Ursula Wells, Senior NIHR Programme Head of Clinical and Cost- Programme Manager, Principal Research Oficer, Manager, Department of Effectiveness, Medicines, Medical Research Council Department of Health Health Pharmacy and Industry Group, Department of Health

Psychological and Community Therapies Panel Members Chair, Dr Steve Cunningham, Ms Mary Nettle, Dr Howard Ring, Professor Scott Weich, Consultant Respiratory Mental Health User Consultant, Consultant & University Professor of Psychiatry, Paediatrician, Lothian Health Gloucestershire Lecturer in Psychiatry, University of Warwick Board University of Cambridge Professor John Potter, Professor Jane Barlow, Dr Anne Hesketh, Professor of Ageing and Stroke Dr Karen Roberts, Professor of Public Health in Senior Clinical Lecturer in Medicine, University of East Nurse/Consultant, Dunston Hill the Early Years, Health Sciences Speech and Language Therapy, Anglia Hospital, Tyne and Wear Research Institute, Warwick University of Manchester Medical School Dr Greta Rait, Dr Karim Saad, Dr Yann Lefeuvre, Senior Clinical Lecturer and Consultant in Old Age Dr Sabyasachi Bhaumik, GP Partner, Burrage Road General Practitioner, University Psychiatry, Coventry & Consultant Psychiatrist, Surgery, London College London Warwickshire Partnership Trust Leicestershire Partnership NHS Trust Dr Jeremy J Murphy, Dr Paul Ramchandani, Dr Alastair Sutcliffe, Consultant Physician & Senior Research Fellow/Cons. Senior Lecturer, University Mrs Val Carlill, Cardiologist, County Durham & Child Psychiatrist, University of College London Service User Representative, Darlington Foundation Trust Oxford Gloucestershire Dr Simon Wright, Mr John Needham, GP Partner, Walkden Medical Service User, Buckingmashire Centre, Manchester

Observers Ms Kay Pattison Dr Morven Roberts, Professor Tom Walley, Dr Ursula Wells, Senior NIHR Programme Clinical Trials Manager, MRC, HTA Programme Director, Policy Research Programme, Manager, Department of London Liverpool DH, London Health

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Current and past membership details of all HTA programme ‘committees’ are available from the HTA website (www.hta.ac.uk) Health Technology Assessment 2010; Vol. 14: Suppl. 2

Expert Advisory Network Members Professor Douglas Altman, Mr Jonothan Earnshaw, Professor Allen Hutchinson, Professor Miranda Mugford, Professor of Statistics in Consultant Vascular Surgeon, Director of Public Health and Professor of Health Economics Medicine, Centre for Statistics Gloucestershire Royal Hospital, Deputy Dean of ScHARR, and Group Co-ordinator, in Medicine, University of Gloucester University of Shefield University of East Anglia Oxford Professor Martin Eccles, Professor Peter Jones, Professor Jim Neilson, Professor John Bond, Professor of Clinical Professor of Psychiatry, Head of School of Reproductive Professor of Social Gerontology Effectiveness, Centre for Health University of Cambridge, & Developmental Medicine & Health Services Research, Services Research, University of Cambridge and Professor of Obstetrics University of Newcastle upon Newcastle upon Tyne and Gynaecology, University of Tyne Professor Stan Kaye, Liverpool Professor Pam Enderby, Cancer Research UK Professor Professor Andrew Bradbury, Dean of Faculty of Medicine, of Medical Oncology, Royal Mrs Julietta Patnick, Professor of Vascular Surgery, Institute of General Practice Marsden Hospital and Institute National Co-ordinator, NHS Solihull Hospital, Birmingham and Primary Care, University of of Cancer Research, Surrey Cancer Screening Programmes, Shefield Shefield Mr Shaun Brogan, Dr Duncan Keeley, Chief Executive, Ridgeway Professor Gene Feder, General Practitioner (Dr Burch Professor Robert Peveler, Primary Care Group, Aylesbury Professor of Primary Care & Ptnrs), The Health Centre, Professor of Liaison Psychiatry, Research & Development, Thame Royal South Hants Hospital, Mrs Stella Burnside OBE, Centre for Health Sciences, Southampton Chief Executive, Regulation Barts and The London School Dr Donna Lamping, and Improvement Authority, of Medicine and Dentistry Research Degrees Programme Professor Chris Price, Belfast Director and Reader in Director of Clinical Research, Mr Leonard R Fenwick, Psychology, Health Services Bayer Diagnostics Europe, Ms Tracy Bury, Chief Executive, Freeman Research Unit, London School Stoke Poges Project Manager, World Hospital, Newcastle upon Tyne of Hygiene and Tropical Confederation for Physical Medicine, London Professor William Rosenberg, Therapy, London Mrs Gillian Fletcher, Professor of Hepatology Antenatal Teacher and Tutor Mr George Levvy, and Consultant Physician, Professor Iain T Cameron, and President, National Chief Executive, Motor University of Southampton Professor of Obstetrics and Childbirth Trust, Henield Neurone Disease Association, Gynaecology and Head of the Northampton Professor Peter Sandercock, School of Medicine, University Professor Jayne Franklyn, Professor of Medical Neurology, of Southampton Professor of Medicine, Professor James Lindesay, Department of Clinical University of Birmingham Professor of Psychiatry for the Neurosciences, University of Dr Christine Clark, Elderly, University of Leicester Edinburgh Medical Writer and Consultant Mr Tam Fry, Pharmacist, Rossendale Honorary Chairman, Child Professor Julian Little, Dr Susan Schonield, Growth Foundation, London Professor of Human Genome Consultant in Public Health, Professor Collette Clifford, Epidemiology, University of Hillingdon Primary Care Trust, Professor of Nursing and Professor Fiona Gilbert, Ottawa Middlesex Head of Research, The Consultant Radiologist and Medical School, University of NCRN Member, University of Professor Alistaire McGuire, Dr Eamonn Sheridan, Birmingham Aberdeen Professor of Health Economics, Consultant in Clinical Genetics, London School of Economics St James’s University Hospital, Professor Barry Cookson, Professor Paul Gregg, Leeds Director, Laboratory of Hospital Professor of Orthopaedic Professor Rajan Madhok, Infection, Public Health Surgical Science, South Tees Medical Director and Director Dr Margaret Somerville, Laboratory Service, London Hospital NHS Trust of Public Health, Directorate Director of Public Health of Clinical Strategy & Public Learning, Peninsula Medical Dr Carl Counsell, Bec Hanley, Health, North & East Yorkshire School, University of Plymouth Clinical Senior Lecturer in Co-director, TwoCan Associates, & Northern Lincolnshire Neurology, University of West Sussex Health Authority, York Professor Sarah Stewart-Brown, Aberdeen Professor of Public Health, Dr Maryann L Hardy, Professor Alexander Markham, Division of Health in the Professor Howard Cuckle, Senior Lecturer, University of Director, Molecular Medicine Community, University of Professor of Reproductive Bradford Unit, St James’s University Warwick, Coventry Epidemiology, Department Hospital, Leeds of Paediatrics, Obstetrics & Mrs Sharon Hart, Professor Ala Szczepura, Gynaecology, University of Healthcare Management Dr Peter Moore, Professor of Health Service Leeds Consultant, Reading Freelance Science Writer, Research, Centre for Health Services Studies, University of Professor Robert E Hawkins, Ashtead Dr Katherine Darton, Warwick, Coventry Information Unit, MIND – The CRC Professor and Director Dr Andrew Mortimore, Mental Health Charity, London of Medical Oncology, Christie Public Health Director, Mrs Joan Webster, CRC Research Centre, Southampton City Primary Consumer Member, Southern Professor Carol Dezateux, Christie Hospital NHS Trust, Care Trust Derbyshire Community Health Professor of Paediatric Manchester Council Epidemiology, Institute of Child Dr Sue Moss, Health, London Professor Richard Hobbs, Associate Director, Cancer Professor Martin Whittle, Head of Department of Primary Screening Evaluation Unit, Clinical Co-director, National Mr John Dunning, Care & General Practice, Institute of Cancer Research, Co-ordinating Centre for Consultant Cardiothoracic University of Birmingham Sutton Women’s and Children’s Surgeon, Papworth Hospital Health, Lymington NHS Trust, Cambridge Professor Alan Horwich, Dean and Section Chairman, The Institute of Cancer Research, London

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