A Supplement to Health Technology Assessment Journal

Health Technology Assessment 2009; Vol. 13: Suppl. 3

Single Technology Appraisals A supplement to Health Technology Assessment Journal

In this issue Lapatinib for HER2-overexpressing breast cancer Infliximab for ulcerative colitis Rimonabant for overweight and obese people Telbivudine for chronic hepatitis B infection SUPPLEMENT Entecavir for chronic hepatitis B infection Febuxostat for hyperuricaemia in people with gout Rivaroxaban for the prevention of venous thromboembolism Cetuximab for recurrent and/or metastatic squamous cell carcinoma of the head and neck Ustekinumab for moderate to severe psoriasis

October 2009

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 13: Supplement 3, October 2009

iii Supplement introduction Health Technology Assessment 2009; Vol. 13: Suppl. 3 1 Lapatinib for the treatment of HER2-overexpressing breast cancer Supplement introduction J Jones, A Takeda, J Picot, C von Keyserlingk and A Clegg

Lapatinib for the treatment of HER2- 7 Infliximab for the treatment of ulcerative colitis overexpressing breast cancer C Hyde, S Bryan, A Juarez-Garcia, L Andronis and A Fry-Smith Infliximab for the treatment of ulcerative colitis 13 Rimonabant for the treatment of overweight and obese people Rimonabant for the treatment of J Burch, C McKenna, S Palmer, G Norman, J Glanville, M Sculpher and N Woolacott overweight and obese people 23 Telbivudine for the treatment of chronic hepatitis B infection Telbivudine for the treatment of chronic D Hartwell, J Jones, P Harris and K Cooper hepatitis B infection 31 Entecavir for the treatment of chronic hepatitis B infection Entecavir for the treatment of chronic J Shepherd, E Gospodarevskaya, G Frampton and K Cooper hepatitis B infection 37 Febuxostat for the treatment of hyperuricaemia in people Febuxostat for the treatment of hyperuricaemia in with gout: a single technology appraisal people with gout: a single technology appraisal M Stevenson and A Pandor Rivaroxaban for the prevention of venous 43 Rivaroxaban for the prevention of venous thromboembolism: a single technology appraisal thromboembolism: a single technology appraisal Cetuximab for the treatment of recurrent M Stevenson, A Scope, M Holmes, A Rees and E Kaltenthaler and/or metastatic squamous cell carcinoma of the head and neck 49 Cetuximab for the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck Mifamurtide for the treatment of osteosarcoma: J Greenhalgh, A Bagust, A Boland, N Fleeman, C McLeod, Y Dundar, C Proudlove a single technology appraisal and R Shaw

Ustekinumab for the treatment of 61 Ustekinumab for the treatment of moderate to severe psoriasis moderate to severe psoriasis E Gospodarevskaya, J Picot, K Cooper, E Loveman and A Takeda

Health Technology Assessment reports published to date

Health Technology Assessment programme 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 defined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care. The research findings from the HTA programme directly influence decision-making bodies such as the National Institute for Health and Clinical Excellence (NICE) and the National Screening Committee (NSC). HTA findings 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 fills 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 scientific 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 specific 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 sufficiently high scientific 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 Aileen Clarke, Professor Chris Hyde, Dr John Powell, Dr Rob Riemsma and Professor Ken Stein

ISSN 1366-5278 © 2009 Queen’s Printer and Controller of HMSO This monograph 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 2009; Vol. 13: Suppl. 3

Supplement introduction

elcome to the third Supplement to the Health approach, manufacturers of technologies, which WTechnology Assessment journal series. The series are, in general, pharmaceuticals close to the time is now over 10 years old and has published more of launch, submit a dossier of evidence aiming to than 400 titles, covering a wide range of health demonstrate effectiveness and cost-effectiveness. technologies in a diverse set of applications. In The independent academic input to NICE’s general, the series publishes each technology process, which continues to be supported by the assessment as a separate issue within each annual TAR centres around the UK under contract to the volume. HTA programme, is to scrutinise, critique and explore this dossier of evidence. The Supplements depart from that format by containing a series of shorter articles. These are all The papers included in this Supplement report products from a ‘call-off contract’, which the HTA on this HTA programme funded work, and we programme holds with a range of academic centres hope that the summaries of the work carried out around the UK, at the universities of Aberdeen, to inform the development of NICE guidance for Birmingham, Exeter, Liverpool, Sheffield, these technologies will be of interest and value to Southampton and York. These centres are retained readers. to provide a highly responsive resource, which meets the needs of national policy makers, notably Further details of each of the NICE Appraisals are the National Institute for Health and Clinical available on the NICE website (www. nice.org.uk) Excellence (NICE). and we welcome comments on the summaries via the HTA website (www.hta.ac.uk/correspond). Until recently, these HTA Technology Assessment Review (TAR) centres provided academic input to Prof. Tom Walley policy making through independent analyses of Director, NIHR HTA programme the impact and value of health technologies. As Editor-In-Chief, Health Technology Assessment many readers will be aware, the perception that the advice NICE provides to the NHS could be made more timely has led to the development of Prof. Ken Stein the ‘Single Technology Appraisal’ process. In this Chair, Editorial Board, Health Technology Assessment

iii

DOI: 10.3310/hta13suppl3/01 Health Technology Assessment 2009; Vol. 13: Suppl. 3

Lapatinib for the treatment of HER2- overexpressing breast cancer

J Jones, A Takeda,* J Picot, C von Keyserlingk and A Clegg Southampton Health Technology Assessments Centre, Wessex Institute for Health Research and Development, University of Southampton, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 07/10/01

This paper presents a summary of the evidence Date of ERG submission: review group (ERG) report into the clinical June 2007 effectiveness and cost-effectiveness of lapatinib for TAR Centre(s): the treatment of advanced or metastatic HER2- Southampton Health Technology Assessments Centre overexpressing breast cancer based upon a review List of authors: of the manufacturer’s submission to the National J Jones, A Takeda, J Picot, C von Keyserlingk and A Clegg Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) Contact details: process. The scope included women with advanced, Andrea Takeda, Southampton Health Technology metastatic or recurrent HER2-overexpressing Assessments Centre, Wessex Institute for Health Research and Development, University of Southampton, breast cancer who have had previous therapy that Mailpoint 728, Boldrewood, Southampton SO16 7PX, includes trastuzumab. Outcomes were time to UK progression, progression-free survival, response rates, overall survival, health-related quality E-mail: [email protected] of life and adverse effects. The submission’s The research reported in this article of the journal evidence came from one randomised controlled supplement was commissioned and funded by the trial (RCT) of reasonable methodological HTA programme on behalf of NICE as project number quality, although it was not powered to detect a 07/10/01. The assessment report began editorial review statistically significant difference in mean overall in May 2008 and was accepted for publication in May survival. Median time to progression was longer 2009. See the HTA programme web site for further in the lapatinib plus capecitabine arm than in project information (www.hta.ac.uk). This summary the capecitabine monotherapy arm {27.1 [95% of the ERG report was compiled after the Appraisal Committee’s review. confidence interval (CI) 17.4 to 49.4] versus 18.6 [95% CI 9.1 to 36.9] weeks; hazard ratio 0.57 [95% The views and opinions expressed therein are those of CI 0.43 to 0.77; p = 0.00013]}. Median overall the authors and do not necessarily reflect those of the survival was very similar between the groups [67.7 Department of Health. (95% CI 58.9 to 91.6) versus 66.6 (95% CI 49.1 Discussion of ERG reports is invited. Visit the HTA to 75.0) weeks; hazard ratio 0.78 (95% CI 0.55 website correspondence forum (www.hta.ac.uk/ to 1.12; p = 0.177)]. Median progression-free correspond). survival was statistically significantly longer in the lapatinib plus capecitabine group than in the capecitabine monotherapy group [27.1 (95% CI 24.1 to 36.9) versus 17.6 (95% CI 13.3 to 20.1) weeks; hazard ratio 0.55 (95% CI 0.41 to 0.74); p = 0.000033]. The manufacturer’s economic model to estimate progression-free and overall 1

survival for patients with HER2-positive advanced/ Description of the metastatic breast cancer who had relapsed underlying health problem following treatment with an anthracycline, a taxane and trastuzumab was appropriate for the disease Breast cancer is the most common cancer in the area. The base-case incremental cost-effectiveness UK, accounting for one-third of all cancers in ratios (ICERs) for lapatinib plus capecitabine women.2 Increasing age is the strongest risk factor compared with capecitabine monotherapy or for breast cancer, and the disease is rare in women vinorelbine monotherapy were higher than would under the age of 40. conventionally be considered cost-effective. When compared with trastuzumab-containing In 2004 there were 36,939 new cases of breast regimes, lapatinib plus capecitabine dominated. cancer in women in England, which represents a In sensitivity analyses the ICER for lapatinib crude rate of 144.6 per 100,000 women.3 In 2005 plus capecitabine compared with capecitabine there were 2364 new registrations in Wales, giving monotherapy or vinorelbine monotherapy was a rate of 155.4 per 100,000 women. These figures robust to variation in assumptions. In all sensitivity equate to age-standardised rates per 100,000 analyses the ICERs remained higher than would population of 120.7 [95% confidence interval conventionally be considered cost-effective. (CI) 119.5 to 121.9] for England and 120.8 (95% ICERs for trastuzumab-containing regimes were CI 115.9 to 125.7) for Wales.4 A recent review by particularly sensitive to assumptions over the the Office for National Statistics5 found a 20-year frequency of treatment, which had a large effect on survival rate of 64% for women diagnosed with the cost-effectiveness of lapatinib plus capecitabine. breast cancer between the ages of 50 and 69 years. In conclusion, there was a general lack of evidence on the effectiveness of comparators included in Breast cancer is classified on a clinical basis the model and on key parameters such as dose according to the internationally recognised adjustments and the model outputs need to be tumour, node, metastases (TNM) staging system.6 interpreted in the light of this uncertainty. At the The TNM system is based on three sets of codes time of writing, NICE were still considering the relating to the primary tumour, involvement of available evidence for this appraisal. lymph nodes and evidence of distant metastases. Four clinical stages are defined by particular Introduction combinations of these codes. Stage IV is metastatic disease, regardless of lymph node assessment or The National Institute for Health and Clinical size of primary tumour. Approximately 25–30% of Excellence (NICE) is an independent organisation people with metastatic breast cancer have HER2- within the NHS that is responsible for providing positive disease, that is, their tumours overexpress national guidance on the treatment and care of the HER2 gene.7 people using the NHS in England and Wales. One of the responsibilities of NICE is to provide guidance to the NHS on the use of selected new Scope of the ERG report and established health technologies, based on an appraisal of those technologies. The ERG critically evaluated the evidence submission from GlaxoSmithKline UK for the NICE’s single technology appraisal (STA) process use of lapatinib for the treatment of advanced is specifically designed for the appraisal of a single or metastatic ErbB2 (HER2: human epidermal product, device or other technology, with a single growth factor receptor 2)-overexpressing breast indication, for which most of the relevant evidence cancer, in accordance with the predicted licensed lies with one manufacturer or sponsor.1 Typically, indication. Lapatinib is a dual kinase inhibitor it is used for new pharmaceutical products close of epidermal growth factor receptor (ErbB1) and to launch. The principal evidence for an STA is HER2 (ErbB2). It works intracellularly and, unlike derived from a submission by the manufacturer/ monoclonal antibodies, it can block signalling sponsor of the technology. In addition, a report through receptors that have lost or mutated their reviewing the evidence submission is submitted extracellular domains. Lapatinib is administered by the evidence review group (ERG), an external orally, in conjunction with capecitabine. organisation independent of NICE. This paper presents a summary of the ERG report for the STA At the time of writing, lapatinib had not yet of the clinical effectiveness and cost-effectiveness received its marketing authorisation. The final of lapatinib for the treatment of metastatic breast scope issued by NICE stated that the population 2 cancer. should be women with advanced, metastatic or Health Technology Assessment 2009; Vol. 13: Suppl. 3

recurrent breast cancer that overexpresses the Median overall survival was very similar between HER2 receptor who have had previous therapy that the two groups [67.7 weeks (95% CI 58.9 to includes trastuzumab. The outcomes stated in the 91.6) versus 66.6 weeks (95% CI 49.1 to 75.0) for manufacturer’s definition of the decision problem lapatinib plus capecitabine versus capecitabine were time to progression (primary end point), monotherapy respectively)]. The hazard ratio was progression-free survival, response rates, overall 0.78 (95% CI 0.55 to 1.12; p = 0.177). survival, health-related quality of life and adverse effects. Median progression-free survival was statistically significantly longer in the lapatinib plus capecitabine group than in the capecitabine Methods monotherapy group [27.1 weeks (95% CI 24.1 to 36.9) versus 17.6 weeks (95% CI 13.3 to The ERG report comprised a critical review of the 20.1); hazard ratio 0.55 (95% CI 0.41 to 0.74); evidence for the clinical effectiveness and cost- p = 0.000033]. effectiveness of the technology based upon the manufacturer’s/sponsor’s submission to NICE as Summary of submitted cost- part of the STA process. effectiveness evidence

The ERG checked the literature searches and The cost-effectiveness analysis used survival applied the NICE critical appraisal checklist to modelling methodology to estimate progression- the included studies and checked the quality of free and overall survival for patients with HER2- the manufacturer’s submission with the Centre positive advanced/metastatic breast cancer who had for Reviews and Dissemination (CRD) quality relapsed following treatment with an anthracycline, assessment criteria for a systematic review. a taxane and trastuzumab. The incremental costs In addition, the ERG checked and provided and consequences of treatment with lapatinib plus commentary on the manufacturer’s model using capecitabine were estimated relative to each of standard checklists. A one-way sensitivity analysis, five different comparator regimes. Comparators scenario analysis and a probabilistic sensitivity were capecitabine monotherapy, vinorelbine analysis (PSA) were undertaken by the ERG. monotherapy, trastuzumab monotherapy, The cost-effectiveness acceptability curves for trastuzumab plus capecitabine and trastuzumab capecitabine monotherapy and lapatinib plus plus vinorelbine. capecitabine from the ERG’s PSA are shown in Figure 1. The model was generally internally consistent and appropriate to metastatic breast cancer in terms of structural assumptions, although it used a different Results approach from previous economic evaluations of 9–13 Summary of submitted treatments for metastatic breast cancer. The clinical evidence cost-effectiveness analysis generally conformed to the NICE reference case and the scope/decision The main evidence in the submission came problem. from one multicentre, multinational, open-label randomised controlled trial (RCT), EGF100151. Treatment effects for lapatinib plus capecitabine Interim analyses from the trial were published in and capecitabine monotherapy were derived from 2006, but the evidence in the report was from a direct clinical trial evidence. In the absence of data later time point. These later data were expected on the effectiveness of vinorelbine monotherapy, it to be published in June 2007,8 but had not been was assumed to be identical to that of capecitabine published when the ERG report and this summary monotherapy. The effectiveness of trastuzumab- were written. containing regimes was based on pooling of data on time to disease progression, which was used in Median time to progression was longer in the an unadjusted indirect comparison. lapatinib plus capecitabine arm than in the capecitabine monotherapy arm [27.1 weeks (95% Utilities for preprogression survival were based CI 17.4 to 49.4) versus 18.6 weeks (95% CI 9.1 to on responses to the EuroQol 5 dimensions (EQ- 36.9)], although the CIs overlapped. The hazard 5D) questionnaire in the EGF100151 trial. There ratio reported in the manufacturer’s submission were substantial missing data for the quality of was 0.57 (95% CI 0.43 to 0.77; p = 0.00013). life assessment in the trial. The utility reduction 3

100 Lapatinib plus 90 capecitabine

80 Capecitabine 70

Probability that strategy is preferred (%) Probability 10

0 0 10 20 30 40 50 60 70 80 90 100 Cost per QALY (£000s)

FIGURE 1 Cost-effectiveness acceptability curves for capecitabine monotherapy and lapatinib plus capecitabine from the ERG’s probabilistic sensitivity analysis. QALY, quality-adjusted life-year.

following disease progression was based on Commentary on a published study,14 which reported general the robustness of population valuations of disease progression and submitted evidence the impact of treatment-related adverse events. Strengths The base-case incremental cost-effectiveness The manufacturer’s submission was well written ratios (ICERs) for lapatinib plus capecitabine and presented a clear description of the evidence compared with capecitabine monotherapy or base. The manufacturer conducted a systematic vinorelbine monotherapy were higher than would review for this appraisal and searched all relevant conventionally be considered cost-effective. When databases using appropriate search strategies. compared with trastuzumab-containing regimes, lapatinib plus capecitabine dominated (i.e. gave The identified RCT EGF100151 appeared to be improved outcome at lower cost). of reasonable methodological quality, although enrolment was terminated before the required Sensitivity analyses reported in the manufacturer’s sample size had been met. submission and undertaken by the ERG showed that the ICER for lapatinib plus capecitabine The economic model presented with the compared with capecitabine monotherapy or manufacturer’s submission used an appropriate vinorelbine monotherapy was robust to variation in approach for the disease area and given the assumptions. In all sensitivity analyses the ICERs available data. remained higher than would conventionally be considered cost-effective. ICERs for trastuzumab- Weaknesses containing regimes were highly sensitive to assumptions over the frequency of treatment There was some deviation from the scope issued (weekly or three-weekly), the distribution of by NICE in terms of the timing of previous lines of weight and body surface area of patients receiving therapy, and of comparator treatments. treatment, and wastage for infusional regimes.

Title: STA 07/10/01 Proof Stage: 1 Figure Number: 01.ai

4 Cactus Design and Illustration Ltd Health Technology Assessment 2009; Vol. 13: Suppl. 3

Only one relevant RCT was identified by the Key issues manufacturer’s systematic review and the The included trial was not powered to detect evidence base for lapatinib plus capecitabine in a statistically significant difference in overall the manufacturer’s submission was largely based survival between lapatinib plus capecitabine and on this one trial. Early termination of enrolment capecitabine monotherapy. meant that there was insufficient power to detect a statistically significant difference in mean overall There was a general lack of evidence on the survival. effectiveness of comparators included in the economic model. A lack of evidence on other key The trastuzumab studies pooled for an indirect parameters (such as dose adjustments) meant that comparison contained a variety of treatment there was a great deal of uncertainty and model regimens. None of the studies contained a outputs need to be interpreted in the light of that capecitabine monotherapy arm and so it was uncertainty. not possible for the manufacturer to perform an adjusted indirect comparison.15 The manufacturer therefore used a methodologically weaker Summary of NICE guidance unadjusted indirect comparison. The resulting issued as a result of the STA pooled mean of median time to progression values for trastuzumab may not be a reliable estimate and At the time of writing, NICE were still considering should therefore be treated with caution. the available evidence for this appraisal.

There was no evidence in the manufacturer’s submission of a systematic search for model Key references parameters, in particular cost inputs and utilities. 1. National Institute for Health and Clinical Excellence. Guide to the single technology (STA) process. 19 September 2006. URL: www.nice.org.uk/page. Conclusions aspx?o=STAprocessguide. Areas of uncertainty 2. Office for National Statistics. Breast cancer: incidence Trastuzumab monotherapy was included as a rises while deaths continue to fall. 2005. URL: www. comparator. Consultation with clinical advisors statistics.gov.uk/cci/nugget_print.asp?ID=575. Cited 1 December 2005. suggested that trastuzumab is used beyond progression in combination with chemotherapy 3. Office for National Statistics. Cancer statistics agents in some primary care trusts, but not others. registrations: registrations of cancer diagnosed in 2004, Clinical advisors indicated that trastuzumab England. Series MB1 No. 35. 2007. URL: www. monotherapy is unlikely to be continued beyond statistics.gov.uk/statbase/Product.asp?vlnk=8843. disease progression. Cited 29 August 2007.

The manufacturer’s submission included a post hoc 4. Welsh Cancer Intelligence and Surveillance Unit. subgroup analysis of patients with brain metastases. Cancer incidence in Wales. 2007. URL: www.wales.nhs. It is likely that this is underpowered and so it uk/sites3/page.cfm?orgid=242&pid=21936. should be treated with caution. 5. Rachet B, Coleman M, Cooper N, Quinn M, Wood H. Breast cancer survival, England and Wales, 1991– There was a lack of robust and reliable evidence 2003. Predicted trends in long-term survival from breast on the effectiveness of the majority of comparators cancer in women: age; and Government office region in included in the economic model (vinorelbine England and Wales. 2006. URL: www.statistics.gov.uk/ monotherapy and all of the trastuzumab- statbase/ssdataset.asp?vlnk=9132&More=Y. Cited 1 containing regimes). December 2005.

There was uncertainty over the pattern of 6. Harris JR, Lippman ME, Veronesi U, Willett W. treatment with trastuzumab if it is continued Breast cancer (2). N Engl J Med 1992;327:390–8. beyond disease progression, in particular whether treatment is weekly or three-weekly. This had a 7. Penault-Llorca F, Vincent-Salomon A, Mathieu M, Trillet-Lenoir V, Khayat D, Marty M, et al. Incidence large effect on the cost-effectiveness of lapatinib and implications of HER2 and hormonal receptor plus capecitabine.

overexpression in newly diagnosed metastatic breast 12. Hutton J, Brown R, Borowitz M, Abrams K, cancer (MBC). J Clin Oncol 2005;23(16S):764. Rothman M, Shakespeare A. A new decision model for cost–utility comparisons of chemotherapy 8. Geyer CE, Forster J, Lindquist D, Chan S, Romieu in recurrent metastatic breast cancer. CG, Pienkowski T, et al. Lapatinib plus capecitabine Pharmacoeconomics 1996;9(Suppl. 2):8–22. for HER2-positive advanced breast cancer [see comment]. N Engl J Med 2006;355:2733–43. 13. Launois R, Reboul-Marty J, Henry B, Bonneterre J. A cost–utility analysis of second-line chemotherapy 9. Brown RE, Hutton J. Cost–utility model comparing in metastatic breast cancer. Docetaxel versus docetaxel and paclitaxel in advanced breast cancer paclitaxel versus vinorelbine. Pharmacoeconomics patients. Anticancer Drugs 1998;9:899–907. 1996;10:504–21.

10. Brown RE, Hutton J, Burrell A. Cost effectiveness of 14. Lloyd A, Nafees B, Narewska J, Dewilde S, Watkins treatment options in advanced breast cancer in the J. Health state utilities for metastatic breast cancer. UK. Pharmacoeconomics 2001;19:1091–1102. Br J Cancer 2006;95:683–90.

11. Cooper NJ, Abrams KR, Sutton AJ, Turner D, 15. Glenny A, Altman D, Song F, Sakarovitch C, Lambert PC. A Bayesian approach to Markov Deeks J, D’Amico R, et al. Indirect comparisons modelling in cost-effectiveness analyses: application of competing interventions. Health Technol Assess to taxane use in advanced breast cancer. J R Stat Soc 2005;9(26). Sers A Stat Soc 2003;166:389–405.

6 DOI: 10.3310/hta13suppl3/02 Health Technology Assessment 2009; Vol. 13: Suppl. 3

Infliximab for the treatment of ulcerative colitis

C Hyde,* S Bryan, A Juarez-Garcia, L Andronis and A Fry-Smith West Midlands Health Technology Assessment Collaboration, Department of Public Health and Epidemiology, University of Birmingham, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 07/12/01

This paper presents a summary of the evidence Date of ERG submission: review group (ERG) report into the clinical July 2007 effectiveness and cost-effectiveness of infliximab TAR Centre(s): for moderately to severely active ulcerative colitis West Midlands Health Technology Assessment (UC) based upon a review of the manufacturer’s Collaboration submission to the National Institute for Health List of authors: and Clinical Excellent (NICE) as part of the C Hyde, S Bryan, A Juarez-Garcia, L Andronis and single technology appraisal (STA) process. The A Fry-Smith submission indicated that the efficacy of infliximab (5 mg/kg) had been demonstrated in terms of Contact details: Chris Hyde, West Midlands Health Technology higher response rates and a sustained response Assessment Collaboration, Department of Public in health-related quality of life. For the cost- Health and Epidemiology, University of Birmingham, effectiveness analysis, the manufacturer built a Edgbaston, Birmingham B15 2TT, UK Markov model to compare infliximab with standard care. It estimated the incremental cost per quality- E-mail: [email protected] adjusted life-year (QALY) gained was between The research reported in this article of the journal £25,044 and £33,866 depending on the strategy supplement was commissioned and funded by the used. The ERG report generally agreed with the HTA programme on behalf of NICE as project evidence on effectiveness of infliximab for subacute number 07/12/01. The assessment report began editorial exacerbations of UC. However, there were several review in November 2008 and was accepted for areas of uncertainty, of which the interpretation publication in May 2009. See the HTA programme web of the importance of the quality of life changes site for further project information (www.hta.ac.uk). This summary of the ERG report was compiled after in the subacute situation and the assessment of the Appraisal Committee’s review. the adequacy of the evidence of effectiveness of infliximab in the acute hospital-based situation The views and opinions expressed therein are those of were considered pre-eminent by the ERG. This the authors and do not necessarily reflect those of the challenged the estimates of cost-effectiveness Department of Health. offered and suggested that there should be a Discussion of ERG reports is invited. Visit the HTA separate assessment of infliximab for acute website correspondence forum (www.hta.ac.uk/ exacerbations of moderately to severely active UC. correspond). The summary of the NICE guidance issued in April 2008 as a result of the STA states that: infliximab is not recommended for the treatment of subacute manifestations of moderately to severely active UC.

Introduction In UC the severity of the symptoms fluctuates unpredictably over time with intervals of remission The National Institute for Health and Clinical or reduced symptoms. Approximately 50% of Excellence (NICE) is an independent organisation patients with UC have a relapse in any year. A within the NHS that is responsible for providing significant minority have frequently relapsing national guidance on the treatment and care of or chronic continuous disease. In total, 25% people using the NHS in England and Wales. of patients with severe UC are admitted to an One of the responsibilities of NICE is to provide inpatient setting with flares of UC that are not guidance to the NHS on the use of selected new responding to steroids. An estimated 20–30% of and established health technologies, based on an patients with pancolitis (disease affecting the entire appraisal of those technologies. colon) will require colectomy.

NICE’s single technology appraisal (STA) process The British Society of Gastroenterology published is specifically designed for the appraisal of a single guidelines for the treatment of UC in 2004. product, device or other technology, with a single The main recommendations for the medical indication, for which most of the relevant evidence management of active left-sided or extensive lies with one manufacturer or sponsor.1 Typically, UC are treatment with oral aminosalicylates it is used for new pharmaceutical products close or corticosteroids. In active distal UC (i.e. to launch. The principal evidence for an STA is colitis confined to the rectum, or rectum and derived from a submission by the manufacturer/ sigmoid colon) treatment options include topical sponsor of the technology. In addition, a report mesalazine, or topical corticosteroids combined reviewing the evidence submission is submitted with oral mesalazine, or systemic corticosteroids. by the evidence review group (ERG), an external When in remission patients with UC should organisation independent of NICE. This paper normally receive maintenance therapy with presents a summary of the ERG report for the STA aminosalicylates, azathioprine or mercaptopurine of infliximab for ulcerative colitis (UC).2 This STA to reduce the risk of relapse. Patients frequently was subsequently split into two parts, infliximab for receive combination therapies. Severe UC should subacute manifestations of UC and infliximab for be managed jointly by a gastroenterologist in acute exacerbations of UC. The latter is the subject conjunction with a colorectal surgeon. of a separate STA and report (08/37/01). Infliximab (Remicade®, Schering-Plough) is a chimeric monoclonal antibody that binds with Description of the high affinity to tumour necrosis factor (TNF)-a, underlying health problem thereby neutralising its activity. It is administered by intravenous infusion and is licensed for use Ulcerative colitis is a chronic condition in which in rheumatoid arthritis, active Crohn’s disease, there is inflammation of the mucosa of the large psoriasis, psoriatic arthritis and ankylosing intestine. The incidence of UC is approximately spondylitis as well as in UC. 10–20 per 100,000 per year with a reported prevalence of 100–200 per 100,000 in the UK. Infliximab is licensed for moderately to severely active UC in patients who have had an inadequate The symptoms of UC vary according to the extent response to conventional therapy including and severity of the inflammation. The classic corticosteroids and 6-mercaptopurine or symptom of UC is bloody diarrhoea. Associated azathioprine, or who are intolerant to or who have symptoms of colicky abdominal pain, urgency medical contraindications to such therapies. or tenesmus may be present. Mildly active UC is defined as less than four bowel movements daily. Moderately active UC is defined as more than Scope of the ERG report four bowel movements daily, but when the patient is not systemically ill. Severe UC is defined as an The purpose of the ERG report is to comment attack in which the patient has more than six bowel on the validity of the manufacturer’s submission movements daily and is systemically ill as shown by on the technology of interest. The scope for this tachycardia, fever and anaemia. Fulminant disease submission and hence the scope for the ERG correlates with more than 10 bowel movements report was to appraise the clinical effectiveness and daily, continuous bleeding, toxicity, abdominal cost-effectiveness of infliximab for moderately to tenderness and distension, blood transfusion severely active UC. 8 requirement and colonic dilatation (expansion). Health Technology Assessment 2009; Vol. 13: Suppl. 3

The population considered was adults with • rerunning searches indicated to have been moderately to severely active UC who have had carried out to inform the manufacturer’s an inadequate response to conventional therapy submission including corticosteroids and 6-mercaptopurine or • extending searches, particularly for ongoing azathioprine, or who are intolerant to or who have trials medical contraindications to such therapies. The • a formal critical appraisal of the systematic intervention was infliximab. review underpinning the manufacturer’s submission, and a related Cochrane review The standard comparators to be considered • reappraisal and checking of data abstraction on included standard care [which may include two key included studies conventional therapy with a combination of • detailed checking of company reports 5-aminosalicylic acid (5-ASA) compounds, (commercial-in-confidence data) of the pivotal corticosteroids and immunomodulators trials (azathioprine or 6-mercaptopurine)], ciclosporin • rerunning of meta-analyses, correcting errors and surgery. in the submission • checking the consistency of the effectiveness The outcome measures to be considered included estimates emerging from the systematic review health-related quality of life, survival, measures of with the parameters used in the economic disease activity, rates of and duration of response, model relapse and remission, rates of hospitalisation, • rerunning of the economic model supplied by reduction in use of corticosteroids, rates of surgical the company intervention and adverse effects of treatment. • correction of an error in the reporting of the results of the economic model For the economic analysis the reference case • additional sensitivity analyses within the limits stipulates that the cost-effectiveness of treatments of the facilities of the submitted model. should be expressed in terms of incremental cost per quality-adjusted life-year (QALY). The time The work was carried out between 20 May 2007 horizon should be long enough to allow reasonable and 22 July 2007. Members of the ERG team estimation of expected costs (including adverse attended and advised the meetings of the NICE events if applicable) and benefits for each of the appraisal committee where this guidance was two clinical situations. Costs were considered from discussed on 22 August 2007 and 20 November an NHS and personal social services perspective. 2007.

When evidence permitted, the appraisal of infliximab for moderate to severely active UC Results was to identify patient subgroups for whom the Summary of submitted technology was most appropriate and to consider clinical evidence the length of treatment required when patients have responded to infliximab. Guidance was only The submission attempted to systematically review to be issued in accordance with the summary of the randomised controlled trial (RCT) evidence product characteristics. comparing infliximab with placebo. It used an existing Cochrane review as its starting point. The submission identified no new RCTs and included Methods five RCTs, reported in four articles, which are well recognised. Three RCTs consider the subacute, The ERG report comprised a critical review of the outpatient application of infliximab and two evidence for the clinical effectiveness and cost- consider the acute, hospital-based application, effectiveness of the technology based upon the which is argued to be ‘off-label’ use. manufacturer’s/sponsor’s submission to NICE as part of the STA process. The submission highlighted that the efficacy of infliximab at a dose of 5 mg/kg has been Specific steps undertaken by the ERG included: demonstrated, particularly by two large RCTs [ACT (Active Ulcerative Colitis Trial) I and II] in terms • discussion of the nature of the problem with a of higher response rates and a sustained response clinical expert in health-related quality of life. Infliximab was well • reanalysis of the nature of the underlying tolerated. clinical question 9

Summary of submitted cost- The submission reported a de novo model-based effectiveness evidence economic evaluation that considered the cost- No published economic evaluations of infliximab effectiveness of infliximab in UC. The use of a in UC were identified and so the cost-effectiveness Markov model is appropriate as the disease is work focused almost entirely on the de novo characterised by progression over time and so a model and economic evaluation undertaken by modelling approach that can deal with transition the manufacturer. A Markov model was built to between states and the timing of events is required. compare two treatment strategies, infliximab The main transition probability inputs were versus standard care, in terms of costs and QALYs. derived from two relevant trials, the ACT trials, The patient group modelled had moderately to and many of the other inputs and parameters were severely active UC and included patients ‘who based on appropriate data. Probabilistic sensitivity have had an inadequate response to conventional analysis (PSA) and one-way sensitivity analyses were therapy including corticosteroids and 6-MP performed. or AZA (6-mercaptopurine or azathioprine respectively), or who are intolerant to or have Weaknesses medical contraindications for such therapies’. The main submission only considered patients in this The review was generally poorly reported. The category (although the manufacturer’s clarification conduct of the review was at best adequate and response included results for patients who were there were some important deficiencies. For more severe, for whom surgery is the comparator instance, several data abstraction errors were considered). The modelling was undertaken, in identified. Also the summary of the results of part, using data from the ACT trials. the included studies lacked clarity and the meta- analyses attempted were incorrect. In the analysis The model followed a cohort of patients with the submission failed to clearly separate the results moderate or severe UC from entry through to 10 relating to subacute applications of infliximab from years, with patients being tracked as they moved the acute applications in hospital. between the nine states in the model. The cycle length was 8 weeks. The disease states in the model Despite the errors in the review of clinical evidence were defined as remission (Mayo score 0–2), mild offered in the submission the ERG’s own summary (Mayo score 3–5) and moderate/severe (Mayo score suggests that portrayal of the effectiveness 6–12). evidence in the manufacturer’s submission remains reasonably faithful. Infliximab is effective in Two separate treatment strategies were evaluated, increasing clinical response, remission and mucosal which differ in the assumption made about healing and in improving health-related quality continuation of infliximab therapy. Strategy of life in moderate to severe UC in the outpatient A modelled the continuation of infliximab setting. in treatment responders who achieved and maintained remission or mild health states. In In terms of the submitted evidence on cost- contrast, strategy B considered a narrower therapy effectiveness there are serious concerns in relation continuation group defined as responders who to the appropriateness of the policy question achieve and maintain remission. The results of the being addressed and a judgement is required as economic analyses indicated that the incremental to whether this question is the question of most cost per QALY gained was £33,866 for strategy A interest to NICE. The manufacturer’s analysis and £25,044 for strategy B. considered the use of infliximab in patients with moderate to severe UC compared with standard care including 5-ASA compounds, corticosteroids Commentary on and immunomodulators (azathioprine or the robustness of 6-mercaptopurine). However, the scope indicated submitted evidence that the question of interest for NICE was the use of infliximab in patients who have had an Strengths inadequate response to conventional therapy for The submission comprehensively ascertained all whom the comparator technologies include surgery of the available RCTs comparing infliximab with or ciclosporin. placebo. This is in agreement with other reviews in the field. Helpful additional information on the key The manufacturer chose not to make use of the included RCTs was made available when requested. health utility data available from the ACT trials, 10 Health Technology Assessment 2009; Vol. 13: Suppl. 3

but rather commission a new cross-sectional study appropriate trials from which to be drawing to gather new health utility data. Given that much data. of the input data for the model were taken from the • A key driver of the model results is the ACT trials, this decision is surprising and requires utility data and so a judgement on the most justification. appropriate source of utility data is required. • The robustness of the assumption concerning The model had a time horizon of 10 years for long-term follow-up to 10 years, given that this the base case, but the longest follow-up in the is based on trial data to 54 weeks. ACT trials was 54 weeks. Thus, the transition probabilities were derived from trial data up to Of these, the interpretation of the importance of 54 weeks and were assumed to remain constant the quality of life changes in the subacute situation through to 10 years. and the assessment of the adequacy of the evidence of effectiveness of infliximab in the acute hospital- The PSA was undertaken in a very partial based situation were considered pre-eminent by the manner, with distributions placed around selected ERG. parameters only. Errors in the interpretation of the PSA and calculation of the cost-effectiveness acceptability curve were identified. Summary of NICE guidance issued as a result of the STA

Conclusions At the time of writing, the guidance document issued by NICE in April 2008 states that: The key areas of uncertainty identified were: Infliximab is not recommended for the treatment • There is evidence on the effectiveness of of subacute manifestations of moderately to infliximab in the acute hospital-based setting severely active ulcerative colitis. in terms of response and avoidance of surgery; however, the results are primarily based on For the purposes of this guidance, a subacute one small study, even though the effect on manifestation of moderately to severely active colectomy rates is highly statistically significant. ulcerative colitis is defined as disease that would • The evidence on colectomy and ostomy rates normally be managed in an outpatient setting in the subacute setting is unclear, and indeed and that does not require hospitalisation or the there are some inconsistencies between consideration of urgent surgical intervention. different reports of hospitalisation rates from ACT I and II. • In ACT I and II, although the statistical Key references significance of the differences in change in 1. National Institute for Health and Clinical quality of life with infliximab compared with Excellence. Guide to the single technology (STA) process. placebo are clear, the importance of these 19 September 2006. URL: www.nice.org.uk/page. changes to the patient is less easy to define, an aspx?o=STAprocessguide. issue with a key bearing on the interpretation of the cost-effectiveness component of the 2. Hyde C, Bryan S, Juarez-Garcia A, Andronis submission. L. Infliximab for ulcerative colitis. Birmingham: • In common with all newly introduced drugs West Midlands Health Technology Assessment Collaboration, University of Birmingham; July the long-term safety of infliximab needs to be 2007. URL: www.nice.org.uk/nicemedia/pdf/ established, particularly with respect to the risk UlcerativeColitisEvidenceReviewGroupReport.pdf. of malignancy. Accessed 1 November 2008. • The definition of the policy question and, depending on the answer to this question, the

DOI: 10.3310/hta13suppl3/03 Health Technology Assessment 2009; Vol. 13: Suppl. 3

Rimonabant for the treatment of overweight and obese people

J Burch,* C McKenna, S Palmer, G Norman, J Glanville, M Sculpher and N Woolacott Centre for Health Economics and Centre for Reviews and Dissemination, University of York, UK

*Corresponding author

Declared competing interests of authors: Mark Sculpher has been a consultant to Sanofi-Aventis and Roche, but in areas unrelated to obesity and/or the products covered in this single technology appraisal. The remaining authors of this report have no conflicts of interest.

Abstract HTA 07/14/01

This paper presents a summary of the evidence Date of ERG submission: review group (ERG) report into the clinical and 5 October 2007 cost-effectiveness of rimonabant for the treatment TAR Centre(s): of obese or overweight patients based upon a Centre for Reviews and Dissemination/Centre for review of the manufacturer’s submission to the Health Economics National Centre for Health and Clinical Excellence List of authors: (NICE) as part of the single technology appraisal J Burch, C McKenna, S Palmer, G Norman, J Glanville, (STA) process. The submission’s main evidence M Sculpher and N Woolacott came from four randomised controlled trials. Rimonabant resulted in a significantly greater Contact details: Jane Burch, Centre for Reviews and Dissemination, benefit than placebo for all primary weight loss University of York, Alcuin ‘B’ Block, Heslington, York outcomes. At 1 year, rimonabant had a statistically YO10 5DD, UK significant beneficial effect on systolic blood pressure, high-density lipoprotein cholesterol, E-mail: [email protected] triglycerides and fasting plasma glucose in diabetics The research reported in this article of the journal and non-diabetics, and glycosylated haemoglobin supplement was commissioned and funded by the in diabetics. Improvements were maintained over 2 HTA programme on behalf of NICE as project number years with rimonabant; withdrawal of rimonabant 07/14/01. The assessment report began editorial review at 1 year resulted in a reduction in weight loss until in October 2008 and was accepted for publication in there was no difference from placebo at 2 years. May 2009. See the HTA programme website for further Psychiatric adverse events were experienced by project information (www.hta.ac.uk). This summary 26% and 14% of rimonabant and placebo patients of the ERG report was compiled after the Appraisal Committee’s review. respectively; figures for symptoms of depression were 9% and 5% respectively. Pairwise comparisons The views and opinions expressed therein are those of of orlistat, sibutramine and rimonabant showed the authors and do not necessarily reflect those of the beneficial effects of rimonabant over orlistat Department of Health. and sibutramine for weight loss outcomes; Discussion of ERG reports is invited. Visit the HTA however, response hurdles imposed on orlistat or website correspondence forum (www.hta.ac.uk/ sibutramine in clinical practice may not have been correspond). applied in the orlistat and sibutramine trials. The manufacturer’s Markov cohort model evaluated rimonabant versus orlistat, sibutramine and diet 13

and exercise alone for three base-case populations. NICE’s single technology appraisal (STA) process The incremental cost-effectiveness ratio (ICER) is specifically designed for the appraisal of a of rimonabant varied from £10,534–£13,236 single product, device or other technology, with a per quality-adjusted life-year (QALY) versus single indication, for which most of the relevant diet and exercise, to £8977–£12,138 per QALY evidence lies with one manufacturer or sponsor versus orlistat, to £1463–£3908 per QALY versus (Sanofi-Aventis).1 Typically, it is used for new sibutramine. In subgroup analysis there was a pharmaceutical products close to launch. The wider variation in the ICER estimates although principal evidence for an STA is derived from none exceeded £20,000 per QALY. The ICER of a submission by the manufacturer/sponsor of rimonabant remained under £20,000 per QALY in the technology to NICE. In addition, a report reanalyses by the manufacturer and the ERG, with reviewing the evidence submission is submitted the results sensitive to the source of health-related by the evidence review group (ERG), an external quality of life (HRQoL) benefits in the model. Four organisation independent of NICE. This paper treatment strategies were modelled in comparisons presents a summary of the ERG report for the STA of rimonabant versus diet and exercise alone and of rimonabant for the treatment of overweight and orlistat and sibutramine in which rimonabant was obese patients,2 which was submitted on 5 October continued only in patients achieving 5% weight loss 2007 to NICE, with a subsequent submission of a at 3, 6, 9 or 12 months. In pairwise comparisons commentary on 24 January 2008. rimonabant remained below a threshold of £30,000 per QALY in 70% of the comparisons reported. In October 2008, the European Medicines Agency The results were most sensitive to the decrement (EMEA), based on new evidence that became applied to depression and the costs of screening available from postmarketing surveillance studies for depression. In conclusion, areas of uncertainty following the NICE appraisal of rimonabant, remain in relation to the clinical effectiveness and concluded that the balance of risks and benefits no cost-effectiveness of rimonabant, for example lack longer supported the use of rimonabant and the of evidence on long-term outcomes and the effect drug was withdrawn from use. It should therefore of rimonabant on cardiovascular events, developing be noted that this report is based only on evidence diabetes and mortality, and lack of data on the available to NICE at the time of its appraisal of HRQoL benefits associated with rimonabant. The rimonabant and does not include any further lack of response hurdles applied to sibutramine evidence that informed the EMEA’s decision on and orlistat means that the comparator strategies withdrawal. were not considered by the ERG to reflect their respective product licenses or current NHS use. The NICE guidance issued as a result of the Description of the STA states that rimonabant is recommended as underlying health problem an adjunct to diet and exercise for adults who are obese or overweight and who have had an Obesity is a chronic condition which is associated inadequate response to, are intolerant of or are with a number of conditions such as type 2 diabetes contraindicated to orlistat and sibutramine. that have a significant impact on morbidity and quality of life and reduce life expectancy. There Introduction are currently several options for the treatment of overweight and obese patients, including The National Institute for Health Research lifestyle changes, drug treatments and bariatric Health Technology Assessment (NIHR HTA) surgery. According to NICE guidelines, the initial programme supports the National Institute for treatments of choice for overweight and obese Health and Clinical Excellence (NICE) by funding patients are multicomponent interventions that independent academic input to NICE technology include behavioural change strategies to promote appraisal activities. NICE is an independent physical activity and improve eating habits. organisation within the NHS that is responsible for providing national guidance on the treatment Three drugs are currently used in practice and care of people using the NHS in England and to treat obesity: orlistat (Xenical®, Roche), Wales. One of the responsibilities of NICE is to sibutramine (Reductil®, Abbott) and rimonabant provide guidance to the NHS on the use of selected (Accomplia®). Orlistat is a specific and long-acting new and established health technologies, based on inhibitor of the enzyme lipase, which results in an appraisal of those technologies. the inability to hydrolyse dietary fat in the form of triglycerides into absorbable free fatty acids 14 Health Technology Assessment 2009; Vol. 13: Suppl. 3

and monoglycerides, therefore preventing fat Methods absorption. The net price per 84-cap pack is £33.58, with an approximate annual cost of £438. The ERG report comprised a critical review of the Sibutramine produces secondary and primary evidence for the clinical effectiveness and cost- amine metabolites that inhibit noradrenaline, effectiveness of the technology based upon the serotonin and dopamine reuptake, which in turn manufacturer’s/sponsor’s submission to NICE as suppresses appetite by producing a feeling of part of the STA process. In addition, the ERG: satiety. The net price per 28-cap pack of 10 mg is £36.90. The net price per 28-cap pack of 15 mg • Generated tables from data provided in is £43.65. The approximate annual cost is £481 the body of the original and clarification for 10 mg and £569 for 15 mg. Rimonabant is a submissions, and the appendices of the selective CB1 cannabinoid receptor antagonist and original submission, in order to present a clear acts by decreasing appetite. The net price per 28- summary of the relative and absolute weight tab pack is £44.00, with an approximate annual effects of rimonabant at 1 year. cost of £574. • Repeated the meta-analyses for the primary weight loss outcomes [except for body mass The manufacturer’s submission to NICE stated index (BMI) as insufficient data were provided] that, since the introduction of rimonabant until the including all four RIO trials (Rimonabant In end of June 2007, approximately 32,500 patients Obesity). have been prescribed rimonabant in England • Compared the results for orlistat and and Wales, accounting for 16.4% of prescription sibutramine included in the submission with initiations for obesity treatments during that those presented in the NICE guidelines3 period. Patients with comorbidities accounted for a because of concerns about how representative large majority of rimonabant prescriptions. of the general literature the trials of orlistat and sibutramine included in the submission Concerns have been raised relating to the licensing were. of rimonabant, both in the UK and in the USA. In • Conducted additional analyses to provide January 2007, the Scottish Medicines Consortium further insight into the potential impact on the decided that the economic case for prescribing cost-effectiveness estimates of key issues and rimonabant had not been demonstrated and uncertainties identified during the structured therefore did not recommend its use within NHS critique of the manufacturer’s submission. Scotland as an adjunct to diet and exercise for the • Conducted additional analyses to clarify the treatment of obese or overweight patients. The US relative importance of the independent effect Food and Drugs Administration (FDA) also did not of BMI on utilities compared with the impact recommend a license for rimonabant in the USA of the other risk factors on cardiovascular because of the risk of psychiatric adverse events, disease (CVD) and diabetes event rates in the particularly the incidence of suicidality and suicidal incremental cost-effectiveness ratio (ICER) ideation. The safety profile of rimonabant was estimates. reviewed by the EMEA and its use in patients with ongoing major depressive illness and/or ongoing antidepressive treatment is now precluded. Results Summary of submitted Scope of the ERG report clinical evidence Effectiveness of rimonabant The ERG report presented a critical evaluation The evaluation of the efficacy of rimonabant of the manufacturer’s submission (Sanofi- focused primarily on the results of four Sanofi- Aventis), which evaluated the evidence for the Aventis-sponsored randomised control trials clinical effectiveness, safety, tolerability and (RCTs): (RIO-Europe4, RIO-North America5, cost-effectiveness of rimonabant in its licensed RIO-Diabetes6 and RIO-Lipids7). Two further indication as an adjunct to diet and exercise, trials were cited but did not contribute to the main relative to other licensed antiobesity drugs (orlistat meta-analyses [SERENADE (Study Evaluating and sibutramine) and diet and exercise alone. Rimonabant Efficacy in drug-NAive DiabEtic patients) and REBA (Riminobant Eating Behaviour Assessment study)]. Data from two unpublished studies were used to inform the analysis of adverse effects (EFC5745 and ACT3801). 15

Rimonabant resulted in a significantly greater density lipoprotein cholesterol, triglycerides and benefit than placebo in terms of all primary weight fasting plasma glucose in both diabetic and non- loss outcomes: diabetic patients, and glycosylated haemoglobin

(HbA1c) in diabetic patients. Weight loss and • change in weight (kg): non-diabetics: weighted improvements in associated cardiovascular and mean difference (WMD) –4.91 [95% confidence diabetes risk factors were maintained over 2 years interval (CI) –5.35 to –4.48]; diabetics: WMD when rimonabant was continued; however, the –3.90 (95% CI –4.57 to –3.23) relative benefit over placebo was lower in year 2. • proportion of patients losing 5% body weight: Following withdrawal of rimonabant treatment at non-diabetics: relative risk (RR) 2.61 (95% CI 1 year, there was a gradual reduction in the rate 2.32 to 2.95); diabetics: RR 3.41 (95% CI 2.58 of weight loss until there was no difference from to 4.50) placebo at 2 years. • proportion of patients losing 10% body weight: non-diabetics: RR 3.48 (95% CI 2.84 to 4.27); In total, 13 adverse events were identified by the diabetics: RR 8.07 (95% CI 3.37 to 17.46) manufacturer as being associated with rimonabant • change in waist circumference (cm): non- at a rate of ≥ 2%, and at a rate of ≥ 1% greater diabetics: WMD –4.01 (95% CI –4.50 to –3.53); than placebo (Table 1). Some form of psychiatric diabetics: WMD –3.30 (95% CI –4.17 to –2.43) adverse event was experienced by 26% of patients • BMI (kg/m2): non-diabetics: WMD –1.76 (95% receiving 20 mg rimonabant across the four RIO CI –1.92 to –1.60); diabetics: WMD –3.90 (95% trials, compared with 14% of patients receiving CI –4.57 to –3.23); for any baseline BMI, the placebo. Symptoms of depression were reported in average weight loss beyond that which can be 9% of patients taking 20 mg rimonabant compared achieved with diet and exercise over a 1-year with 5% of patients taking placebo. These rates period is around 5 kg, with a fall in BMI of were broken down further, with the most commonly 1.7 kg/m2. reported psychiatric adverse events as stated in the FDA briefing shown in Table 2.8 The ERG generated pooled estimates using data from all four of the RIO trials. The results for Two separate instruments were used to evaluate the the change in weight and the proportion who effect of rimonabant on health-related quality of achieved 5% weight loss are shown in Figures 1 life (HRQoL). One was the obesity-specific Impact and 2 respectively. These analyses show that the a of Weight on Quality of Life-Lite (IWQOL-Lite) priori decision by the manufacturer to pool data and the other the generic Medical Outcomes Study for diabetics and non-diabetics separately was Short Form-36 (SF-36). Rimonabant provided justified statistically as well as clinically. However, benefits in some areas of HRQoL, particularly although the mean weight loss and placebo- physical functioning, but was associated with a subtracted reduction in BMI in the RIO-Diabetes significant deterioration in mental health. trial were slightly lower than in the other RIO trials, the other primary outcomes did not indicate On request, the manufacturer provided analyses any materially different treatment effect in this of responder and non-responder data for 3, 6, population. 9 and 12 months. These analyses were based on patients with complete weight measurements Two of the RIO trials (RIO-North America, RIO- for months 3, 6 and 9. Data at 12 months were Lipids) reported significantly greater reductions based on an intention-to-treat (ITT) analysis in body weight in patients achieving at least 5% using last observation carried forward (LOCF). weight loss with rimonabant than with placebo. For rimonabant-treated patients, responders lost None of the trials reported significantly greater more weight than non-responders. Comparison of reductions in body weight in patients achieving at the 12-month response data based on the LOCF least 10% weight loss with rimonabant, or in waist and completer analysis indicates the use of the circumference in patients achieving at least 5% or completer analysis is likely to result in higher 10% weight loss with rimonabant compared with response rates than the LOCF approach (e.g. placebo. 49.3% using LOCF compared with 64.4% using a completer analysis for one of the two populations At 1 year, rimonabant had a statistically significant considered, 49.4% versus 56% for the other). beneficial effect on systolic blood pressure, high- In addition, the manufacturer provided an assessment of the diagnostic value of predicting a 16 Health Technology Assessment 2009; Vol. 13: Suppl. 3

Review: Rimonabant Comparison: 01 Rim 20 mg vs placebo Outcome: 01 Change in weight kg

Study or Rimonabant Placebo WMD (ﬁxed) Weight WMD (ﬁxed) sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI

RIO–EU 595 −6.60 (7.20) 302 −1.80 (6.40) 15.65 −4.80 (−5.73 to −3.87) RIO–NA 1189 −6.30 (7.10) 590 −1.60 (5.70) 35.77 −4.70 (−5.31 to −4.09) RIO–diabetes 336 −5.30 (5.20) 345 −1.40 (3.60) 29.53 −3.90 (−4.57 to −3.23) RIO–lipids 344 −6.90 (6.10) 334 −1.50 (5.00) 19.05 −5.40 (−6.24 to −4.56)

Total (95% CI) 2464 1571 100.00 −4.61 (−4.98 to −4.25) Test for heterogeneity: χ2 = 7.93, df = 3 (p = 0.05), I2 = 62.1% Test for overall effect z = 24.70 (p < 0.00001) –10 –5 0 5 10 Favours rimonabant Favours placebo

FIGURE 1 Meta-analyses for change in weight (kg) from baseline to 1 year (intention to treat data) (ERG generated). CI, confidence interval; SD, standard deviation; WMD, weighted mean difference.

Review: Rimonabant Comparison: 01 Rim 20 mg vs placebo Outcome: 02 Proportion 5% weight loss

Study or Rimonabant Placebo RR (ﬁxed) Weight RR (ﬁxed) sub-category n/N n/N 95% CI % 95% CI

RIO–EU 303/595 58/302 21.98 2.65 (2.08 to 3.39) RIO–NA 578/1189 118/590 45.05 2.43 (2.05 to 2.89) RIO–diabetes 166/336 50/343 14.13 3.39 (2.57 to 4.48) RIO–lipids 201/344 65/334 18.84 3.00 (2.37 to 3.80)

Total (95% CI) 2464 1569 100.00 2.72 (2.44 to 3.04) Total events: 1248 (rimonabant), 291 (placebo) Test for heterogeneity: χ2 = 4.77, df = 3 (p = 0.19), I2 = 37.1% Test for overall effect z = 17.74 (p < 0.00001) 0.1 0.2 0.5 12 5 10 Favours placebo Favours rimonabant

FIGURE 2 Proportion of patients achieving 5% weight loss. CI, confidence interval; RR, relative risk.

1-year response at earlier time points by calculating population. In addition, rimonabant compared the sensitivity and specificity of these time points. favourably with orlistat in terms of body weight At 3 months sensitivity was 0.57 and specificity (non-diabetics, diabetics and dyslipidaemics); waist 0.89; sensitivity increased at 6 and 9 months (0.85 circumference (non-diabetics and dyslipidaemics); and 0.91 respectively) and specificity remained change in BMI (non-diabetics); patients who high (0.80 and 0.81 respectively). achieved 5% weight loss (non-diabetics and diabetics); and patients who achieved 10% weight Comparison of rimonabant with loss (non-diabetics and diabetics). There was no orlistat and sibutramine comparison of adverse events or HRQoL between In the absence of head-to-head trials, the rimonabant and orlistat or sibutramine. manufacturer provided tabulated comparisons between the placebo-subtracted results for orlistat, sibutramine and rimonabant. On request, Summary of submitted pairwise comparisons between rimonabant and cost-effectiveness evidence sibutramine and orlistat were provided for the primary outcomes. These pairwise comparisons Only one previously published study reporting on showed a significant increase in the number of the cost-effectiveness of rimonabant was identified. patients achieving 5% weight loss with rimonabant This study evaluated the cost-effectiveness of compared with sibutramine in the non-diabetic rimonabant compared with diet and exercise 17

TABLE 1 The proportion of patients experiencing adverse events at a rate of ≥ 2% in the rimonabant group and ≥ 1% more than in the placebo group; results are pooled from seven trials for the 1-year data (the four RIO trials, REBA, EFC5745 and ACT3801) and two trials for the 2-year data (RIO-North America and RIO-Europe)

Year 1

Rimonabant (n = 2742) Placebo (n = 2474) Any event 86.3 81.4 Nausea 13.6 4.7 Diarrhoea 7.7 5.8 Vomiting 4.7 2.3 Dizziness 7.3 4.1 Anxiety 5.9 2.1 Insomnia 5.8 3.4 Mood alterations with depressive symptoms 4.7 2.8 Depressive disorders 3.9 1.7 Influenza 10.3 9.1 Asthenia/fatigue 6.1 4.4 Gastroenteritis 4.5 3.5 Contusion 3.1 1.1 Hot flush 2 0.8

TABLE 2 The number (%) of patients experiencing psychiatric symptoms across the four RIO trials as reported in the US Food and Drugs Administration briefing document8

20 mg rimonabant Placebo Any psychiatric adverse event 569 (26.2) 226 (14.1) Anxiety 131 (6.02) 40 (2.50) Insomnia 118 (5.42) 53 (3.31) Depressed mood 83 (3.81) 45 (2.81) Depression 74 (3.40) 23 (1.44) Irritability 1.93% 0.56% Stress 38 (1.75) 28 (1.75) Nervousness 31 (1.42) 5 (0.31) Depressive symptoms 23 (1.06) 12 (0.75) Sleep disorder 21 (0.97) 7 (0.44) Nightmare 21 (0.97) 3 (0.19)

alone. No published studies were identified that The Markov model evaluated the following had compared rimonabant with other licensed treatment comparisons: (1) lifetime rimonabant antiobesity drugs. plus diet and exercise versus lifetime diet and exercise alone; (2) lifetime rimonabant plus diet The manufacturer’s submission was based on a de and exercise versus lifetime orlistat plus diet and novo economic evaluation of rimonabant compared exercise; and (3) 1-year rimonabant plus diet and with orlistat, sibutramine and diet and exercise exercise versus 1-year sibutramine plus diet and alone. Separate models were presented based on a exercise. The results of the economic evaluation Markov cohort model and a patient-level approach were presented for three base-case populations: (1) using discrete event simulation. The main overweight or obese patients with treated type 2 submission focused on the Markov cohort model. diabetes (diabetic group); (2) overweight or obese patients with dyslipidaemia, not treated with a 18 statin and without type 2 diabetes (dyslipidaemic Health Technology Assessment 2009; Vol. 13: Suppl. 3

group); and (3) obese patients with or without that several important caveats and uncertainties comorbidities (obese group). A number of remained. additional subgroups were considered as part of the sensitivity analysis. On request, the manufacturer provided comparisons of rimonabant versus diet and In the absence of direct head-to-head RCT data exercise alone and orlistat and sibutramine; in each for the alternative strategies, indirect approaches analysis, four treatment strategies were modelled were employed to assess the relative effectiveness in which treatment with rimonabant was continued of each treatment strategy in terms of its impact only in patients achieving 5% weight loss at 3, 6, 9 on a number of established risk factors for CVD or 12 months. Further modifications to the model and diabetes. A series of published risk equations included: discontinuation of treatment when a was used to translate changes in these risk factors patient returned to their original weight while to a reduced risk of CVD and, in patients without on treatment; a disutility for depressive adverse diabetes, to a reduced risk of developing diabetes. events associated with rimonabant; inclusion of The effect of the treatments on BMI was also costs of screening/monitoring for depression for assumed independently to influence HRQoL patients treated with rimonabant; and long-term beyond that attributed to the effect on CVD and deterioration of efficacy of all treatments after 1 diabetes risks. These approaches were used as year. the basis for estimating quality-adjusted life-years (QALYs) over a lifetime time horizon. Costs were Compared with diet and exercise alone, the based on the drug acquisition and monitoring response hurdles for rimonabant of between 6 costs, adverse events and the costs of CVD and and 9 months were demonstrated to be more diabetes. Costs and QALYs were compared and cost-effective than a response hurdle of 3 months ICERs of rimonabant estimated when appropriate. in the analyses of overweight or obese patients The robustness of the results was assessed using with diabetes and obese patients with or without deterministic and probabilistic sensitivity analyses. risk factors. When compared with orlistat and sibutramine, the ICER of rimonabant employing a Across the base-case populations, the ICER of 6-month response hurdle was £30,743 per QALY rimonabant varied from £10,534 to £13,236 per compared with a 3-month response hurdle for QALY versus diet and exercise, from £8977 to sibutramine for overweight or obese patients with £12,138 per QALY versus orlistat and from £1463 diabetes, and £23,644 per QALY for obese patients to £3908 per QALY versus sibutramine. In the with or without risk factors. additional subgroups considered there was a wider variation in the ICER estimates; however, none Pairwise comparisons were presented, showing the of the individual pairwise ICERs for rimonabant upper and lower ICERs for rimonabant versus the exceeded £20,000 per QALY in any of the three comparators. Rimonabant was reported to subgroups. The ICER estimates across the majority remain below a threshold of £30,000 per QALY in of the sensitivity analyses were broadly consistent 70% of the pairwise comparisons reported. The with the base-case results. results appeared most sensitive to the decrement applied to depression and the costs of screening for The ERG considered that the original submission depression. contained a number of important uncertainties and issues which potentially compromised the validity of the model results. A number of these issues Commentary on were addressed by the manufacturer as part of the robustness of their response to the ERG’s points for clarification. submitted evidence The ERG identified a number of remaining issues related to the manufacturer’s response and Strengths several of these were subsequently addressed with The manufacturer’s submission presented a clear additional analyses conducted by the ERG. The overview of the four major trials (RIO trials4–7) ICER of rimonabant remained relatively robust conducted with rimonabant in overweight or obese throughout the reanalyses by the manufacturer patients with data for up to 2 years. The submission and the ERG (< £20,000 per QALY), although also included a comparison with the appropriate the results did appear to be sensitive to the source comparators orlistat and sibutramine. of HRQoL benefits assumed in the model, with markedly less favourable ICER estimates using data The manufacturer used appropriate criteria to from the RIO trials. However, the ERG considered assess the quality of the RIO trials, although 19

the ERG noted some discrepancies between the The comparison of the effects of rimonabant with assessments provided in the submission and the those of orlistat and sibutramine on weight loss information available in published trial reports. outcomes is uncertain given the differences in diet The ERG assumes that the manufacturer had and exercise that might have been employed across access to the full trial reports. the different trials. There was no comparison of 2-year data between rimonabant and orlistat. There The manufacturer’s submission was considered are differences in the licensing of rimonabant to comprise the most relevant source of cost- compared with that of orlistat and sibutramine; effectiveness evidence relating to the use of orlistat and sibutramine are subject to response rimonabant. The ERG identified a number of ‘hurdles’ in practice that may not be applied in strengths in the manufacturer’s cost-effectiveness trials and therefore any additional benefit of analysis. The overall model structure, approaches rimonabant over orlistat or sibutramine may be to estimating long-term costs and outcomes overestimated and may not be apparent in normal (expressed using QALYs), the time horizon clinical practice. employed and the approach to handling parameter uncertainty were all consistent with the NICE Overall, the ERG found the presentation of the reference case for cost-effectiveness analysis. data unclear, particularly that for orlistat and The ERG also noted that the manufacturer had sibutramine. The ERG has concerns over how compared rimonabant against other licensed representative of the general literature the trials of antiobesity drugs as well as against diet and orlistat and sibutramine in the submission are, and exercise alone. A broad range of sensitivity how objectively the data have been used. analyses was also undertaken to explore alternative assumptions. Variation in the cost-effectiveness The ERG identified a number of potential estimates for rimonabant was considered in a weaknesses in the manufacturer’s cost-effectiveness number of different patient subgroups. The ERG analysis. The most significant was considered to be also felt that the validation approaches employed the lack of response hurdles applied to sibutramine by the company (including presenting the results and orlistat, such that the comparator strategies of a separate discrete event simulation) were a were not considered by the ERG to reflect their relative strength of the submission. Finally, the respective product licenses or current NHS use. ERG felt that the manufacturer had attempted to Although this issue was partially addressed by address a number of areas of uncertainty identified the manufacturer in the response to the ERG by the ERG in their response to the points for points for clarification, the ERG did not consider clarification. that this aspect had been robustly considered by the manufacturer and hence it represents In general, the ERG felt that the revised a major limitation. The revised submission by submission provided by the manufacturer had the manufacturer addressed this issue further. adequately addressed the main clarification However, there remained potential inconsistency points raised. The ERG noted that several of the in the approaches used to estimate the response assumptions employed by the manufacturer to rates for the alternative time points representing address these points were conservative towards continuation hurdles for rimonabant; at 3, 6, rimonabant; however, a more limited range of and 9 months completer data were used and at subgroups was considered in the resubmission – 12 months LOCF was used. Although the ERG data on overweight and obese patients with risk recognises that the manufacturer presented a more factors other than diabetes were omitted. consistent approach as part of their clarification, the ERG considers that the full ITT LOCF would Weaknesses represent a more conservative approach and that the current analyses may overstate the response The four included trials may not be generalisable rates at 3, 6 and 9 months. In addition, there was to the UK population, both in terms of baseline a lack of conditional response data for sibutramine BMI and the differences in lifestyle, diet and and orlistat (the change in individual risk factors attitudes towards alcohol consumption and exercise for responders and non-responders) resulting in between the UK and the USA and other European the use of different approaches to estimate the countries. Furthermore, the diabetic patients cost-effectiveness of rimonabant versus diet and included in the manufacturer’s submission did exercise alone (patient-level data from the RIO not include insulin-dependant diabetics and so trials) and versus orlistat and sibutramine [applying may not be generalisable to the broader diabetic the average change in risk factors reported for the 20 population. active treatments (regardless of response status) to Health Technology Assessment 2009; Vol. 13: Suppl. 3

responders, and the average change in risk factors manufacturer has identified no direct evidence for diet and exercise to non-responders]. for the effect of rimonabant on hard clinical end points, such as cardiovascular events, developing The ERG also considered the manufacturer’s diabetes and mortality. The manufacturer states approach to evaluating HRQoL benefits to be that results from an ongoing trial, CRESCENDO subject to a number of important uncertainties. (Comprehensive Rimonabant Evaluation Study The ERG considered that the manufacturer’s of Cardiovascular Endpoints and Outcomes), reliance on external utility estimates, as opposed which is evaluating the effect of rimonabant to the HRQoL data reported in the RIO trials, on cardiovascular morbidity and mortality, are was a potential weakness. Indeed, the HRQoL expected to be available in 2011. benefits associated with rimonabant remain highly uncertain and need more detailed investigation by Given the lack of head-to-head comparisons the manufacturer. between rimonabant and orlistat or sibutramine with all three drugs given as per license, it is unclear whether the pairwise comparisons Conclusions between rimonabant and orlistat and sibutramine, Key issues presented in the clarification submission, will reflect that seen in clinical practice; response The adequacy of the cost-effectiveness modelling hurdles imposed on orlistat or sibutramine in and assumptions regarding strategies utilising clinical practice may not have been applied in the response hurdles for rimonabant and comparator orlistat and sibutramine trials. treatments is a key concern. Also, the use of external evidence on the HRQoL impact of BMI With respect to cost-effectiveness, a number of independent of longer-term clinical events rather issues and uncertainties were addressed by the than estimates from the trials, and the choice of manufacturer in their response to the ERG’s this external evidence, are key issues. points for clarification. Some remaining issues relating to the manufacturer’s response were The lack of evidence on the effect of rimonabant subsequently addressed with additional analyses on ‘hard’ end points, such as CVD, diabetes conducted by the ERG and a revised submission and mortality, is a major limitation. Data are by the manufacturer. However, some caveats and also lacking on the effectiveness and safety of uncertainties remain with respect to the modelling rimonabant beyond 2 years. In addition, the of the comparator technologies and the HRQoL appropriateness of incorporating the link between benefits associated with rimonabant. BMI reductions and a lower risk of diabetes and CVD and the choice of evidence to inform this link are questionable. Summary of NICE guidance issued as a result of the STA There are concerns over the psychiatric morbidity associated with rimonabant and, given the The guidance issued by NICE in March 2008 states lack of long-term data, the cumulative data on that: less common side-effects are uncertain. The generalisability to the UK overweight and obese Rimonabant, within its licensed indications, is population is uncertain, particularly in the broader recommended as an adjunct to diet and exercise diabetic population as there are no data on the for adults who are obese or overweight and effectiveness or safety of rimonabant in insulin- who have had an inadequate response to, are dependant diabetics. intolerant of or are contraindicated to orlistat and sibutramine. Areas of uncertainty Rimonabant treatment should be continued Areas of uncertainty remain in relation to the beyond 6 months only if the person has lost at clinical effectiveness and safety of rimonabant. A least 5% of their initial body weight since starting major area where data are lacking relates to the rimonabant treatment. long-term outcomes, with no effectiveness or safety data presented for rimonabant beyond 2 years Rimonabant treatment should be discontinued if and limited data available beyond 1 year. Also, the a person returns to their original weight while on rimonabant treatment. 21

Rimonabant treatment should not be continued overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005;365:1389–97. for longer than 2 years without a formal clinical assessment and discussion of the individual risks 5. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, and benefits with the person receiving treatment. Rosenstock J, RIO-North America Study Group. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors Key references in overweight or obese patients: RIO-North 1. National Institute for Health and Clinical America: a randomized controlled trial. JAMA Excellence. Guide to the single technology (STA) process. 2006;295:761–75. 19 September 2006. URL: www.nice.org.uk/page. aspx?o=STAprocessguide. 6. Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF. Efficacy and tolerability of rimonabant 2. McKenna C, Palmer S, Burch J, Norman G, in overweight or obese patients with type 2 Glanville J, Sculpher M, et al. Rimonabant for the diabetes: a randomised controlled study. Lancet treatment of overweight and obese patients. Evidence 2006;368:1660–72. review group report for NICE. London: NICE; 2007. 7. Despres JP, Golay A, Sjöström L, Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant 3. National Institute for Health and Clinical on metabolic risk factors in overweight patients with Excellence. CG43 obesity: full guideline. 2006. URL: dyslipidemia. N Engl J Med 2005;353:2121–34. www.nice.org.uk/CG043fullguideline. Cited 26 September 2007. 8. Food and Drug Administration. Rimonabant briefing document. Endocrine and Metabolic Drugs 4. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Advisory Committee Meeting, 13 June 2007. NDA Rossner S, RIO-Europe Study Group. Effects of 21–888. URL: www.fda.gov/ohrms/dockets/AC/07/ the cannabinoid-1 receptor blocker rimonabant on briefing/2007–4306b1-fda-backgrounder.pdf. Cited weight reduction and cardiovascular risk factors in 27 September 2007.

22 DOI: 10.3310/hta13suppl3/04 Health Technology Assessment 2009; Vol. 13: Suppl. 3

Telbivudine for the treatment of chronic hepatitis B infection

D Hartwell,* J Jones, P Harris and K Cooper Southampton Health Technology Assessments Centre (SHTAC), University of Southampton, First Floor, Epsilon House, Enterprise Road, Southampton Science Park, Southampton, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 07/66/01

This paper presents a summary of the evidence Date of ERG submission: review group (ERG) report into the clinical February 2008 effectiveness and cost-effectiveness of telbivudine TAR Centre(s): for the treatment of chronic hepatitis B (CHB) in Southampton Health Technology Assessments Centre adults based upon a review of the manufacturer’s (SHTAC) submission to the National Institute for Health List of authors: and Clinical Excellence (NICE) as part of the D Hartwell, J Jones, P Harris and K Cooper single technology appraisal (STA) process. The submission’s evidence came from one randomised Contact details: controlled trial (RCT) (GLOBE) of reasonable Debbie Hartwell, Southampton Health Technology Assessments Centre (SHTAC), University of methodological quality comparing telbivudine Southampton, First Floor, Epsilon House, Enterprise with lamivudine. One other RCT that appeared Road, Southampton Science Park, Southampton to meet the inclusion criteria was excluded from SO16 7NS, UK the submission. For the primary outcome of therapeutic response telbivudine was statistically E-mail: [email protected] superior to lamivudine at weeks 52 and 104 for The research reported in this article of the journal hepatitis B e antigen (HBeAg)-positive patients, supplement was commissioned and funded by the and at week 104 for HBeAg-negative patients. HTA programme on behalf of NICE as project number There were statistically significant differences in 07/66/01. The assessment report began editorial review favour of telbivudine for some secondary outcomes in August 2008 and was accepted for publication in Aril at 2 years including hepatitis B virus (HBV) 2009. See the HTA programme web site for further DNA reduction, HBV DNA non-detectability and project information (www.hta.ac.uk). This summary of the ERG report was compiled after the Appraisal alanine aminotransferase normalisation though Committee’s review. not for HBeAg-positive patients. In HBeAg- positive patients there was no significant difference The views and opinions expressed therein are those of between treatment groups for HBeAg loss or the authors and do not necessarily reflect those of the seroconversion at any time point. The incidence Department of Health. of adverse events was similar between treatments. Discussion of ERG reports is invited. Visit the HTA Two RCTs comparing entecavir with lamivudine website correspondence forum (www.hta.ac.uk/ were included in the indirect comparison; however, correspond). this was poorly conducted and the results should be treated with caution. The manufacturer developed two economic models to determine the cost-effectiveness of telbivudine. Evidence on the efficacy of telbivudine and lamivudine was taken from the GLOBE trial; efficacy of adefovir was 23

based on assumption. There was a lack of critical presents a summary of the ERG report for the STA assessment and assurance of the quality of the data of the clinical effectiveness and cost-effectiveness of used to populate the models. The manufacturer telbivudine for the treatment of chronic hepatitis B concluded that telbivudine is a cost-effective option (CHB) in adults. compared with lamivudine using evidence from the viral load model [HBeAg-positive patients/ HBeAg-negative patients: mean incremental Description of the cost £19,087/£49,003, mean quality-adjusted underlying health problem life-year (QALY) gain 1.30/4.67, incremental cost-effectiveness ratio (ICER) £14,665/£10,497 Hepatitis B is an infectious disease of the liver per QALY]. Resubmitted results after a request caused by the hepatitis B virus (HBV). The majority for clarification by the ERG gave less favourable of people who are infected as adults recover ICERs (HBeAg-positive patients/HBeAg-negative spontaneously, but around 5% develop CHB, patients: mean incremental cost £23,983/£41,910, defined as viraemia and hepatic inflammation for mean QALY gain 1.56/2.07, ICER £15,377/£20,256 more than 6 months.2 If not successfully treated per QALY). The manufacturer concluded that it can lead to progressive liver damage, including telbivudine is a cost-effective option (on its own cirrhosis, hepatocellular carcinoma (HCC) and or followed by adefovir) for patients who have death. Patients with CHB may be hepatitis B e developed resistance to first-line telbivudine antigen (HBeAg) positive or HBeAg negative, treatment; however, the presentation of the results depending on the presence or absence of the ‘e’ was not ideal. In conclusion, although telbivudine antigen. was statistically superior to lamivudine for most antiviral outcomes, the difference was not clinically The Department of Health2 and the British Liver significant; in addition, the cost-effectiveness Trust3 estimate that the prevalence of CHB in evidence for telbivudine presented in the the UK is approximately 150,000–200,000, with manufacturer’s submission was limited. The NICE around 7000 estimated new cases every year guidance issued as a result of the STA states that (mostly from immigration of established HBV telbivudine is not recommended for the treatment carriers). However, the Hepatitis B Foundation4 of chronic hepatitis B and that people currently recently estimated that prevalence may have receiving telbivudine should have the option to increased to 325,000, and it is thought likely to continue therapy until they and their clinicians increase further as a consequence of increasing consider it appropriate to stop. rates of immigration of people from countries with a high CHB prevalence. Introduction The main goal of antiviral therapy is to suppress The National Institute for Health and Clinical the level of the virus (HBV DNA) for a prolonged Excellence (NICE) is an independent organisation period of time to reduce the risk of disease within the NHS that is responsible for providing progression and HCC, and also to improve long- national guidance on the treatment and care of term outcomes. HBV DNA is one of the key people using the NHS in England and Wales. markers of disease management, as well as HBeAg One of the responsibilities of NICE is to provide seroconversion, alanine aminotransferase (ALT) guidance to the NHS on the use of selected new levels and, over the longer term, histological and established health technologies, based on an response. appraisal of those technologies.

NICE’s single technology appraisal (STA) process Scope of the ERG report is specifically designed for the appraisal of a single product, device or other technology, with a single The ERG critically evaluated the evidence indication, for which most of the relevant evidence submission from Novartis for the use of telbivudine lies with one manufacturer or sponsor.1 Typically, for the treatment of CHB, in accordance with it is used for new pharmaceutical products close the licensed indication. Telbivudine is a synthetic to launch. The principal evidence for an STA is thymidine nucleoside analogue that inhibits HBV derived from a submission by the manufacturer/ DNA polymerase and thus HBV replication. It is sponsor of the technology. In addition, a report licensed for the treatment of CHB in adult patients reviewing the evidence submission is submitted with compensated liver disease and evidence by the evidence review group (ERG), an external of viral replication, persistently elevated serum 24 organisation independent of NICE. This paper Health Technology Assessment 2009; Vol. 13: Suppl. 3

ALT levels and histological evidence of active positive patients, and at week 104 for HBeAg- inflammation and/or fibrosis. negative patients.

The outcomes stated in the manufacturer’s In terms of secondary outcomes there were definition of the decision problem were HBV statistically significant differences in favour of DNA virological response, seroconversion rate, telbivudine for HBV DNA reduction, HBV DNA histological improvement, biochemical response, non-detectability, ALT normalisation (although viral resistance, time to treatment failure, survival, not for HBeAg-negative patients), virological health-related quality of life and adverse effects. breakthrough and HBV resistance at 2 years. In HBeAg-positive patients there was no significant difference between treatment groups for HBeAg Methods loss or seroconversion at any time point. There were no significant differences in histological The ERG report comprised a critical review of the response or change in fibrosis score at 1 year, evidence for the clinical effectiveness and cost- with the exception of histological improvement effectiveness of the technology based upon the in HBeAg-positive patients, which was greater in manufacturer’s/sponsor’s submission to NICE as telbivudine patients than in lamivudine patients. part of the STA process. In terms of adverse events there appeared to be no difference between treatments. The ERG checked the literature searches and applied the NICE critical appraisal checklist to In the elevated ALT subset analysis of the HBeAg- the included studies and checked the quality of positive subgroup, telbivudine was statistically the manufacturer’s submission with the Centre superior to lamivudine for most outcomes. In for Reviews and Dissemination (CRD) quality the ethnicity subgroup analysis, telbivudine was assessment criteria for a systematic review. significantly more favourable than lamivudine In addition, the ERG checked and provided in Asian patients, but there were no statistically commentary on the manufacturer’s model using significant differences between treatments for standard checklists. A one-way sensitivity analysis, HBeAg-positive Caucasian patients and few scenario analysis and a probabilistic sensitivity differences for HBeAg-negative Caucasian patients. analysis (Figures 1 and 2) were undertaken by the ERG. Two RCTs comparing entecavir with lamivudine were included in the indirect comparison, one in HBeAg-positive patients6 and one in HBeAg- Results negative patients.7 In the indirect comparison Summary of submitted of telbivudine and entecavir, the manufacturer’s clinical evidence submission reported that there were no statistically significant differences for any efficacy outcome. The manufacturer’s submission presented clinical evidence for telbivudine in patients with Summary of submitted cost- compensated CHB based on one multicentre, effectiveness evidence international, double-blind randomised controlled trial (RCT) (the GLOBE trial).5 This was the The manufacturer’s submission presented evidence pivotal registration trial for telbivudine. The trial on the cost-effectiveness of telbivudine using two compared telbivudine with lamivudine in patients economic models, referred to as the viral load and with HBeAg-positive and HBeAg-negative CHB for seroconversion models. Evidence on the efficacy of 104 weeks. The 2-year data presented throughout telbivudine and lamivudine, in terms of reducing the manufacturer’s submission are unpublished, viral load, the probability of normalising ALT although publications of earlier results from the and HBeAg seroconversion, was taken from the GLOBE trial are available. GLOBE trial for a subgroup of patients with ALT levels ≥ two times the upper limit of normal (ULN). For the primary outcome of therapeutic response The benefit of these outcomes is that they are (suppression of HBV DNA < 5 log copies/ml plus associated with reduced probability of progression either clearance of detectable HBeAg or ALT to advanced liver disease. Efficacy of adefovir was normalisation) telbivudine was statistically superior based on assumption. to lamivudine at weeks 52 and 104 for HBeAg- The viral load model, the manufacturer’s preferred approach, stratified response to treatment and 25

(a)

1.00

0.75

0.50

Probability of being cost-effective Probability 0.25

0.00 0 10,000 20,000 30,000 40,000 50,000 60,000 70,000 80,000 90,000 100,000 Willingness to pay per QALY (£)

(b)

1.00

0.75

0.50

Probability of being cost-effective Probability 0.25

0.00 0 10,000 20,000 30,000 40,000 50,000 60,000 70,000 80,000 90,000 100,000 Willingness to pay per QALY (£)

Figure 1 CEACs from ERG probabilistic analysis using viral load model. a, CEAC for telbivudine compared with lamivudine (HBeAg- positive cohort – prior =0); b, CEAC for telbivudine compared with lamivudine (HBeAg-negative cohort – prior = 0). CEAC, cost-effectiveness acceptability curve; ERG, evidence review group; HBeAg, hepatitis B e antigen; QALY, quality-adjusted life-year.

Title: STA 07/66/01 Proof Stage: 1 Figure Number: 01.ai 26 Cactus Design and Illustration Ltd

Title: STA 07/66/01 Proof Stage: 1 Figure Number: 02.ai

Cactus Design and Illustration Ltd Health Technology Assessment 2009; Vol. 13: Suppl. 3

1.00

BSC 0.75 LAM LAM-ADV TBV-ADV

0.50

Probability of being cost-effective Probability 0.25

0.00 0 10,000 20,000 30,000 40,000 50,000

Willingness to pay per QALY (£)

FIGURE 2 Cost-effectiveness frontier from seroconversion model (ERG’s probabilistic sensitivity analysis). BSC, best supportive care; ERG, evidence review group; LAM, lamivudine; LAM→ADV; lamivudine followed by adefovir; QALY, quality-adjusted life-year;TBV→ADV, telbivudine followed by adefovir.

the development of resistance by five viral load cost-effectiveness ratios (ICERs) were estimated levels and regarded reducing viral load as a key against different comparators (depending on the determinant of disease progression. This model model used) in the manufacturer’s submission. The is relevant both to patients with HBeAg-positive comparator in the viral load model was lamivudine, CHB and to those with HBeAg-negative CHB. whereas in the seroconversion model there were The viral load model incorporated a multivariate multiple competing interventions (lamivudine, risk model to derive transition probabilities for telbivudine and adefovir alone or in sequence the development of progressive liver disease as well as best supportive care). All ICERs in the based on viral load levels, the probability of ALT seroconversion model were calculated relative to normalisation and HBeAg serological status (for best supportive care. HBeAg-positive patients). Two versions of the viral load model were submitted. The first used the The manufacturer’s submission concluded that observed proportion of patients moving between telbivudine is a cost-effective option compared states to estimate transition probabilities (referred with lamivudine using evidence from the viral load to as ‘zero prior’). In the second model an arbitrary model (mean incremental cost of £19,087, mean value of 0.5 was added to all numerators and QALY gain of 1.30 with an ICER of £14,665 per denominators (referred to as ‘0.5 prior’). QALY gained for HBeAg-positive patients and mean incremental cost of £49,003, mean QALY The seroconversion model was an attempt to gain of 4.67 with an ICER of £10,497 per QALY replicate the model used in a recent NICE gained for HBeAg-negative patients). In response assessment2 and was structured with HBeAg to a request for clarification from the ERG the seroconversion as the key determinant of disease manufacturer noted that there were errors in the progression. By definition this model is relevant models originally submitted and therefore in the only to patients with HBeAg-positive CHB. results reported in the submission. Resubmitted results gave less favourable ICERs, particularly for Both models adopted a lifetime horizon and HBeAg-negative patients (mean incremental cost Title: STAextrapolated 07/66/01 lifetime costs and quality-adjustedProof life- Stage:of £23,983,2 meanFigure QALY Number: gain 03.ai of 1.56 with an ICER years (QALYs) for patients treated with telbivudine of £15,377 per QALY gained for HBeAg-positive Cactus Designand and each Illustration of the includedLtd comparators. Incremental patients and mean incremental cost of £41,910, 27

mean QALY gain of 2.07 with an ICER of £20,256 Weaknesses per QALY gained for HBeAg-negative patients). The manufacturer’s submission did not include all of the comparators specified in the scope. The manufacturer’s submission concluded that telbivudine is a cost-effective option – on its own Despite a systematic search and screen of the or followed by adefovir – for patients who have literature, only one RCT was included. The developed resistance to first-line telbivudine manufacturer’s submission is therefore largely treatment. The manufacturer’s submission reported dependent upon this one trial. Further high-quality ICERs for seven treatment strategies relative to best RCT evidence for the effectiveness of telbivudine in supportive care. This is not an ideal presentation the patient group meeting the licensed indication of the results of competing treatment strategies. would be beneficial. The ERG derived appropriate comparisons, based on the manufacturer’s results, using the Literature searches were poorly documented, cost-effectiveness frontier, estimating ICERs of lacking clarity and transparency throughout. £7887, £19,680 and £24,277 per QALY gained for Search filters were extremely precise at the lamivudine, telbivudine and telbivudine followed expense of sensitivity. The processes undertaken by adefovir respectively. The sequence of treatment by the manufacturer for data extraction and options implied is problematic as the strategy applying quality criteria to the GLOBE trial were of using telbivudine followed by adefovir (for not detailed and no formal quality assessment patients who develop resistance to telbivudine) is was undertaken on the comparator trials. These not accessible to patients who have lamivudine as factors limit the robustness of the systematic their first-line treatment. To provide the treatment review. In addition, one RCT8 that appeared to strategy of telbivudine followed by adefovir meet the inclusion criteria was excluded from the (which yields the greatest QALY gain of all of the submission. strategies in the seroconversion model and which is optimal at a willingness to pay greater than The indirect comparison with entecavir was poorly £25,000 per QALY) telbivudine must be available conducted and should be treated with caution. It as a first-line treatment. was reported as a visual comparison and then as a statistical comparison, which the manufacturer deemed invalid. An inadequate description of the Commentary on methodology was provided and the conclusions the robustness of are based largely on a visual comparison of efficacy submitted evidence outcomes. Strengths The economic models used data from a subgroup The manufacturer conducted a systematic search of patients in the GLOBE study and these data for clinical effectiveness studies of telbivudine. It were not presented in detail in the clinical appears unlikely that any additional trials would evidence section of the manufacturer’s submission. have met the inclusion criteria had the search been No information was given on the baseline widened to include other databases. characteristics of the subgroup of patients with ALT levels ≥ two times the ULN. The GLOBE trial appears to be of reasonable methodological quality (with some limitations) In the cost-effectiveness section of the submission and measured a range of outcomes that are as the manufacturer paid insufficient attention to appropriate and clinically relevant as possible, appraising the data used to populate the economic although health-related quality of life was not models. Denominators used for calculation of some reported. On the whole, the manufacturer’s transition probabilities appear inconsistent and submission appears to represent an unbiased some input values (e.g. resistance rates calculated estimate of the antiviral treatment effect of using data reported in appendices) are substantially telbivudine based on the results of one trial. lower than those reported for all patients in the GLOBE study. These discrepancies were not The methods adopted for the economic evaluation discussed in the submission. of telbivudine were broadly consistent with those adopted for previous evaluations of antiviral The electronic models submitted are complex and treatment of CHB, including the recent NICE highly reliant on Visual Basic programming to assessment of adefovir and pegylated interferon.2 28 Health Technology Assessment 2009; Vol. 13: Suppl. 3

produce any analyses. There is a large amount of manufacturer’s submission contained no discussion reprocessing of data within the models that was not of alternative modelling strategies that might clearly documented or readily apparent to the user. reduce the impact of sparsity of data nor did it clearly indicate which input variables were most There was little discussion in the manufacturer’s affected by differences in prior values. submission of uncertainty around the mean estimates reported as the base case for both Key issues the viral load and seroconversion models. The NICE guide to methods of technology appraisal Although telbivudine was statistically superior describes confidence ellipses and scatter plots on to lamivudine for most antiviral outcomes, the the cost-effectiveness plane and cost-effectiveness difference was not clinically significant, having acceptability curves as the most appropriate an effectiveness advantage of only about 2% in ways of presenting uncertainty in probabilistic patients treated between the two drugs. Viral sensitivity analysis. These were not presented for breakthrough (> 1 log increase over nadir) for all comparisons and were submitted in appendices, telbivudine was 28.6% at 2 years; although this without commentary, rather than in the main body is significantly lower than that for lamivudine of the report. (45.5%), the ERG’s clinical advisor asserts that it is still high in clinical terms.

Conclusions The conclusions from the indirect comparison were Areas of uncertainty based largely on a visual comparison of efficacy outcomes and a statistical indirect comparison, The results of the key efficacy outcomes were which the manufacturer’s submission states was broken down by HBeAg status, study treatment and not considered valid in the absence of any meta- (1) race/ethnicity or (2) ALT levels. It is not clear analyses. Telbivudine seems to have approximately whether the GLOBE study was powered to detect the same efficacy as entecavir for viral suppression, differences in these subgroups. Without confidence but markedly higher rates of viral resistance (as per intervals and standard deviations in the reporting the rates for entecavir reported in the published of the results it is not possible to ascertain how trials). much variance there was among the subgroups/ patients. The exclusion of entecavir from all of the economic models and the restricted comparison included The rates of viral resistance to entecavir were not in the viral load model – telbivudine versus reported in the manufacturer’s submission and lamivudine, with no follow-up antiviral treatments therefore do not allow for a comparison with the – means that the cost-effectiveness evidence for resistance rates for telbivudine. telbivudine presented in the manufacturer’s submission is limited. Lack of critical assessment The adjustments to the Cox proportional and assurance of the quality of the data used to hazards models used to estimate the probability populate the model (apparent inconsistencies and of developing compensated cirrhosis and HCC incomplete data for lamivudine and telbivudine were inadequately reported as was the process of from the GLOBE trial along with the absence recalibration. These values enter the viral model of systematic searches for evidence on the deterministically – there is no assessment of comparative effectiveness of adefovir) further parameter uncertainty for the risk models used limits the evidence reported in the manufacturer’s in the viral model, nor of the methodological submission. uncertainty around the adjustment or recalibration.

The lack of quality assurance of input data for Summary of NICE guidance both models introduces uncertainty – the impact issued as a result of the STA of the prior value (zero or 0.5) on the model outcomes suggests that sparsity of data may be a NICE guidance, published August 2008,9 states problem, particularly for the model of HBeAg- that: negative patients. This is not surprising, given that data on around 250 patients were stratified across 1.1 Telbivudine is not recommended for the viral load levels, ALT and serological status. The treatment of chronic hepatitis B.

1.2 People currently receiving telbivudine should chronic_hepatitis_b_infection_in_the_uk. Accessed 29 January 2008. have the option to continue therapy until they and their clinicians consider it appropriate to stop. 5. GLOBE study NV-02B-007. Week 104 clinical study report. 2007.

Key references 6. Chang TT, Gish RG, de Man R, Gadano A, Sollano 1. National Institute for Health and Clinical J, Chao YC, et al. A comparison of entecavir and Excellence. Guide to the single technology (STA) process. lamivudine for HBeAg-positive chronic hepatitis B. 19 September 2006. URL: www.nice.org.uk/page. N Engl J Med 2006;354:1001–10. aspx?o=STAprocessguide. 7. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer 2. National Institute for Health and Clinical H, Goodman Z, et al. Entecavir versus lamivudine Excellence. Adefovir dipivoxil and peginterferon for patients with HBeAg-negative chronic hepatitis alfa-2a for the treatment of chronic hepatitis B. NICE B. N Engl J Med 2006;354:1011–20. Technology Appraisal 96. London: NICE; 2006. 8. Hou J, Yin Y-K, Xu D, Tan D, Niu J, Zhou X, 3. British Liver Trust. How prevalent is HBV? URL: et al. Telbivudine versus lamivudine in Chinese www.britishlivertrust.org.uk/home/health- patients with chronic hepatitis B: results at 1 year professionals/literature-for-professionals/a- of a randomized, double-blind trial. Hepatology professionals-guide-to-hepatitis-b/how-prevalent-is- 2007;47:447–54. hbv.aspx. Accessed 17 December 2007. 9. National Institute for Heath and Clinical 4. The Hepatitis B Foundation. Rising curve: chronic Excellence. Telbivudine for the treatment of chronic hepatitis B infection in the UK. URL: www.hepb.org. hepatitis B. NICE Technology Appraisal 154. uk/news/archive/spring_2008_03_03/rising_curve_ London: NICE; 2008.

30 DOI: 10.3310/hta13suppl3/05 Health Technology Assessment 2009; Vol. 13: Suppl. 3

Entecavir for the treatment of chronic hepatitis B infection

J Shepherd,* E Gospodarevskaya, G Frampton and K Cooper Southampton Health Technology Assessments Centre (SHTAC), Wessex Institute for Health Research and Development, University of Southampton, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 07/67/01

This paper presents a summary of the evidence Date of ERG submission: review group (ERG) report into the clinical and February 2008 cost-effectiveness of entecavir for the treatment TAR Centre(s): of chronic hepatitis B (CHB) in adults based Southampton Health Technology Assessments Centre upon a review of the manufacturer’s submission (SHTAC) to the National Institute for Health and Clinical List of authors: Excellence (NICE) as part of the single technology J Shepherd, E Gospodarevskaya, G Frampton and K appraisal (STA) process. The submission’s Cooper evidence came from five randomised controlled trials (RCTs), of good methodological quality and Contact details: Jonathan Shepherd, Southampton Health Technology measuring a range of clinically relevant outcomes, Assessments Centre, Wessex Institute for Health comparing entecavir with lamivudine. After 1 year Research and Development, University of Southampton, of treatment entecavir was statistically superior Mailpoint 728, Boldrewood, Southampton SO16 7PX, to lamivudine in terms of the proportion of UK. patients achieving hepatitis B virus (HBV) DNA suppression, alanine aminotransferase (ALT) E-mail: [email protected] normalisation and histological improvement, but The research reported in this article of the journal not in terms of the proportion of patients achieving supplement was commissioned and funded by the hepatitis B e antigen (HBeAg) seroconversion. HTA programme on behalf of NICE as project number The incidence of adverse or serious adverse events 07/67/01. The assessment report began editorial review was similar for both treatments. The results of in August 2008 and was accepted for publication in April the manufacturer’s mixed treatment comparison 2009. See the HTA programme web site for further project information (www.hta.ac.uk). This summary (MTC) model to compare entecavir with the of the ERG report was compiled after the Appraisal comparator drugs in nucleoside-naive patients were Committee’s review. considered to be uncertain because of concerns over its conduct and reporting. For the economic The views and opinions expressed therein are those of evaluation the manufacturer constructed two the authors and do not necessarily reflect those of the Markov state transition models, one in HBeAg- Department of Health. positive and one in HBeAg-negative patients. The Discussion of ERG reports is invited. Visit the HTA modelling approach was considered reasonable website correspondence forum (www.hta.ac.uk/ subject to some uncertainties and concerns over correspond). some of the structural assumptions. In HBeAg- positive patients the base-case incremental cost- effectiveness ratios (ICER) for entecavir compared with lamivudine and pegylated interferon alpha-2a were £14,329 and £8403 per quality-adjusted life- 31

year (QALY) respectively. Entecavir was dominated by the evidence review group (ERG), an external by telbivudine. In HBeAg-negative patients the organisation independent of NICE. This paper base-case ICERs for entecavir compared with presents a summary of the ERG report for the STA lamivudine, pegylated interferon alpha-2a and of entecavir for the treatment of chronic hepatitis B telbivudine were £13,208, £7511 and £6907 per (CHB). QALY respectively. In HBeAg-positive lamivudine- refractory patients entecavir dominated adefovir added to lamivudine. In one-way deterministic Description of the sensitivity analysis on all key input parameters for underlying health problem entecavir compared with lamivudine in nucleoside- naive patients, ICERs generally remained under Hepatitis B is an infectious disease of the liver £30,000 per QALY. In probabilistic sensitivity caused by the hepatitis B virus (HBV). It is analysis in nucleoside-naive HBeAg-positive transmitted through blood-to-blood contact patients the probability of the ICER for entecavir (e.g. through sharing of blood-contaminated being below £20,000 per QALY was 57%, 82% needles by drug users) and sexual contact. It is and 45% compared with lamivudine, pegylated also transmitted vertically from mother to infant interferon alpha-2a and telbivudine respectively. during or soon after birth. Infected individuals In nucleoside-naive HBeAg-negative patients the develop an acute infection, which may or may not probabilities were 90%, 100% and 96% respectively. result in symptoms. The majority of those infected The manufacturer’s lifetime treatment scenario for during adulthood make a full recovery and acquire HBeAg-negative patients and the ERG’s 20-year immunity from future infection. Only about 2–10% treatment scenario for HBeAg-positive patients of infected adults will develop CHB, defined as increased the ICERs, particularly in the latter viraemia and hepatic inflammation that persists for case. Amending the HBeAg-negative model so more than 6 months after acute infection with HBV. that patients with compensated cirrhosis would In contrast, almost 100% of infected neonates and also receive lifetime treatment gave probabilities about 50% of infected young children will develop of entecavir being cost-effective at a willingness CHB if infected with HBV. to pay of £20,000 and £30,000 of 4% and 40% respectively. The NICE guidance issued in August Active infection can be described as HBeAg 2008 as a result of the STA states that entecavir is positive or HBeAg negative according to whether recommended as an option for the treatment of hepatitis B ‘e’ antigen (HBeAg) is secreted. HBeAg people with chronic HBeAg-positive or HBeAg- is an indicator of viral replication, although some negative hepatitis B in whom antiviral treatment is variant forms of the virus do not express HBeAg. indicated. The response to treatment and rates of progression differ between the two forms. People can be Introduction infected with the so-called HBeAg-negative form of the virus initially, or the viral mutation can emerge The National Institute for Health and Clinical later in the course of infection in people initially Excellence (NICE) is an independent organisation infected with the HBeAg-positive form of the virus. within the NHS that is responsible for providing Chronic infection with mutant strains of HBV national guidance on the treatment and care of that do not produce the ‘e’ antigen (i.e. HBeAg people using the NHS in England and Wales. negative) is associated with a fluctuating course and One of the responsibilities of NICE is to provide a poor prognosis. guidance to the NHS on the use of selected new and established health technologies, based on an The Department of Health estimates that about appraisal of those technologies. 180,000 people in the UK have CHB. There are about 7700 new cases of CHB each year. Of these, NICE’s single technology appraisal (STA) process around 300 people were infected within the UK; is specifically designed for the appraisal of a single the remainder (mainly immigrants to the UK) product, device or other technology, with a single were infected abroad, generally in areas of high indication, for which most of the relevant evidence prevalence where the virus is frequently transmitted lies with one manufacturer or sponsor.1 Typically, from mother to child. it is used for new pharmaceutical products close to launch. The principal evidence for an STA is The progression to cirrhosis occurs at an annual derived from a submission by the manufacturer/ rate of 2–5.5%, with a cumulative 5-year rate of sponsor of the technology. In addition, a report progression of 8–20% in HBeAg-positive CHB and 32 reviewing the evidence submission is submitted an annual rate of 8–10% in HBeAg-negative CHB. Health Technology Assessment 2009; Vol. 13: Suppl. 3

Scope of the ERG report commentary on the manufacturer’s model using standard checklists. A one-way sensitivity analysis, The ERG critically evaluated the evidence scenario analysis and a probabilistic sensitivity submission from Bristol Myers Squibb on the use analysis were undertaken by the ERG. of entecavir for the treatment of CHB. Entecavir has a marketing authorisation in the UK for the treatment of chronic HBV infection in adults Results with compensated liver disease and evidence Summary of submitted of active viral replication, persistently elevated clinical evidence serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or The manufacturer’s systematic review included fibrosis. five randomised controlled trials (RCTs), all of which compared entecavir with lamivudine. Three The population considered in the scope was adults of the trials were conducted in nucleoside-naive with CHB according to the licensed indication. patients (one in HBeAg-positive patients, one Patient subgroups included those with HBeAg- in HBeAg-negative patients and one in a mixed positive and HBeAg-negative CHB and those HBeAg-positive and HBeAg-negative status group). who are treatment (nucleoside analogue) naive or The other two were conducted in lamivudine- refractory to lamivudine (e.g. those with persistent refractory patients (one in HBeAg-positive viraemia and/or genotypical resistance). Patients patients, the other in a mixed HBeAg-positive with coinfections were excluded in accordance with and HBeAg-negative status group). Outcome the scope. The intervention was entecavir alone in data were reported for up to 1 year of treatment, the treatment of CHB. and for a subset of patients who did not achieve a complete response and who continued treatment Comparators included the nucleoside analogues in year 2. Cumulative proportions of all patients lamivudine and telbivudine; the nucleotide ever attaining a treatment response up to 2 years analogue adefovir dipivoxil; and the immune were also presented. Some of the patients from modifiers interferon alpha-2a and -2b and the RCTs have entered long-term observational pegylated interferon alpha-2a. extension studies, with treatment continuing for up to 5 years; however, fully published data are not yet Outcomes included HBeAg/HBsAg seroconversion available. rate, virological response (HBV DNA), histological improvement (liver inflammation and fibrosis), After 1 year of treatment entecavir was statistically biochemical response (e.g. ALT levels), superior to lamivudine in terms of the proportion development of viral resistance and adverse events. of patients achieving HBV DNA suppression, ALT Outcomes included in the scope and decision normalisation and histological improvement. problem, but not reported in the submission There was no statistically significant difference include time to treatment failure, survival (unless between the treatments in the proportion of within the context of adverse events) and health- patients achieving HBeAg seroconversion (HBeAg- related quality of life. positive patients only, by definition). Most of the entecavir-treated patients did not have any detectable resistance-associated substitutions at Methods 1 year of treatment. The proportions of patients with any adverse events or serious adverse events The ERG report comprised a critical review of the were similar for entecavir and lamivudine. The evidence for the clinical effectiveness and cost- proportions of patients who withdrew during the effectiveness of the technology based upon the first year because of adverse events were similar manufacturer’s/sponsor’s submission to NICE as for entecavir and lamivudine except in one trial part of the STA process. in which significantly more lamivudine patients withdrew. The number of deaths during treatment The ERG checked the literature searches and was low (< 1% in all cases). applied the NICE critical appraisal checklist to the included studies and checked the quality of The manufacturer also constructed a mixed the manufacturer’s submission with the Centre treatment comparison (MTC) model to compare for Reviews and Dissemination (CRD) quality entecavir with the comparator drugs in nucleoside- assessment criteria for a systematic review. naive patients. An MTC was not considered In addition, the ERG checked and provided possible in lamivudine-refractory patients because 33

of lack of evidence. The results of the MTC One-way deterministic sensitivity analysis for generally accord with the results of the RCTs in entecavir compared with lamivudine on all key that, with the exception of HBeAg seroconversion, input parameters, and performed for nucleoside- entecavir was superior to lamivudine across naive patients, showed that the results were most outcomes. The MTC suggests that entecavir is sensitive to the baseline transition probabilities either significantly better or equivalent to the other from CHB to seroconversion (spontaneous comparators, depending on the outcome measure seroconversion) and active cirrhosis, the baseline and the time point. transition probability from active cirrhosis to decompensated cirrhosis, baseline cirrhosis risk Summary of submitted cost- and treatment effects. ICERs generally remained effectiveness evidence under £30,000 per QALY.

The manufacturer’s economic evaluation The probabilistic sensitivity analysis in nucleoside- comprised a systematic review of economic naive HBeAg-positive patients showed that evaluations of CHB treatments and a cost–utility the probability of the ICER for entecavir being analysis based on a de novo economic model. below £20,000 per QALY was 57% compared with lamivudine, 82% compared with pegylated Two Markov state transition models were interferon alpha-2a and 45% compared with constructed, one in HBeAg-positive patients and telbivudine. In nucleoside-naive HBeAg-negative one in HBeAg-negative patients. The models patients the probabilities were 90%, 100% and 96% estimated progression to 14 health states (15 respectively. in the HBeAg-negative model) representative of progressive CHB-related liver disease (e.g. The manufacturer included a lifetime treatment compensated and decompensated cirrhosis, scenario in HBeAg-negative patients and the ERG hepatocellular carcinoma). The models had a included a scenario of up to 20 years treatment for lifetime horizon and a cycle length of 1 year. HBeAg-positive patients. The ICERs increased as a consequence, particularly in the latter case. In HBeAg-positive and -negative nucleoside-naive patients, the models compared entecavir with The ERG updated the sensitivity analyses with lamivudine, pegylated interferon alpha-2a and utilities and drug costs varied by ± 20%. The model telbivudine. Treatment lasted for 2 years in HBeAg- for HBeAg-positive patients was most sensitive to positive patients and 5 years in HBeAg-negative changes in response and CHB utility rates and the patients (with the exception of pegylated interferon transition probabilities from CHB to compensated alpha-2a, which was given for only 1 year). In cirrhosis and CHB to seroconversion. The model HBeAg-positive patients who were refractory to for HBeAg-negative patients was most sensitive lamivudine, entecavir was compared with adefovir to changes in the response rates and resistance added to lamivudine for 2 years. Response to utility and the transition probabilities between treatment was defined by HBeAg seroconversion compensated cirrhosis and decompensated and undetectable HBV DNA. cirrhosis and between CHB treatment and compensated cirrhosis. In HBeAg-positive patients the base-case incremental cost-effectiveness ratio (ICER) for The ERG conducted a probabilistic sensitivity entecavir compared with lamivudine was £14,329 analysis using wider uncertainty around the utilities per quality-adjusted life-year (QALY). Compared (± 10%) and drug costs (± 20%) than presented with pegylated interferon alpha-2a the ICER was in the manufacturer’s submission. In the HBeAg- £8403 per QALY. Entecavir was associated with positive model, patients with CHB were treated for the same number of QALYs as telbivudine, but 2 years with entecavir, lamivudine or telbivudine, at a slightly higher total cost and was therefore but it was considered more appropriate for them to dominated. In HBeAg-negative patients the be treated for longer. The ERG attempted to run base-case ICERs for entecavir compared with the HBeAg-positive model for a longer duration lamivudine, pegylated interferon alpha-2a and but the results were inconsistent with those from telbivudine were £13,208, £7511 and £6907 per the deterministic scenario analyses. QALY respectively. In HBeAg-positive lamivudine- refractory patients entecavir dominated adefovir The ERG ran the HBeAg-negative model for added to lamivudine. a lifetime treatment duration. The model was

34 Health Technology Assessment 2009; Vol. 13: Suppl. 3

amended so that patients with compensated judged to be internally and externally consistent, cirrhosis would also receive treatment, lasting subject to some uncertainties (see Conclusions). until they developed decompensated cirrhosis, hepatocellular carcinoma or died. As can be seen Disease progression pathways assumed in the from Figure 1 the probability of entecavir being economic models were generally consistent with the cost-effective at a willingness to pay of £20,000 and natural history of CHB, although there were some £30,000 was 4% and 40% respectively. concerns about some of the structural assumptions (see Conclusions).

Commentary on Weaknesses the robustness of submitted evidence The MTC suffers from certain limitations in conduct and reporting, including small numbers Strengths of studies/single studies in some networks, no The manufacturer conducted a systematic search assessment or discussion of heterogeneity and for clinical effectiveness and cost-effectiveness no reporting of criteria for judging statistical studies of entecavir. It appears unlikely that the significance or equivalence. searches missed any additional trials that would have met the inclusion criteria. Conclusions The five entecavir RCTs identified were of Areas of uncertainty generally good methodological quality and measured a range of outcomes that are appropriate Given the concerns about the conduct and and clinically relevant, although health-related reporting of the MTC the ERG considers its results quality of life was not reported. Overall, the to be uncertain. This limits any conclusions that manufacturer’s submission presents an unbiased can be drawn regarding the comparative efficacy estimate of the efficacy of entecavir versus of entecavir and telbivudine and entecavir and lamivudine, based on the results of the five RCTs. pegylated interferon alpha-2a in nucleoside-naive patients (notwithstanding the head-to-head RCT Overall, the manufacturer’s economic evaluation evidence comparing entecavir with lamivudine). accords with the decision problem and the NICE reference case. The approach to modelling was There is relatively limited clinical effectiveness generally considered reasonable and the model was and cost-effectiveness evidence for entecavir in

1.0 ENT LAM 0.8 TEL PegIFN

0.6

0.4 Probabilty of cost-effective Probabilty 0.2

0.0 0 10000 20000 30000 40000 50000 Willingness to pay (£)

FIGURE 1 Cost effectiveness acceptability curves for entecavir, lamivudine, telbivudine and pegylated interferon for the HBeAg-negative model. ENT, entecavir; LAM, lamivudine; PEG IFN, pegylated interferon alpha; TEL, telbivudine. 35

Title: 07/67/01 Proof Stage: 1 Figure Number: 1.ai

Cactus Design and Illustration Ltd Entecavir for the treatment of chronic hepatitis B infection

lamivudine-refractory patients. Head-to-head RCT Contrary to the assumptions in the manufacturer’s evidence is available for entecavir versus ongoing economic evaluation, a certain proportion of lamivudine but only in HBeAg-positive patients. CHB patients will first present with compensated Smaller RCTs have been published comparing cirrhosis. Moreover, it is unlikely that treatment switching to adefovir versus adding adefovir to will be terminated once patients progress to the ongoing lamivudine, but these have not been active cirrhosis stage of disease. Changing these compared in a statistical indirect comparison assumptions to reflect a more realistic scenario to entecavir. The manufacturer presented cost- increased the ICER for entecavir compared with effectiveness estimates only for HBeAg- positive, lamivudine. not HBeAg-negative, lamivudine-refractory patients. Summary of NICE guidance Structural assumptions in both the HBeAg-positive issued as a result of the STA and HBeAg-negative disease models precluded the patients with response from directly entering The Final Appraisal Determination issued by NICE the active/compensated cirrhosis health state. The in June 2008 states that: rationale for this assumption was not clear and it is not possible to estimate the impact of these Entecavir, within its marketing authorisation, is structural assumptions. recommended as an option for the treatment of people with chronic HBeAg-positive or HBeAg- Treatment of CHB in many patients will be negative hepatitis B in whom antiviral treatment is longer than the 2 and 5 years assumed in the indicated. HBeAg-positive and HBeAg-negative disease models respectively. However, there is a paucity of published clinical effectiveness data from Key references RCTs beyond the second year of treatment [long- 1. National Institute for Health and Clinical term observational studies (up to 5 years) are in Excellence. Guide to the single technology (STA) process. progress]. Increasing the treatment duration in 19 September 2006. URL: www.nice.org.uk/page. scenario analysis resulted in higher ICERs. aspx?o=STAprocessguide.

No data were presented in the submission on the efficacy and safety of entecavir in combination with other licensed agents.

36 DOI: 10.3310/hta13suppl3/06 Health Technology Assessment 2009; Vol. 13: Suppl. 3

Febuxostat for the treatment of hyperuricaemia in people with gout: a single technology appraisal

M Stevenson* and A Pandor School of Health and Related Research (ScHARR), University of Sheffield, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 07/69/01

This paper presents a summary of the evidence Date of ERG submission: review group (ERG) report into the clinical March 2008 effectiveness and cost-effectiveness of febuxostat TAR Centre(s): for the management of hyperuricaemia in The School of Health and Related Research (ScHARR) patients with gout based upon a review of the List of authors: manufacturer’s submission to the National Institute M Stevenson and A Pandor for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) Contact details: process. The submission’s evidence came from Matt Stevenson, Technical Director ScHARR-TAG, two randomised controlled trials comparing the ScHARR, University of Sheffield, Regent Court, 30 Regent Street, Sheffield S1 4DA, UK efficacy and safety of febuxostat with allopurinol. The trials were of reasonable methodological E-mail: [email protected] quality and measured a clinically relevant range The research reported in this article of the journal of outcomes. A pooled clinical efficacy analysis supplement was commissioned and funded by the showed that a daily dose of 80 mg or 120 mg HTA programme on behalf of NICE as project number of febuxostat was significantly more effective 07/69/01. The assessment report began editorial review than fixed-dose allopurinol (300/100 mg/day) at in October 2008 and was accepted for publication lowering serum uric acid (sUA) levels to therapeutic in April 2009. See the HTA programme web site for targets (< 6 mg/dl); however, a large percentage further project information (www.hta.ac.uk). This of febuxostat patients did not achieve the summary of the ERG report was compiled after the primary end point and the fixed-dose allopurinol Appraisal Committee’s review. regimen may have introduced bias. There were no The views and opinions expressed therein are those of differences between treatments in more clinically the authors and do not necessarily reflect those of the important outcomes such as gout flares and Department of Health. tophi resolution after 52 weeks of treatment. No Discussion of ERG reports is invited. Visit the HTA subgroup analyses were conducted for patients with website correspondence forum (www.hta.ac.uk/ renal impairment, non-responders to allopurinol correspond). or patients with severe disease. Supplementary data from a 2-year open-label extension study were also provided, but were difficult to interpret and poorly reported. The incidence of adverse events was similar between treatments, although more febuxostat recipients discontinued treatment prematurely. A decision tree model was 37

developed to determine the cost-effectiveness Description of the of febuxostat. The scope was limited to the underlying health problem comparison of continual febuxostat treatment with continual allopurinol treatment. Switching Gout is a metabolic disorder that causes acute, between treatments or withdrawing treatment intermittent and painful attacks of arthritis in the in patients whose sUA levels had not decreased joints of the foot (especially the big toe), knee, was not permitted. The model predicted a cost- hand and wrist. Gout occurs when there is a effectiveness of £16,324 [95% confidence interval sudden onset of inflammation as a result of excess (CI) £6281 to £239,928] per quality-adjusted uric acid (crystals of monosodium urate) in the life-year (QALY) gained for febuxostat compared blood (hyperuricaemia) and tissues. Urate crystals with allopurinol after 2 years of treatment. The deposited in and around joints and tissue are incremental cost per QALY was below £20,000 in known as tophi,4 which can cause significant pain. 63% of the simulations undertaken. Changes in the time horizon did not materially affect the results. The incidence of gout has been estimated to range The ERG believes that the modelling structure from 11.9 to 18.0 cases per 10,000 patient-years.�5 employed was not appropriate to estimate the Incidence is affected by both age and gender, cost-effectiveness of febuxostat within a treatment with men aged from 65 to 84 years having an algorithm. In addition, there were concerns incidence rate approximately 60 times greater than about the methodology used for collecting data that in women aged below 45 years.5 The overall on key model inputs. Given these reservations prevalence of gout in the UK has been estimated the cost-effectiveness of febuxostat could not be at 1.4%,5,6 with this value being 7.3% among men determined. The guidance issued by NICE in aged from 65 to 75 years.5 August 2008 as a result of the STA states that febuxostat is recommended as an option for the management of chronic hyperuricaemia in gout Scope of the ERG report only for people who are intolerant of allopurinol or for whom allopurinol is contraindicated. The objective of the appraisal was to assess the clinical effectiveness and cost-effectiveness of Introduction febuxostat for the management of hyperuricaemia in adults with gout in whom urate deposition The National Institute of Health and Clinical has already occurred (including a history or Excellence (NICE) is an independent organisation presence of tophus and/or gouty arthritis). The within the NHS that is responsible for providing comparators included: allopurinol, alternative national guidance on the treatment and care of standard care (including sulphinpyrazone, people using the NHS in England and Wales. benzbromarone, probenecid or a combination One of the responsibilities of NICE is to provide of these) for adults unresponsive to or with guidance to the NHS on the use of selected new hypersensitivity to allopurinol, and allopurinol and established health technologies, based on an (dose adjusted according to glomerular filtration appraisal of those technologies. rate), benzbromarone or a combination of these for adults with renal impairment. The outcomes NICE’s single technology appraisal (STA) process measured included surrogate [serum uric acid is specifically designed for the appraisal of a single levels (sUA)] and clinical outcomes (gout flares, product, device or other technology, with a single reduction in tophi size), tolerance and health- indication, for which most of the relevant evidence related quality of life. lies with one manufacturer or sponsor.1,2 Typically, it is used for new pharmaceutical products close The main evidence presented in support of the to launch. The principal evidence for an STA is clinical effectiveness of febuxostat was based on two derived from a submission by the manufacturer/ head-to-head, phase III, randomised controlled sponsor of the technology. In addition, a report trials [the Febuxostat Allopurinol Controlled reviewing the manufacturer’s evidence submission Trial (FACT) study7 and the Allopurinol and is submitted by the evidence review group (ERG), Placebo-controlled Efficacy study of febuXostat an external organisation independent of NICE. (APEX) trial8] comparing the efficacy and safety This paper presents a summary of the ERG report of febuxostat with fixed-dose allopurinol. The for the STA of febuxostat for the management of manufacturer did not present comparisons with hyperuricaemia in patients with gout.3 alternative comparators (such as sulphinpyrazone,

38 Health Technology Assessment 2009; Vol. 13: Suppl. 3

benzbromarone, probenecid or a combination of there were generally no differences between these) for adults unresponsive to, or intolerant of, treatments in more clinically important outcomes allopurinol or with renal impairment. such as gout flares and tophi resolution (secondary end points). The scope of the manufacturer’s cost-effectiveness submission was limited to the comparison of A post hoc subgroup analysis showed that continual febuxostat treatment with continual febuxostat was more effective than allopurinol in allopurinol treatment. Switching between decreasing sUA levels to < 6 mg/dl in patients with treatments was not permitted, nor was there the baseline sUA concentrations of < 9 mg/dl, between possibility of withdrawing treatment in patients 9 and 10 mg/dl and > 10 mg/dl. In addition, whose sUA levels had not decreased. Although significantly more febuxostat recipients than fixed- the dosage level of febuxostat was allowed to vary, dose allopurinol recipients achieved a reduction in increasing from 80 mg daily to 120 mg daily in sUA levels to therapeutic targets (< 5 mg/dl). No patients not initially responding to treatment, the subgroup analyses were conducted for patients with dose of allopurinol was assumed fixed at 300 mg renal impairment, non-responders to allopurinol per day. Costs were considered from an NHS or patients with severe disease. and personal social services perspective. Cost- effectiveness was expressed in terms of incremental Supplementary data from an ongoing, long-term, cost per quality-adjusted life-year (QALY) gained, open-label extension study (EXCEL – fEbuXostat/ with a time horizon of 2 years used for the base- allopurinol Comparative Extension Long-term case results. study) of the two head-to-head trials showed that more patients on febuxostat (80 mg/day and 120 mg/day) than on fixed-dose allopurinol (300/100 Methods mg/day) remained on initial treatment after more than 24 months of follow-up, and the number of The ERG report comprised a critical review of the tophi and gout flares were reduced over time in evidence for the clinical effectiveness and cost- these patients. However, these data need to be effectiveness of the technology based upon the interpreted with caution as the manufacturer’s manufacturer’s/sponsor’s submission to NICE as submission does not provide statistical analysis part of the STA process. A narrative critique of the of event rates over time or data on withdrawals submitted evidence was presented. The economic because of gout flares, adverse events or non- model submitted by the manufacturer was regarded response. as inappropriate to assess the decision problem. Although the adverse event profile was similar in those receiving febuxostat compared with Results those receiving allopurinol, more febuxostat Summary of submitted recipients discontinued treatment prematurely clinical evidence [the statistical analysis comparing the rates of discontinuation between the treatment groups was A pooled (not meta-analysed) clinical efficacy not reported in the manufacturer’s submission or analysis of two head-to-head, multiarm, in the requested supplementary data; however, randomised, double-blind, controlled trials (52- the primary published peer-reviewed clinical week FACT study7 and 28-week APEX trial8) paper for the FACT study reports that the rates comparing the efficacy and safety of febuxostat of discontinuation were significantly higher in with fixed-dose allopurinol in 1689 patients with febuxostat recipients (p < 0.04) than in those hyperuricaemia (sUA levels ≥ 8 mg/dl) and gout receiving allopurinol]. Reasons for withdrawal showed that febuxostat (80 mg/day and 120 mg/ included gout flares and adverse events such as day) was significantly more effective than fixed- liver function test abnormalities. dose allopurinol (300/100 mg/day) at reducing sUA levels to < 6 mg/dl. However, a large percentage of Summary of submitted cost- patients on febuxostat did not achieve the primary effectiveness evidence end point and the fixed-dose regimen employed for allopurinol patients may have introduced bias. A decision tree model was developed in Microsoft excel. The model subdivided patients into four Despite the significantly greater effect on sUA mutually exclusive categories of sUA levels, which levels with febuxostat (including mean percentage were related to both the expected number of gout reduction from baseline) than with allopurinol, flares and the underlying utility of a patient. Two 39

identical cohorts of men and women entered the The ERG considered the modelling structure model with an assumed baseline sUA acid level of ≥ inappropriate. Given the nature of the disease 8 mg/dl. One cohort was assumed to receive 80 mg/ and the interventions it was deemed likely that a day of febuxostat treatment, increased to 120 mg/ treatment algorithm that started all patients on the day in those patients who did not adequately relatively inexpensive allopurinol and which treated respond; the remaining cohort was assumed to those who did not respond with the more expensive receive 300 mg/day of allopurinol. The primary febuxostat would be more cost-effective than the analysis was for a period of 2 years; however, strategies evaluated in the submission. The ERG sensitivity analyses were undertaken using different requested that the following analysis be undertaken time periods. at a minimum: allopurinol – febuxostat – no treatment; febuxostat – allopurinol – no treatment; The manufacturer’s submission predicted a allopurinol – no treatment and febuxostat – no cost-effectiveness of £16,324 (95% CI £6281 treatment; however, the manufacturer did not to £239,928) per QALY gained for febuxostat comply with this request. compared with allopurinol after 2 years of treatment. The incremental cost per QALY Even overlooking the inappropriateness of the was below £20,000 in 63% of the simulations model structure there were a number of errors undertaken. Changes in the time horizon did not within the analyses presented. For example, the materially affect the results. price of allopurinol was incorrect and the price of febuxostat was altered within the probabilistic sensitivity analyses. Reanalyses were not undertaken Commentary on by the manufacturer despite these issues being the robustness of raised. submitted evidence The ERG has serious concerns regarding the data The manufacturer conducted an adequate selected to estimate the relationship between sUA systematic search for clinical effectiveness and cost- levels and the number of gout flares expected. A effectiveness studies of febuxostat for the treatment large portion of the data collected to develop this of gout. It appears unlikely that any additional linkage was excluded (accounting for 51% of all trials would have met the inclusion criteria had the patients and 77% of UK patients), and the ERG search been widened to include other databases. was not convinced by the arguments provided to The processes undertaken by the manufacturer for exclude these data. screening studies, data extraction and applying quality criteria to included studies are not explicitly The ERG has additional serious concerns about clear in the submission. These factors limit the the interpretation of the multivariate analyses. It robustness of the systematic review. is indicated that there is no significant association between sUA levels and the number of gout flares The two identified trials, which represent the reported within the data set used. This analysis has main clinical efficacy evidence, were of reasonable apparently been overlooked in favour of a bivariate methodological quality (with some limitations) analysis that does not include other confounders. and measured a range of outcomes that are as Note that, although no statistically significant appropriate and clinically relevant as possible. relationship was found within this data set, this Although a simple pooled analysis of the individual does not mean that such a relationship does not patient level data from the two head-to-head exist, as indicated in clinical guidelines. trials was undertaken by the manufacturer, the methods for this type of data pooling were not The ERG noted that the chronic utility gain explicitly described. The statistical approach for associated with reduced sUA levels was a key driver combining the data appears to be inappropriate as in the cost per QALY gained ratio. It was noted it fails to preserve randomisation and introduces that the relationship between sUA level and chronic bias and confounding. The resulting pooled utility had been modelled assuming a linear data should therefore be treated with caution. A relationship. The evidence for this assumption was meta-analysis undertaken by the ERG showed uncertain and not clearly established. that the methodology used by the manufacturer to synthesise the data was unlikely to alter the The ERG noted that the derivation of the disutility conclusions on efficacy. associated with a gout flare came from data that did

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not appear internally consistent, with some people conditions 700–900 mg/day). Nevertheless, the giving greater utility to a health state associated manufacturer’s submission and our clinical advisors with a gout flare than to one without such a flare. suggest that dose escalation is rarely used by most clinicians in clinical practice. The ERG further noted that the dose of allopurinol was assumed to be fixed, whereas guidelines allow Although measures such as gout flares and tophi for the upwards titration of this dose. Although the resolution were secondary outcomes, these are manufacturer reported that the dose of allopurinol more clinically important. Randomised controlled commonly used was 300 mg/day, this does not trial evidence shows that even though more represent best practice, which allows for doses of febuxostat recipients achieved the recommended 900 mg/day of allopurinol. biochemical goal (< 6 mg/dl) this did not translate into an advantage over allopurinol in clinically important outcomes. Conclusions As previously described, the ERG has serious The clinical evidence, based on a simple pooled concerns regarding the model structure (and analysis of the patient level data from two choice of treatment algorithms compared) and the randomised controlled trials, showed that a robustness of key parameters within the model. daily dose of 80 mg or 120 mg of febuxostat was significantly more efficacious than allopurinol at Areas of uncertainty the commonly used fixed daily dose of 300 mg in lowering sUA levels to therapeutic targets (< 6 mg/ There is uncertainty around the clinical dl). However, a large percentage of patients effectiveness and cost-effectiveness of febuxostat in on febuxostat did not achieve the primary end comparison to other relevant treatments (including point and the fixed-dose regimen employed for sulphinpyrazone, benzbromarone, probenecid or allopurinol patients may have introduced bias. a combination of these) for adults unresponsive In general, there were no differences between to, or intolerant of, allopurinol or with renal treatments in more clinically important outcomes impairment. In addition, long-term efficacy and such as gout flares and tophi resolution after 52 safety data are limited on febuxostat and there is weeks of treatment. No subgroup analyses were uncertainty around the relationship between sUA conducted for patients with renal impairment, levels and the expected number of gout flares. non-responders to allopurinol or patients with severe disease. Supplementary data from a 2-year The incremental costs per QALY of sequential open-label extension study were also provided, but approaches of treatment are uncertain as these were difficult to interpret (no statistical analysis approaches have not been modelled. The inclusion undertaken) and poorly reported. of sequential treatments is likely to produce a more cost-effective solution than allowing only one The ERG believes that the modelling structure treatment for the duration of the model. Moreover, employed was not appropriate to estimate the there is uncertainty in the relationship between cost-effectiveness of febuxostat within a treatment sUA levels and underlying patient utility. algorithm. In addition, there were concerns about the methodology used for collecting data on key model inputs. Given these reservations Summary of NICE guidance the cost-effectiveness of febuxostat could not be issued as a result of the STA determined. The appraisal consultation document issued by Key issues NICE in May 2008 stated that:

The head-to-head trials presented in the Febuxostat is not recommended for the manufacturer’s submission directly compared management of chronic hyperuricaemia in people febuxostat with fixed-dose allopurinol. However, with gout. gout management guidelines and the allopurinol summary of product characteristics generally The manufacturer appealed against the recommend dose titration of allopurinol according preliminary decision and produced additional to therapeutic targets (usual maintenance dose in evidence not contained in the STA submission mild conditions 100–200 mg/day, in moderately that compared febuxostat with no treatment. This severe conditions 300–600 mg/day, in severe evidence was not formally critiqued by the ERG. 41

In August 2008 the final appraisal determination 3. Stevenson M, Pandor A. Febuxostat for the management of hyperuricaemia in patients with gout: a single was released with the guidance that febuxostat, technology appraisal. 2008. URL: www.ncchta.org/erg/ within its marketing authorisation, is recommended reports/1704.pdf. as an option for the management of chronic hyperuricaemia in gout only for people who are 4. Falasca GF. Metabolic diseases: gout. Clin Dermatol intolerant of allopurinol or for whom allopurinol is 2006;24:498–508. contraindicated. 5. Mikuls TR, Farrar JT, Bilker WB, Fernandes S, Intolerance of allopurinol was defined as: Schumacher HR, Saag KG. Gout epidemiology: results from the UK General Practice Research adverse effects that are sufficiently severe to Database, 1990–1999. Ann Rheum Dis 2005;64:267– warrant its discontinuation, or to prevent full 72. dose escalation for optimal effectiveness as 6. Annemans L, Spaepen E, Gaskin M, Bonnemaire appropriate within its marketing authorisation. M, Malier V, Gilbers T, et al. Gout in the UK and Germany: prevalence, comorbidities and At the time of writing the manufacturer was management in general practice 2000–2005. Ann appealing this decision. Rheum Dis 2007;8;67:960–6.

7. Becker MA, Schumacher R, Wortmann RL, Key references MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients 1. National Institute for Health and Clinical with hyperuricemia and gout. N Engl J Med Excellence. Single technology appraisal (STA) – 2005;353:2450–61. specification for manufacturer/sponsor submission of evidence. URL: www.nice.org.uk/niceMedia/pdf/ 8. Schumacher HR, Becker MA, Wortmann RL, STASpecManufacturerSubofEvidence.pdf. MacDonald PA, Hunt B, Streit J, et al. Febuxostat vs allopurinol and placebo in subjects with 2. National Institute for Health and Clinical hyperuricemia and gout: the 28-week APEX study. Excellence. Guide to the single technology (STA) process. Poster presented at the Annual Scientific meeting of 19 September 2006. URL: www.nice.org.uk/page. the American College of Rheumatology, San Diego, aspx?o=STAprocessguide. CA, 16–17 November 2005.

42 DOI: 10.3310/hta13suppl3/07 Health Technology Assessment 2009; Vol. 13: Suppl. 3

Rivaroxaban for the prevention of venous thromboembolism: a single technology appraisal

M Stevenson,* A Scope, M Holmes, A Rees and E Kaltenthaler School of Health and Related Research (ScHARR), University of Sheffield, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 08/03/01

This paper presents a summary of the evidence Date of ERG submission: review group (ERG) report into the clinical 13 March 2009 effectiveness and cost-effectiveness of rivaroxaban TAR Centre(s): for the prevention of venous thromboembolism School of Health and Related Research (ScHARR) (VTE) in adult patients undergoing elective hip List of authors: or knee replacement surgery based upon a review M Stevenson, A Scope, M Holmes, A Rees and E of the manufacturer’s submission to the National Kaltenthaler Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal Contact details: (STA) process. The submission’s evidence came Matt Stevenson, School of Health and Related Research (ScHARR), 30 Regent Street, University of Sheffield, from four randomised controlled trials (RCTs) Sheffield S1 4DA, UK comparing rivaroxaban with enoxaparin [RECORD (Regulation of Coagulation in Orthopedic E-mail: [email protected] surgery to pRevent Deep venous thrombosis and The research reported in this article of the journal pulmonary embolism) 1–4] and three comparing supplement was commissioned and funded by the dabigatran with enoxaparin [RE-NOVATE (the HTA programme on behalf of NICE as project number prevention of venous thromboembolism after 08/03/01. The assessment report began editorial review total hip replacement trial), RE-MODEL (the in February 2009 and was accepted for publication prevention of venous thromboembolism after total in April 2009. See the HTA programme website for knee replacement trial) and RE-MOBILIZE (the further project information (www.hta.ac.uk). This prevention of venous thromboembolism after total summary of the ERG report was compiled after the knee arthroplasty trial)]. The evidence from the Appraisal Committee’s review. four RECORD trials indicates that rivaroxaban had The views and opinions expressed therein are those of superior efficacy over enoxaparin after total hip the authors and do not necessarily reflect those of the replacement (THR) and total knee replacement Department of Health. (TKR). For the composite primary outcome Discussion of ERG reports is invited. Visit the HTA of any deep vein thrombosis (DVT), non-fatal website correspondence forum (www.hta.ac.uk/ pulmonary embolism (PE) and death from all correspond). causes the relative risk reductions were 70–79% in THR and 31–49% in TKR. Rivaroxaban also had superior efficacy over enoxaparin for the secondary outcome major VTE. Rivaroxaban was not inferior to enoxaparin on the safety outcome of major bleeding. After the correction of some errors found by the ERG, the manufacturer’s economic model represented a reasonable model 43

of patients receiving prophylaxis for THR or NICE’s single technology appraisal (STA) process TKR. In the base-case analyses rivaroxaban is specifically designed for the appraisal of a single dominated both enoxaparin and dabigatran. The product, device or other technology, with a single incremental costs saved and quality-adjusted life- indication, for which most of the relevant evidence years (QALYs) gained were small (below £200 lies with one manufacturer or sponsor.1 Typically, and 0.005, respectively, per person). Analyses it is used for new pharmaceutical products close were conducted sampling from the distributions to launch. The principal evidence for an STA is observed from the RCTs. When all parameters were derived from a submission by the manufacturer/ sampled rivaroxaban dominated enoxaparin in sponsor of the technology. In addition, a report all scenarios except for two, in which enoxaparin reviewing the evidence submission is submitted produced more QALYs than rivaroxaban and had by the evidence review group (ERG), an external an incremental cost per QALY gained of £5000 organisation independent of NICE. This paper and £8000 respectively. Rivaroxaban dominated presents a summary of the ERG report for the dabigatran when RECORD 1 and RECORD 2, STA of rivaroxaban for the prevention of venous individually or pooled, were compared with RE- thromboembolism (VTE),2 which followed a NOVATE and when all four rivaroxaban RCTs manufacturer’s submission by Bayer Schering pooled were compared with all three dabigatran Pharma.3 RCTs. Dabigatran dominated rivaroxaban comparing RECORD 4 with RE-MODEL and RE-MOBILIZE, and was more cost-effective than Description of the rivaroxaban comparing RECORD 3 (incremental underlying health problem cost per QALY gained of rivaroxaban compared with dabigatran of £123,000) or RECORD 3 The manufacturer’s submission reported that there and RECORD 4 pooled (incremental cost per are approximately 25,000 deaths each year in QALY gained of dabigatran compared with England due to VTE. This figure includes not only rivaroxaban of £400) with RE-MODEL and those undergoing surgery but also those admitted RE-MOBILIZE. In conclusion, the evidence to hospital for the medical care of serious illnesses indicates that rivaroxaban is not inferior to and will overestimate deaths associated with total enoxaparin in terms of the primary and secondary hip and knee replacement.3 outcomes. The submission presents a reasonable estimation of the cost-effectiveness of rivaroxaban compared with enoxaparin and dabigatran, Scope of the ERG report although the uncertainty in the decision has been underestimated. The results are particularly The manufacturer’s submission reported on the sensitive to any assumed difference in the number clinical and cost-effectiveness of rivaroxaban of fatal PEs, but the ERG does not believe there is (Xarelto®) for the prevention of VTE in adult sufficient evidence to support a difference between patients undergoing elective hip or knee interventions. The NICE guidance issued as a replacement surgery. The recommended dose result of the STA states that: riveroxaban, within of rivaroxaban is 10 mg taken orally once daily. its marketing authorisation, is recommended The duration of treatment recommended in the as an option for the prevention of venous summary of product characteristics depends on the thromboembolism in adults having elective THR or type of orthopaedic surgery. Patients undergoing elective TKB. total hip replacement (THR) have a recommended treatment duration of 5 weeks; this value is 2 weeks Introduction for total knee replacement (TKR). The acquisition cost of rivaroxaban reported in the manufacturer’s The National Institute of Health and Clinical submission was £4.50 per day. Excellence (NICE) is an independent organisation within the NHS that is responsible for providing The manufacturer’s submission considered national guidance on the treatment and care of enoxaparin, a low-molecular-weight heparin people using the NHS in England and Wales. (LMWH), as the most relevant comparator, as One of the responsibilities of NICE is to provide reflected in the scope. A weighted comparison guidance to the NHS on the use of selected new against all LMWHs was presented as a sensitivity and established health technologies, based on an analysis assuming equal efficacy between all appraisal of those technologies. LMWHs. Indirect comparisons with dabigatran

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(which NICE has recommended as an option for the ERG and no additional relevant trials were the primary prevention of venous thromboembolic identified. The ERG is confident that all relevant events in adults who have undergone elective studies were included in the manufacturer’s THR or elective TKR4) were undertaken. The submission and details of ongoing trials that are majority of outcome measures identified in the likely to be reporting additional evidence within scope [mortality, incidence of symptomatic and 12 months were reported. The inclusion/exclusion asymptomatic VTE, pulmonary embolism (PE)], criteria appeared to be appropriate; they included and safety outcomes (bleeding events), were appropriate detail and a rationale for the inclusion reported. However, outcomes relating to knee and and exclusion criteria was provided. The reasons hip joints, although identified in the scope, were provided for excluding studies were all justified. not reported. The manufacturer’s submission reported on efforts Clinical data on effectiveness were taken from four to ensure blinding but did not report if any of these randomised controlled trials (RCTs) of rivaroxaban studies assessed the success of blinding, as required compared with enoxaparin [RECORD (Regulation by point 11 on the Consolodated Standards of of Coagulation in Orthopedic surgery to pRevent Reporting Trials (CONSORT) checklist (www. Deep venous thrombosis and pulmonary embolism) consort-statement.org/). The view of the ERG is 1–45–8] and from three RCTs of dabigatran that such assessments were not undertaken. compared with enoxaparin [RE-NOVATE (the prevention of venous thromboembolism after The manufacturer’s submission answered total hip replacement trial),9 RE-MODEL(the the questions suggested by NICE for validity prevention of venous thromboembolism after total assessment. The ERG assessed the validity of the knee replacement trial)10 and RE-MOBILIZE (the three published trials (RECORD 1, RECORD 2 prevention of venous thromboembolism after total and RECORD 3) and the trial information for knee arthroplasty trial)11]. RECORD 4. This was found to be satisfactory and of adequate methodological quality. The manufacturer submitted a model in Microsoft excel. The model was divided into a prophylaxis The manufacturer’s submission used the modified stage (a period of 35 days for THR and 12 days intention-to-treat (MITT) population in the for TKR), a postprophylaxis stage (until 3 months analyses of the trials. The MITT population was after surgery) and a long-term complication stage defined as the number of patients who were: (1) (assumed to end when a patient died or became valid for safety analysis; (2) had the appropriate 101 years of age). The initial two stages were surgery; and (3) had an adequate assessment of assessed using a decision trees, whereas the third thromboembolism. The ERG judged this to be an phase was divided into a 5-year period, in which appropriate approach. VTE, post-thrombotic syndrome (PTS) or death could occur, followed by a duration in which only The manufacturer’s submission contained a series transitions to death were allowed. The base case in of meta-analyses. Each comparison was conducted the manufacturer’s submission assumed that only initially using a fixed-effects model, with a those parameters that were statistically significantly random-effects model performed if heterogeneity different would be varied between rivaroxaban and was observed between studies. Theoretically this the comparator. Additional analyses requested by approach is incorrect as a decision on the most the ERG used all variables regardless of statistical appropriate model should be made before analysis, significance. but this methodology did not materially affect the conclusions.

Methods The deterministic results produced by the model matched those reported in the manufacturer’s The ERG report comprised a critical review of the submission. The results from probabilistic evidence for the clinical effectiveness and cost- sensitivity analyses were not checked because effectiveness of the technology based upon the the ERG found errors within the model. These manufacturer’s/sponsor’s submission to NICE as errors were identified by a thorough, although part of the STA process. not exhaustive, review of the model structure and internal logic and the responsiveness of the results The searches performed by the manufacturer to changes in parameter values. were examined by the ERG and found to be satisfactory. Repeat searches were performed by 45

Results generated in the remaining parameters as largely Summary of submitted redundant. Using RECORD 4 alone, enoxaparin clinical evidence produced more QALYs than rivaroxaban and had an incremental cost per QALY gained of In RECORD 1, 3 and 4, rivaroxaban was approximately £5000; using the pooled results demonstrated to have superior efficacy over this value was approximately £8000. These results enoxaparin after THR and TKR. RECORD 2 also imply that enoxaparin was more cost-effective demonstrated superiority comparing 35 days of than rivaroxaban in both of these scenarios using rivaroxaban with 12–14 days of enoxaparin. Based current recommended thresholds.12 on the composite primary end point of any deep vein thrombosis (DVT), non-fatal PE and death When dabigatran was used as the comparator, from all causes the relative risk reductions were rivaroxaban dominated dabigatran when RECORD 70–79% in THR and 31–49% in TKR. Rivaroxaban 1 individually, RECORD 2 individually or the was also demonstrated to have superior efficacy pooled results from RECORD 1 and RECORD over enoxaparin in RECORD 1, 2 and 3 for the 2 were compared with RENOVATE and when all secondary end point of major VTE. Superior four rivaroxaban RCTs pooled were compared efficacy was also shown for the symptomatic VTE with all three dabigatran RCTs. Dabigatran end point in RECORD 2 and RECORD 3. dominated rivaroxaban using RECORD 4 compared with RE-MODEL and RE-MOBILIZE, There were no adverse events that were and was more cost-effective than rivaroxaban significantly different between rivaroxaban and using RECORD 3 compared with RE-MODEL and enoxaparin. Major bleeding occurred more RE-MOBILIZE (an incremental cost per QALY frequently in patients on rivaroxaban. Individually gained of rivaroxaban compared with dabigatran there was no statistically significant difference of approximately £123,000) and when RECORD 3 in major bleed rates between patients receiving and RECORD 4 were pooled and compared with rivaroxaban and those receiving enoxaparin, RE-MODEL and RE-MOBILIZE (an incremental although all point estimates favoured enoxaparin cost per QALY gained of dabigatran compared with treatment. On meta-analysing all four RCTs, the rivaroxaban of approximately £400). results remained non-significant in a fixed-effects model (p = 0.697). The point estimate favoured enoxaparin rather than rivaroxaban (relative Commentary on risk 1.8516, 95% CI 0.9434 to 3.6340). Clinical the robustness of evidence, where not commercial-in-confidence, submitted evidence is presented in Chapter 6 of the manufacturer’s submission. Appropriate analyses and comparisons were included in the manufacturer’s submission. Data The indirect comparison with dabigatran was on the final primary outcome measure (all-cause marked as commercial-in-confidence in the mortality) were not presented or meta-analysed. manufacturer’s submission. The ERG have inferred that this was due to no additional deaths bar fatal PE, the data for which Summary of submitted cost- were presented as commercial-in-confidence. The effectiveness evidence ERG has no concerns with the methodology used for the evidence syntheses. The reporting and In the base-case analyses rivaroxaban was shown interpretation of the safety data were good. to dominate [i.e. produce more quality-adjusted life-years (QALYs) at a lower cost] both enoxaparin Following dialogue iterations with the ERG team, and dabigatran. The incremental costs saved and the resultant excel file was a reasonable model of QALYs gained were small (typically below £200 and patients receiving prophylaxis for THR or TKR. 0.005, respectively, per person). The iterations were needed to amend errors found by the ERG, which included incorrect use of Analyses were conducted sampling from the standard errors, probabilities becoming negative distributions observed from the RCTs (or indirect and some cells being incorrectly cleared. comparison with dabigatran) regardless of statistical significance. These results were firmly driven by The probabilistic sensitivity analyses did not the assumed impact on fatal PE. Unfortunately this capture all of the uncertainty present within parameter was excluded within the probabilistic the decision. The number of total VTEs for 46 sensitivity analyses, which rendered the uncertainty rivaroxaban is assumed to equal the rates observed Health Technology Assessment 2009; Vol. 13: Suppl. 3

in the appropriate RCT(s). For both rivaroxaban interpretation. The manufacturer’s submission and the comparator the proportions of total VTEs appears to contain an unbiased estimate of the that are symptomatic, non-fatal and fatal are fixed treatment effect of rivaroxaban in relation to the at the rates observed in the appropriate RCTs. relevant outcomes and the comparator enoxaparin. These are relatively small numbers. For example, in Overall the evidence from the four RECORD trials RECORD 1 there were 18 VTEs of which four were in the manufacturer’s submission indicates that non-fatal PE; fixing the proportion of non-fatal rivaroxaban 10 mg once daily is not inferior to PEs to 0.22 (4/18) of the total VTEs will result in the comparator enoxaparin in terms of the total considerable uncertainty being excluded compared VTE and all-cause mortality, symptomatic VTE, with a more appropriate approach of sampling non-fatal PE and fatal PE. Rivaroxaban was also this value from a beta distribution. The long-term indicated not to be inferior to the comparator on effects of major bleeding, in particular those that the safety outcome of major bleeding. are intracranial, were excluded from the model, although the manufacturer subsequently conducted The ERG believes that, following iterations with an external calculation which showed that this the ERG, the manufacturer’s submission represents omission did not markedly affect the results for the a reasonable estimation of the cost-effectiveness comparison with enoxaparin. The ERG conducted of rivaroxaban compared with enoxaparin a similar calculation for the comparison with and dabigatran, although the uncertainty in dabigatran, with similar conclusions. the decision has been underestimated. This is important as the costs and QALYs accrued by all Following the postprophylaxis stage of the model interventions were similar and the incremental all VTE events are assumed to be DVT. This is differences reported were small, typically below conservative and will be unfavourable to the £200 and 0.005, respectively, per person. intervention that has the lowest number of VTEs, which is generally rivaroxaban. The ERG notes that the results are particularly sensitive to any assumed difference in the number The utility of a patient was set to that of a 50-year- of fatal PEs, but does not believe that there is old and does not decline as the simulated patient sufficient evidence to support a difference between ages. This will favour the intervention that interventions. has the greater estimated number of patients alive following the postprophylaxis stage. The manufacturer conducted additional analyses to Summary of NICE guidance assess the impact of altering the underlying utility, issued as a result of the STA with only a minor reduction in the incremental QALYs gained associated with rivaroxaban. The The guidance states that: manufacturer concluded that the inaccuracy introduced by not altering the utility will be small. Rivaroxaban, within its marketing authorisation, is The ERG agrees with this conclusion. recommended as an option for the prevention of venous thromboembolism in adults having elective THR or elective TKB. Conclusions Key references The manufacturer’s search strategy was adequately 1. National Institute for Health and Clinical reported and the submission appears to contain all Excellence. Guide to the single technology (STA) process. of the relevant head-to-head RCTs. The outcomes 19 September 2006. URL: www.nice.org.uk/page. selected were relevant and appropriate, although aspx?o=STAprocessguide. joint outcomes, included in the final scope issued by NICE, were excluded as none of the trials 2. Stevenson M, Scope A, Holmes M, Rees A, reported this. Kaltenthaler E. Rivoroxaban for the treatment of venous thromboembolism: a single technology appraisal. URL: www.ncchta.org/project/1773. Processes and validation of study screening and asp?SearchText=erglisting. data extraction appear to be appropriate. Statistical methods were explicitly described for the meta- 3. Bayer Healthcare, Bayer Schering Pharma. Single analyses and indirect comparisons and all relevant technology appraisal (STA) of rivaroxaban (Xarelto) for analyses were performed, although reporting of the prevention of venous thromboemobolism (VTE) in the results of these analyses were limited because adult patients undergoing elective hip or knee replacement of the omission of conclusions or plots to aid surgery. Manufacturer submission to NICE; 2008. 47

4. ‌Dabigatran etexilate for the prevention of venous 9. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, thromboembolism after hip or knee replacement surgery in van Dijk CN, Frostick SP, et al.; RE-NOVATE study adults: a single technology appraisal. URL: www.nice. group. Dabigatran etexilate versus enoxaparin for org.uk/nicemedia/pdf/TA157Guidance.pdf. prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non- 5. Eriksson BI, Borris LC, Friedman RJ, Haas S, inferiority trial. Lancet 2007;370:949–56. Huisman MV, Kakkar AK. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip 10. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, arthroplasty. N Engl J Med 2008;358:2765–75. van Dijk CN, Frostick SP. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention 6. Kakkar AK, Brenner B, Dahl OE, Eriksson BI, of venous thromboembolism after total knee Mouret P, Muntz J. Extended duration rivaroxaban replacement: the RE-MODEL randomized trial. J versus short-term enoxaparin for the prevention of Thromb Haemost 2007;5:2178–85. venous thromboemolism after total hip arthroplasty. Lancet 2008;372:31–9. 11. Ginsberg JS, Davidson BL, Comp PC, Francis CW, Friedman RJ, Huo MH. The RE-MOBILIZE Writing 7. Lassen MR, Ageno W, Borris LC, Lieberman JR, Committee. The oral inhibitor dabigatran etexilate Rosencher N, Bandel TJ. Rivaroxaban versus vs the North American enoxaparin regimen for the enoxaparin for thromboprophylaxis after total knee prevention of venous thromboembolism after knee arthroplasty. N Engl J Med 2008;358:2776–86. arthroplasty surgery. J Arthroplasty 2009; in press.

8. Bayer Healthcare. Pharmaceutical amendment A 12. National Institute for Health and Clinical to RECORD 4 study: REgulation of Coagulation Excellence. Guide to the methods of technology appraisal. in ORthopedic surgery to prevent DVT and PE: a June 2008. URL: www.nice.org.uk/media/B52/A7/ controlled, double-blind, randomised study of BAY TAMethodsGuideUpdatedJune2008.pdf. 59–7939 (rivaroxaban) in the prevention of VTE in subjects undergoing elective total knee replacement. Study number 11355. Report No. MRR A41857; 2008.

48 DOI: 10.3310/hta13suppl3/08 Health Technology Assessment 2009; Vol. 13: Suppl. 3

Cetuximab for the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck

J Greenhalgh,* A Bagust, A Boland, N Fleeman, C McLeod, Y Dundar, C Proudlove and R Shaw Liverpool Reviews and Implementation Group, University of Liverpool, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 08/40/01

This paper presents a summary of the evidence Date of ERG submission: review group (ERG) report into the clinical November 2008 effectiveness and cost-effectiveness of cetuximab TAR Centre(s): for recurrent and/or metastatic squamous cell Liverpool Reviews and Implementation Group carcinoma of the head and neck (SCCHN) List of authors: based upon a review of the manufacturer’s J Greenhalgh, A Bagust, A Boland, N Fleeman, C McLeod, submission to the National Institute for Health Y Dundar, C Proudlove and R Shaw and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. Contact details: The submission’s evidence came from a single Janette Greenhalgh, Liverpool Reviews and Implementation Group, University of Liverpool, Room reasonably high-quality randomised controlled BO5, Whelan Building, The Quadrangle, Brownlow Hill, trial (RCT) [EXTREME (Erbitux in First-Line Liverpool L69 3GB, UK Treatment of Recurrent or Metastatic Head and Neck Cancer); n = 442] comparing cetuximab plus E-mail: [email protected] chemotherapy (CTX) with CTX alone. Cetuximab The research reported in this article of the journal plus CTX had significant effects compared with supplement was commissioned and funded by the CTX alone on the primary outcome of overall HTA programme on behalf of NICE as project survival (10.1 versus 7.4 months respectively) number 08/40/01. The assessment report began and the secondary outcomes of progression-free editorial review in January 2009 and was accepted for survival (PFS) (5.6 versus 3.3 months), best overall publication in March 2009. See the HTA programme response to therapy (35.6% versus 19.5%), disease web site for further project information (www.hta. control rate (81.1% versus 60%) and time-to- ac.uk). This summary of the ERG report was compiled after the Appraisal Committee’s review. treatment failure (4.8 versus 3.0 months), but not on duration of response (5.6 months versus 4.7 The views and opinions expressed therein are those of months). No safety issues with cetuximab arose the authors and do not necessarily reflect those of the beyond those already previously documented. The Department of Health. manufacturer developed a two-arm state-transition Discussion of ERG reports is invited. Visit the HTA Markov model to evaluate the cost-effectiveness website correspondence forum (www.hta.ac.uk/ of cetuximab plus CTX versus CTX alone, using correspond). clinical data from the EXTREME trial. The ERG recalculated the base-case cost-effectiveness results taking changes in parameters and assumptions into account. Subgroup and threshold analyses were also explored. The manufacturer reported 49

an incremental cost-effectiveness ratio (ICER) of Description of the £121,367 per quality-adjusted life-year (QALY) underlying health problem gained and an incremental cost per life-year gained of £92,226. Univariate sensitivity analysis showed The term head and neck cancer covers a that varying the cost of day-case infusion and the wide variety of different cancers [30 different utility values in the stable/response health state International Classification of Diseases (ICD) of the cetuximab plus CTX arm had the greatest codes] occurring in the tissues of the head and impact on the ICER. Probabilistic sensitivity neck. As a group they account for over 8000 cancer analysis illustrated that cetuximab plus CTX registrations in England and Wales.3 Around is unlikely to be cost-effective for patients with 90% of head and neck cancers are squamous cell. recurrent and/or metastatic SCCHN, even at what SCCHN most commonly arises in the oral cavity, would usually be considered very high levels of pharynx and larynx.3 The number of registrations willingness to pay for an additional QALY. With for these subgroups was 5833 in England in 20054 regard to the economic model the appropriateness and 446 in Wales in 2006,5 with a ratio of male to and reliability of parametric survival projection female cases of approximately 70:30. beyond the duration of trial data could not be fully explored because of lack of information. The ERG There is no standard treatment for all patients also questioned the appropriateness of economic with recurrent or metastatic disease; guidelines modelling in this STA as evidence is available recommend the tailoring of therapy to the only from a single RCT. In conclusion, the ERG individual patient.3,6 In some patients the tumour considers that patients with metastatic SCCHN may still be amenable to surgery or radiotherapy were not shown to receive a significant survival with curative intent; however, in patients with benefit from cetuximab plus CTX compared with metastatic disease or who have previously received CTX alone and that even setting a lower price for radiotherapy for the initial tumour, this may not cetuximab would not strengthen the manufacturer’s be possible. For this group of patients palliative case for cost-effectiveness. CTX is the mainstay of treatment if they are able to tolerate it. The most commonly used Introduction chemotherapeutic treatments for recurrent and/ or metastatic SCCHN include methotrexate, The National Institute of Health and Clinical bleomycin, 5-fluorouracil (5-FU) and platinum Excellence (NICE) is an independent organisation compounds. The prognosis for recurrent and/or within the NHS that is responsible for providing metastatic SCCHN subjects is poor with a median national guidance on the treatment and care of survival time of only 6–9 months. people using the NHS in England and Wales. One of the responsibilities of NICE is to provide guidance to the NHS on the use of selected new Scope of the ERG report and established health technologies, based on an appraisal of those technologies. The ERG report presents the results of the assessment of the manufacturer (Merck Serono) NICE’s single technology appraisal (STA) process evidence submission regarding the use of is specifically designed for the appraisal of a single cetuximab with platinum-based CTX (cisplatin product, device or other technology, with a single plus fluorouracil or carboplatin plus fluorouracil) indication, for which most of the relevant evidence compared with platinum-based CTX alone for the lies with one manufacturer or sponsor.1 Typically, first-line treatment of recurrent and/or metastatic it is used for new pharmaceutical products close SCCHN. The report includes an assessment of to launch. The principal evidence for an STA is both the clinical effectiveness and cost-effectiveness derived from a submission by the manufacturer/ evidence submitted by the manufacturer. The sponsor of the technology. In addition, a report primary clinical outcome measure was overall reviewing the evidence submission is submitted survival (OS), with secondary outcomes of by the evidence review group (ERG), an external progression-free survival (PFS), response to organisation independent of NICE. This paper therapy, safety and quality of life (QoL). The presents a summary of the ERG report for the cost-effectiveness measures were incremental cost- STA of cetuximab for recurrent and/or metastatic effectiveness ratio (ICER) and incremental cost per squamous cell carcinoma of the head and neck life-year (LY) gained. (SCCHN).2

50 Health Technology Assessment 2009; Vol. 13: Suppl. 3

Cetuximab (Erbitux®) is a monoclonal antibody European countries and included 442 patients. The that inhibits the action of the epidermal growth results of the EXTREME trial showed significant factor receptor (EGFR), which is highly expressed effects of cetuximab plus CTX compared with in nearly all SCCHN tumours. Whilst the ERG CTX alone on the primary outcome of OS (10.1 report was in progress, a positive opinion from the months versus 7.4 months respectively). There European Medicines Agency (EMEA) Committee was also a significant effect of cetuximab plus for Medicinal Products for Human Use (CHMP) CTX compared with CTX alone on the secondary to extend the use of cetuximab to include the end points of median PFS (5.6 months versus 3.3 treatment of patients with recurrent and/or months), best overall response to therapy (35.6% metastatic SCCHN in combination with platinum- versus 19.5%), disease control rate (81.1% versus based CTX was issued. Final approval was given by 60%) and median time-to-treatment failure (TTF) the EMEA after the submission of the ERG report. (4.8 months versus 3.0 months). No significant Neither the EMEA nor NICE limited the indication difference was noted in the median duration of to first-line use; this limitation was imposed by the response between the cetuximab plus CTX and manufacturer. CTX alone groups (5.6 months versus 4.7 months). The results are summarised in Table 1. The QoL data described were very limited; the manufacturer Methods states that there was no difference in QoL between the two treatment groups. No safety issues related The ERG report comprised a critical review of the to cetuximab arose beyond those already previously evidence for the clinical effectiveness and cost- documented. effectiveness of the technology based upon the manufacturer’s/sponsor’s submission to NICE as Summary of submitted cost- part of the STA process. effectiveness evidence

The ERG evaluated the quality of the In the absence of UK-based economic evaluations, manufacturer’s clinical effectiveness review. the manufacturer conducted a de novo economic Searches conducted by the manufacturer were evaluation. A two-arm state-transition Markov assessed for completeness and the single trial put model was developed to evaluate the cost- forward as evidence of effectiveness was critically effectiveness of cetuximab plus CTX compared appraised using a standard tool (CASP7 – Critical with CTX alone. The clinical data used in the Appraisal Skills Programme). With regard to economic evaluation were generated from the cost-effectiveness evidence, the ERG assessed EXTREME trial. Although the economic evaluation the manufacturer’s searches for completeness, was trial based there was also a modelling critically appraised the submitted economic model component with regard to the extrapolation of using a standard assessment tool (Drummond and health effects beyond the period of the trial (24 Jefferson8) and conducted a detailed evaluation months). The economic evaluation adopted a of the model. The ERG recalculated the base- lifetime horizon for the consideration of costs and case cost-effectiveness results taking changes in benefits and the perspective is that of the UK NHS parameters and assumptions into account, for and personal social services. example revised drug costs, mid-cycle correction, overall PFS utility value. Subgroup and threshold The manufacturer reported an ICER of £121,367 analyses were also explored by the ERG. per quality-adjusted life-year (QALY) gained and an incremental cost per LY gained of £92,226. In addition to the main results, ICERs for selected Results subgroups were also presented. Univariate Summary of submitted sensitivity analysis showed that varying (1) the cost clinical evidence of day-case infusion and (2) the utility values in the stable/response health state of the cetuximab plus The clinical effectiveness evidence described CTX arm had the greatest impact on the ICER. in the manufacturer’s submission was derived Probabilistic sensitivity analysis illustrated that from a single phase III open-label randomised cetuximab plus CTX is unlikely to be cost-effective controlled trial (RCT) that compared the use for patients with recurrent and/or metastatic of cetuximab plus CTX with CTX alone. The SCCHN, even at what would usually be considered EXTREME (Erbitux in First-Line Treatment of very high levels of willingness to pay for an Recurrent or Metastatic Head and Neck Cancer) additional QALY. trial was conducted in 80 centres within 17 51

TABLE 1 Key results of the EXTREME trial

Cetuximab plus Hazard ratio (HR)/ Outcome CTX (n = 222) CTX (n = 220) odds ratio (OR) p-value

Primary OS (months), median (95% CI) 10.1 (8.6–11.2) 7.4 (6.4–8.3) HR 0.797 (0.644–0.986) 0.00362a Secondary PFS (months), median (95% CI)a 5.6 (5.0–6.0) 3.3 (2.9–4.3) HR 0.538 (0.431–0.672) < 0.001 Best overall response 35.6% (29.3–42.3) 19.5% (14.5–25.4) OR 2.326 (1.504–3.600) < 0.001b Disease control rate (95% CI)c 81% (75.3–86.0) 60% (53.2–66.5) OR 2.881 (1.870–4.441) < 0.001d Time to treatment failure (months) (95% CI)a 4.8 (4.0–5.6) 3.0 (2.8–3.4) HR 0.59 (0.48–0.73) < 0.001b Duration of response (months) (95% CI)e 5.6 (4.7–6.0) 4.7 (3.6–5.9) HR 0.76 (0.50–1.17) 0.21b

CI, confidence interval; CTX, chemotherapy; OS, overall survival; PFS, progression-free survival. p-values, hazard ratios and odds ratios are stratified according to receipt or non-receipt of previous chemotherapy and Karnofsky Performance Status at randomisation. a Number of months estimated using Kaplan–Meier method. b p-value calculated using the log-rank test. c Disease control includes complete response, partial response and stable disease. d p-value calculated using Cochrane–Mantel–Haenszel test. e Data on duration of response were available for 62 patients in the cetuximab group and 36 patients in the CTX alone group; data on disease progression in these patients were available at the time of analysis. The number of months was estimated using the Kaplan–Meier method.

The manufacturer argued that the assessment of treatment for patients with recurrent and/or QoL associated with the use of cetuximab plus CTX metastatic SCCHN; hence, there is no discussion may misrepresent the real health gain for patients of the costs and benefits of second-line treatment with recurrent and/or metastatic SCCHN. The options for this patient group. Neither the final manufacturer would prefer that other indicators of scope issued by NICE nor the EMEA CHMP benefit (e.g. socioeconomic status) are taken into positive opinion limits the use of cetuximab to first- account. line treatment only.

The ERG was confident that neither model Commentary on assumptions nor parameter values were likely to the robustness of introduce sufficient uncertainty to allow cetuximab submitted evidence plus CTX to be cost-effective for this group of patients. A number of key issues and parameters in The manufacturer cited evidence from a reasonably the economic model did not seem to be justified. high-quality trial (EXTREME) of the clinical The results of the ERG’s threshold analysis indicate benefit of cetuximab plus CTX compared with that cetuximab plus CTX may not be cost-effective CTX alone. The trial was well designed, used at any price according to current NICE guidance. robust randomisation techniques and was suitably The ERG identified a number of different areas in powered to show differences between the treatment the economic model in which it was appropriate to groups. Appropriate exploratory subgroup analyses correct or revise model assumptions, which taken were carried out and statistical reporting was together increased the size of the ICER (Table 2). generally good.

However, the clinical effectiveness evidence was Conclusions based only on this single trial, which was open label and relied on the unblinded assessment of clinical The EXTREME trial demonstrated the superior outcomes. Despite designing the trial to include a clinical effectiveness of cetuximab plus CTX over comprehensive analysis of QoL, very limited QoL CTX alone. However, whether or not the patients data were collected and reported. in the EXTREME trial are sufficiently similar (in terms of age and Karnofsky Performance Status) The manufacturer provided clinical evidence to patients in England and Wales with recurrent 52 to support the use of cetuximab as a first-line and/or metastatic SCCHN who require treatment Health Technology Assessment 2009; Vol. 13: Suppl. 3 Incremental cost/QALY cost/QALY Incremental gained £121,367 £114,484 (–£6884) £147,817 (+£26,449) £139,390 (+£18,023) £119,808 (–£1560) £143,519 (+£22,152) £121,692 (+£325) £122,199 (+£831) £121,177 (–£191) £132,361 (+£10,993) £121,437 (+£69) £166,307 (+£44,939) £208,266 (+£86,899) Incremental cost/LY cost/LY Incremental gained £92,226 £86,353 (–£5873) £127,149 (+£34,923) £92,226 £92,226 £109,059 (+£16,833) £92,473 (+£247) £92,858 (+£632) £92,081 (–£145) £100,580 (+£8354) £92,297 (+£71) £111,784 (+£19,558) £154,420 (+£62,194) Incremental QALYs Incremental 0.1424 0.1414 (–0.0011) 0.1134 (–0.0290) 0.1240 (–0.0184) 0.1443 (+0.0019) 0.1424 0.1424 0.1424 0.1424 0.1424 0.1423 (–0.0001) 0.1259 (–0.0166) 0.0976 (–0.0449) Incremental survivalIncremental 0.1874 0.1874 0.1318 (–0.0556) 0.1874 0.1874 0.1874 0.1874 0.1874 0.1874 0.1874 0.1873(–0.0002) 0.1873 (–0.0002) 0.1317 (–0.0558) Incremental costs Incremental £17,286 £16,185 (–£1101) £16,760 (–£526) £17,286 £17,286 £20,441 (+£3155) £17,332 (+£46) £17,404 (+£118) £17,259 (–£27) £18,852 (+£1566) £17,283 (–£3) £20,932 (+£3646) £20,331 (+£3045) ERG modifications to manufacturer’s economic model ERG modifications to manufacturer’s

Model/amendment Base case Mid-cycle correction Limit to 24 months Overall PFS utility value Overall Adverse event utility adjustment event Adverse Revised drug costs Revised 100% cisplatin use Cetuximab dose adjustment Cisplatin dose adjustment Rebase unit costs Revised discounting Revised Base case + all changes – full life Base case + all changes – 24 months LY, life-year; PFS, progression-free survival; QALY(s), quality-adjusted life-year(s). QALY(s), survival; progression-free PFS, life-year; LY, to the base case. indicate the change relative Numbers in parentheses

TABLE 2 TABLE 53

is uncertain. There is also no clinical evidence Key references available to demonstrate the effectiveness of 1. National Institute for Health and Clinical cetuximab plus CTX in patients who are not Excellence. Guide to the single technology (STA) process. cetuximab naive. Finally, the ERG considered 19 September 2006. URL: www.nice.org.uk/page. that patients with metastatic SCCHN were not aspx?o=STAprocessguide. shown to receive a significant survival benefit from cetuximab plus CTX compared with CTX alone. 2. Greenhalgh J, Bagust A, Boland A, Fleeman N, McLeod C, Dundar Y, et al. Cetuximab for recurrent With regards to the economic model, some and/or metastatic squamous cell carcinoma of the head and neck (SCCHN): a single technology appraisal. LRiG, questions over the appropriateness and reliability University of Liverpool; 2008. of parametric survival projection beyond the duration of trial data could not be fully explored 3. National Institute for Health and Clinical by the ERG because of lack of information; in Excellence. Guidance on cancer services: improving particular, the appropriateness of employing outcomes in head and neck cancers: the manual. Weibull modelling for all patient groups may London: NICE; 2004. benefit from further examination. The ERG also questioned the appropriateness of economic 4. Office for National Statistics. Cancer statistics modelling in this STA as many health economists – registrations: registrations of cancer diagnosed in would prefer to carry out direct evaluation of trial England, 2005. Series MB1 no. 36. URL: www. data when evidence is available only from a single statistics.gov.uk/downloads/theme_health/MB1_36/ MB1_No36_2005.pdf. Cited 2008. RCT. 5. Welsh Cancer Intelligence and Surveillance Unit. The cost per QALY figures reported in the Cancer incidence in Wales 2002–2006. WCISU Annual manufacturer’s submission were high (in excess Publication No. SA8/01. URL: www.wales.nhs.uk/ of £100,000 per QALY gained). Both the original sites3/Documents/242/incpub2006%5F31Jan08.pdf. model submitted by the manufacturer and the Cited 2008. model corrected/adjusted by the ERG yielded ICERs that far exceed accepted values. Given 6. Scottish Intercollegiate Guidelines Network. the high cost of cetuximab plus CTX and the Diagnosis and management of head and neck cancer: marginal health benefits gained in comparison to a national clinical guideline. Edinburgh: Scottish CTX, discussion of further economic issues within Intercollegiate Guidelines Network; 2006. NICE’s current acceptability range (from £20,000 7. Public Health Resource Unit England. Critical to £30,000 per QALY) seemed unnecessary. The Appraisal Skills Programme (CASP) – making sense ERG concluded that even setting a lower price for of evidence: 10 questions to help you make sense of cetuximab would not strengthen the manufacturer’s randomised controlled trials. 2006. URL: www.phru. case for cost-effectiveness. nhs.uk/Doc_Links/rct%20appraisal%20tool.pdf. Cited 2008.

Summary of NICE guidance 8. Drummond MF, Jefferson TO. Guidelines for issued as a result of the STA authors and peer reviewers of economic submissions to the BMJ. The BMJ Economic Evaluation At the time of writing, the guidance has not been Working Party. BMJ1996;313:275–83. issued by NICE.

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08/77/01 Mifamurtide for osteosarcoma This synopsis has been removed

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08/77/01 Mifamurtide for osteosarcoma This synopsis has been removed

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08/77/01 Mifamurtide for osteosarcoma This synopsis has been removed

60 DOI: 10.3310/hta13suppl3/10 Health Technology Assessment 2009; Vol. 13: Suppl. 3

Ustekinumab for the treatment of moderate to severe psoriasis

E Gospodarevskaya, J Picot, K Cooper, E Loveman* and A Takeda Southampton Health Technology Assessments Centre, University of Southampton, UK

*Corresponding author

Declared competing interests of authors: none

Abstract HTA 08/93/01

This paper presents a summary of the evidence Date of ERG submission: review group (ERG) report into the clinical March 2009 effectiveness and cost-effectiveness of ustekinumab TAR Centre(s): for the treatment of moderate to severe psoriasis Southampton Health Technology Assessments Centre based upon a review of the manufacturer’s List of authors: submission to the National Institute for Health E Gospodarevskaya, J Picot, K Cooper, E Loveman and and Clinical Excellence (NICE) as part of the A Takeda single technology appraisal (STA) process. The submission’s main evidence came from three Contact details: randomised controlled trials (RCTs), of reasonable Emma Loveman, Southampton Health Technology Assessments Centre, University of Southampton, First methodological quality and measuring a range of Floor, Epsilon House, Enterprise Road, Southampton clinically relevant outcomes. Higher proportions Science Park, Southampton SO16 7NS, UK of participants treated with ustekinumab (45 mg and 90 mg) than with placebo or etanercept E-mail: [email protected] achieved an improvement on the Psoriasis Area The research reported in this article of the journal and Severity Index (PASI) of at least 75% (PASI supplement was commissioned and funded by the 75) after 12 weeks. There were also statistically HTA programme on behalf of NICE as project number significant differences in favour of ustekinumab 08/93/01. The assessment report began editorial review over placebo for PASI 50 and PASI 90 results, in May 2009 and was accepted for publication in May and for ustekinumab over etanercept for PASI 90 2009. See the HTA programme website for further results. A weight-based subgroup dosing analysis project information (www.hta.ac.uk). This summary for each trial was presented, but the methodology of the ERG report was compiled after the Appraisal Committee’s review. was poorly described and no statistical analysis to support the chosen weight threshold was presented. The views and opinions expressed therein are those of The manufacturer carried out a mixed treatment the authors and do not necessarily reflect those of the comparison (MTC); however, the appropriateness Department of Health. of some of the methodological aspects of the Discussion of ERG reports is invited. Visit the HTA MTC is uncertain. The incidence of adverse website correspondence forum (www.hta.ac.uk/ events was similar between groups at 12 weeks and correspond). withdrawals due to adverse events were low and less frequent in the ustekinumab than in the placebo or etanercept groups; however, statistical comparisons were not reported. The manufacturer’s economic model of treatments for psoriasis compared ustekinumab with other biological therapies. The 61

model used a reasonable approach; however, presents a summary of the ERG report for the STA it is not clear whether the clinical effectiveness of ustekinumab for the treatment of psoriasis. estimates from the subgroup analysis, used in the base-case analysis, were methodologically appropriate. The base-case incremental cost- Description of the effectiveness ratio for ustekinumab versus underlying health problem supportive care was £29,587 per quality-adjusted life-year (QALY). In one-way sensitivity analysis Psoriasis is a chronic systemic inflammatory skin the model was most sensitive to the number of disease. The most common form of psoriasis is hospital days associated with supportive care, the chronic plaque psoriasis. This is characterised by cost estimate for intermittent etanercept 25 mg exacerbations of thickened, erythematous, scaly and the utility scores used. In the ERG’s scenario patches of skin that can occur at any skin site but analysis the model was most sensitive to the price commonly appear on the elbows, knees, scalp of ustekinumab 90 mg, the proportion of patients and trunk. Estimates suggest that psoriasis affects with baseline weight > 100 kg and the relative approximately 2% of the population in the UK.2 risk of intermittent versus continuous etanercept Psoriasis is associated with a significant negative 25 mg. In the ERG’s probabilistic sensitivity impact on heath-related quality of life. analysis ustekinumab had the highest probability of being cost-effective at conventional NICE The severity of psoriasis is determined by thresholds, assuming the same price for the 45-mg several factors and can vary from mild, through and 90-mg doses; however, doubling the price of to moderate and severe. A number of different ustekinumab 90 mg resulted in ustekinumab no criteria are available for determining the severity longer dominating the comparators. In conclusion, of psoriasis. One of the main accepted systems for the clinical effectiveness and cost-effectiveness of classifying the severity of psoriasis is the Psoriasis ustekinumab in relation to other drugs in this class Area and Severity Index (PASI). The limitations is uncertain. Provisional NICE guidance issued of this measure have been well documented3 but as a result of the STA states that ustekinumab is despite its shortcomings it is the measure used in recommended as a treatment option for adults with most clinical trials. Body surface area (BSA) and plaque psoriasis when a number of criteria are met. the Dermatology Life Quality Index (DLQI) are Final guidance is anticipated in September 2009. also commonly used. Severe psoriasis is generally accepted as a PASI ≥ 10 when combined with a DLQI > 102 or, if taken alone, a PASI > 12.4 Introduction Moderate psoriasis is generally defined as a PASI between 7 and 12.4 The National Institute for Health and Clinical Excellence (NICE) is an independent organisation within the NHS that is responsible for providing Scope of the ERG report national guidance on the treatment and care of people using the NHS in England and Wales. The ERG critically evaluated the evidence One of the responsibilities of NICE is to provide submission from Janssen-Cilag on the use of guidance to the NHS on the use of selected new ustekinumab for the treatment of moderate to and established health technologies, based on an severe plaque psoriasis. appraisal of those technologies. Ustekinumab is a fully human monoclonal NICE’s single technology appraisal (STA) process antibody. The licensed indication for ustekinumab is specifically designed for the appraisal of a single for injection is for the treatment of adults with product, device or other technology, with a single moderate to severe chronic plaque psoriasis who indication, for which most of the relevant evidence have had an inadequate response to or who have a lies with one manufacturer or sponsor.1 Typically, contraindication to or who are intolerant to other it is used for new pharmaceutical products close systemic therapies. to launch. The principal evidence for an STA is derived from a submission by the manufacturer/ The outcomes stated in the manufacturer’s sponsor of the technology. In addition, a report definition of the decision problem were measures reviewing the evidence submission is submitted of severity of psoriasis, remission rate, relapse rate, by the evidence review group (ERG), an external adverse effects of treatment and health-related organisation independent of NICE. This paper quality of life. 62 Health Technology Assessment 2009; Vol. 13: Suppl. 3

Methods analysis for each of the three included trials, but the methodological description of these analyses The ERG report comprised a critical review of the was limited and no statistical analysis to support evidence for the clinical effectiveness and cost- the chosen weight threshold was presented. effectiveness of the technology based upon the manufacturer’s/sponsor’s submission to NICE as The manufacturer’s submission did not present a part of the STA process. narrative or quantitative synthesis of the data from the three included trials except as part of a mixed The ERG checked the literature searches and treatment comparison (MTC). The MTC was applied the NICE critical appraisal checklist to conducted using data from the ustekinumab trials the included studies and checked the quality of in two ways, either all participants as randomised the manufacturer’s submission with the Centre or subgroups of participants from the dose by for Reviews and Dissemination (CRD) quality weight analysis noted above. The result from the assessment criteria for a systematic review. all participant analysis MTC for treatment with In addition, the ERG checked and provided 45 mg ustekinumab was a mean probability of commentary on the manufacturer’s model using achieving a PASI 75 response to treatment of 69%, standard checklists. One-way sensitivity analyses, with a different result obtained from the weight- scenario analyses and a probabilistic sensitivity based ustekinumab analysis MTC. For the 90-mg analysis were undertaken by the ERG. ustekinumab dose the all participant analysis MTC resulted in a mean probability of achieving a PASI 75 response to treatment of 74%; again, a Results different result was obtained from the weight-based Summary of submitted ustekinumab analysis MTC. For the PASI 75 MTC clinical evidence outcome the probability of response was greatest for infliximab, and the probability of response with The main evidence on efficacy in the submission ustekinumab was greater than those of the other came from three randomised controlled trials comparators, except for infliximab. (RCTs), two comparing ustekinumab with placebo and one comparing ustekinumab with etanercept. For the reported secondary outcomes there were One further RCT contributed to the evidence on statistically significant differences in favour of adverse events. ustekinumab over placebo and etanercept in the Physician’s Global Assessment score, and in Higher proportions of participants treated with favour of ustekinumab over placebo in the DLQI. ustekinumab (at both the 45-mg and 90-mg doses) The DLQI outcome was not reported for the than with placebo (two trials) or etanercept (one ustekinumab versus etanercept trial. The incidence trial) achieved an improvement on the PASI of at of adverse events appeared to be similar in the least 75% (PASI 75) after 12 weeks. No statistical treatment and placebo arms at 12 weeks although comparisons between the two ustekinumab doses this was not statistically tested. Withdrawals due were presented for any of the trials. There were to adverse events were low and appeared to occur also statistically significant differences in favour of less often in the ustekinumab groups than in either ustekinumab (at both the 45-mg and 90-mg doses) the placebo or the etanercept groups, although over placebo for the proportion of participants a statistical comparison was not reported in the achieving a PASI 50 and a PASI 90 (two trials), manufacturer’s submission. but again no statistical comparisons between the two ustekinumab doses were presented. In the Summary of submitted cost- trial comparing ustekinumab with etanercept, effectiveness evidence PASI 50 results appeared to be similar across the three treatment groups (45 mg ustekinumab, The manufacturer’s economic evaluation included 90 mg ustekinumab and etanercept), but no a review of the published economic literature on statistical comparison of these data was presented. therapies used for psoriasis and a report of an In contrast, both doses of ustekinumab led to economic evaluation undertaken for the NICE statistically significantly higher proportions of STA process, which included a cost-effectiveness participants achieving a PASI 90 than was observed model of treatments for psoriasis comparing in the etanercept group. ustekinumab with other biological therapies. The analysis estimated the number of individuals who The manufacturer’s submission also presented responded to treatment at each time interval, PASI 75 data from a weight-based subgroup dosing the mean length of time that an individual 63

would respond to treatment and the utility gains higher cost-effectiveness ratio for ustekinumab associated with this response. The model was based in comparison to supportive care then the cost- closely on the model reported in Woolacott and effectiveness ratio estimated in the base-case colleagues.3 analysis).

The model was generally internally consistent Scenario analyses were presented in the and appropriate to psoriasis in terms of structural manufacturer’s submission that compared assumptions. The cost-effectiveness analysis outcomes from the model when the efficacy generally conformed to the NICE reference case, estimates came from (1) the MTC subgroup the scope and the decision problem. data in which the ustekinumab dose regimen depends on the baseline weight and (2) the The evidence-based treatment effectiveness was all patients according to their randomisation reported in terms of the probability of achieving outcome. Scenario analysis conducted by the ERG a specified PASI response with each of the showed that the model was most sensitive to the treatment alternatives and supportive care by the assumptions about the price of ustekinumab 90 mg, end of the trial period. Evidence was synthesised the proportion of patients with baseline weight from a variety of trials for ustekinumab and the > 100 kg and the relative risk of intermittent comparators using an MTC model. In the base-case etanercept 25 mg in comparison to continuous analysis it was assumed that those under a weight etanercept 25 mg. of 100 kg (80% of patients in base case) received 45 mg ustekinumab whereas those over 100 kg The ERG amended the manufacturer’s probabilistic (20% of patients) received 90 mg ustekinumab. sensitivity analysis to include distributions for The manufacturer’s submission proposed a patient parameters not previously included in the model. access scheme (PAS) providing ustekinumab 90 mg Figure 1 shows the cost-effectiveness acceptability at an equivalent cost to ustekinumab 45 mg and the curve assuming the same price for the 45-mg and model assumed these costs in the base case. 90-mg doses of ustekinumab. According to these results ustekinumab has the highest probability Patients who achieved improvements in PASI of being cost-effective at conventional NICE score were assigned an associated improvement in thresholds, whereas all other biologics have a zero quality of life (a utility gain), with higher responses probability of being cost-effective. The probability associated with larger improvements in quality of ustekinumab being cost-effective at thresholds of life. Two approaches were used to achieve of £20,000 and £30,000 per QALY is 10% and 47% this task. In the first the observed patient-level respectively. changes in DLQI were used as surrogate outcomes in the statistical modelling that related the PASI scores to utility gains assessed using the EuroQol Commentary on 5 dimension (EQ-5D) questionnaire. The EQ-5D the robustness of utility values derived from the DLQI were used submitted evidence in the base-case analysis. In the second approach the observed patient-level Short Form-36 (SF-36) Strengths scores were converted into Short Form-6D (SF-6D) The manufacturer conducted a systematic search utility values and aggregated according to the PASI for clinical effectiveness and cost-effectiveness response categories. The SF-6D utility estimates studies of ustekinumab. It appears unlikely that the were used in the sensitivity analysis. searches missed any additional trials that would have met the inclusion criteria. The base-case incremental cost-effectiveness ratio for ustekinumab compared with supportive care The three key ustekinumab trials identified for patients with severe psoriasis was £29,587 per and systematically reviewed were of reasonable quality-adjusted life-year (QALY). The one-way methodological quality and measured a range of sensitivity analysis reported in the manufacturer’s outcomes that are as appropriate and clinically submission shows that the model was most sensitive relevant as possible. Overall, the manufacturer’s to the number of hospital days associated with submission presents an unbiased estimate of supportive care, the estimate of the cost of dosing treatment efficacy for ustekinumab at 12 weeks for intermittent etanercept 25 mg and the use of based on the results of two placebo-controlled SF-6D utility scores instead of EQ-5D utility scores trials and one trial comparing ustekinumab with (with SF-6D utility scores associated with a much etanercept. 64 Health Technology Assessment 2009; Vol. 13: Suppl. 3

1.0 Etanercept 50mg 0.9 Efalizumab Ustekinumab 0.8 Etanercept 25mg Infliximab 0.7 Frontier Etanercept 25mg cont 0.6 Adalimumab Supportive care 0.5

0.4

0.3 Probability of being cost-effective Probability

0.2

0.1

0.0 0 25,000 50,000 75,000 100,000 125,000 150,000 Maximim WTP per QALY gained (£)

FIGURE 1 ERG analysis of the cost-effectiveness acceptability curve for biologics in the base case. QALY, quality-adjusted life-year; WTP, willingness to pay.

The economic model presented in the The clinical effectiveness and cost-effectiveness of manufacturer’s submission used a reasonable ustekinumab in relation to other drugs in the class approach. is uncertain. A number of factors contribute to this uncertainty, including the two points above but also Weaknesses the assumption about the proportion of patients with baseline weight > 100 kg and the assumptions There is a lack of information regarding the about the relative risk of intermittent etanercept methodology used for the subgroup analysis and 25 mg in comparison to continuous etanercept it was therefore difficult for the ERG to determine 25 mg. whether the methods used were appropriate and whether the subgroup analysis supports the weight- It is not clear whether the estimates from the based categorisation presented. These clinical subgroup analysis, which were used in the base- effectiveness estimates of the subgroup data were case analysis in the manufacturer’s submission, used in the base-case analysis of the modelled were methodologically appropriate. The choice Title: 08/93/01economic evaluation of ustekinumab presented Proofin Stage:of utility 1 estimatesFigure used Number: for the 1.ai cost-effectiveness the manufacturer’s submission. analysis has a major impact on the estimated cost- Cactus Design and Illustration Ltd effectiveness of ustekinumab.

Conclusions Key issues Areas of uncertainty Two of the trials of ustekinumab efficacy presented The reliability of the estimates of clinical by the manufacturer were placebo-controlled trials. effectiveness derived from subgroups of There was also one head-to-head RCT that directly participants receiving differential weight-based compared ustekinumab with etanercept 50 mg. dosing is uncertain. In addition, the impact on No studies were identified that directly compared MTC outcomes of using a fixed-effect model rather ustekinumab with the other possible comparators than a random-effects model (which was used by included within the STA. the assessment group who developed the original MTC) is unclear. 65

The manufacturer’s submission did not present than 100 kg at the same total cost as for a the results of the subgroup analysis according to single 45 mg vial. NICE methodological guidance and therefore the ERG was unable to determine whether the weight- Ustekinumab treatment should be stopped based categorisation used in the cost-effectiveness in people whose psoriasis has not responded analysis was justified. adequately by 16 weeks after starting treatment. An adequate response is defined as either: Although the manufacturers carried out an MTC, the effectiveness of ustekinumab in relation to • a 75% reduction in the PASI score (PASI 75) other drugs of this type remains unclear because of from when treatment started or uncertainties about the appropriateness of some of • a 50% reduction in the PASI score (PASI 50) the methodological aspects of the MTC. and a 5-point reduction in the DLQI score from when treatment started. All of the economic outcomes in the manufacturer’s submission were conditional on the price of When using the DLQI, healthcare professionals ustekinumab 90 mg as indicated in the PAS. should take into account any physical, sensory or Doubling the price of ustekinumab 90 mg resulted learning disabilities, or communication difficulties, in ustekinumab no longer dominating the that could affect the responses to the DLQI and comparators at a cost-effectiveness threshold of make any adjustments they consider appropriate. £20,000–30,000 per QALY. Key references Summary of NICE guidance 1. National Institute for Health and Clinical issued as a result of the STA Excellence. Guide to the single technology (STA) process. 19 September 2006. URL: www.nice.org.uk/page. The NICE guidance issued as a result of the STA aspx?o=STAprocessguide. states that ustekinumab is recommended as a treatment option for adults with plaque psoriasis 2. National Institute for Health and Clinical when the following criteria are met: Excellence. Etanercept and efalizumab for the treatment of adults with psoriasis. Technology Appraisal Guidance No. 103. London: NICE; 2006. • The disease is severe, as defined by a total Psoriasis Area Severity Index (PASI) score of 10 3. Woolacott N, Bravo VY, Hawkins N, Kainth A, or more and a Dermatology Life Quality Index Khadjesari Z, Misso K, et al. Etanercept and (DLQI) score of more than 10. infliximab for the treatment of psoriatic arthritis: a • The psoriasis has not responded to standard systematic review and economic evaluation. Health systemic therapies, includingciclosporin, Technol Assess 2006;10(31):iii–239. methotrexate and PUVA (psoralen and long- wave ultraviolet radiation), or the person is 4. Schmitt J, Wozel G. The Psoriasis Area and Severity intolerant of or has a contraindication to these Index is the adequate criterion to define severity treatments. in chronic plaque-type psoriasis. Dermatology • The manufacturer provides the 90 mg dose 2005;210:194–9. (2 × 45 mg vials) for people who weigh more

66 Health Technology Assessment 2009; Vol. 13: Suppl. 3

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Volume 1, 1997 No. 11 No. 6 Newborn screening for inborn errors of Effectiveness of hip prostheses in No. 1 metabolism: a systematic review. primary total hip replacement: a critical Home parenteral nutrition: a systematic By Seymour CA, Thomason MJ, review of evidence and an economic review. Chalmers RA, Addison GM, Bain MD, model. By Richards DM, Deeks JJ, Sheldon Cockburn F, et al. By Faulkner A, Kennedy LG, Baxter TA, Shaffer JL. K, Donovan J, Wilkinson M, Bevan G. No. 12 No. 2 Routine preoperative testing: a No. 7 Diagnosis, management and screening systematic review of the evidence. Antimicrobial prophylaxis in colorectal of early localised prostate cancer. By Munro J, Booth A, Nicholl J. surgery: a systematic review of A review by Selley S, Donovan J, randomised controlled trials. Faulkner A, Coast J, Gillatt D. No. 13 By Song F, Glenny AM. Systematic review of the effectiveness of No. 3 No. 8 laxatives in the elderly. The diagnosis, management, treatment Bone marrow and peripheral By Petticrew M, Watt I, Sheldon T. and costs of prostate cancer in England blood stem cell transplantation for and Wales. malignancy. No. 14 A review by Chamberlain J, Melia J, A review by Johnson PWM, When and how to assess fast-changing Moss S, Brown J. Simnett SJ, Sweetenham JW, Morgan GJ, technologies: a comparative study of Stewart LA. No. 4 medical applications of four generic Screening for fragile X syndrome. technologies. No. 9 A review by Murray J, Cuckle H, A review by Mowatt G, Bower DJ, Screening for speech and language Taylor G, Hewison J. Brebner JA, Cairns JA, Grant AM, delay: a systematic review of the McKee L. literature. No. 5 By Law J, Boyle J, Harris F, A review of near patient testing in Harkness A, Nye C. primary care. Volume 2, 1998 By Hobbs FDR, Delaney BC, No. 10 Fitzmaurice DA, Wilson S, Hyde CJ, No. 1 Resource allocation for chronic Thorpe GH, et al. Antenatal screening for Down’s stable angina: a systematic review of effectiveness, costs and No. 6 syndrome. cost-effectiveness of alternative Systematic review of outpatient services A review by Wald NJ, Kennard A, for chronic pain control. Hackshaw A, McGuire A. interventions. By McQuay HJ, Moore RA, Eccleston By Sculpher MJ, Petticrew M, C, Morley S, de C Williams AC. No. 2 Kelland JL, Elliott RA, Holdright DR, Screening for ovarian cancer: a Buxton MJ. No. 7 systematic review. Neonatal screening for inborn errors of By Bell R, Petticrew M, Luengo S, No. 11 metabolism: cost, yield and outcome. Sheldon TA. Detection, adherence and control of A review by Pollitt RJ, Green A, hypertension for the prevention of McCabe CJ, Booth A, Cooper NJ, No. 3 stroke: a systematic review. Leonard JV, et al. Consensus development methods, By Ebrahim S. 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 Stewart-Brown SL. surgery: a systematic review. CFB, Askham J, et al. By McQuay HJ, Moore RA. No. 9 No. 4 Implications of socio-cultural contexts No. 13 A cost–utility analysis of interferon beta for the ethics of clinical trials. Choosing between randomised and for multiple sclerosis. A review by Ashcroft RE, Chadwick nonrandomised studies: a systematic DW, Clark SRL, Edwards RHT, Frith L, By Parkin D, McNamee P, Jacoby A, review. 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 efficiency 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. 67

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 A review by Edwards SJL, Lilford RJ, By Grieve R, Beech R, Vincent J, acceptability. Annex: Antenatal HIV Mazurkiewicz J. Braunholtz DA, Jackson JC, Hewison J, testing – assessment of a routine Thornton J. voluntary approach. By Simpson WM, Johnstone FD, No. 16 Boyd FM, Goldberg DJ, Hart GJ, No. 16 Qualitative research methods in health Gormley SM, et al. Positron emission tomography: technology assessment: a review of the establishing priorities for health technology assessment. literature. No. 5 Methods for evaluating area-wide and A review by Robert G, Milne R. By Murphy E, Dingwall R, organisation-based interventions in Greatbatch D, Parker S, Watson P. 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 benefits 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) Assessing the costs of healthcare Turner J, Yates D. 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 impact. Hutton J, Roderick P, Cullingworth J, No. 18 By Hallam L, Henthorne K. et al. A systematic literature review of spiral and electron beam computed No. 8 tomography: with particular reference No. 19 Screening for cystic fibrosis. Systematic reviews of trials and other A review by Murray J, Cuckle H, to clinical applications in hepatic studies. Taylor G, Littlewood J, Hewison J. lesions, pulmonary embolus and By Sutton AJ, Abrams KR, Jones DR, coronary artery disease. No. 9 By Berry E, Kelly S, Hutton J, Sheldon TA, Song F. A review of the use of health status Harris KM, Roderick P, Boyce JC, et al. measures in economic evaluation. No. 20 By Brazier J, Deverill M, Green C, No. 19 Primary total hip replacement surgery: Harper R, Booth A. What role for statins? A review and a systematic review of outcomes economic model. No. 10 and modelling of cost-effectiveness By Ebrahim S, Davey Smith Methods for the analysis of quality- associated with different prostheses. G, McCabe C, Payne N, Pickin M, A review by Fitzpatrick R, Shortall of-life and survival data in health technology assessment. Sheldon TA, et al. E, Sculpher M, Murray D, Morris R, A review by Billingham LJ, Lodge M, et al. Abrams KR, Jones DR. No. 20 Factors that limit the quality, number No. 11 and progress of randomised controlled Volume 3, 1999 Antenatal and neonatal trials. haemoglobinopathy screening in the A review by Prescott RJ, Counsell CE, No. 1 UK: review and economic analysis. Gillespie WJ, Grant AM, Russell IT, By Zeuner D, Ades AE, Karnon J, Informed decision making: an Kiauka S, et al. Brown J, Dezateux C, Anionwu EN. annotated bibliography and systematic No. 21 review. No. 12 By Bekker H, Thornton JG, Assessing the quality of reports of Antimicrobial prophylaxis in total hip Airey CM, Connelly JB, Hewison J, randomised trials: implications for the replacement: a systematic review. By Glenny AM, Song F. Robinson MB, et al. conduct of meta-analyses. A review by Moher D, Cook DJ, No. 22 No. 2 Jadad AR, Tugwell P, Moher M, 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 The role of expectancies in the placebo No. 14 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, 68 Hart J, Kimber A, Thomas H. Adams J, Normand C, Frater A, et al. Littlejohns P, Ross FM, Axford JS. Health Technology Assessment 2009; Vol. 13: Suppl. 3

Volume 4, 2000 No. 11 No. 21 Cost and outcome implications of the Systematic reviews of wound care No. 1 organisation of vascular services. management: (3) antimicrobial agents The estimation of marginal time By Michaels J, Brazier J, for chronic wounds; (4) diabetic foot preference in a UK-wide sample Palfreyman S, Shackley P, Slack R. ulceration. (TEMPUS) project. By O’Meara S, Cullum N, Majid M, A review by Cairns JA, No. 12 Sheldon T. van der Pol MM. Monitoring blood glucose control in diabetes mellitus: a systematic review. No. 22 No. 2 By Coster S, Gulliford MC, Seed PT, Using routine data to complement Geriatric rehabilitation following Powrie JK, Swaminathan R. and enhance the results of randomised fractures in older people: a systematic controlled trials. By Lewsey JD, Leyland AH, Murray review. No. 13 GD, Boddy FA. By Cameron I, Crotty M, Currie C, The effectiveness of domiciliary Finnegan T, Gillespie L, Gillespie W, health visiting: a systematic review of international studies and a selective No. 23 et al. review of the British literature. Coronary artery stents in the treatment of ischaemic heart disease: a rapid and No. 3 By Elkan R, Kendrick D, Hewitt M, Robinson JJA, Tolley K, Blair M, et al. systematic review. Screening for sickle cell disease and By Meads C, Cummins C, Jolly K, thalassaemia: a systematic review with No. 14 Stevens A, Burls A, Hyde C. supplementary research. The determinants of screening uptake By Davies SC, Cronin E, Gill M, and interventions for increasing No. 24 Greengross P, Hickman M, Normand C. uptake: a systematic review. Outcome measures for adult critical By Jepson R, Clegg A, Forbes C, care: a systematic review. No. 4 Lewis R, Sowden A, Kleijnen J. By Hayes JA, Black NA, Jenkinson C, Community provision of hearing aids Young JD, Rowan KM, Daly K, et al. and related audiology services. No. 15 A review by Reeves DJ, Alborz A, The effectiveness and cost-effectiveness No. 25 Hickson FS, Bamford JM. of prophylactic removal of wisdom A systematic review to evaluate the teeth. effectiveness of interventions to No. 5 A rapid review by Song F, O’Meara S, promote the initiation of breastfeeding. By Fairbank L, O’Meara S, False-negative results in screening Wilson P, Golder S, Kleijnen J. programmes: systematic review of Renfrew MJ, Woolridge M, Sowden AJ, impact and implications. No. 16 Lister-Sharp D. By Petticrew MP, Sowden AJ, Ultrasound screening in pregnancy: No. 26 Lister-Sharp D, Wright K. a systematic review of the clinical Implantable cardioverter defibrillators: effectiveness, cost-effectiveness and arrhythmias. A rapid and systematic No. 6 women’s views. review. By Bricker L, Garcia J, Henderson J, Costs and benefits of community By Parkes J, Bryant J, Milne R. postnatal support workers: a Mugford M, Neilson J, Roberts T, et al. randomised controlled trial. No. 27 No. 17 By Morrell CJ, Spiby H, Stewart P, Treatments for fatigue in multiple Walters S, Morgan A. A rapid and systematic review of the sclerosis: a rapid and systematic review. effectiveness and cost-effectiveness of By Brañas P, Jordan R, Fry-Smith A, No. 7 the taxanes used in the treatment of Burls A, Hyde C. Implantable contraceptives (subdermal advanced breast and ovarian cancer. implants and hormonally impregnated By Lister-Sharp D, McDonagh MS, No. 28 intrauterine systems) versus other Khan KS, Kleijnen J. Early asthma prophylaxis, natural forms of reversible contraceptives: two history, skeletal development and 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 Randomised controlled trial of non- No. 8 Screening for hypercholesterolaemia directive counselling, cognitive– versus case finding for familial An introduction to statistical methods behaviour therapy and usual general hypercholesterolaemia: a systematic for health technology assessment. 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 By Marks D, Wonderling Brown PJ. 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/IIIa No. 10 is patients’ outcome influenced by GPs’ antagonists in the medical management Publication and related biases. referral for plain radiography? 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. 69

No. 31 Volume 5, 2001 No. 11 A randomised controlled trial Effectiveness of autologous chondrocyte of prehospital intravenous fluid No. 1 transplantation for hyaline cartilage replacement therapy in serious trauma. Clinical and cost-effectiveness defects in knees: a rapid and systematic By Turner J, Nicholl J, Webber L, of donepezil, rivastigmine and review. Cox H, Dixon S, Yates D. galantamine for Alzheimer’s disease: a By Jobanputra P, Parry D, Fry-Smith rapid and systematic review. A, Burls A. No. 32 By Clegg A, Bryant J, Nicholson T, No. 12 Intrathecal pumps for giving opioids in 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, No. 2 The clinical effectiveness and cost- By Ramsay CR, Grant AM, Wallace Towlerton G. SA, Garthwaite PH, Monk AF, Russell IT. effectiveness of riluzole for motor neurone disease: a rapid and systematic No. 33 No. 13 Combination therapy (interferon review. The effectiveness and cost-effectiveness alfa and ribavirin) in the treatment By Stewart A, Sandercock J, Bryan S, of temozolomide for the treatment of of chronic hepatitis C: a rapid and Hyde C, Barton PM, Fry-Smith A, et al. recurrent malignant glioma: a rapid systematic review. and systematic review. By Shepherd J, Waugh N, No. 3 By Dinnes J, Cave C, Huang S, Hewitson P. Equity and the economic evaluation of Major K, Milne R. healthcare. No. 34 By Sassi F, Archard L, Le Grand J. No. 14 A systematic review of comparisons of A rapid and systematic review of effect sizes derived from randomised No. 4 the clinical effectiveness and cost- and non-randomised studies. Quality-of-life measures in chronic effectiveness of debriding agents in treating surgical wounds healing by By MacLehose RR, Reeves BC, diseases of childhood. By Eiser C, Morse R. secondary intention. Harvey IM, Sheldon TA, Russell IT, By Lewis R, Whiting P, ter Riet G, Black AMS. No. 5 O’Meara S, Glanville J. Eliciting public preferences for No. 35 healthcare: a systematic review of No. 15 Intravascular ultrasound-guided techniques. Home treatment for mental health interventions in coronary artery By Ryan M, Scott DA, Reeves C, Bate problems: a systematic review. disease: a systematic literature review, A, van Teijlingen ER, Russell EM, et al. By Burns T, Knapp M, Catty J, with decision-analytic modelling, of Healey A, Henderson J, Watt H, et al. outcomes and cost-effectiveness. No. 6 No. 16 By Berry E, Kelly S, Hutton J, General health status measures for How to develop cost-conscious Lindsay HSJ, Blaxill JM, Evans JA, et al. people with cognitive impairment: guidelines. learning disability and acquired brain No. 36 By Eccles M, Mason J. injury. A randomised controlled trial to By Riemsma RP, Forbes CA, No. 17 evaluate the effectiveness and cost- Glanville JM, Eastwood AJ, Kleijnen J. effectiveness of counselling patients The role of specialist nurses in multiple sclerosis: a rapid and systematic review. with chronic depression. No. 7 By De Broe S, Christopher F, By Simpson S, Corney R, An assessment of screening strategies Waugh N. Fitzgerald P, Beecham J. for fragile X syndrome in the UK. By Pembrey ME, Barnicoat AJ, No. 18 No. 37 Carmichael B, Bobrow M, Turner G. A rapid and systematic review Systematic review of treatments for of the clinical effectiveness and atopic eczema. No. 8 cost-effectiveness of orlistat in the By Hoare C, Li Wan Po A, Issues in methodological research: management of obesity. Williams H. perspectives from researchers and By O’Meara S, Riemsma R, commissioners. Shirran L, Mather L, ter Riet G. No. 38 By Lilford RJ, Richardson A, Stevens Bayesian methods in health technology A, Fitzpatrick R, Edwards S, Rock F, et al. No. 19 assessment: a review. The clinical effectiveness and cost- By Spiegelhalter DJ, Myles JP, No. 9 effectiveness of pioglitazone for Jones DR, Abrams KR. Systematic reviews of wound type 2 diabetes mellitus: a rapid and care management: (5) beds; systematic review. By Chilcott J, Wight J, Lloyd Jones No. 39 (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, Extended scope of nursing practice: Innes M, Soo S, Barton P, et al. Flemming K, Sheldon T. a multicentre randomised controlled trial of appropriately trained nurses No. 40 No. 10 and preregistration house officers 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 Griffiths 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, 70 Williams HC. Storey L, Gage H, Foxcroft D, et al. Reilly C, et al. Health Technology Assessment 2009; Vol. 13: Suppl. 3

No. 21 No. 31 No. 5 Systematic reviews of the effectiveness Design and use of questionnaires: a The clinical effectiveness and cost- of day care for people with severe review of best practice applicable to effectiveness of inhaler devices used mental disorders: (1) Acute day hospital surveys of health service staff and in the routine management of chronic versus admission; (2) Vocational patients. asthma in older children: a systematic rehabilitation; (3) Day hospital versus By McColl E, Jacoby A, Thomas L, review and economic evaluation. outpatient care. Soutter J, Bamford C, Steen N, et al. By Peters J, Stevenson M, Beverley C, By Marshall M, Crowther R, Lim J, Smith S. Almaraz- Serrano A, Creed F, Sledge W, No. 32 Kluiter H, et al. A rapid and systematic review of No. 6 the clinical effectiveness and cost- The clinical effectiveness and cost- No. 22 effectiveness of paclitaxel, docetaxel, effectiveness of sibutramine in the The measurement and monitoring of gemcitabine and vinorelbine in non- management of obesity: a technology surgical adverse events. small-cell lung cancer. assessment. By Bruce J, Russell EM, Mollison J, By Clegg A, Scott DA, Sidhu M, By O’Meara S, Riemsma R, Shirran Krukowski ZH. Hewitson P, Waugh N. L, Mather L, ter Riet G.

No. 23 No. 33 No. 7 Action research: a systematic review and Subgroup analyses in randomised The cost-effectiveness of magnetic guidance for assessment. controlled trials: quantifying the risks resonance angiography for carotid By Waterman H, Tillen D, Dickson R, of false-positives and false-negatives. artery stenosis and peripheral vascular de Koning K. By Brookes ST, Whitley E, Peters TJ, disease: a systematic review. Mulheran PA, Egger M, Davey Smith G. By Berry E, Kelly S, Westwood ME, No. 24 Davies LM, Gough MJ, Bamford JM, A rapid and systematic review of No. 34 et al. the clinical effectiveness and cost- Depot antipsychotic medication effectiveness of gemcitabine for the in the treatment of patients with No. 8 treatment of pancreatic cancer. schizophrenia: (1) Meta-review; (2) Promoting physical activity in South By Ward S, Morris E, Bansback N, Patient and nurse attitudes. Asian Muslim women through ‘exercise Calvert N, Crellin A, Forman D, et al. By David AS, Adams C. on prescription’. By Carroll B, Ali N, Azam N. No. 25 No. 35 No. 9 A rapid and systematic review of the A systematic review of controlled Zanamivir for the treatment of evidence for the clinical effectiveness trials of the effectiveness and cost- influenza in adults: a systematic review and cost-effectiveness of irinotecan, effectiveness of brief psychological and economic evaluation. oxaliplatin and raltitrexed for the treatments for depression. By Burls A, Clark W, Stewart T, treatment of advanced colorectal By Churchill R, Hunot V, Corney R, Preston C, Bryan S, Jefferson T, et al. cancer. Knapp M, McGuire H, Tylee A, et al. By Lloyd Jones M, Hummel S, No. 10 Bansback N, Orr B, Seymour M. No. 36 Cost analysis of child health A review of the natural history and surveillance. epidemiology of multiple sclerosis: No. 26 implications for resource allocation and Comparison of the effectiveness of By Sanderson D, Wright D, Acton C, Duree D. health economic models. inhaler devices in asthma and chronic By Richards RG, Sampson FC, obstructive airways disease: a systematic Beard SM, Tappenden P. review of the literature. By Brocklebank D, Ram F, Wright J, Volume 6, 2002 No. 11 Barry P, Cates C, Davies L, et al. Screening for gestational diabetes: No. 1 a systematic review and economic No. 27 A study of the methods used to select evaluation. The cost-effectiveness of magnetic review criteria for clinical audit. By Scott DA, Loveman E, McIntyre resonance imaging for investigation of By Hearnshaw H, Harker R, L, Waugh N. the knee joint. Cheater F, Baker R, Grimshaw G. By Bryan S, Weatherburn G, Bungay No. 12 H, Hatrick C, Salas C, Parry D, et al. No. 2 The clinical effectiveness and cost- Fludarabine as second-line therapy for effectiveness of surgery for people with No. 28 B cell chronic lymphocytic leukaemia: a morbid obesity: a systematic review and A rapid and systematic review of technology assessment. economic evaluation. the clinical effectiveness and cost- By Hyde C, Wake B, Bryan S, Barton By Clegg AJ, Colquitt J, Sidhu MK, effectiveness of topotecan for ovarian P, Fry-Smith A, Davenport C, et al. Royle P, Loveman E, Walker A. cancer. By Forbes C, Shirran L, Bagnall A-M, No. 3 No. 13 Duffy S, ter Riet G. Rituximab as third-line treatment for The clinical effectiveness of refractory or recurrent Stage III or IV trastuzumab for breast cancer: a No. 29 follicular non-Hodgkin’s lymphoma: systematic review. Superseded by a report published in a a systematic review and economic By Lewis R, Bagnall A-M, Forbes C, later volume. evaluation. Shirran E, Duffy S, Kleijnen J, et al. By Wake B, Hyde C, Bryan S, Barton No. 30 P, Song F, Fry-Smith A, et al. No. 14 The role of radiography in primary The clinical effectiveness and cost- care patients with low back pain of at No. 4 effectiveness of vinorelbine for breast least 6 weeks duration: a randomised A systematic review of discharge cancer: a systematic review and (unblinded) controlled trial. arrangements for older people. economic evaluation. By Kendrick D, Fielding K, Bentley By Parker SG, Peet SM, McPherson By Lewis R, Bagnall A-M, King S, E, Miller P, Kerslake R, Pringle M. A, Cannaby AM, Baker R, Wilson A, et al. Woolacott N, Forbes C, Shirran L, et al. 71

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 The clinical effectiveness and cost- A systematic review update of the saline, daily and alternate-day rhDNase effectiveness of bupropion and nicotine clinical effectiveness and cost- in children with cystic fibrosis. 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. Mather LC, Sowden AJ, Song FJ, et al. No. 35 No. 26 A systematic review of the costs and No. 17 A systematic review of the effectiveness, effectiveness of different models of A systematic review of effectiveness cost-effectiveness and barriers to paediatric home care. and economic evaluation of new drug implementation of thrombolytic and By Parker G, Bhakta P, Lovett CA, treatments for juvenile idiopathic neuroprotective therapy for acute Paisley S, Olsen R, Turner D, et al. 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. 18 No. 27 No. 1 Clinical effectiveness and cost- A randomised controlled crossover trial How important are comprehensive effectiveness of growth hormone in of nurse practitioner versus doctor- literature searches and the assessment children: a systematic review and led outpatient care in a bronchiectasis of trial quality in systematic reviews? economic evaluation. clinic. Empirical study. By Bryant J, Cave C, Mihaylova B, By Caine N, Sharples LD, By Egger M, Jüni P, Bartlett C, Hollingworth W, French J, Keogan M, Chase D, McIntyre L, Gerard K, et al. Holenstein F, Sterne J. Exley A, et al. No. 19 No. 2 No. 28 Clinical effectiveness and cost- Systematic review of the effectiveness Clinical effectiveness and cost – effectiveness of growth hormone and cost-effectiveness, and economic consequences of selective serotonin in adults in relation to impact on evaluation, of home versus hospital or reuptake inhibitors in the treatment of quality of life: a systematic review and satellite unit haemodialysis for people sex offenders. economic evaluation. with end-stage renal failure. By Adi Y, Ashcroft D, Browne K, By Bryant J, Loveman E, Chase D, By Mowatt G, Vale L, Perez J, Wyness Beech A, Fry-Smith A, Hyde C. Mihaylova B, Cave C, Gerard K, et al. L, Fraser C, MacLeod A, et al. No. 29 No. 3 No. 20 Treatment of established osteoporosis: Systematic review and economic Clinical medication review by a a systematic review and cost–utility evaluation of the effectiveness of pharmacist of patients on repeat analysis. infliximab for the treatment of Crohn’s prescriptions in general practice: a By Kanis JA, Brazier JE, Stevenson disease. randomised controlled trial. M, Calvert NW, Lloyd Jones M. By Clark W, Raftery J, Barton P, By Zermansky AG, Petty DR, Raynor Song F, Fry-Smith A, Burls A. DK, Lowe CJ, Freementle N, Vail A. No. 30 Which anaesthetic agents are cost- No. 4 No. 21 effective in day surgery? Literature A review of the clinical effectiveness The effectiveness of infliximab and review, national survey of practice and and cost-effectiveness of routine anti-D etanercept for the treatment of randomised controlled trial. prophylaxis for pregnant women who rheumatoid arthritis: a systematic By Elliott RA Payne K, Moore JK, are rhesus negative. review and economic evaluation. Davies LM, Harper NJN, St Leger AS, By Chilcott J, Lloyd Jones M, Wight By Jobanputra P, Barton P, Bryan S, et al. J, Forman K, Wray J, Beverley C, et al. Burls A. No. 31 No. 5 No. 22 Screening for hepatitis C among Systematic review and evaluation of the A systematic review and economic injecting drug users and in use of tumour markers in paediatric evaluation of computerised cognitive genitourinary medicine clinics: oncology: Ewing’s sarcoma and behaviour therapy for depression and systematic reviews of effectiveness, neuroblastoma. anxiety. modelling study and national survey of By Riley RD, Burchill SA, By Kaltenthaler E, Shackley P, current practice. Abrams KR, Heney D, Lambert PC, Stevens K, Beverley C, Parry G, By Stein K, Dalziel K, Walker A, Jones DR, et al. Chilcott J. McIntyre L, Jenkins B, Horne J, et al. No. 6 No. 23 No. 32 The cost-effectiveness of screening for A systematic review and economic The measurement of satisfaction with Helicobacter pylori to reduce mortality evaluation of pegylated liposomal healthcare: implications for practice and morbidity from gastric cancer and doxorubicin hydrochloride for ovarian from a systematic review of the peptic ulcer disease: a discrete-event cancer. literature. simulation model. By Forbes C, Wilby J, Richardson G, By Crow R, Gage H, Hampson S, By Roderick P, Davies R, Raftery J, 72 Sculpher M, Mather L, Reimsma R. Hart J, Kimber A, Storey L, et al. Crabbe D, Pearce R, Bhandari P, et al. Health Technology Assessment 2009; Vol. 13: Suppl. 3

No. 7 No. 16 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 By Dalziel K, Stein K, Round A, A multicentre randomised controlled Evaluating non-randomised Garside R, Royle P. trial assessing the costs and benefits intervention studies. of using structured information and By Deeks JJ, Dinnes J, D’Amico R, No. 18 analysis of women’s preferences in the Sowden AJ, Sakarovitch C, Song F, et al. management of menorrhagia. Towards efficient 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, A randomised controlled trial to assess et al. 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 Effectiveness and cost-effectiveness of photodynamic therapy for wet consultations on disease management of acute hospital-based spinal cord age-related macular degeneration: and satisfaction in inflammatory bowel injuries services: systematic review. a systematic review and economic disease. evaluation. By Bagnall A-M, Jones L, Richardson By Kennedy A, Nelson E, Reeves D, By Meads C, Salas C, Roberts T, G, Duffy S, Riemsma R. Richardson G, Roberts C, Robinson A, Moore D, Fry-Smith A, Hyde C. et al. No. 20 No. 10 Prioritisation of health technology No. 29 Evaluation of molecular tests for assessment. The PATHS model: The effectiveness of diagnostic tests for prenatal diagnosis of chromosome methods and case studies. the assessment of shoulder pain due abnormalities. By Townsend J, Buxton M, to soft tissue disorders: a systematic By Grimshaw GM, Szczepura A, Harper G. review. Hultén M, MacDonald F, Nevin NC, By Dinnes J, Loveman E, McIntyre L, Sutton F, et al. No. 21 Waugh N. Systematic review of the clinical No. 11 No. 30 effectiveness and cost-effectiveness of First and second trimester antenatal The value of digital imaging in diabetic tension-free vaginal tape for treatment screening for Down’s syndrome: retinopathy. of urinary stress incontinence. the results of the Serum, Urine and By Sharp PF, Olson J, Strachan F, Ultrasound Screening Study (SURUSS). By Cody J, Wyness L, Wallace S, Hipwell J, Ludbrook A, O’Donnell M, By Wald NJ, Rodeck C, Hackshaw Glazener C, Kilonzo M, Stearns S, et al. et al. AK, Walters J, Chitty L, Mackinson AM. No. 22 No. 31 No. 12 The clinical and cost-effectiveness of Lowering blood pressure to prevent The effectiveness and cost-effectiveness patient education models for diabetes: myocardial infarction and stroke: a new of ultrasound locating devices for a systematic review and economic preventive strategy. central venous access: a systematic evaluation. By Law M, Wald N, Morris J. review and economic evaluation. By Loveman E, Cave C, Green C, By Calvert N, Hind D, McWilliams Royle P, Dunn N, Waugh N. No. 32 RG, Thomas SM, Beverley C, Clinical and cost-effectiveness of Davidson A. No. 23 capecitabine and tegafur with uracil for 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. antipsychotics in schizophrenia. By Chilcott J, Brennan A, Booth A, evaluation. By Bagnall A-M, Jones L, Lewis R, Karnon J, Tappenden P. By Ward S, Kaltenthaler E, Cowan J, Ginnelly L, Glanville J, Torgerson D, Brewer N. et al. No. 24 Cost–benefit evaluation of routine No. 33 Clinical and cost-effectiveness of new influenza immunisation in people and emerging technologies for early No. 14 65–74 years of age. localised prostate cancer: a systematic Prostate Testing for Cancer and By Allsup S, Gosney M, Haycox A, review. Treatment (ProtecT) feasibility study. Regan M. By Donovan J, Hamdy F, Neal D, By Hummel S, Paisley S, Morgan A, Currie E, Brewer N. Peters T, Oliver S, Brindle L, et al. No. 25 The clinical and cost-effectiveness of No. 15 No. 34 pulsatile machine perfusion versus cold Early thrombolysis for the treatment Literature searching for clinical and of acute myocardial infarction: a storage of kidneys for transplantation cost-effectiveness studies used in health systematic review and economic retrieved from heart-beating and non- technology assessment reports carried evaluation. heart-beating donors. out for the National Institute for By Boland A, Dundar Y, Bagust A, By Wight J, Chilcott J, Holmes M, Clinical Excellence appraisal system. Haycox A, Hill R, Mujica Mota R, et al. Brewer N. By Royle P, Waugh N. 73

No. 35 No. 2 No. 11 Systematic review and economic Systematic review and modelling of the The use of modelling to evaluate decision modelling for the prevention investigation of acute and chronic chest new drugs for patients with a chronic and treatment of influenza A and B. pain presenting in primary care. condition: the case of antibodies By Turner D, Wailoo A, Nicholson K, By Mant J, McManus RJ, Oakes RAL, against tumour necrosis factor in Cooper N, Sutton A, Abrams K. Delaney BC, Barton PM, Deeks JJ, et al. rheumatoid arthritis. By Barton P, Jobanputra P, Wilson J, No. 36 No. 3 Bryan S, Burls A. A randomised controlled trial The effectiveness and cost-effectiveness No. 12 to evaluate the clinical and cost- of microwave and thermal balloon Clinical effectiveness and cost- effectiveness of Hickman line insertions endometrial ablation for heavy effectiveness of neonatal screening in adult cancer patients by nurses. menstrual bleeding: a systematic review for inborn errors of metabolism using By Boland A, Haycox A, Bagust A, and economic modelling. tandem mass spectrometry: a systematic Fitzsimmons L. By Garside R, Stein K, Wyatt K, review. Round A, Price A. By Pandor A, Eastham J, Beverley C, No. 37 Chilcott J, Paisley S. Redesigning postnatal care: a No. 4 randomised controlled trial of protocol- A systematic review of the role of No. 13 based midwifery-led care focused bisphosphonates in metastatic disease. Clinical effectiveness and cost- on individual women’s physical and By Ross JR, Saunders Y, effectiveness of pioglitazone and psychological health needs. Edmonds PM, Patel S, Wonderling D, rosiglitazone in the treatment of type By MacArthur C, Winter HR, Normand C, et al. 2 diabetes: a systematic review and Bick DE, Lilford RJ, Lancashire RJ, economic evaluation. Knowles H, et al. No. 5 By Czoski-Murray C, Warren E, Systematic review of the clinical Chilcott J, Beverley C, Psyllaki MA, No. 38 effectiveness and cost-effectiveness Cowan J. Estimating implied rates of discount in of capecitabine (Xeloda®) for locally No. 14 healthcare decision-making. advanced and/or metastatic breast Routine examination of the newborn: By West RR, McNabb R, Thompson cancer. the EMREN study. Evaluation of an AGH, Sheldon TA, Grimley Evans J. By Jones L, Hawkins N, Westwood M, extension of the midwife role including Wright K, Richardson G, Riemsma R. a randomised controlled trial of No. 39 appropriately trained midwives and Systematic review of isolation policies No. 6 paediatric senior house officers. in the hospital management of Effectiveness and efficiency of guideline By Townsend J, Wolke D, Hayes J, methicillin-resistant Staphylococcus dissemination and implementation Davé S, Rogers C, Bloomfield L, et al. aureus: a review of the literature strategies. with epidemiological and economic By Grimshaw JM, Thomas RE, No. 15 modelling. MacLennan G, Fraser C, Ramsay CR, Involving consumers in research and By Cooper BS, Stone SP, Kibbler CC, Vale L, et al. development agenda setting for the Cookson BD, Roberts JA, Medley GF, NHS: developing an evidence-based et al. No. 7 approach. Clinical effectiveness and costs of the By Oliver S, Clarke-Jones L, Rees R, No. 40 Sugarbaker procedure for the treatment Milne R, Buchanan P, Gabbay J, et al. Treatments for spasticity and pain in of pseudomyxoma peritonei. No. 16 multiple sclerosis: a systematic review. By Bryant J, Clegg AJ, Sidhu MK, A multi-centre randomised controlled By Beard S, Hunn A, Wight J. Brodin H, Royle P, Davidson P. trial of minimally invasive direct coronary bypass grafting versus No. 41 No. 8 percutaneous transluminal coronary The inclusion of reports of randomised Psychological treatment for insomnia angioplasty with stenting for proximal trials published in languages other than in the regulation of long-term hypnotic stenosis of the left anterior descending English in systematic reviews. drug use. coronary artery. By Moher D, Pham B, Lawson ML, By Morgan K, Dixon S, Mathers N, By Reeves BC, Angelini GD, Bryan Klassen TP. Thompson J, Tomeny M. AJ, Taylor FC, Cripps T, Spyt TJ, et al.

No. 42 No. 9 No. 17 The impact of screening on future Improving the evaluation of Does early magnetic resonance imaging health-promoting behaviours and therapeutic interventions in multiple influence management or improve health beliefs: a systematic review. sclerosis: development of a patient- outcome in patients referred to By Bankhead CR, Brett J, Bukach C, based measure of outcome. secondary care with low back pain? A Webster P, Stewart-Brown S, Munafo M, By Hobart JC, Riazi A, Lamping DL, pragmatic randomised controlled trial. et al. Fitzpatrick R, Thompson AJ. By Gilbert FJ, Grant AM, Gillan MGC, Vale L, Scott NW, Campbell MK, et al. No. 10 A systematic review and economic Volume 8, 2004 No. 18 evaluation of magnetic resonance The clinical and cost-effectiveness No. 1 cholangiopancreatography compared of anakinra for the treatment of What is the best imaging strategy for with diagnostic endoscopic retrograde rheumatoid arthritis in adults: a acute stroke? cholangiopancreatography. systematic review and economic By Wardlaw JM, Keir SL, Seymour J, By Kaltenthaler E, Bravo Vergel Y, analysis. Lewis S, Sandercock PAG, Dennis MS, Chilcott J, Thomas S, Blakeborough T, By Clark W, Jobanputra P, Barton P, 74 et al. Walters SJ, et al. Burls A. Health Technology Assessment 2009; Vol. 13: Suppl. 3

No. 19 No. 28 No. 37 A rapid and systematic review and Effectiveness and cost-effectiveness Rituximab (MabThera®) for aggressive economic evaluation of the clinical of imatinib for first-line treatment non-Hodgkin’s lymphoma: systematic and cost-effectiveness of newer drugs of chronic myeloid leukaemia in review and economic evaluation. for treatment of mania associated with chronic phase: a systematic review and By Knight C, Hind D, Brewer N, bipolar affective disorder. economic analysis. Abbott V. By Bridle C, Palmer S, Bagnall A-M, By Dalziel K, Round A, Stein K, Darba J, Duffy S, Sculpher M, et al. Garside R, Price A. No. 38 Clinical effectiveness and cost- No. 29 No. 20 effectiveness of clopidogrel and Liquid-based cytology in cervical VenUS I: a randomised controlled trial modified-release dipyridamole in the screening: an updated rapid and of two types of bandage for treating secondary prevention of occlusive systematic review and economic venous leg ulcers. vascular events: a systematic review and analysis. By Iglesias C, Nelson EA, Cullum By Karnon J, Peters J, Platt J, NA, Torgerson DJ, on behalf of the economic evaluation. Chilcott J, McGoogan E, Brewer N. VenUS Team. By Jones L, Griffin S, Palmer S, Main C, Orton V, Sculpher M, et al. No. 21 No. 30 Systematic review of the long-term Systematic review of the effectiveness No. 39 effects and economic consequences of and cost-effectiveness, and economic Pegylated interferon α-2a and -2b treatments for obesity and implications evaluation, of myocardial perfusion in combination with ribavirin in the for health improvement. scintigraphy for the diagnosis and treatment of chronic hepatitis C: By Avenell A, Broom J, Brown TJ, management of angina and myocardial a systematic review and economic Poobalan A, Aucott L, Stearns SC, et al. infarction. evaluation. By Mowatt G, Vale L, Brazzelli M, By Shepherd J, Brodin H, Cave C, Hernandez R, Murray A, Scott N, et al. No. 22 Waugh N, Price A, Gabbay J. Autoantibody testing in children No. 31 with newly diagnosed type 1 diabetes No. 40 A pilot study on the use of decision mellitus. Clopidogrel used in combination with By Dretzke J, Cummins C, theory and value of information analysis as part of the NHS Health aspirin compared with aspirin alone Sandercock J, Fry-Smith A, Barrett T, Technology Assessment programme. in the treatment of non-ST-segment- Burls A. By Claxton K, Ginnelly L, Sculpher elevation acute coronary syndromes: a systematic review and economic No. 23 M, Philips Z, Palmer S. evaluation. Clinical effectiveness and cost- No. 32 By Main C, Palmer S, Griffin S, Jones effectiveness of prehospital intravenous The Social Support and Family Health fluids in trauma patients. L, Orton V, Sculpher M, et al. Study: a randomised controlled trial By Dretzke J, Sandercock J, Bayliss and economic evaluation of two S, Burls A. No. 41 alternative forms of postnatal support Provision, uptake and cost of cardiac for mothers living in disadvantaged No. 24 rehabilitation programmes: improving inner-city areas. Newer hypnotic drugs for the short- services to under-represented groups. By Wiggins M, Oakley A, Roberts I, term management of insomnia: a By Beswick AD, Rees K, Griebsch I, Turner H, Rajan L, Austerberry H, et al. systematic review and economic Taylor FC, Burke M, West RR, et al. evaluation. No. 33 No. 42 By Dündar Y, Boland A, Strobl J, Psychosocial aspects of genetic Dodd S, Haycox A, Bagust A, et al. screening of pregnant women and Involving South Asian patients in newborns: a systematic review. clinical trials. No. 25 By Green JM, Hewison J, Bekker HL, By Hussain-Gambles M, Leese B, Development and validation of Bryant, Cuckle HS. Atkin K, Brown J, Mason S, Tovey P. methods for assessing the quality of diagnostic accuracy studies. No. 34 No. 43 By Whiting P, Rutjes AWS, Dinnes J, Evaluation of abnormal uterine Clinical and cost-effectiveness of Reitsma JB, Bossuyt PMM, Kleijnen J. bleeding: comparison of three continuous subcutaneous insulin outpatient procedures within cohorts infusion for diabetes. No. 26 defined by age and menopausal status. By Colquitt JL, Green C, Sidhu MK, EVALUATE hysterectomy trial: By Critchley HOD, Warner P, Lee AJ, Hartwell D, Waugh N. a multicentre randomised trial Brechin S, Guise J, Graham B. comparing abdominal, vaginal and No. 44 laparoscopic methods of hysterectomy. No. 35 Identification and assessment of By Garry R, Fountain J, Brown J, Coronary artery stents: a rapid ongoing trials in health technology Manca A, Mason S, Sculpher M, et al. systematic review and economic assessment reviews. evaluation. By Song FJ, Fry-Smith A, Davenport No. 27 By Hill R, Bagust A, Bakhai A, Methods for expected value of Dickson R, Dündar Y, Haycox A, et al. C, Bayliss S, Adi Y, Wilson JS, et al. information analysis in complex health economic models: developments on No. 36 No. 45 the health economics of interferon-β Review of guidelines for good practice Systematic review and economic and glatiramer acetate for multiple in decision-analytic modelling in health evaluation of a long-acting insulin sclerosis. technology assessment. analogue, insulin glargine By Tappenden P, Chilcott JB, By Philips Z, Ginnelly L, Sculpher M, By Warren E, Weatherley-Jones E, Eggington S, Oakley J, McCabe C. Claxton K, Golder S, Riemsma R, et al. Chilcott J, Beverley C. 75

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 outflow 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. By Willis BH, Barton P, Pearmain P, economic analysis. Karim O, Yang Q. Bryan S, Hyde C. By McCarthy CJ, Mills PM, Pullen R, No. 5 Richardson G, Hawkins N, Roberts CR, No. 14 A pragmatic randomised controlled et al. Laparoscopic surgery for inguinal trial of the cost-effectiveness of hernia repair: systematic review of No. 47 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 Shenfine J, McNamee P, Steen N, Fraser C, Cook J, McIntosh E, et al. potency topical corticosteroids for Bond J, Griffin 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 specificity of screening mammography. and economic evaluation. No. 48 By Taylor P, Champness J, Given- By Wilby J, Kainth A, Hawkins N, Epstein D, McIntosh H, McDaid C, et al. Acupuncture of chronic headache Wilson R, Johnston K, Potts H. disorders in primary care: randomised No. 7 No. 16 controlled trial and economic analysis. A randomised controlled trial to By Vickers AJ, Rees RW, Zollman CE, Issues in data monitoring and interim analysis of trials. compare the cost-effectiveness of McCarney R, Smith CM, Ellis N, et al. tricyclic antidepressants, selective By Grant AM, Altman DG, Babiker serotonin reuptake inhibitors and AB, Campbell MK, Clemens FJ, No. 49 lofepramine. Generalisability in economic evaluation Darbyshire JH, et al. By Peveler R, Kendrick T, Buxton M, studies in healthcare: a review and case Longworth L, Baldwin D, Moore M, et al. studies. No. 8 By Sculpher MJ, Pang FS, Manca A, Lay public’s understanding of equipoise No. 17 and randomisation in randomised Drummond MF, Golder S, Urdahl H, Clinical effectiveness and cost- controlled trials. et al. 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 evaluation. Virtual outreach: a randomised Edwards SJ, et al. By Hartwell D, Colquitt J, Loveman controlled trial and economic No. 9 E, Clegg AJ, Brodin H, Waugh N, et al. evaluation of joint teleconferenced Clinical and cost-effectiveness of medical consultations. electroconvulsive therapy for depressive No. 18 By Wallace P, Barber J, Clayton W, illness, schizophrenia, catatonia A randomised controlled comparison of Currell R, Fleming K, Garner P, et al. and mania: systematic reviews and alternative strategies in stroke care. economic modelling studies. By Kalra L, Evans A, Perez I, Knapp M, Swift C, Donaldson N. By Greenhalgh J, Knight C, Hind D, Volume 9, 2005 Beverley C, Walters S. No. 19 The investigation and analysis of No. 1 No. 10 Randomised controlled multiple critical incidents and adverse events in 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 Do the findings of case series studies Clinical effectiveness and cost- No. 21 vary significantly according to effectiveness of drotrecogin alfa Clinical and cost-effectiveness of newer methodological characteristics? (activated) (Xigris®) for the treatment immunosuppressive regimens in renal By Dalziel K, Round A, Stein K, of severe sepsis in adults: a systematic transplantation: a systematic review and modelling study. Garside R, Castelnuovo E, Payne L. review and economic evaluation. 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: findings 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 76 Haites NE, et al. Roderick P. Nigris E, Brewer N, Davis S, Oakley J. Health Technology Assessment 2009; Vol. 13: Suppl. 3

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 benefits 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 By Thomas KJ, MacPherson population screening) versus routine difficult asthma. H, Ratcliffe J, Thorpe L, Brazier J, practice for the detection of atrial By Smith JR, Mugford M, Holland Campbell M, et al. fibrillation in people aged 65 and over. R, Candy B, Noble MJ, Harrison BDW, The SAFE study. et al. No. 33 By Hobbs FDR, Fitzmaurice DA, Cost-effectiveness and safety of Mant J, Murray E, Jowett S, Bryan S, No. 24 epidural steroids in the management et al. An evaluation of the costs, effectiveness of sciatica. and quality of renal replacement No. 41 By Price C, Arden N, Coglan L, therapy provision in renal satellite units Displaced intracapsular hip fractures Rogers P. in England and Wales. in fit, older people: a randomised By Roderick P, Nicholson T, Armitage comparison of reduction and fixation, No. 34 A, Mehta R, Mullee M, Gerard K, et al. bipolar hemiarthroplasty and total hip The British Rheumatoid Outcome arthroplasty. No. 25 Study Group (BROSG) randomised By Keating JF, Grant A, Masson M, Imatinib for the treatment of patients controlled trial to compare the Scott NW, Forbes JF. 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 behaviour therapy clinical trials in By Wilson J, Connock M, Song F, C, Davies L, Dawes P, Scott DL. central Scotland. Yao G, Fry-Smith A, Raftery J, et al. By Durham RC, Chambers JA, No. 35 Power KG, Sharp DM, Macdonald RR, No. 26 Conceptual framework and systematic Major KA, et al. Indirect comparisons of competing review of the effects of participants’ interventions. and professionals’ preferences in No. 43 By Glenny AM, Altman DG, Song F, randomised controlled trials. The effectiveness and cost-effectiveness Sakarovitch C, Deeks JJ, D’Amico R, By King M, Nazareth I, Lampe F, of dual-chamber pacemakers compared et al. Bower P, Chandler M, Morou M, et al. with single-chamber pacemakers for bradycardia due to atrioventricular No. 27 No. 36 block or sick sinus syndrome: systematic Cost-effectiveness of alternative review and economic evaluation. The clinical and cost-effectiveness of strategies for the initial medical By Castelnuovo E, Stein K, Pitt M, implantable cardioverter defibrillators: management of non-ST elevation acute Garside R, Payne E. a systematic review. coronary syndrome: 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- No. 37 effectiveness analysis. No. 28 A trial of problem-solving by By Knowles R, Griebsch I, Outcomes of electrically stimulated community mental health nurses for Dezateux C, Brown J, Bull C, Wren C. gracilis neosphincter surgery. anxiety, depression and life difficulties 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 By Kendrick T, Simons L, left ventricular assist devices for end- The effectiveness and cost-effectiveness Mynors-Wallis L, Gray A, Lathlean J, stage heart failure: a systematic review of pimecrolimus and tacrolimus for Pickering R, et al. and economic evaluation. atopic eczema: a systematic review and By Clegg AJ, Scott DA, Loveman E, economic evaluation. No. 38 Colquitt J, Hutchinson J, Royle P, et al. By Garside R, Stein K, Castelnuovo The causes and effects of socio- E, Pitt M, Ashcroft D, Dimmock P, et al. demographic exclusions from clinical No. 46 trials. The effectiveness of the Heidelberg No. 30 Retina Tomograph and laser diagnostic By Bartlett C, Doyal L, Ebrahim S, Systematic review on urine albumin glaucoma scanning system (GDx) in Davey P, Bachmann M, Egger M, et al. testing for early detection of diabetic detecting and monitoring glaucoma. complications. By Kwartz AJ, Henson DB, Harper No. 39 By Newman DJ, Mattock MB, RA, Spencer AF, McLeod D. Is hydrotherapy cost-effective? Dawnay ABS, Kerry S, McGuire A, A randomised controlled trial of Yaqoob M, et al. 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. 77

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. A-M, Ritchie G, Light K, Riemsma R. KR, Turner DA, Sutton AJ, Chapple C, 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 The clinical effectiveness and cost- for the prevention of venous No. 16 thromboembolism: systematic effectiveness of newer drugs for Systematic review of the effectiveness reviews of mechanical methods, oral children with epilepsy. A systematic and cost-effectiveness of HealOzone® anticoagulation, dextran and regional review. for the treatment of occlusal pit/fissure anaesthesia as thromboprophylaxis. By Connock M, Frew E, Evans B-W, 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: exploring the uncertainty through The effectiveness and cost-effectiveness No. 17 systematic review, expert workshop and of parent training/education Randomised controlled trials of economic modelling. programmes for the treatment conventional antipsychotic versus By Garside R, Pitt M, Somerville M, of conduct disorder, including new atypical drugs, and new atypical Stein K, Price A, Gilbert N. oppositional defiant disorder, in drugs versus clozapine, in people with children. No. 9 schizophrenia responding poorly to, or By Dretzke J, Frew E, Davenport C, Topotecan, pegylated liposomal intolerant of, current drug treatment. Barlow J, Stewart-Brown S, Sandercock J, doxorubicin hydrochloride and By Lewis SW, Davies L, Jones PB, et al. paclitaxel for second-line or subsequent Barnes TRE, Murray RM, Kerwin R, treatment of advanced ovarian cancer: et al. a systematic review and economic Volume 10, 2006 evaluation. No. 18 By Main C, Bojke L, Griffin S, Diagnostic tests and algorithms used No. 1 Norman G, Barbieri M, Mather L, et al. in the investigation of haematuria: The clinical and cost-effectiveness of systematic reviews and economic donepezil, rivastigmine, galantamine No. 10 evaluation. Evaluation of molecular techniques and memantine for Alzheimer’s By Rodgers M, Nixon J, Hempel S, disease. in prediction and diagnosis Aho T, Kelly J, Neal D, et al. By Loveman E, Green C, Kirby J, of cytomegalovirus disease in Takeda A, Picot J, Payne E, et al. immunocompromised patients. By Szczepura A, Westmoreland D, No. 19 Cognitive behavioural therapy in No. 2 Vinogradova Y, Fox J, Clark M. FOOD: a multicentre randomised trial addition to antispasmodic therapy for evaluating feeding policies in patients No. 11 irritable bowel syndrome in primary admitted to hospital with a recent Screening for thrombophilia in high- care: randomised controlled trial. stroke. risk situations: systematic review By Kennedy TM, Chalder T, By Dennis M, Lewis S, Cranswick G, and cost-effectiveness analysis. The McCrone P, Darnley S, Knapp M, Forbes J. Thrombosis: Risk and Economic Jones RH, et al. Assessment of Thrombophilia No. 3 Screening (TREATS) study. No. 20 The clinical effectiveness and cost- By Wu O, Robertson L, Twaddle S, A systematic review of the Lowe GDO, Clark P, Greaves M, et al. effectiveness of computed tomography clinical effectiveness and cost- screening for lung cancer: systematic effectiveness of enzyme replacement No. 12 reviews. A series of systematic reviews to inform therapies for Fabry’s disease and By Black C, Bagust A, Boland A, a decision analysis for sampling and mucopolysaccharidosis type 1. 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 benefits 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. No. 5 UK Mild Hepatitis C Trial Investigators. Comparison of conference abstracts No. 14 and presentations with full-text articles The cost-effectiveness of screening for No. 22 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, 78 Walley T, Haycox A, Williamson PR. et al. Iglesias CP, Hawkins K, Cullum NA, et al. Health Technology Assessment 2009; Vol. 13: Suppl. 3

No. 23 No. 31 No. 40 A systematic review and economic Etanercept and infliximab 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 deficit By Woolacott N, Bravo Vergel Y, Trial (MINuET). Hawkins N, Kainth A, Khadjesari Z, hyperactivity disorder in children and By Williams J, Russell I, Durai D, Misso K, et al. adolescents. Cheung W-Y, Farrin A, Bloor K, et al. By King S, Griffin 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 systematic review and economic effectiveness of enzyme replacement J, Pitt M, Cramp M, Siebert U, Price A, et al. therapy for Gaucher’s disease: a evaluation. systematic review. By Pandor A, Eggington S, Paisley S, No. 33 By Connock M, Burls A, Frew E, Tappenden P, Sutcliffe P. Computerised cognitive behaviour Fry-Smith A, Juarez-Garcia A, McCabe C, therapy for depression and anxiety et al. No. 42 update: a systematic review and A systematic review of the effectiveness economic evaluation. of adalimumab, etanercept and No. 25 By Kaltenthaler E, Brazier J, infliximab for the treatment of Effectiveness and cost-effectiveness De Nigris E, Tumur I, Ferriter M, of salicylic acid and cryotherapy for Beverley C, et al. rheumatoid arthritis in adults and cutaneous warts. An economic decision an economic evaluation of their cost- model. No. 34 effectiveness. By Thomas KS, Keogh-Brown MR, Cost-effectiveness of using prognostic By Chen Y-F, Jobanputra P, Barton P, Chalmers JR, Fordham RJ, Holland RC, information to select women with breast Jowett S, Bryan S, Clark W, et al. 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, Ferriter M, Parry G, Dent-Brown K, et al. perioperative allogeneic blood No. 27 transfusion: a systematic review and A review of the evidence on the effects No. 36 economic model. and costs of implantable cardioverter Clinical effectiveness and cost- By Davies L, Brown TJ, Haynes S, defibrillator 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. 37 No. 28 By Murray A, Lourenco T, de Verteuil Cognitive behavioural therapy Adefovir dipivoxil and pegylated R, Hernandez R, Fraser C, McKinley A, in chronic fatigue syndrome: a interferon alfa-2a for the treatment of randomised controlled trial of an et al. chronic hepatitis B: a systematic review outpatient group programme. and economic evaluation. By O’Dowd H, Gladwell P, Rogers No. 46 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 five strategies for the prevention Mason A, Kainth A, Khadjesari Z, Bravo effectiveness of pulmonary artery of nonsteroidal anti-inflammatory 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. By Harvey S, Stevens K, Harrison D, Systematic reviews of clinical decision 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, No. 30 No. 39 Clamp S, Keen J, Verde P, et al. 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. 79

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 analysis. effectiveness of immunosuppressive randomised controlled trial. By Kanis JA, Stevenson M, therapy for renal transplantation in McCloskey EV, Davis S, Lloyd-Jones M. By Weindling AM, Cunningham CC, children. Glenn SM, Edwards RT, Reeves DJ. By Yao G, Albon E, Adi Y, Milford D, No. 8 Bayliss S, Ready A, et al. Epidemiological, social, diagnostic and No. 17 economic evaluation of population Screening for type 2 diabetes: literature No. 50 screening for genital chlamydial review and economic modelling. Amniocentesis results: investigation of infection. By Waugh N, Scotland G, McNamee By Low N, McCarthy A, Macleod J, anxiety. The ARIA trial. P, Gillett M, Brennan A, Goyder E, et al. By Hewison J, Nixon J, Fountain J, Salisbury C, Campbell R, Roberts TE, et al. Cocks K, Jones C, Mason G, et al. No. 18 No. 9 The effectiveness and cost-effectiveness Methadone and buprenorphine for the of cinacalcet for secondary Volume 11, 2007 management of opioid dependence: hyperparathyroidism in end-stage renal a systematic review and economic disease patients on dialysis: a systematic No. 1 evaluation. review and economic evaluation. Pemetrexed disodium for the treatment By Connock M, Juarez-Garcia A, By Garside R, Pitt M, Anderson R, of malignant pleural mesothelioma: Jowett S, Frew E, Liu Z, Taylor RJ, et al. Mealing S, Roome C, Snaith A, et al. a systematic review and economic evaluation. No. 10 Exercise Evaluation Randomised No. 19 By Dundar Y, Bagust A, Dickson R, Trial (EXERT): a randomised trial The clinical effectiveness and cost- Dodd S, Green J, Haycox A, et al. comparing GP referral for leisure effectiveness of gemcitabine for centre-based exercise, community-based metastatic breast cancer: a systematic No. 2 walking and advice only. review and economic evaluation. A systematic review and economic By Isaacs AJ, Critchley JA, See Tai model of the clinical effectiveness S, Buckingham K, Westley D, Harridge By Takeda AL, Jones J, Loveman E, and cost-effectiveness of docetaxel SDR, et al. Tan SC, Clegg AJ. in combination with prednisone or prednisolone for the treatment of No. 11 No. 20 hormone-refractory metastatic prostate Interferon alfa (pegylated and non- A systematic review of duplex pegylated) and ribavirin for the cancer. ultrasound, magnetic resonance treatment of mild chronic hepatitis angiography and computed By Collins R, Fenwick E, Trowman R, C: a systematic review and economic Perard R, Norman G, Light K, et al. evaluation. tomography angiography for By Shepherd J, Jones J, Hartwell D, the diagnosis and assessment of No. 3 Davidson P, Price A, Waugh N. symptomatic, lower limb peripheral A systematic review of rapid diagnostic arterial disease. tests for the detection of tuberculosis No. 12 By Collins R, Cranny G, Burch J, infection. Systematic review and economic Aguiar-Ibáñez R, Craig D, Wright K, evaluation of bevacizumab and By Dinnes J, Deeks J, Kunst H, et al. Gibson A, Cummins E, Waugh N, et al. cetuximab for the treatment of 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. By Stevenson M, Davis S, Lloyd-Jones beta and darbepoetin alfa in anaemia By Colquitt JL, Kirby J, Green C, M, Beverley C. associated with cancer, especially that attributable to cancer treatment. Cooper K, Trompeter RS. No. 5 By Wilson J, Yao GL, Raftery J, No. 22 A systematic review of quantitative and Bohlius J, Brunskill S, Sandercock J, et al. 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 Raynor DK, Blenkinsopp of coronary events. By Fayter D, Nixon J, Hartley S, A, Knapp P, Grime J, Nicolson DJ, By Ward S, Lloyd Jones M, Pandor A, Rithalia A, Butler G, Rudolf M, et al. Pollock K, et al. Holmes M, Ara R, Ryan A, et al. No. 23 No. 6 No. 15 Systematic review of the effectiveness of A systematic review of the effectiveness Oral naltrexone as a treatment for preventing and treating Staphylococcus and cost-effectiveness of different aureus carriage in reducing peritoneal relapse prevention in formerly opioid- models of community-based respite 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, 80 Jowett S, Frew E, Day E, et al. K, Arksey H, Golder S, Adamson J, et al. et al. Health Technology Assessment 2009; Vol. 13: Suppl. 3

No. 24 No. 32 No. 40 The clinical effectiveness and cost Current practice, accuracy, effectiveness Taxanes for the adjuvant treatment of of repetitive transcranial magnetic and cost-effectiveness of the school early breast cancer: systematic review stimulation versus electroconvulsive entry hearing screen. and economic evaluation. therapy in severe depression: a By Bamford J, Fortnum H, Bristow By Ward S, Simpson E, Davis S, Hind multicentre pragmatic randomised K, Smith J, Vamvakas G, Davies L, et al. D, Rees A, Wilkinson A. controlled trial and economic analysis. By McLoughlin DM, Mogg A, Eranti No. 33 No. 41 S, Pluck G, Purvis R, Edwards D, et al. The clinical effectiveness and cost- The clinical effectiveness and cost- effectiveness of inhaled insulin in effectiveness of screening for open No. 25 diabetes mellitus: a systematic review angle glaucoma: a systematic review A randomised controlled trial and and economic evaluation. and economic evaluation. economic evaluation of direct versus By Black C, Cummins E, Royle P, By Burr JM, Mowatt G, Hernández indirect and individual versus group Philip S, Waugh N. R, Siddiqui MAR, Cook J, Lourenco T, modes of speech and language therapy et al. for children with primary language No. 34 impairment. Surveillance of cirrhosis for No. 42 By Boyle J, McCartney E, Forbes J, hepatocellular carcinoma: systematic Acceptability, benefit and costs of early O’Hare A. review and economic analysis. screening for hearing disability: a study By Thompson Coon J, Rogers G, of potential screening tests and models. No. 26 Hewson P, Wright D, Anderson R, By Davis A, Smith P, Ferguson M, Hormonal therapies for early breast Cramp M, et al. Stephens D, Gianopoulos I. cancer: systematic review and economic evaluation. No. 35 No. 43 By Hind D, Ward S, De Nigris E, The Birmingham Rehabilitation Contamination in trials of educational Uptake Maximisation Study (BRUM). Simpson E, Carroll C, Wyld L. interventions. Homebased compared with hospital- By Keogh-Brown MR, Bachmann No. 27 based cardiac rehabilitation in a multi- MO, Shepstone L, Hewitt C, Howe A, Cardioprotection against the toxic ethnic population: cost-effectiveness Ramsay CR, et al. effects of anthracyclines given to and patient adherence. children with cancer: a systematic By Jolly K, Taylor R, Lip GYH, No. 44 review. Greenfield S, Raftery J, Mant J, et al. Overview of the clinical effectiveness of By Bryant J, Picot J, Levitt G, positron emission tomography imaging Sullivan I, Baxter L, Clegg A. No. 36 in selected cancers. A systematic review of the clinical, By Facey K, Bradbury I, Laking G, No. 28 public health and cost-effectiveness of Payne E. Adalimumab, etanercept and infliximab rapid diagnostic tests for the detection for the treatment of ankylosing and identification of bacterial intestinal No. 45 spondylitis: a systematic review and pathogens in faeces and food. The effectiveness and cost-effectiveness economic evaluation. By Abubakar I, Irvine L, Aldus CF, of carmustine implants and By McLeod C, Bagust A, Boland A, Wyatt GM, Fordham R, Schelenz S, et al. temozolomide for the treatment of Dagenais P, Dickson R, Dundar Y, et al. No. 37 newly diagnosed high-grade glioma: No. 29 A randomised controlled trial a systematic review and economic Prenatal screening and treatment examining the longer-term outcomes evaluation. strategies to prevent group B of standard versus new antiepileptic By Garside R, Pitt M, Anderson R, streptococcal and other bacterial drugs. The SANAD trial. Rogers G, Dyer M, Mealing S, et al. infections in early infancy: cost- By Marson AG, Appleton R, Baker effectiveness and expected value of GA, Chadwick DW, Doughty J, Eaton B, No. 46 information analyses. et al. Drug-eluting stents: a systematic review By Colbourn T, Asseburg C, Bojke L, and economic evaluation. Philips Z, Claxton K, Ades AE, et al. No. 38 By Hill RA, Boland A, Dickson R, Clinical effectiveness and cost- Dündar Y, Haycox A, McLeod C, et al. No. 30 effectiveness of different models Clinical effectiveness and cost- of managing long-term oral anti- No. 47 effectiveness of bone morphogenetic coagulation therapy: a systematic The clinical effectiveness and proteins in the non-healing of fractures review and economic modelling. cost-effectiveness of cardiac and spinal fusion: a systematic review. By Connock M, Stevens C, Fry-Smith resynchronisation (biventricular pacing) By Garrison KR, Donell S, Ryder J, A, Jowett S, Fitzmaurice D, Moore D, for heart failure: systematic review and Shemilt I, Mugford M, Harvey I, et al. et al. economic model. By Fox M, Mealing S, Anderson R, No. 31 No. 39 Dean J, Stein K, Price A, et al. A randomised controlled trial of A systematic review and economic postoperative radiotherapy following model of the clinical effectiveness No. 48 breast-conserving surgery in a and cost-effectiveness of interventions Recruitment to randomised trials: minimum-risk older population. The for preventing relapse in people with strategies for trial enrolment and PRIME trial. bipolar disorder. participation study. The STEPS study. By Prescott RJ, Kunkler IH, Williams By Soares-Weiser K, Bravo Vergel Y, By Campbell MK, Snowdon C, LJ, King CC, Jack W, van der Pol M, Beynon S, Dunn G, Barbieri M, Duffy S, Francis D, Elbourne D, McDonald AM, et al. et al. 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No. 49 No. 4 No. 12 Cost-effectiveness of functional Does befriending by trained lay workers The clinical effectiveness and cost- cardiac testing in the diagnosis and improve psychological well-being and effectiveness of central venous catheters management of coronary artery quality of life for carers of people treated with anti-infective agents in disease: a randomised controlled trial. with dementia, and at what cost? A preventing bloodstream infections: The CECaT trial. randomised controlled trial. a systematic review and economic By Sharples L, Hughes V, Crean A, By Charlesworth G, Shepstone L, evaluation. Dyer M, Buxton M, Goldsmith K, et al. Wilson E, Thalanany M, Mugford M, By Hockenhull JC, Dwan K, Boland Poland F. A, Smith G, Bagust A, Dundar Y, et al. No. 50 No. 13 Evaluation of diagnostic tests when No. 5 Stepped treatment of older adults on there is no gold standard. A review of A multi-centre retrospective cohort laxatives. The STOOL trial. methods. study comparing the efficacy, safety By Mihaylov S, Stark C, McColl E, By Rutjes AWS, Reitsma and cost-effectiveness of hysterectomy Steen N, Vanoli A, Rubin G, et al. JB, Coomarasamy A, Khan KS, and uterine artery embolisation for Bossuyt PMM. the treatment of symptomatic uterine No. 14 fibroids. The HOPEFUL study. A randomised controlled trial of No. 51 By Hirst A, Dutton S, Wu O, Briggs cognitive behaviour therapy in Systematic reviews of the clinical A, Edwards C, Waldenmaier L, et al. adolescents with major depression effectiveness and cost-effectiveness of treated by selective serotonin reuptake proton pump inhibitors in acute upper No. 6 inhibitors. The ADAPT trial. gastrointestinal bleeding. Methods of prediction and prevention By Goodyer IM, Dubicka B, By Leontiadis GI, Sreedharan of pre-eclampsia: systematic reviews of Wilkinson P, Kelvin R, Roberts C, A, Dorward S, Barton P, Delaney B, accuracy and effectiveness literature Byford S, et al. Howden CW, et al. with economic modelling. By Meads CA, Cnossen JS, Meher S, No. 15 No. 52 Juarez-Garcia A, ter Riet G, Duley L, The use of irinotecan, oxaliplatin A review and critique of modelling in et al. and raltitrexed for the treatment of prioritising and designing screening advanced colorectal cancer: systematic programmes. No. 7 review and economic evaluation. By Karnon J, Goyder E, Tappenden The use of economic evaluations in By Hind D, Tappenden P, Tumur I, P, McPhie S, Towers I, Brazier J, et al. NHS decision-making: a review and Eggington E, Sutcliffe P, Ryan A. empirical investigation. No. 16 No. 53 By Williams I, McIver S, Moore D, Ranibizumab and pegaptanib for An assessment of the impact of the Bryan S. the treatment of age-related macular NHS Health Technology Assessment degeneration: a systematic review and Programme. No. 8 economic evaluation. By Hanney S, Buxton M, Green C, Stapled haemorrhoidectomy By Colquitt JL, Jones J, Tan SC, Coulson D, Raftery J. (haemorrhoidopexy) for the treatment Takeda A, Clegg AJ, Price A. of haemorrhoids: a systematic review and economic evaluation. No. 17 Volume 12, 2008 By Burch J, Epstein D, Baba-Akbari Systematic review of the clinical A, Weatherly H, Fox D, Golder S, et al. effectiveness and cost-effectiveness No. 1 of 64-slice or higher computed A systematic review and economic No. 9 tomography angiography as an model of switching from The clinical effectiveness of diabetes alternative to invasive coronary nonglycopeptide to glycopeptide education models for Type 2 diabetes: a angiography in the investigation of antibiotic prophylaxis for surgery. systematic review. coronary artery disease. By Cranny G, Elliott R, Weatherly H, By Loveman E, Frampton GK, By Mowatt G, Cummins E, Waugh N, Chambers D, Hawkins N, Myers L, et al. Clegg AJ. Walker S, Cook J, Jia X, et al.

No. 2 No. 10 No. 18 ‘Cut down to quit’ with nicotine Payment to healthcare professionals for Structural neuroimaging in psychosis: replacement therapies in smoking patient recruitment to trials: systematic a systematic review and economic cessation: a systematic review of review and qualitative study. evaluation. By Albon E, Tsourapas A, Frew E, effectiveness and economic analysis. By Raftery J, Bryant J, Powell J, Davenport C, Oyebode F, Bayliss S, et al. By Wang D, Connock M, Barton P, Kerr C, Hawker S. Fry-Smith A, Aveyard P, Moore D. No. 19 No. 11 Systematic review and economic No. 3 Cyclooxygenase-2 selective non- analysis of the comparative A systematic review of the effectiveness steroidal anti-inflammatory drugs effectiveness of different inhaled of strategies for reducing fracture risk (etodolac, meloxicam, celecoxib, corticosteroids and their usage with in children with juvenile idiopathic rofecoxib, etoricoxib, valdecoxib and long-acting beta2 agonists for the arthritis with additional data on long- lumiracoxib) for osteoarthritis and treatment of chronic asthma in adults term risk of fracture and cost of disease rheumatoid arthritis: a systematic and children aged 12 years and over. management. review and economic evaluation. By Shepherd J, Rogers G, Anderson By Thornton J, Ashcroft D, O’Neill T, By Chen Y-F, Jobanputra P, Barton P, R, Main C, Thompson-Coon J, 82 Elliott R, Adams J, Roberts C, et al. Bryan S, Fry-Smith A, Harris G, et al. Hartwell D, et al. Health Technology Assessment 2009; Vol. 13: Suppl. 3

No. 20 No. 28 Volume 13, 2009 Systematic review and economic Intravenous magnesium sulphate analysis of the comparative and sotalol for prevention of atrial No. 1 effectiveness of different inhaled fibrillation after coronary artery Deferasirox for the treatment of iron corticosteroids and their usage with bypass surgery: a systematic review and overload associated with regular blood transfusions (transfusional long-acting beta agonists for the economic evaluation. 2 haemosiderosis) in patients suffering treatment of chronic asthma in children By Shepherd J, Jones J, Frampton GK, Tanajewski L, Turner D, Price A. with chronic anaemia: a systematic under the age of 12 years. review and economic evaluation. By Main C, Shepherd J, Anderson R, No. 29 By McLeod C, Fleeman N, Kirkham Rogers G, Thompson-Coon J, Liu Z, J, Bagust A, Boland A, Chu P, et al. Absorbent products for urinary/faecal et al. incontinence: a comparative evaluation No. 2 of key product categories. No. 21 Thrombophilia testing in people with By Fader M, Cottenden A, Getliffe K, Ezetimibe for the treatment of venous thromboembolism: systematic Gage H, Clarke-O’Neill S, Jamieson K, hypercholesterolaemia: a systematic review and cost-effectiveness analysis. et al. By Simpson EL, Stevenson MD, review and economic evaluation. Rawdin A, Papaioannou D. By Ara R, Tumur I, Pandor A, No. 30 Duenas A, Williams R, Wilkinson A, et al. A systematic review of repetitive No. 3 functional task practice with modelling Surgical procedures and non-surgical No. 22 of resource use, costs and effectiveness. devices for the management of non- Topical or oral ibuprofen for chronic By French B, Leathley M, Sutton C, apnoeic snoring: a systematic review of knee pain in older people. The TOIB McAdam J, Thomas L, Forster A, et al. clinical effects and associated treatment study. costs. By Underwood M, Ashby D, Carnes No. 31 By Main C, Liu Z, Welch K, Weiner D, Castelnuovo E, Cross P, Harding G, The effectiveness and cost-effectivness G, Quentin Jones S, Stein K. et al. of minimal access surgery amongst people with gastro-oesophageal reflux No. 4 Continuous positive airway pressure No. 23 disease – a UK collaborative study. The devices for the treatment of obstructive reflux trial. A prospective randomised comparison sleep apnoea–hypopnoea syndrome: a By Grant A, Wileman S, Ramsay C, of minor surgery in primary and systematic review and economic analysis. Bojke L, Epstein D, Sculpher M, et al. secondary care. The MiSTIC trial. By McDaid C, Griffin S, Weatherly H, By George S, Pockney P, Primrose J, Durée K, van der Burgt M, van Hout S, No. 32 Smith H, Little P, Kinley H, et al. Akers J, et al. Time to full publication of studies of anti-cancer medicines for breast cancer No. 24 No. 5 and the potential for publication bias: a A review and critical appraisal Use of classical and novel biomarkers short systematic review. of measures of therapist–patient as prognostic risk factors for localised By Takeda A, Loveman E, Harris P, prostate cancer: a systematic review. interactions in mental health settings. Hartwell D, Welch K. By Sutcliffe P, Hummel S, Simpson E, By Cahill J, Barkham M, Hardy G, Young T, Rees A, Wilkinson A, et al. Gilbody S, Richards D, Bower P, et al. No. 33 Performance of screening tests for No. 6 No. 25 child physical abuse in accident and The harmful health effects of The clinical effectiveness and cost- emergency departments. recreational ecstasy: a systematic review effectiveness of screening programmes By Woodman J, Pitt M, Wentz R, of observational evidence. for amblyopia and strabismus in Taylor B, Hodes D, Gilbert RE. By Rogers G, Elston J, Garside R, children up to the age of 4–5 years: Roome C, Taylor R, Younger P, et al. a systematic review and economic No. 34 No. 7 evaluation. Curative catheter ablation in atrial Systematic review of the clinical fibrillation and typical atrial flutter: By Carlton J, Karnon J, Czoski- effectiveness and cost-effectiveness systematic review and economic Murray C, Smith KJ, Marr J. of oesophageal Doppler monitoring evaluation. in critically ill and high-risk surgical No. 26 By Rodgers M, McKenna C, Palmer patients. A systematic review of the clinical S, Chambers D, Van Hout S, Golder S, By Mowatt G, Houston G, Hernández effectiveness and cost-effectiveness et al. R, de Verteuil R, Fraser C, Cuthbertson and economic modelling of minimal B, et al. No. 35 incision total hip replacement Systematic review and economic approaches in the management of No. 8 modelling of effectiveness and cost The use of surrogate outcomes in arthritic disease of the hip. utility of surgical treatments for men model-based cost-effectiveness analyses: By de Verteuil R, Imamura M, Zhu S, with benign prostatic enlargement. a survey of UK Health Technology Glazener C, Fraser C, Munro N, et al. By Lourenco T, Armstrong N, N’Dow Assessment reports. J, Nabi G, Deverill M, Pickard R, et al. By Taylor RS, Elston J. No. 27 A preliminary model-based assessment No. 36 No. 9 of the cost–utility of a screening Immunoprophylaxis against respiratory Controlling Hypertension and programme for early age-related syncytial virus (RSV) with palivizumab Hypotension Immediately Post Stroke macular degeneration. in children: a systematic review and (CHHIPS) – a randomised controlled By Karnon J, Czoski-Murray C, economic evaluation. trial. By Potter J, Mistri A, Brodie F, Smith K, Brand C, Chakravarthy U, By Wang D, Cummins C, Bayliss S, Chernova J, Wilson E, Jagger C, et al. Davis S, et al. Sandercock J, Burls A. 83

No. 10 No. 19 No. 27 Routine antenatal anti-D prophylaxis Dipsticks and diagnostic algorithms in Paracetamol and ibuprofen for the for RhD-negative women: a systematic urinary tract infection: development treatment of fever in children: the review and economic evaluation. and validation, randomised trial, PITCH randomised controlled trial. By Pilgrim H, Lloyd-Jones M, Rees A. economic analysis, observational cohort By Hay AD, Redmond NM, Costelloe and qualitative study. C, Montgomery AA, Fletcher M, No. 11 By Little P, Turner S, Rumsby K, Hollinghurst S, et al. Amantadine, oseltamivir and zanamivir Warner G, Moore M, Lowes JA, et al. for the prophylaxis of influenza No. 28 (including a review of existing guidance No. 20 A randomised controlled trial to no. 67): a systematic review and Systematic review of respite care in the compare minimally invasive glucose economic evaluation. frail elderly. monitoring devices with conventional By Tappenden P, Jackson R, Cooper By Shaw C, McNamara R, Abrams monitoring in the management of K, Rees A, Simpson E, Read R, et al. K, Cannings-John R, Hood K, Longo insulin-treated diabetes mellitus M, et al. (MITRE). No. 12 By Newman SP, Cooke D, Casbard A, Improving the evaluation of No. 21 Walker S, Meredith S, Nunn A, et al. therapeutic interventions in multiple Neuroleptics in the treatment of sclerosis: the role of new psychometric aggressive challenging behaviour for No. 29 methods. people with intellectual disabilities: Sensitivity analysis in economic By Hobart J, Cano S. a randomised controlled trial evaluation: an audit of NICE current (NACHBID). practice and a review of its use and No. 13 By Tyrer P, Oliver-Africano P, Romeo value in decision-making. By Andronis L, Barton P, Bryan S. Treatment of severe ankle sprain: a R, Knapp M, Dickens S, Bouras N, et al. pragmatic randomised controlled trial Suppl. 1 comparing the clinical effectiveness No. 22 Trastuzumab for the treatment of and cost-effectiveness of three types of Randomised controlled trial to primary breast cancer in HER2-positive mechanical ankle support with tubular determine the clinical effectiveness women: a single technology appraisal. bandage. The CAST trial. and cost-effectiveness of selective By Ward S, Pilgrim H, Hind D. By Cooke MW, Marsh JL, Clark M, serotonin reuptake inhibitors plus Nakash R, Jarvis RM, Hutton JL, et al., supportive care, versus supportive care Docetaxel for the adjuvant treatment on behalf of the CAST trial group. alone, for mild to moderate depression of early node-positive breast cancer: a with somatic symptoms in primary single technology appraisal. No. 14 care: the THREAD (THREshold for By Chilcott J, Lloyd Jones M, Non-occupational postexposure AntiDepressant response) study. Wilkinson A. prophylaxis for HIV: a systematic By Kendrick T, Chatwin J, Dowrick C, review. Tylee A, Morriss R, Peveler R, et al. The use of paclitaxel in the By Bryant J, Baxter L, Hird S. management of early stage breast No. 23 cancer. No. 15 Diagnostic strategies using DNA testing By Griffin S, Dunn G, Palmer S, Blood glucose self-monitoring in type 2 for hereditary haemochromatosis in Macfarlane K, Brent S, Dyker A, et al. diabetes: a randomised controlled trial. at-risk populations: a systematic review Rituximab for the first-line treatment By Farmer AJ, Wade AN, French DP, and economic evaluation. of stage III/IV follicular non-Hodgkin’s Simon J, Yudkin P, Gray A, et al. By Bryant J, Cooper K, Picot J, Clegg lymphoma. A, Roderick P, Rosenberg W, et al. By Dundar Y, Bagust A, Hounsome J, No. 16 McLeod C, Boland A, Davis H, et al. How far does screening women for No. 24 domestic (partner) violence in different Enhanced external counterpulsation Bortezomib for the treatment of health-care settings meet criteria for for the treatment of stable angina and multiple myeloma patients. a screening programme? Systematic heart failure: a systematic review and By Green C, Bryant J, Takeda A, reviews of nine UK National Screening economic analysis. Cooper K, Clegg A, Smith A, et al. Committee criteria. By McKenna C, McDaid C, Fludarabine phosphate for the first- By Feder G, Ramsay J, Dunne D, Suekarran S, Hawkins N, Claxton K, line treatment of chronic lymphocytic Rose M, Arsene C, Norman R, et al. Light K, et al. leukaemia. By Walker S, Palmer S, Erhorn S, No. 17 No. 25 Brent S, Dyker A, Ferrie L, et al. Spinal cord stimulation for chronic Development of a decision support pain of neuropathic or ischaemic tool for primary care management of Erlotinib for the treatment of relapsed origin: systematic review and economic patients with abnormal liver function non-small cell lung cancer. evaluation. tests without clinically apparent liver By McLeod C, Bagust A, Boland A, By Simpson, EL, Duenas A, Holmes disease: a record-linkage population Hockenhull J, Dundar Y, Proudlove C, MW, Papaioannou D, Chilcott J. cohort study and decision analysis et al. (ALFIE). Cetuximab plus radiotherapy for the No. 18 By Donnan PT, McLernon D, Dillon treatment of locally advanced squamous The role of magnetic resonance JF, Ryder S, Roderick P, Sullivan F, et al. cell carcinoma of the head and neck. imaging in the identification of By Griffin S, Walker S, Sculpher M, suspected acoustic neuroma: a No. 26 White S, Erhorn S, Brent S, et al. systematic review of clinical and cost- A systematic review of presumed effectiveness and natural history. consent systems for deceased organ Infliximab for the treatment of adults By Fortnum H, O’Neill C, Taylor R, donation. with psoriasis. Lenthall R, Nikolopoulos T, Lightfoot By Rithalia A, McDaid C, Suekarran By Loveman E, Turner D, Hartwell 84 G, et al. S, Norman G, Myers L, Sowden A. D, Cooper K, Clegg A. Health Technology Assessment 2009; Vol. 13: Suppl. 3

No. 30 No. 38 Alteplase for the treatment of acute Psychological interventions for The effectiveness and cost-effectiveness ischaemic stroke: a single technology postnatal depression: cluster of methods of storing donated kidneys appraisal. randomised trial and economic from deceased donors: a systematic By Lloyd Jones M, Holmes M. evaluation. The PoNDER trial. review and economic model. By Morrell CJ, Warner R, Slade P, By Bond M, Pitt M, Akoh J, Moxham Rituximab for the treatment of Dixon S, Walters S, Paley G, et al. T, Hoyle M, Anderson R. rheumatoid arthritis. By Bagust A, Boland A, Hockenhull No. 31 No. 39 J, Fleeman N, Greenhalgh J, Dundar Y, The effect of different treatment Rehabilitation of older patients: day et al. durations of clopidogrel in patients hospital compared with rehabilitation Omalizumab for the treatment of with non-ST-segment elevation acute at home. A randomised controlled trial. severe persistent allergic asthma. coronary syndromes: a systematic By Parker SG, Oliver P, Pennington By Jones J, Shepherd J, Hartwell D, review and value of information M, Bond J, Jagger C, Enderby PM, et al. Harris P, Cooper K, Takeda A, et al. analysis. By Rogowski R, Burch J, Palmer S, No. 40 Rituximab for the treatment of relapsed Craigs C, Golder S, Woolacott N. Breastfeeding promotion for infants in or refractory stage III or IV follicular neonatal units: a systematic review and non-Hodgkin’s lymphoma. No. 32 economic analysis By Boland A, Bagust A, Hockenhull Systematic review and individual By Renfrew MJ, Craig D, Dyson L, J, Davis H, Chu P, Dickson R. patient data meta-analysis of diagnosis McCormick F, Rice S, King SE, et al. of heart failure, with modelling of Adalimumab for the treatment of implications of different diagnostic No. 41 psoriasis. strategies in primary care. The clinical effectiveness and cost- By Turner D, Picot J, Cooper K, By Mant J, Doust J, Roalfe A, Barton effectiveness of bariatric (weight loss) Loveman E. surgery for obesity: a systematic review and P, Cowie MR, Glasziou P, et al. Dabigatran etexilate for the prevention economic evaluation. of venous thromboembolism in patients By Picot J, Jones J, Colquitt JL, No. 33 undergoing elective hip and knee Gospodarevskaya E, Loveman E, Baxter A multicentre randomised controlled surgery: a single technology appraisal. L, et al. trial of the use of continuous positive By Holmes M, C Carroll C, airway pressure and non-invasive Papaioannou D. positive pressure ventilation in the early No. 42 treatment of patients presenting to the Rapid testing for group B streptococcus Romiplostim for the treatment emergency department with severe during labour: a test accuracy study of chronic immune or idiopathic acute cardiogenic pulmonary oedema: with evaluation of acceptability and thrombocytopenic purpura: a single the 3CPO trial. cost-effectiveness. technology appraisal. By Gray AJ, Goodacre S, Newby By Daniels J, Gray J, Pattison H, By Mowatt G, Boachie C, Crowther DE, Masson MA, Sampson F, Dixon Roberts T, Edwards E, Milner P, et al. M, Fraser C, Hernández R, Jia X, et al. S, et al., on behalf of the 3CPO study investigators. No. 43 Sunitinib for the treatment of Screening to prevent spontaneous gastrointestinal stromal tumours: a No. 34 preterm birth: systematic reviews of critique of the submission from Pfizer. Early high-dose lipid-lowering therapy accuracy and effectiveness literature By Bond M, Hoyle M, Moxham T, to avoid cardiac events: a systematic with economic modelling. Napier M, Anderson R. review and economic evaluation. By Honest H, Forbes CA, Durée KH, By Ara R, Pandor A, Stevens J, Rees Norman G, Duffy SB, Tsourapas A, et al. No. 45 A, Rafia R. Vitamin K to prevent fractures in No. 44 older women: systematic review and No. 35 The effectiveness and cost-effectiveness economic evaluation. Adefovir dipivoxil and pegylated of cochlear implants for severe to By Stevenson M, Lloyd-Jones M, interferon alpha for the treatment profound deafness in children and Papaioannou D. of chronic hepatitis B: an updated adults: a systematic review and systematic review and economic economic model. 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A double-blind randomised placebo- controlled trial of topical intranasal corticosteroids in 4- to 11-year-old children with persistent bilateral otitis media with effusion in primary care. By Williamson I, Benge S, Barton S, Petrou S, Letley L, Fasey N, et al.

Health Technology Assessment 2009; Vol. 13: Suppl. 3

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 Sheffield 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 Officer, Director, NIHR HTA HTA Medicine, University of Oxford NETSCC and NETSCC, HTA programme, Professor of Clinical Pharmacology, Dr Peter Davidson, Dr Nick Hicks, Dr Ruairidh Milne, University of Liverpool Director of Science Support, Director of NHS Support, Director of Strategy and NETSCC, HTA NETSCC, HTA Development, NETSCC 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 Section Head, NHS R&D Unit, University of Sheffield Director, West Midlands Centre Specialist, National Programme, 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 Sheffield 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, Chair, London School of Hygiene and Professor of Health Economics, Professor Jon Nicholl, Tropical Medicine Dr Martin J Landray, University of York Director, Medical Care Research Reader in Epidemiology, Unit, University of Sheffield Professor Peter Croft, Honorary Consultant Physician, Professor Helen Smith, Director of Primary Care Clinical Trial Service Unit, Professor of Primary Care, Deputy Chair, Sciences Research Centre, Keele University of Oxford University of Brighton Dr Andrew Farmer, University Senior Lecturer in General Professor Stuart Logan, Professor Kate Thomas, Practice, Department of Professor Nicky Cullum, Director of Health & Social Professor of Complementary & Primary Health Care, Director of Centre for Evidence- Care Research, The Peninsula Alternative Medicine Research, University of Oxford Based Nursing, University of Medical School, Universities of University of Leeds York Exeter and Plymouth Professor Ann Ashburn, Professor David John Professor of Rehabilitation Professor Jenny Donovan, Dr Rafael Perera, Torgerson, and Head of Research, Professor of Social Medicine, Lecturer in Medical Statisitics, Director of York Trials Unit, Southampton General Hospital University of Bristol Department of Primary Health University of York Care, Univeristy of Oxford Professor Steve Halligan, Professor Hywel Williams, Professor of Gastrointestinal Professor of Dermato- Radiology, University College Epidemiology, University of Hospital, London Nottingham

Observers

Ms Kay Pattison, Dr Morven Roberts, Section Head, NHS R&D Clinical Trials Manager, Programme, Department of Medical Research Council Health 87

Diagnostic Technologies & Screening Panel Members

Chair, Dr Stephanie Dancer, Dr Anne Mackie, Dr W Stuart A Smellie, Professor Paul Glasziou, Consultant Microbiologist, Director of Programmes, UK Consultant in Chemical Professor of Evidence-Based Hairmyres Hospital, East National Screening Committee Pathology, Bishop Auckland Medicine, University of Oxford Kilbride General Hospital Dr Michael Millar, Deputy Chair, Professor Glyn Elwyn, Consultant Senior Lecturer in Dr Nicholas Summerton, Dr David Elliman, Primary Medical Care Research Microbiology, Barts and The Consultant Clinical and Public Consultant Paediatrician and Group, Swansea Clinical School, London NHS Trust, Royal Health Advisor, NICE Honorary Senior Lecturer, University of Wales London Hospital Great Ormond Street Hospital, Ms Dawn Talbot, London Dr Ron Gray, Mr Stephen Pilling, Service User Representative Consultant Clinical Director, Centre for Outcomes, Professor Judith E Adams, Epidemiologist, Department Research & Effectiveness, Dr Graham Taylor, Consultant Radiologist, of Public Health, University of Joint Director, National Scientific Advisor, Regional Manchester Royal Infirmary, Oxford Collaborating Centre for DNA Laboratory, St James’s Central Manchester & Mental Health, University University Hospital, Leeds Manchester Children’s Professor Paul D Griffiths, College London Professor of Radiology, Professor Lindsay Wilson University Hospitals NHS Trust, Turnbull, and Professor of Diagnostic University of Sheffield Mrs Una Rennard, Service User Representative Scientific Director of the Radiology, Imaging Science Dr Jennifer J Kurinczuk, Centre for Magnetic Resonance and Biomedical Engineering, Consultant Clinical Dr Phil Shackley, Investigations and YCR Cancer & Imaging Sciences, Epidemiologist, National Senior Lecturer in Health Professor of Radiology, Hull University of Manchester Perinatal Epidemiology Unit, Economics, School of Royal Infirmary Ms Jane Bates, Oxford Population and Health Consultant Ultrasound Sciences, University of Dr Susanne M Ludgate, Newcastle upon Tyne Practitioner, Ultrasound Medical Director, Medicines & Department, Leeds Teaching Healthcare Products Regulatory Hospital NHS Trust Agency, London

Observers

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

Pharmaceuticals Panel Members

Chair, Dr Peter Elton, Professor Jonathan Ledermann, Dr Martin Shelly, Professor Robin Ferner, Director of Public Health, Professor of Medical Oncology General Practitioner, Leeds, Consultant Physician and Bury Primary Care Trust and Director of the Cancer and Associate Director, NHS Director, West Midlands Centre Research UK and University Clinical Governance Support for Adverse Drug Reactions, Dr Ben Goldacre, College London Cancer Trials Team, Leicester City Hospital NHS Trust, Research Fellow, Division of Centre Birmingham Psychological Medicine and Dr Gillian Shepherd, Psychiatry, King’s College Dr Yoon K Loke, Director, Health and Clinical Deputy Chair, London Senior Lecturer in Clinical Excellence, Merck Serono Ltd Professor Imti Choonara, Pharmacology, University of Professor in Child Health, Mrs Barbara Greggains, East Anglia Mrs Katrina Simister, University of Nottingham Service User Representative Assistant Director New Professor Femi Oyebode, Medicines, National Prescribing Mrs Nicola Carey, Dr Bill Gutteridge, Consultant Psychiatrist Centre, Liverpool Senior Research Fellow, Medical Adviser, London and Head of Department, School of Health and Social Strategic Health Authority University of Birmingham Mr David Symes, Service User Representative Care, The University of Dr Dyfrig Hughes, Reading Dr Andrew Prentice, Reader in Pharmacoeconomics Senior Lecturer and Consultant Dr Lesley Wise, Mr John Chapman, and Deputy Director, Centre Obstetrician and Gynaecologist, Unit Manager, Service User Representative for Economics and Policy in The Rosie Hospital, University Pharmacoepidemiology Health, IMSCaR, Bangor of Cambridge Research Unit, VRMM, University Medicines & Healthcare Products Regulatory Agency Observers Mr Simon Reeve, Dr Heike Weber, Dr Ursula Wells, Ms Kay Pattison, Head of Clinical and Cost- Programme Manager, Principal Research Officer, Section Head, NHS R&D Effectiveness, Medicines, Medical Research Council Department of Health Programme, Department of Pharmacy and Industry Group, Health 88 Department of Health

Current and past membership details of all HTA programme ‘committees’ are available from the HTA website (www.hta.ac.uk) Health Technology Assessment 2009; Vol. 13: Suppl. 3

Therapeutic Procedures Panel Members

Chair, Mrs Val Carlill, Mr Paul Hilton, Dr Kate Radford, Dr John C Pounsford, Service User Representative Consultant Gynaecologist Senior Lecturer (Research), Consultant Physician, North and Urogynaecologist, Royal Clinical Practice Research Bristol NHS Trust Mrs Anthea De Barton-Watson, Victoria Infirmary, Newcastle Unit, University of Central Service User Representative upon Tyne Lancashire, Preston Deputy Chair, Professor Scott Weich, Mr Mark Emberton, Professor Nicholas James, Mr Jim Reece Professor of Psychiatry, Division Senior Lecturer in Oncological Professor of Clinical Oncology, Service User Representative of Health in the Community, Urology, Institute of Urology, University of Birmingham, University of Warwick, University College Hospital, and Consultant in Clinical Dr Karen Roberts, Coventry London Oncology, Queen Elizabeth Nurse Consultant, Dunston Hill Hospital Hospital Cottages Professor Jane Barlow, Professor Steve Goodacre, Professor of Public Health in Professor of Emergency Dr Peter Martin, the Early Years, Health Sciences Medicine, University of Consultant Neurologist, Research Institute, Warwick Sheffield Addenbrooke’s Hospital, Medical School, Coventry Professor Christopher Griffiths, Cambridge Ms Maree Barnett, Professor of Primary Care, Barts Acting Branch Head of Vascular and The London School of Programme, Department of Medicine and Dentistry Health

Observers

Dr Phillip Leech, Dr Morven Roberts, Professor Tom Walley, Dr Ursula Wells, Principal Medical Officer for Clinical Trials Manager, Director, NIHR HTA Principal Research Officer, Primary Care, Department of Medical Research Council programme, Professor of Department of Health Health Clinical Pharmacology, University of Liverpool Ms Kay Pattison, Section Head, NHS R&D Programme, Department of Health Disease Prevention Panel Members Chair, Dr John Jackson, Dr Julie Mytton, Dr Kieran Sweeney, Dr Edmund Jessop, General Practitioner, Parkway Locum Consultant in Public Honorary Clinical Senior Medical Adviser, National Medical Centre, Newcastle Health Medicine, Bristol Lecturer, Peninsula College Specialist, National upon Tyne Primary Care Trust of Medicine and Dentistry, Commissioning Group (NCG), Universities of Exeter and London Professor Mike Kelly, Miss Nicky Mullany, Plymouth Director, Centre for Public Service User Representative Deputy Chair, Health Excellence, NICE, Professor Carol Tannahill, Dr David Pencheon, London Professor Ian Roberts, Glasgow Centre for Population Director, NHS Sustainable Professor of Epidemiology and Health Development Unit, Cambridge Dr Chris McCall, Public Health, London School General Practitioner, The of Hygiene & Tropical Medicine Professor Margaret Thorogood, Dr Elizabeth Fellow-Smith, Hadleigh Practice, Corfe Professor of Epidemiology, Medical Director, West London Mullen, Dorset Professor Ken Stein, University of Warwick Medical Mental Health Trust, Middlesex Senior Clinical Lecturer in School, Coventry Ms Jeanett Martin, Public Health, University of Director of Nursing, BarnDoc Exeter Limited, Lewisham Primary Care Trust

Observers

Ms Christine McGuire, Dr Caroline Stone, Research & Development, Programme Manager, Medical Department of Health Research Council

Expert Advisory Network Members

Professor Douglas Altman, Mr Jonothan Earnshaw, Professor Alan Horwich, Professor Miranda Mugford, Professor of Statistics in Consultant Vascular Surgeon, Dean and Section Chairman, Professor of Health Economics Medicine, Centre for Statistics Gloucestershire Royal Hospital, The Institute of Cancer and Group Co-ordinator, in Medicine, University of Gloucester Research, London University of East Anglia Oxford Professor Martin Eccles, Professor Allen Hutchinson, Professor Jim Neilson, Professor John Bond, Professor of Clinical Director of Public Health and Head of School of Reproductive Professor of Social Gerontology Effectiveness, Centre for Health Deputy Dean of ScHARR, & Developmental Medicine & Health Services Research, Services Research, University of University of Sheffield and Professor of Obstetrics University of Newcastle upon Newcastle upon Tyne and Gynaecology, University of Tyne Professor Peter Jones, Liverpool Professor Pam Enderby, Professor of Psychiatry, Professor Andrew Bradbury, Dean of Faculty of Medicine, University of Cambridge, Mrs Julietta Patnick, Professor of Vascular Surgery, Institute of General Practice Cambridge National Co-ordinator, NHS Solihull Hospital, Birmingham and Primary Care, University of Cancer Screening Programmes, Sheffield Professor Stan Kaye, Sheffield Mr Shaun Brogan, Cancer Research UK Professor Chief Executive, Ridgeway Professor Gene Feder, of Medical Oncology, Royal Professor Robert Peveler, Primary Care Group, Aylesbury Professor of Primary Care Marsden Hospital and Institute Professor of Liaison Psychiatry, Research & Development, of Cancer Research, Surrey Royal South Hants Hospital, Mrs Stella Burnside OBE, Centre for Health Sciences, Southampton Chief Executive, Regulation Barts and The London School Dr Duncan Keeley, and Improvement Authority, of Medicine and Dentistry General Practitioner (Dr Burch Professor Chris Price, Belfast & Ptnrs), The Health Centre, Director of Clinical Research, Mr Leonard R Fenwick, Thame Bayer Diagnostics Europe, Ms Tracy Bury, Chief Executive, Freeman Stoke Poges Project Manager, World Hospital, Newcastle upon Tyne Dr Donna Lamping, Confederation for Physical Research Degrees Programme Professor William Rosenberg, Therapy, London Mrs Gillian Fletcher, Director and Reader in Professor of Hepatology Antenatal Teacher and Tutor Psychology, Health Services and Consultant Physician, Professor Iain T Cameron, and President, National Research Unit, London School University of Southampton Professor of Obstetrics and Childbirth Trust, Henfield of Hygiene and Tropical Gynaecology and Head of the Medicine, London Professor Peter Sandercock, School of Medicine, University Professor Jayne Franklyn, Professor of Medical Neurology, of Southampton Professor of Medicine, Mr George Levvy, Department of Clinical University of Birmingham Chief Executive, Motor Neurosciences, University of Dr Christine Clark, Neurone Disease Association, Edinburgh Medical Writer and Consultant Mr Tam Fry, Northampton Pharmacist, Rossendale Honorary Chairman, Child Dr Susan Schonfield, Growth Foundation, London Professor James Lindesay, Consultant in Public Health, Professor Collette Clifford, Professor of Psychiatry for the Hillingdon Primary Care Trust, Professor of Nursing and Professor Fiona Gilbert, Elderly, University of Leicester Middlesex Head of Research, The Consultant Radiologist and Medical School, University of NCRN Member, University of Professor Julian Little, Dr Eamonn Sheridan, Birmingham Aberdeen Professor of Human Genome Consultant in Clinical Genetics, Epidemiology, University of St James’s University Hospital, Professor Barry Cookson, Professor Paul Gregg, Ottawa Leeds Director, Laboratory of Hospital Professor of Orthopaedic Infection, Public Health Surgical Science, South Tees Professor Alistaire McGuire, Dr Margaret Somerville, Laboratory Service, London Hospital NHS Trust Professor of Health Economics, Director of Public Health London School of Economics Learning, Peninsula Medical Dr Carl Counsell, Bec Hanley, School, University of Plymouth Clinical Senior Lecturer in Co-director, TwoCan Associates, Professor Rajan Madhok, Neurology, University of West Sussex Medical Director and Director Professor Sarah Stewart-Brown, Aberdeen of Public Health, Directorate Professor of Public Health, Dr Maryann L Hardy, of Clinical Strategy & Public Division of Health in the Professor Howard Cuckle, Senior Lecturer, University of Health, North & East Yorkshire Community, University of Professor of Reproductive Bradford & Northern Lincolnshire Warwick, Coventry Epidemiology, Department Health Authority, York of Paediatrics, Obstetrics & Mrs Sharon Hart, Professor Ala Szczepura, Gynaecology, University of Healthcare Management Professor Alexander Markham, Professor of Health Service Leeds Consultant, Reading Director, Molecular Medicine Research, Centre for Health Services Studies, University of Professor Robert E Hawkins, Unit, St James’s University Dr Katherine Darton, Hospital, Leeds Warwick, Coventry Information Unit, MIND – The CRC Professor and Director Mental Health Charity, London of Medical Oncology, Christie Dr Peter Moore, Mrs Joan Webster, CRC Research Centre, Freelance Science Writer, Consumer Member, Southern Professor Carol Dezateux, Christie Hospital NHS Trust, Ashtead Derbyshire Community Health Professor of Paediatric Manchester Council Epidemiology, Institute of Child Dr Andrew Mortimore, Health, London Professor Richard Hobbs, Public Health Director, Professor Martin Whittle, Head of Department of Primary Southampton City Primary Clinical Co-director, National Mr John Dunning, Care & General Practice, Care Trust Co-ordinating Centre for Consultant Cardiothoracic University of Birmingham Women’s and Children’s Surgeon, Papworth Hospital Dr Sue Moss, Health, Lymington NHS Trust, Cambridge Associate Director, Cancer Screening Evaluation Unit, Institute of Cancer Research, Sutton 90

Current and past membership details of all HTA programme ‘committees’ are available from the HTA website (www.hta.ac.uk)

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