Finckh A, Bansback N, Marra CA, Anis AH, Michaud K, Lubin S, White M, Sizto S, Liang MH

BACKGROUND: Long-term control or remission of rheumatoid arthritis (RA) may be possible with very early treatment. However, no optimal first therapeutic strategy has been determined. OBJECTIVE: To assess the potential cost-effectiveness of major therapeutic strategies for very early RA. DESIGN: Decision analytic model with probabilistic sensitivity analyses. DATA SOURCES: Published data, the National Data Bank for Rheumatic Diseases, and actual 2007 hospital costs. TARGET POPULATION: U.S. adults with very early RA (symptom duration <or=3 months). TIME HORIZON: Lifetime. PERSPECTIVE: Health care provider and societal. INTERVENTION: 3 management strategies were compared: a symptomatic or “pyramid” strategy with initial nonsteroidal anti-inflammatory drugs, patient education, pain management, and low-dose glucocorticoids, and disease-modifying antirheumatic drugs (DMARDs) at 1 year for nonresponders; early DMARD therapy with methotrexate; and early therapy with biologics and methotrexate. OUTCOME MEASURES: Cost per quality-adjusted life-year (QALY) gained. RESULTS OF BASE-CASE ANALYSIS: By reducing the progression of joint erosions and subsequent functional disability, both early intervention strategies increase quality-adjusted life more than the pyramid strategy and save long-term costs. When the cost of very early intervention is factored in, the cost-effectiveness ratio of the early DMARD strategy is $4849 per QALY (95% CI, $0 to $16 354 per QALY) compared with the pyramid strategy, whereas the benefits gained through the early biologic strategy come at a substantial incremental cost. The early DMARD strategy maximizes the effectiveness of early DMARDs and reserves the use of biologics for patients with more treatment-resistant disease of longer duration, for which the incremental benefit of biologics is greater.Results of Sensitivity Analysis:The early biologic strategy becomes more cost-effective if drug prices are reduced, risk for death is permanently lowered through biologic therapy, patients experience drug-free remission, responders can be selected before therapy initiation, or effective alternative antirheumatic agents are available for patients for whom several biologics have failed. LIMITATIONS: Data on the long-term effect of very early therapeutic interventions on the natural progression in disability and joint erosions are limited. The study considered only tumor necrosis factor inhibitors and not the newer biologics. CONCLUSION: According to the most objective measures of RA progression, very early intervention with conventional DMARDs is cost-effective. The cost-effectiveness of very early intervention with biologics remains uncertain.

Ann Intern Med. 2009 Nov 3;151(9):612-21

Bansback N, Ara R, Ward S, Anis A, Choi HK

HMG-CoA reductase inhibitors (statins) are potentially excellent candidate agents for patients with rheumatoid arthritis (RA). They reduce both cardiovascular risks and RA disease activity. To evaluate the potential long-term effects of statin therapy among patients with RA, and to determine their associated cost effectiveness by incorporating both the cardiovascular and the anti-rheumatic benefits. A Markov decision-analytic model was developed to simulate cardiovascular and RA disease profiles over time. The impact of statin therapy was estimated by adjusting the risk of coronary heart disease (CHD) events and changes in the RA Disease Activity Score (DAS28), based on the results of a randomized trial. The benefits (QALYs) and costs (in year 2005 values) were evaluated from a US payer perspective. A full uncertainty analysis, including a value-of-information (VOI) analysis, was undertaken to evaluate the importance of individual parameters. Using a 10-year time horizon, the additional cost and QALYs of statin therapy were estimated to be USD4690 and 0.44 QALYs, respectively, resulting in an incremental cost-effectiveness ratio (ICER) of USD10 650 per QALY (95% CI 1525, 156 565). The QALY gain associated with statin therapy depended more on the anti-rheumatic effects of statin therapy than on its cardiovascular prevention effect. The VOI analysis found the long-term benefit of statin therapy (i.e. >or=12 months) and the consequent impact on quality of life to be the most uncertain and, therefore, influential parameters. Our analysis indicates that the dual anti-inflammatory/cardiovascular benefits of statins could make this therapy highly cost effective in RA. However, uncertainties remain in the available data, warranting further research on refining the precise RA disease-activity benefits and health-utility changes associated with statin therapy, at least over a 12-month period.

Pharmacoeconomics. 2009;27(1):25-37. doi: 10.2165/00019053-200927010-00004

Kopec JA, Sayre EC, Flanagan WM, Fines P, Cibere J, Rahman MM, Bansback NJ, Anis AH, Jordan JM, Sobolev B, Aghajanian J, Kang W, Greidanus NV, Garbuz DS, Hawker GA, Badley EM

OBJECTIVES: The purpose of the study was to develop a population-based simulation model of osteoarthritis (OA) in Canada that can be used to quantify the future health and economic burden of OA under a range of scenarios for changes in the OA risk factors and treatments. In this article we describe the overall structure of the model, sources of data, derivation of key input parameters for the epidemiological component of the model, and preliminary validation studies. DESIGN: We used the Population Health Model (POHEM) platform to develop a stochastic continuous-time microsimulation model of physician-diagnosed OA. Incidence rates were calibrated to agree with administrative data for the province of British Columbia, Canada. The effect of obesity on OA incidence and the impact of OA on health-related quality of life (HRQL) were modeled using Canadian national surveys. RESULTS: Incidence rates of OA in the model increase approximately linearly with age in both sexes between the ages of 50 and 80 and plateau in the very old. In those aged 50+, the rates are substantially higher in women. At baseline, the prevalence of OA is 11.5%, 13.6% in women and 9.3% in men. The OA hazard ratios for obesity are 2.0 in women and 1.7 in men. The effect of OA diagnosis on HRQL, as measured by the Health Utilities Index (HUI3), is to reduce it by 0.10 in women and 0.14 in men. CONCLUSIONS: We describe the development of the first population-based microsimulation model of OA. Strengths of this model include the use of large population databases to derive the key parameters and the application of modern microsimulation technology. Limitations of the model reflect the limitations of administrative and survey data and gaps in the epidemiological and HRQL literature.

Osteoarthritis Cartilage. 2009 Oct 23

Harrison MJ, Davies LM, Bansback NJ, McCoy MJ, Verstappen SM, Watson K, Symmons DP; The British Society for Rheumatology Biologics Register Control Centre Consortium, on behalf of the BSRBR

PURPOSE: Comparative evidence regarding the responsiveness of the EQ-5D and SF-6D in arthritis patients is conflicting and insufficient across the range of disease severity. We examined the comparative responsiveness of the EQ-5D and SF-6D in cohorts of patients with early inflammatory disease through to severe rheumatoid arthritis (RA). METHODS: Responsiveness was tested using the effect size (ES) and standardised response mean (SRM). Correlation of change in EQ-5D and SF-6D with disease specific measures was tested using Pearson correlations and the Steiger’s Z test. Treatment response and self-reported change were used as anchors of important change. RESULTS: The EQ-5D was more responsive to deterioration (ES ratio (EQ-5D/SF-6D): 1.6-3.0) and the SF-6D more responsive to improvement (ES ratio (SF-6D/EQ-5D): 1.1-1.8) in health. The SF-6D did not respond well to deterioration in patients with established severe RA (ES and SRM 0.08). The EQ-5D provided larger absolute mean change estimates but with greater variance compared to the SF-6D. CONCLUSIONS: The comparative responsiveness of the EQ-5D and SF-6D differs according to the direction of change. The level of mean change of the EQ-5D relative to the SF-6D has implications for cost-effectiveness analysis. Use of the SF-6D in patients with severe progressive disease may be inappropriate.

Qual Life Res. 2009 Sep 24

Harrison MJ, Davies LM, Bansback NJ, McCoy MJ, Farragher TM, Verstappen SM, Hassell A, Symmons DP

OBJECTIVE: Using inflammatory arthritis patients as an example, we investigate EuroQol-5D (EQ-5D) profiles resulting in states worse than death (WTD), and the heath status of patients occupying these states. METHODS: Baseline data from two UK trials were used that reflected the range of arthritis states/severity found in routine practice. EQ-5D profiles resulting in negative valuations (i.e., states WTD) based on UK weights were identified. EQ-5D scores for these profiles from alternative valuation sets, including a reanalysis of the UK weights, were compared. The health status and characteristics of patients, and factors associated with patients in the low distribution of the EQ-5D and those with WTD EQ-5D scores were identified. RESULTS: Seven hundred patients were included in the analysis. Sixty-two (9%) patients occupied states WTD. Patients occupied 9 of the possible 84 health profiles with negative scores (53% occupied one profile); this profile was not rated WTD by any of the alternative EQ-5D scoring algorithms. All WTD profiles included severe pain/discomfort plus moderate problems in >or=3 other domains. Patients with WTD valuations reported higher levels of pain, and feeling downhearted and low on alternative health status measures. CONCLUSIONS: Pain was the predominant factor in the WTD EQ-5D profiles occupied by arthritis patients. Patients occupying states WTD have poorer health-related quality of life than patients in low “better than death” states. Valuations of profiles vary according to how sets of preference weights for health profiles were developed. Further research should explore whether WTD valuations are supported by qualitative evidence and reflect the patient’s health and experience of disease.

Value Health. 2009 Sep;12(6):1026-34

Bansback N, Ara R, Ward S, Anis A, Choi HK.

HMG-CoA reductase inhibitors (statins) are potentially excellent candidate agents for patients with rheumatoid arthritis (RA). They reduce both cardiovascular risks and RA disease activity. To evaluate the potential long-term effects of statin therapy among patients with RA, and to determine their associated cost effectiveness by incorporating both the cardiovascular and the anti-rheumatic benefits. A Markov decision-analytic model was developed to simulate cardiovascular and RA disease profiles over time. The impact of statin therapy was estimated by adjusting the risk of coronary heart disease (CHD) events and changes in the RA Disease Activity Score (DAS28), based on the results of a randomized trial. The benefits (QALYs) and costs (in year 2005 values) were evaluated from a US payer perspective. A full uncertainty analysis, including a value-of-information (VOI) analysis, was undertaken to evaluate the importance of individual parameters. Using a 10-year time horizon, the additional cost and QALYs of statin therapy were estimated to be USD4690 and 0.44 QALYs, respectively, resulting in an incremental cost-effectiveness ratio (ICER) of USD10 650 per QALY (95% CI 1525, 156 565). The QALY gain associated with statin therapy depended more on the anti-rheumatic effects of statin therapy than on its cardiovascular prevention effect. The VOI analysis found the long-term benefit of statin therapy (i.e. >or=12 months) and the consequent impact on quality of life to be the most uncertain and, therefore, influential parameters. Our analysis indicates that the dual anti-inflammatory/cardiovascular benefits of statins could make this therapy highly cost effective in RA. However, uncertainties remain in the available data, warranting further research on refining the precise RA disease-activity benefits and health-utility changes associated with statin therapy, at least over a 12-month period.

Pharmacoeconomics. 2009;27(1):25-37

Nixon RM, O’Hagan A, Oakley J, Madan J, Stevens JW, Bansback N, Brennan A

The development of a new drug is a major undertaking and it is important to consider carefully the key decisions in the development process. Decisions are made in the presence of uncertainty and outcomes such as the probability of successful drug registration depend on the clinical development programmme.The Rheumatoid Arthritis Drug Development Model was developed to support key decisions for drugs in development for the treatment of rheumatoid arthritis. It is configured to simulate Phase 2b and 3 trials based on the efficacy of new drugs at the end of Phase 2a, evidence about the efficacy of existing treatments, and expert opinion regarding key safety criteria.The model evaluates the performance of different development programmes with respect to the duration of disease of the target population, Phase 2b and 3 sample sizes, the dose(s) of the experimental treatment, the choice of comparator, the duration of the Phase 2b clinical trial, the primary efficacy outcome and decision criteria for successfully passing Phases 2b and 3. It uses Bayesian clinical trial simulation to calculate the probability of successful drug registration based on the uncertainty about parameters of interest, thereby providing a more realistic assessment of the likely outcomes of individual trials and sequences of trials for the purpose of decision making.In this case study, the results show that, depending on the trial design, the new treatment has assurances of successful drug registration in the range 0.044-0.142 for an ACR20 outcome and 0.057-0.213 for an ACR50 outcome. Copyright (c) 2009 John Wiley & Sons, Ltd.

Pharm Stat. 2009 Apr 1

Nixon RM, Bansback N, Stevens JW, Brennan A, Madan J

A model is presented to generate a distribution for the probability of an ACR response at six months for a new treatment for rheumatoid arthritis given evidence from a one- or three-month clinical trial. The model is based on published evidence from 11 randomized controlled trials on existing treatments. A hierarchical logistic regression model is used to find the relationship between the proportion of patients achieving ACR20 and ACR50 at one and three months and the proportion at six months. The model is assessed by Bayesian predictive P-values that demonstrate that the model fits the data well. The model can be used to predict the number of patients with an ACR response for proposed six-month clinical trials given data from clinical trials of one or three months duration. Copyright 2008 John Wiley & Sons, Ltd.

Pharm Stat. 2009 Apr-Jun;8(2):150-62

Bansback N, Marra CA, Finckh A, Anis A

Recent years have witnessed a shift in the therapeutic approach for patients with early rheumatoid arthritis (RA). The focus of interest has been the improved outcomes achieved through the use of early aggressive disease-modifying therapy, including the use of biologic agents. Such strategies have acquisition costs which typically exceed those of older anti-rheumatic strategies. However, improved outcomes might lead to fewer hospitalizations and physician visits and improved employability, leading to future cost savings. This is in addition to the health benefits which patients value as improvements in quality of life. With many services competing to spend often limited health-care budgets, information on the relative benefits and costs of new approaches for treating RA can be useful in deciding on efficient allocation and treatment decisions.

Best Pract Res Clin Rheumatol. 2009 Feb;23(1):83-92

Bansback N, Ara R, Karnon J, Anis A

We reviewed the clinical measures used in rheumatoid arthritis (RA) economic evaluations with respect to their relevance and sensitivity to changes in survival, health-related quality of life (HR-QOL) and costs. We compared the measures from the economic perspective and discussed the validity of methods used to extrapolate beyond the trial data. Cost-effectiveness evaluations of disease-modifying antirheumatic drugs in RA were identified by searching MEDLINE, EMBASE, Econlit and NHS EED databases. Studies were retained if they extrapolated beyond randomized controlled trial evidence using relationships between clinical measures, costs and utilities. In the 22 studies identified, clinical severity was measured using the Health Assessment Questionnaire (HAQ) Disability Index, the American College of Rheumatology (ACR) response criteria, the Disease Activity Score (DAS) or a combination of the HAQ and DAS. The HAQ is correlated with mortality, costs and HR-QOL instruments, and several studies used linear relationships to model these associations. However, a polynomial relationship or discrete states may be more appropriate for patients at the extremes of the disease spectrum, and numerous HAQ health states may be required to capture differences in mortality risk. While the ACR response criteria is a more comprehensive measure than the HAQ, it is a relative measure, which creates difficulties when estimating absolute changes in HR-QOL, costs and mortality risk. The evidence base linking DAS scores with HR-QOL instruments, costs and mortality is less robust, possibly due to the comparatively recent development of the measure and the limited number of possible scores (mild/moderate/severe). While there is some evidence of a relationship between DAS scores and costs, the DAS does not capture all aspects of HR-QOL, and no significant relationship has been established with mortality risk. Evidence suggests the HAQ to be the primary clinical measure for use in economic evaluations as it is measured in almost all clinical studies, and is closely correlated to health utilities, mortality and costs. While new developments suggest the sensitivity of health states may be improved by combining the HAQ with measures such as the DAS, further research is required in this area. Further research is also required to explore the advantages in using either continuous or discrete health states.

Pharmacoeconomics. 2008;26(5):395-408

Zhang W, Bansback N, Guh D, Li X, Nosyk B, Marra CA, Anis AH

OBJECTIVE: To evaluate the shortterm effect of adalimumab on work productivity in patients with moderate to severe active rheumatoid arthritis (RA). METHODS: In a substudy of the Canadian Adalimumab Clinical Trial (CanAct), clinical, health status, and productivity outcomes were measured at baseline and 12 weeks. Patients were classified as responders and nonresponders by the 20% American College of Rheumatology (ACR20) improvement criterion and the minimum clinically important difference (MCID) of the Health Assessment Questionnaire (HAQ) score (0.22), respectively. The Health and Labour Questionnaire (HLQ) was used to measure productivity outcomes and costs. RESULTS: Included in the analysis were 389 patients completing both baseline and 12-week HLQ questionnaire. Absenteeism (a decrease of 0.5 workdays per 2 weeks) and unpaid work productivity (3.5 fewer hours unpaid help per 2 weeks) were improved significantly after 12 weeks. Improvements in productivity outcomes were associated with clinical response. Bootstrapping results suggest that responders achieved statistically significant improvement in presenteeism (ACR20) and unpaid work productivity (ACR20 and HAQ) versus nonresponders. The costs saved by responders were up to $155.04 per 2 weeks more than those by nonresponders. CONCLUSION: The costs of adalimumab were partially offset, even in the short term, by cost savings induced by clinical response among Canadian patients with moderate to severe RA. These findings complement results of other study analyses that demonstrate early and sustained benefits of adalimumab.

J Rheumatol. 2008 Sep;35(9):1729-36

Bansback N, Harrison M, Brazier J, Davies L, Kopec J, Marra C, Symmons D, Anis A.

Arthritis Rheum. 2008 Jul 15;59(7):1018-26

Wailoo AJ, Bansback N, Brennan A, Michaud K, Nixon RM, Wolfe F

OBJECTIVE: Since the introduction of the Medicare Prescription Drug Improvement and Modernization Act and its associated demonstration project, coverage of selected biologic drugs has been expanded for Medicare beneficiaries. For rheumatoid arthritis, coverage was extended to etanercept, adalimumab, and anakinra in addition to the previously covered infliximab. We undertook to develop a model to compare the costs and quality-adjusted life years (QALYs) generated by each of the 4 biologic agents. METHODS: Data were drawn from meta-analysis of randomized controlled trials and from a large longitudinal outcomes databank. Uncertainty was addressed using probabilistic and one-way sensitivity analyses. A lifetime horizon and Medicare viewpoint were adopted. RESULTS: In the base case analysis, anakinra was the least effective and least costly strategy. Etanercept, adalimumab, and infliximab were similar in terms of effectiveness, but infliximab was more costly. If decision makers are willing to pay a maximum of $50,000/QALY, the probability that infliximab is cost-effective is <1%. Findings were robust to a range of sensitivity analyses. Only if the dose of infliximab remains constant over time is this likely to be a cost-effective strategy. CONCLUSION: Infliximab is unlikely to be cost-effective in the Medicare population compared with either etanercept or adalimumab. Anakinra is substantially less costly but is also less effective than the 3 tumor necrosis factor alpha inhibitors.

Arthritis Rheum. 2008 Apr;58(4):939-46

Harrison MJ, Davies LM, Bansback NJ, Ingram M, Anis AH, Symmons DP

OBJECTIVE: Cost-utility analysis is increasingly important as healthcare providers aim to invest scarce resources in interventions offering the greatest health benefit. The ability to attach utility values to health states is essential, and is increasingly performed using generic scales. However, the evidence regarding the validity of generic utility scales in rheumatoid arthritis (RA) is unclear. We summarize and review evidence on the validity and comparative performance of generic utility scales in RA. METHODS: We searched the English-language medical literature for studies using utilities in RA between 1980 and mid-2006. Reports describing primary evidence of the validity or performance of a generic utility scale in RA were selected, summarized, and reviewed using the OMERACT filter. RESULTS: In total 923 articles were identified, of which 228 reported the use of utility scales in RA; 26 studies related to the validation or evidence of generic utility scales in RA, the EQ-5D, Health Utility Index-2 (HUI2) and HUI3, SF-6D, and Quality of Well-Being Scale. The EQ-5D, HUI2 and HUI3, and SF-6D all have consistent evidence of construct validity and responsiveness in RA, but each has limitations. CONCLUSION:The EQ-5D and HUI3 have been the most extensively studied instruments and show validity and responsiveness for use in RA, but both instruments have limitations. The SF-6D is relatively new and appears to have potential for use in milder RA, but needs further evaluation. More longitudinal head-to-head evaluation of measures is needed across the spectrum of RA disease severity to further investigate their comparative properties, and to seek consensus on the best utility measure for use in economic evaluation.

J Rheumatol. 2008 Apr;35(4):592-602

Wailoo A, Bansback N, Chilcott J

Rheumatology (Oxford). 2008 Feb;47(2):119-20

Bansback N, Marra C, Tsuchiya A, Anis A, Guh D, Hammond T, Brazier J

OBJECTIVE: To estimate the relationship between preference-based measures, EuroQol (EQ-5D) and SF-6D, and the Health Assessment Questionnaire (HAQ) disability index (DI) in patients with rheumatoid arthritis (RA), and to characterize components that are predictors of health utility. METHODS: Patients with RA participating in 2 studies in the UK (n = 151) and Canada (n = 319) completed the HAQ, EQ-5D, and Short Form 36 (SF-36). The SF-36, a generic measure of quality of life, was converted into the preference-based SF-6D. From these results we developed models of the relationship between the HAQ and SF-6D and EQ-5D using various regression analyses. RESULTS: The optimal model developed for the EQ-5D entered levels for each item as independent variables (model 5). A root mean square error (RMSE) of 0.18 suggested relatively good predictive ability. For the SF-6D, RMSEs were lower (0.09), suggesting better predictions than for the EQ-5D, but models with more explanatory variables did not improve results (model 2 or 4 optimal). The models were able to predict actual SF-6D and EQ-5D across the range of the HAQ DI. CONCLUSION: Our approach enabled calculations of quality-adjusted life years from existing trials where only the HAQ was measured. All aspects of the HAQ may not be reflected in the preference-based measures, and this method is suboptimal to direct measurement of health state utility in clinical trials. Given this limitation, our approach provides an alternative for researchers who need health-state utility values, but had not included a preference-based measure in their clinical study because of resource constraints or a desire to limit patient burden.

Arthritis Rheum. 2007 Aug 15;57(6):963-71

Brennan A, Bansback N, Nixon R, Madan J, Harrison M, Watson K, Symmons D

OBJECTIVE: To evaluate the cost effectiveness of TNF-alpha antagonist therapies for rheumatoid arthritis (RA) in the United Kingdom using data from the British Society for Rheumatology Biologics Registry (BSRBR). METHODS: A simulation model is constructed to quantify the cost effectiveness of the TNF-alpha antagonist therapies (infliximab, etanercept and adalimumab) as a group versus traditional disease-modifying anti-rheumatic drugs, with a time horizon over the full patient lifetime. Participants are UK NHS patients in the BSRBR with RA who have failed at least two traditional disease-modifying anti-rheumatic drugs. The BSRBR aims to recruit all RA patients starting on a TNF-alpha antagonist agent and follows them 6 monthly via consultant and patient administered questionnaires. Data collected include disease activity scores (DAS28), the Health Assessment Questionnaire and the SF-36. Costs include drug, monitoring and hospitalisations. Benefits are measured in disability and quality of life improvements. The main outcome measure is the incremental cost per quality adjusted life-year gained (discounted). RESULTS: The basecase cost per quality adjusted life-year gained by using TNF-alpha antagonist therapies is estimated at pound23 882, with probabilistic uncertainty analysis suggesting that the probability that treatments are below 30,000 pounds per QALY is around 84%. The results are most sensitive to assumptions concerning long-term disability progression, discount rates and the validity or otherwise of SF6D derived utility measures. Subgroup analysis, monotherapy versus combination with methotrexate, and a limited analysis of sequential therapy with two TNF-alpha antagonist agents, suggest cost-effectiveness ratios around 20,000 pounds to 30,000 pounds. CONCLUSIONS: The BSRBR data provide valuable evidence for estimating cost-effectiveness. The analysis concludes that current policies and practice for the use of TNF-alpha antagonist therapies, after RA patients have failed at least two traditional disease-modifying anti-rheumatic drugs, appear cost-effective in the context of the NICE re-appraisal of 2006 for England and Wales, thus supporting their decision to continue their reimbursement. Decision-makers worldwide might adapt this analysis because differential costs, discount rates and other factors could affect results. There remains uncertainty, particularly on long-term disease progression. Further data collection using the BSRBR is recommended, together with a revision to this analysis when data become available.

Rheumatology (Oxford). 2007 Aug;46(8):1345-54

Nixon R, Bansback N, Brennan A

OBJECTIVE: New treatments that inhibit the cytokines tumour necrosis factor alpha (TNFalpha) and interleukin 1 (IL-1) in the treatment of rheumatoid arthritis have proven clinical effect against placebo and methotrexate (MTX) in several clinical trials in early and late-stage disease and different severity groups. Since there are no head-to-head randomized controlled trials directly comparing the currently available treatments, etanercept, adalimumab, infliximab or anakinra, we perform a meta-analysis that adjusts for differences between study characteristics, and allows indirect comparisons between treatments. METHODS: Thirteen trials of cytokine antagonists were included from a systematic review of the literature. They reported the primary outcome of American College of Rheumatology (ACR) response criteria at 6 months or beyond. Meta-analytical methods are used to quantify relative treatment effects, using the log odds ratio of an ACR20 or ACR50 response at 6 months, whilst adjusting for study-level variables. RESULTS: In each of the trials, cytokine treatment was efficacious in comparison with placebo or MTX. For each treatment, the inclusion of MTX in combination improved the response. After adjustment for study-level variables, we found TNFalpha antagonists to be more efficacious compared with anakinra (P < 0.05). Indirect comparisons between the three TNFalpha antagonists indicated no difference in efficacy. Sensitivity analysis using a different statistical model structure confirmed these results. CONCLUSION: When the outcome of interest is the probability of an ACR20 or ACR50 response at 6 months we found: (i) treatment with the IL-1 antagonist anakinra is better than placebo; (ii) for each treatment, the use of combination MTX improves the probability of response; (iii) treatment with any of the TNFalpha antagonists is better than with the IL-1 antagonist anakinra; and (iv) all drugs in the TNFalpha antagonist class are no different from each other.

Rheumatology (Oxford). 2007 Jul;46(7):1140-7

Bansback N, Maetzel A, Drummond M, Anis A, Marra C, Conway P, Boers M, Tugwell P, Boonen A

Since healthcare resources are scarce, choices have to be made on how they will be allocated. The use of economic evaluations using cost-effectiveness analyses has increased rapidly as policymakers have realized their value in maximizing the population’s benefits (in terms of length of life and health status) within a given budget. Following efforts by OMERACT to create reference case definitions for the conduct of economic evaluation in rheumatoid arthritis, osteoporosis, and osteoarthritis, we review various methodological areas and research decisions that could benefit from a consensus between researchers, clinicians, and drug developers in terms of an ankylosing spondylitis (AS) reference case. Ten methodological issues are presented that will be important for future development of evaluations. Tentative proposals to define the issues in a reference case for AS are made, along with recommendations for further research.

J Rheumatol. 2007 May;34(5):1178-83

Nixon RM, Bansback N, Brennan A

Mixed treatment comparison (MTC) is a generalization of meta-analysis. Instead of the same treatment for a disease being tested in a number of studies, a number of different interventions are considered. Meta-regression is also a generalization of meta-analysis where an attempt is made to explain the heterogeneity between the treatment effects in the studies by regressing on study-level covariables. Our focus is where there are several different treatments considered in a number of randomized controlled trials in a specific disease, the same treatment can be applied in several arms within a study, and where differences in efficacy can be explained by differences in the study settings. We develop methods for simultaneously comparing several treatments and adjusting for study-level covariables by combining ideas from MTC and meta-regression. We use a case study from rheumatoid arthritis. We identified relevant trials of biologic verses standard therapy or placebo and extracted the doses, comparators and patient baseline characteristics. Efficacy is measured using the log odds ratio of achieving six-month ACR50 responder status. A random-effects meta-regression model is fitted which adjusts the log odds ratio for study-level prognostic factors. A different random-effect distribution on the log odds ratios is allowed for each different treatment. The odds ratio is found as a function of the prognostic factors for each treatment. The apparent differences in the randomized trials between tumour necrosis factor alpha (TNF- alpha) antagonists are explained by differences in prognostic factors and the analysis suggests that these drugs as a class are not different from each other. Copyright (c) 2006 John Wiley & Sons, Ltd.

Stat Med. 2007 Mar 15;26(6):1237-54

Bansback NJ, Ara R, Barkham N, Brennan A, Fraser AD, Conway P, Reynolds A, Emery P

OBJECTIVES: Tumour necrosis factor (TNF) has been shown to improve the outcomes in patients with psoriatic arthritis (PsA). We estimate the long-term impact on health status of prescribing the TNF antagonist etanercept, and evaluate the cost-effectiveness in a health economic model. METHODS: The relationship between disability (Health Assessment Questionnaire) and health state utility was explored to estimate the quality-adjusted life years (QALYs) gained from the TNF antagonist etanercept. A model was then used to compare sequences of treatments for PsA after failure of two conventional disease modifying anti-rheumatic drugs (DMARDs). One arm commences on etanercept therapy and this is compared with a strategy commencing with combination therapy of methotrexate and ciclosporin and another commencing with leflunomide. Individual patient data from Phase III etanercept trials is used to populate the model supported by published evidence from extensive literature searches. By incorporating a life table specific for a PsA population, and using a number of evidence- and expert opinion-based assumptions for disease progression, the model was extended beyond the trial duration to a 10-yr time horizon. Cost offsets were produced by avoiding surgery through delayed progression; drug and monitoring costs were also modelled. RESULTS: Over the 10 yrs, modelled etanercept treatment gave 0.82 more QALYs when compared with combination therapy with methotrexate and ciclosporin, and 0.65 more QALYs in comparison with leflunomide. This equates to a central estimate for the cost per QALY of pound28 189 and pound28 189 for ciclosporin and leflunomide, respectively. Sensitivity analyses demonstrated this could vary by as much as +/-28%. CONCLUSIONS: With limited data currently available, the potential cost-effectiveness of etanercept in DMARD failures for adults with PsA appears encouraging. The result for other TNF antagonists will depend on how their relative efficacy and drug price compares with etanercept. A number of limitations are described and priorities for further research suggested.

Rheumatology (Oxford). 2006 Aug;45(8):1029-38

Bansback N, Young A, Brennan A, Dixey J

OBJECTIVE: To construct a prognostic algorithm to predict 5-year functional outcome in rheumatoid arthritis (RA), based on the Health Assessment Questionnaire (HAQ). METHODS: Data from all patients with 5-year followup (n = 985) were used from an inception cohort, the Early Rheumatoid Arthritis Study (ERAS). Possibly relevant prognostic factors considered in the initial stage of the model-building process were standard clinical, radiological, and laboratory features measured at baseline and at 1 year. Multivariate analysis was performed using logistic regression, and the predictive performance of the model was tested using measures of discrimination and calibration. RESULTS: Bootstrap resampling identified 6 variables that consistently predicted severe functional outcome. Functional grade III/IV (odds ratio 6.7) and HAQ at 1 year (odds ratio 2.4) were the most important. Other variables included socioeconomic status, hemoglobin, and radiographic and disease activity scores. Estimates of the regression coefficients and performance were corrected for over-fitting. Reasonably large values for the c-index (0.82) and the Nagelkerke R(2) (0.39) indicate that the set of prognostic factors explains the variation in outcome to a degree that implies good prediction for individual patients. CONCLUSION: The algorithm identifies patients in the first year of RA who are likely to have poor function by 5 years and who could potentially benefit from aggressive drug therapy. A nomogram is produced for simple application of the model in clinical practice. While further external validation is necessary, this model could allow clinicians to target aggressive therapy earlier in a patient’s disease course.

J Rheumatol. 2006 Aug;33(8):1503-10

Bansback NJ, Regier DA, Ara R, Brennan A, Shojania K, Esdaile JM, Anis AH, Marra CA

Rheumatoid arthritis (RA) is a chronic, progressive, inflammatory disease that affects approximately 0.5-1% of the adult population. The introduction of new disease-modifying antirheumatic drugs (DMARDs) such as leflunomide, anakinra and the tumour necrosis factor (TNF)-alpha antagonists (infliximab, etanercept and adalimumab) have transformed the management of RA. In particular, the last class of agents has generated substantial controversy. Costing between 16,000 US dollars and 20,000 US dollars per patient-year (2001 values), the potential greater efficacy of treatment with TNFalpha antagonists comes at much higher drug costs, making these agents natural candidates for cost-effectiveness analyses (CEAs).A MEDLINE search (until 31 January 2004) identified six original CEAs evaluating TNFalpha antagonists in RA. The aim of a CEA is to facilitate the allocation of scarce health resources and to inform policy decisions. However, to enhance the reliability and relevance of these analyses to policy makers, there must be similarity between the methodologies used. Recently, the OMERACT (Outcome Measures in Rheumatoid Arthritis Clinical Trials) group produced a document to define such a reference case; the OMERACT document was used as a foundation to structure comparisons and highlight discrepancies. The methodologies employed in each analysis differed; in particular, disparate time horizons, comparators, quantities of drug and treatment sequences prohibit the comparison of cost effectiveness between studies. Outcomes also differed between the analyses. Most reported health-related quality of life (HR-QOL) in quality-adjusted life-years (QALYs). The QALYs metric was based on preference scores that were typically derived from linear regressions using the Health Assessment Questionnaire (HAQ). However, models also used American College of Rheumatology (ACR) criteria, as well as the disease activity score (DAS). Common to all studies was the lack of data from long-term randomised studies where efficacy and resource consumption in comparison with standard care has been investigated. As such, investigators combined short-term randomised control trial data with that of a long-term observational cohort, and modelled cost effectiveness over an appropriate time horizon. In addition, most analyses lacked rigorous sensitivity analysis to examine the impact of uncertainty in the parameters. Those analyses that examined time horizons of 6 months and 1 year published incremental cost-effectiveness ratios (ICERs) of 34,800 US dollars per ACR 70% response criteria (ACR70) weighted response (duration 6 months, 1999 values) and 96,166 US dollars (duration 1 year, 2002 values). Analyses that modelled costs and health outcomes beyond the first year reported ICER estimates ranging between 26,800 US dollars (patients’ lifetime, 1998 values) and 40,308 US dollars (10 years, 2002 values). In terms of HR-QOL, the analyses reported incremental QALYs that ranged from 0.116 (over 19 years) to 1.6 (over 10 years). Discounted costs of therapy ranged from 30,362 US dollars (10 years, 2002 values) to 93,000 US dollars (22 years, 1998 values), and comparator costs ranged from 22,593 US dollars (10 years, 2002 values) to 84,000 US dollars (22 years, 1998 values).

Drugs. 2005;65(4):473-96

Bansback N, Brennan A, Anis AH

The past 10 years has witnessed a major transformation in the treatment of rheumatoid arthritis, a chronic condition that leads to significant morbidity, impairment in quality of life and mortality. Adalimumab joins a class of biologic response modifiers that prevent joint destruction and maintain functional status. For expensive interventions such as biologic response modifiers to be a valuable use of healthcare resources, they must lower healthcare costs by reducing the prevalence of hospitalizations, assist people with rheumatoid arthiritis in maintaining employment and improve patient quality of life. The rheumatoid artiritis market is competitive and growing quickly. Policy makers are faced with decisions surrounding the value of biologic response modifiers over conventional therapies, and whether one biologic response modifier has an advantage over another.

Expert Rev Pharmacoecon Outcomes Res. 2005 Oct;5(5):519-29

Bansback NJ, Brennan A, Ghatnekar O

BACKGROUND: Societal decision makers increasingly emphasise their need for evidence based economic analyses to make reimbursement decisions. OBJECTIVE: To analyse the cost utility of adalimumab, on both incremental cost and incremental quality adjusted life years (QALYs), versus traditional disease modifying antirheumatic drugs and the other tumour necrosis factor (TNF) antagonists suitable for submission to the Swedish LFN (Pharmaceutical Benefit Board). METHODS: Swedish unit costs and treatment guidelines from a lifetime perspective were implemented. A mathematical model, incorporating data from seven trials, simulated the experiences of 10 000 hypothetical patients with moderate to severe rheumatoid arthritis (RA). The primary outcome measure-QALYs-was derived from utility values calculated from a relationship between the Health Assessment Questionnaire (HAQ) Disability Index (DI) and Health Utility Index-III (HUI-3) from adalimumab trial results. The model followed the progression of HAQ-DI through a number of treatments in a sequence accounting for mortality, drug and monitoring costs, and other direct costs. RESULTS: When using ACR50 as a response threshold for determining successful treatment, adalimumab plus methotrexate showed the greatest number of QALYs gained (2.3 from one study and 2.1 from the pooled results of two trials). The etanercept plus methotrexate strategy yielded QALY gains similar to the pooled adalimumab results. Except for the infliximab strategy, the costs results were between 35 000 and 42 000, a range normally considered cost effective in other European countries. CONCLUSION: Adalimumab appears to be cost effective for the treatment of moderate to severe RA. The results suggest that adalimumab is at least as cost effective as other TNF antagonists.

Ann Rheum Dis. 2005 Jul;64(7):995-1002

Bansback NJ, Brennan A, Ghatnekar O

BACKGROUND: Societal decision makers increasingly emphasise their need for evidence based economic analyses to make reimbursement decisions. OBJECTIVE: To analyse the cost utility of adalimumab, on both incremental cost and incremental quality adjusted life years (QALYs), versus traditional disease modifying antirheumatic drugs and the other tumour necrosis factor (TNF) antagonists suitable for submission to the Swedish LFN (Pharmaceutical Benefit Board). METHODS: Swedish unit costs and treatment guidelines from a lifetime perspective were implemented. A mathematical model, incorporating data from seven trials, simulated the experiences of 10 000 hypothetical patients with moderate to severe rheumatoid arthritis (RA). The primary outcome measure-QALYs-was derived from utility values calculated from a relationship between the Health Assessment Questionnaire (HAQ) Disability Index (DI) and Health Utility Index-III (HUI-3) from adalimumab trial results. The model followed the progression of HAQ-DI through a number of treatments in a sequence accounting for mortality, drug and monitoring costs, and other direct costs. RESULTS: When using ACR50 as a response threshold for determining successful treatment, adalimumab plus methotrexate showed the greatest number of QALYs gained (2.3 from one study and 2.1 from the pooled results of two trials). The etanercept plus methotrexate strategy yielded QALY gains similar to the pooled adalimumab results. Except for the infliximab strategy, the costs results were between 35 000 and 42 000, a range normally considered cost effective in other European countries. CONCLUSION: Adalimumab appears to be cost effective for the treatment of moderate to severe RA. The results suggest that adalimumab is at least as cost effective as other TNF antagonists.

Ann Rheum Dis. 2005 Jul;64(7):995-1002

Brennan A, Bansback N, Reynolds A, Conway P

OBJECTIVES: This model examines the cost-effectiveness of etanercept monotherapy under British Society for Rheumatology guidelines, i.e. adults previously failing two disease-modifying anti-rheumatic drugs (DMARDs). It compares a DMARD sequence with etanercept third line against the same sequence excluding etanercept. METHOD: The 6-monthly trend in Health Assessment Questionnaire (HAQ) disability score is simulated for 10 000 patients’ lifetimes using clinical trial data and published literature. Switching to the next treatment is triggered by lack of response, loss of efficacy or adverse events. Patient mortality depends on rheumatoid arthritis life-tables and on epidemiological evidence relating reduced risk to HAQ improvement. Regression of HAQ/EuroQol (EQ-5D) utility provides quality-adjusted life years (QALY) gained. Primary analysis includes drug costs, monitoring and hospitalizations. RESULTS: The central estimate cost per QALY is pound 16 330. Sensitivity analyses ( pound 7800 to pound 42 000) showed long-term HAQ progression (etanercept, DMARDs, non-responders) as most sensitive variables. The inclusion of potential avoided nursing home admissions and indirect costs/lost employment further improves the cost-effectiveness. CONCLUSIONS: For adults in the UK, the results suggest that etanercept is cost-effective when compared with non-biologic agents. The National Institute for Clinical Excellence has accepted that etanercept is cost-effective and recommended its availability for use in patients who have failed at least two DMARDs. This model was an important component of that decision. The model is further suitable for use for a wide range of other cost-effectiveness questions in rheumatoid arthritis.

Rheumatology (Oxford). 2004 Jan;43(1):62-72