NCCHTA 09 July 2008 Protocol for methodological work on the health economic modelling of new drugs (2 TAR units) A. Details of the review team Lead researcher and corresponding author: Barton, Pelham, Dr 1 Lecturer in Mathematical Modelling Other members: Bryan, Stirling, Dr 1 Senior Lecturer in Health Economics Burls, Amanda, Dr 2 Senior Clinical Lecturer Jobanputra, Paresh, Dr 3 Consultant Rheumatologist Clark, Wendy 4 Information Pharmacist Additional Researcher to be identified Addresses: 1. Health Services Management Centre University of Birmingham Park House 40 Edgbaston Park Road Birmingham B15 2RT Tel: 0121 414 3170 Fax: 0121 414 7051 E-mail: [email protected]; [email protected] 2 Department of Public Health and Epidemiology University of Birmingham Edgbaston Birmingham B15 2TT Tel: 0121 414 7508 Fax: 0121 414 7878 E-mail:[email protected] 3 Department of Rheumatology University Hospitals Birmingham Selly Oak Hospital Raddlebarn Road, Selly Oak, Birmingham, B29 6JD. 4. Department of Medicines Management Keele University Keele Staffordshire ST5 5BG University of Birmingham 1 Final protocol for methodological TAR Sent to NCCHTA 15 th December 2001 B. Full title of the research question What are the limitations of economic models that use inappropriate comparators? A case study from the use of selected anti-TNFs in rheumatoid arthritis. C. Clarification of the research question and scope Introduction As part of a recent TAR commission, the research team from the University of Birmingham undertook a review and provisional economic analysis of two new drug treatments in rheumatoid arthritis (RA) for the National Institute for Excellence (NICE). The NICE appraisal committee considered this on 12 July 2001. Within the time-frame and availability of existing data, the health economics modelling components of the work were necessarily limited in scope. However the model showed that industry models, that used trial data and compared drug to placebo for their modelling, were inadequate representations of real-life clinical practice. Many new technologies are still compared with placebo in clinical trials instead of being compared with other available interventions used in routine practice. This raises ethical concerns and is also an important consideration when developing economic models for new technologies. One of the central aims of this proposal is to allow the limitations of models that use inappropriate comparators to be investigated further and to explore possible solutions to this problem.. We propose to examine this by developing our preliminary economic model and determining its sensitivity to a more detailed consideration of factors such as mortality, joint replacement, hospitalisation and quality of life. Outline of Birmingham Preliminary Model The Birmingham Preliminary Model (BPM) follows patients with RA from the time at which they start using disease modifying anti-rheumatic drugs (DMARDs). It is assumed that DMARDs are used for the remainder of that patient’s life, if possible. When the model is run, a large number of individual (virtual) patient histories are generated, both with and without anti-TNF (this term refers to infliximab or etanercept therapy). The mean costs and quality-adjusted life-years (QALYs) for the two arms of the model are compared to produce an incremental cost-effectiveness ratio (ICER). We constructed the model using TreeAge DATA 3.5. We used tracker variables to overcome the restrictions inherent in standard Markov models. It was not the purpose of the BPM to assess different orders of using other DMARDs, so a fixed order, reflecting acceptable clinical practice, was used for the “without anti-TNF” branch. University of Birmingham 2 Final protocol for methodological TAR Sent to NCCHTA 15 th December 2001 The order used was as follows: 1. sulphasalazine (SSZ) 2. methotrexate (MTX) 3. gold (GST) 4. azathioprine (AZA) 5. penicillamine (D-Pen) 6. hydroxychloroquine (HCQ) 7. leflunomide (LEF) 8. cyclosporin (CyA) Any patient who lives long enough to fail on all the above is then given combination therapy (Comb) consisting of CyA plus MTX, provided that neither of these has proved toxic. After combination therapy, or if combination therapy cannot be given, patients are given palliative treatment (Pall). The diagram shows the patient pathways in the model. The model was populated with data concerning patient lifetimes, time spent on each DMARD and costs and quality of life (QoL) effects associated with treatment. A simplifying assumption was made that QoL effects of all DMARDs other that SSZ, MTX and anti-TNFs were the same. Further details of the model and its provisional results are contained in the report submitted to the NICE Appraisal Committee. Limitations of the Birmingham Preliminary Model Structural Issues 1. The BPM takes no account of any possible effects of DMARDs on mortality. This serious limitation has potentially significant effects on the results. University of Birmingham 3 Final protocol for methodological TAR Sent to NCCHTA 15 th December 2001 2. The model assumes a fixed order for the DMARDs apart from anti-TNFs. 3. The model assumes a fixed pattern of effect of DMARDs on quality of life. This assumption prevents the model from allowing for mortality effects. 4. The model does not consider the effect of DMARDs on disease progression, joint replacement or hospitalisation. Data issues 1. The time spent on each DMARD is obtained by fitting a curve to a limited number of data points and extrapolating the fitted curve beyond the data. 2. The costing data were obtained from a limited range of sources. 3. Quality of life effects of DMARDs were estimated from very limited data on changes in Health Assessment Questionnaire (HAQ) score. (HAQ is a commonly used disability index in RA.) 4. No data on general pattern on quality of life of RA patients were included. Proposed scope of this work We intend to address the structural issues relating to mortality and quality of life effects. To do this, we will need to identify and/or collect data on the general pattern of quality of life of RA patients. To obtain an estimate of how quality of life changes over time, we intend to combine existing longitudinal data on HAQ scores with data from a cross- sectional study on utilities associated with RA health states. This will allow us to establish the effect of DMARDs and joint replacement surgery on health-related utility. In addition, we will use existing data to extend the model to take account of the effect of DMARDs on mortality, joint replacement and hospitalisation. This work is important for three reasons: 1. It allows for realistic economic evaluation of DMARDs, especially for newer expensive drugs of proven effectiveness for a serious condition. 2. It provides the opportunity to develop further a novel approach to economic modelling, using tracker variables to create models with more realistic assumptions than standard Markov models. 3. This approach is potentially applicable to other conditions, especially those where a sequential approach to therapeutic options exists. D. Methods 1. Search for and/or collection of additional data For all treatment states in the model data are required for the effect of treatment on mortality, need for joint replacement surgery, hospitalisation and quality of life. By contrast to the preliminary model, data are required on actual quality of life rather than difference in quality of life attributable to treatment. Such data will be identified where possible from the literature. Given that the focus for this work is broader than the original TAR, since we are now concerned with identifying data for all treatment states in our model, further published data may be available. University of Birmingham 4 Final protocol for methodological TAR Sent to NCCHTA 15 th December 2001 However, we do not expect to find all the data we require from published sources. We therefore intend to collect some data as part of this TAR project. The precise methods of data collection will be determined as the project progresses, seeking ethical approval where required. On the basis of our initial searches of the literature, we expect that the focus for this work will be health-related quality of life associated with the range of disease severity. We intend to adopt the approach of a cross- sectional survey of a cohort of patients currently with a diagnosis of rheumatoid arthritis. We may be unable to find adequate data on other parameters from either published sources or routinely available data. In such cases, we will collect such data by appropriate methods if possible, otherwise indicating the need for further data collection through the sensitivity analysis in our modelling. 2. Modelling The model will be updated in the following ways: - the structure of the model will be expanded to include new tracker variables that will allow for the effects of DMARDs on mortality, hospitalisation rates (if possible) and need for joint replacement - quality of life calculations will, if possible, be based on an actual QoL measure rather than assumed difference due to treatment - sensitivity analysis will be expanded to include issues such as curve fitting for time on DMARDs and uncertainties in unit cost estimates - we will assess the impact of using anti-TNFs later in the sequence of DMARDs E. Project Management a. Timetable/milestones The proposed project timetable and milestone dates are as follows: Draft protocol submission End October 2001 Finalised protocol submission End December 2001 Progress report submission 9 May 2002 End of data collection Mid May 2002 End of modelling Mid June 2002 Draft report ready for peer review End June 2002 Draft final report submission 30 July 2002 b. Competing interests Members of the review team declare no competing interests. c. External reviewers The protocol and draft report will be subject to external peer review. Reviewers will be chosen according to academic seniority and content expertise and will be agreed with NCCHTA.