available at

Transcription

1 Journal of Crohn's and Colitis (2009) 3, available at An economic evaluation comparing once daily with twice daily mesalazine for maintaining remission based on results from a randomised controlled clinical trial Mark P. Connolly a,, Sandy K. Nielsen b, Craig J. Currie c, Chris D. Poole d, Simon P.L. Travis e a Global Market Access Solutions, St Prex, Switzerland b Ferring Pharmaceuticals, St Prex, Switzerland c Cardiff University, Cardiff, UK d Pharmatelligence, Cardiff, UK e John Radcliffe Hospital, Oxford, UK Received 26 August 2008; received in revised form 25 October 2008; accepted 27 October 2008 KEYWORDS Cost; Economic evaluation; Ulcerative colitis; Cost-effectiveness analysis; Mesalazine Abstract Background and aims: Standard practice to maintain remission in ulcerative colitis (UC) consists of daily mesalazine therapy. However, frequent dosing is associated with poor adherence and increased failure rates. The (Pentasa Once Daily In UC Maintenance) randomised control trial showed 2 g once daily (OD) to be superior to twice daily (BD) dosing for maintaining remission. We sought to determine whether this alternative dosing regimen is cost-effective. Methods: An economic evaluation was conducted to compare costs and outcomes of OD with twice daily (BD) dosing. The main outcome considered was quality-adjusted life years (QALYs) based on health state utilities derived from the primary outcome measure, remission without relapse at 12 months defined by a UCDAI score 1. The economic evaluation consisted of two health states: (1) remission and (2) active UC. Results: Annual average treatment costs for OD and BD dosing were 654 (95% CI: ) and 747 ( ), respectively with an average per person savings of 93 per year. Average annual costs of ancillary care for relapse for OD and BD dosing were 307 ( ) and 396 ( ), respectively. Treatment with OD 2 g mesalazine resulted in an incremental QALY improvement of units, indicating that it was the dominant treatment option (i.e. improved Disclosures: Sandy Nielsen is an employee of Ferring Pharmaceuticals. Mark Connolly worked as independent consultant on this project. Craig Currie and Chris Poole worked as independent non-remunerated advisors to this project. Simon Travis received a nominal fee to cover his activities in support of this project. Results from an earlier version of model described in this paper were accepted as a poster presentation at a scientific meeting. Corresponding author. Global Market Access Solutions, Ch. De Penguey 6B.22, St Prex, 1162, Switzerland. Tel.: , (Mobile). addresses: mark@gmasoln.com (M.P. Connolly), skn@ferring.com (S.K. Nielsen), currie@cardiff.ac.uk (C.J. Currie), drchrispoole@googl .com (C.D. Poole), Simon.Travis@ndm.ox.ac.uk (S.P.L. Travis) /$ - see front matter 2008 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi: /j.crohns

2 Economic evaluation of once versus twice daily mesalazine 33 outcomes and cost-saving). Variations in parameter estimates in the sensitivity analysis indicated that mesalazine had N0.95 probability of being cost-effective compared to BD based on accepted willingness to pay thresholds applied by the UK National Health Service. Conclusions: Once daily 2 g mesalazine for maintaining remission in UC is cost-saving compared with 1 g twice daily. Cost-savings with 2 g once daily were achieved by differences in ancillary care attributed to higher failure rates observed with 1 g twice daily European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. 1. Introduction Ulcerative colitis (UC) is a chronic inflammatory disease of the rectum and colon, requiring lifetime management. The disease is characterised by periods of remission with occasional, unpredictable episodes of relapse causing acute rectal bleeding, urgent diarrhoea and abdominal discomfort. The age of onset is between 20 and 40 years of age although the disease is found in allagegroups.ineuropeprevalenceofucrangesfrom21to243 per 100,000 population, 1 and has been reported to be 40% greaterinnortherneuropecomparedwithsoutherneurope. 2 The chronic nature of UC and the fact that it predominantly affects working age populations can have a significant economic impact on those diagnosed with the disease. A retrospective pan-european cost assessment established an annual cost per patient of 1524 where medical and surgical costs accounted for 45% of total costs. 4 An economic impact of IBD on employment, likelihood of receiving disability payments and sick leave has also been observed. 5 Further studies have examined the influence of active UC on work productivity and employment opportunities; improvements were observed for those patients achieving remission compared with those unable to achieve remission. 6 For the past 20 years the standard of care for maintaining remission in UC has been daily mesalazine to prevent recurrent flares. During periods of remission patients are relatively symptom free, which paradoxically increases the likelihood of nonadherence to prescribed medication. Maintenance therapy has traditionally involved frequent oral dosing (two to four times daily, excluding any topical therapy) with available 5-ASA presentations, which have an adverse impact on patient convenience and quality of life that is likely to influence treatment adherence. 7 Studies of UC in remission suggest 40% overall adherence to therapy, with dose frequency 3/day, or polypharmacy (N4 prescriptions) associated with poor adherence, among other factors. 8 The impact of poor adherence has been documented in a prospective study where it was shown that people with UC in remission who collected b80% of prescribed mesalazine according to pharmacy records had N5-fold increased risk of relapse compared to compliant patients. 9 There has consequently been a move towards once daily dosing to improve patient compliance without compromising efficacy. The Pentasa Once Daily In UC Maintenance () randomised study, based on a non-inferiority design, actually showed that improved outcomes could be achieved using OD compared to BD dosing. 10 Inlightofthiswesoughttoestablish whether the simplified OD strategy with improved outcomes was a cost-effective treatment strategy in UC. Because the goals of treatment aim both to induce and maintain remission in ordertoimprovepatientqualityoflifewehaveconducteda cost-utility analysis (CUA) which incorporates patient-reported preferences for UC disease states with costs required to achieve these outcomes Materials and methods 2.1. Model design A decision-analytic model was constructed to compare the costeffectiveness between OD and BD mesalazine. The model was constructed using Treeage Pro 2008 (Treeage Software, Inc. Williamstown, MA, USA). The methodological approach was a cost-utility analysis (CUA) with two health states: (1) remission and (2) active disease. The time frame for the economic evaluation was one year and thus consistent with the duration of the randomised clinical trial. The perspective applied in the analysis was the UK National Health Service (NHS) and all costs are presented in Pound Sterling ( ; indexed to 2007 values). Treatment pathways described in the model during periods of relapse are based on British Society of Gastroenterology and European Crohn's and Colitis Organisation (ECCO) guidelines, as well as systematic reviews articles Briefly, patients experiencing relapse during the study period were assumed to undergo diagnostic examinations which included sigmoidoscopy, full blood count, C-reactive protein (CRP), microbiological and electrolyte testing. The costs of therapy in active UC were based on 4 g oral mesalazine with 1 g/100 ml topical enema; the probability of success was defined by observed remissions rates in a randomised study of this therapy. 15 Subjects refractory to oral and topical therapy were assumed to be treated using 40 mg prednisolone for four weeks. 14,17 Patients unresponsive to prednisolone were treated using infliximab 5 mg/kg at 0, 2 and 6 weeks. 12,14 The model did not account for long-term use of infliximab which reflects the mild to moderate nature of the trial population. The alternative treatment option in steroid-refractory subjects with off-label ciclosporin has not been considered in this evaluation. Within the one year followup period none of the patients in remission at entry to the study progressed to surgery, so this was not considered in the treatment pathway, although it is a potential outcome of relapse. Were it included, surgery would increase costs in a group subject to more frequent relapse Clinical data The economic evaluation was based on clinical data on obtained from the randomised control trial. was a one year prospective, single-blind, multi-centre study where patients with UC in remission were randomised to receive 2 g once daily (OD) mesalazine (Pentasa sachet, Ferring Pharmaceuticals, St Prex, Switzerland), compared to 1 g twice daily

3 34 M.P. Connolly et al. (BD) mesalazine (Pentasa sachet). The primary study objective was to demonstrate that 2 g OD mesalazine was noninferior to 1 g BD mesalazine in terms of remission rate in patients with mild to moderate UC. The primary endpoint was measured based on changes from baseline at month 4, 8, and 12 using the ulcerative colitis disease activity index (UCDAI). Patients with an establish UC diagnosis in clinical remission defined as scoring b2 on the UCDAI were enrolled into the study. Investigators remained blinded to treatment assignment to avoid bias in scoring the UCDAI. Observed clinical remission rates at 4, 8, and 12 months based on UCDAI scores for both study populations were used to derive the outcome measures in the model. At study endpoint a significant difference in clinical and endoscopic remission rates were observed of 74% and 64% for patients using OD and BD mesalazine, respectively. There was no significant difference in treatment emergent adverse events between groups, so costs attributable to the low frequency of these events were not been considered Outcome measure The outcome of interest in the decision-analytic model was the average QALY change based on the intention-to-treat population. QALYs were derived from individual UCDAI scores reported for each patient and mapped to the health state utility instrument EuroQol-5D (EQ-5D) index. Mapping has become an accepted methodology for converting descriptive measures of health into QALY weights for use in economic evaluation. 18 For this study, the relationship between the UCDAI and the EQ-5D was applied to the clinical data to determine the QALY weight for each of the two UC health states. 19 Previous studies have shown the EQ-5D to be a valid and reliable instrument for use in IBD patients. 20 EQ-5D scores for the UC remission state and relapse health states used in the model were 0.94 and 0.76, respectively. 19 A pivotal parameter in economic evaluation was the duration of relapse for those subjects failing treatment during the study period. In the cost per QALYevaluation, time is weighted accordingtothepreferencethatpatientshaveforeachofthetwo health states. The base assumption applied in the model was that relapse lasted for four weeks at the reduced utility value described. This is an approximation for the median time to remission, but is likely to be conservative since the remission rate at 8 weeks for the selected active treatment was 64% Characteristics of study subjects Eligibility criteria in the study were patients with UC in remission (UCDAI b2), who had experienced a relapse requiring adjustments to their maintenance therapy within the past year. Patients with proctitis (UC 15 cm from the anal verge) were excluded. Patient characteristics were well matched between OD and BD dosing groups for age, sex, duration of illness and smoking habits Cost data Cost data in the model were derived from published UK sources (Table 1). Major costs in the economic evaluation were those related to mesalazine treatment, clinical consultations during periods of relapse, diagnostic examinations (e.g., sigmoidoscopy, blood tests) and acute treatment costs. Costs related to scheduled follow up or protocol driven procedures are not considered in this evaluation. Based on previous reports in a similar cohort we assume an average of 2.2 UC related general practitioner (GP) consultations per year. 3 The costs of mesalazine were obtained from the British National Formulary (April 2008) where 1 g 50-sachet pack costs Annual treatment cost assuming 100% compliance is per patient. Annual mesalazine treatment costs were adjusted to reported compliance rates from the trial, being and for OD and BD, respectively. Endoscopic evaluation is required as part of the UCDAI scoring. However, endoscopy was only conducted at study entry and as part of the final study evaluation at 12 months. Those subjects experiencing relapse during the study underwent an additional endoscopic evaluation, so this cost was applied to treatment failures Sensitivity analysis To reflect variation in critical model parameters we conducted probabilistic sensitivity analysis (PSA). Also referred to as second-order analysis, PSA is recommended by national technology appraisal organizations such as the National Institute for Health and Clinical Excellence in the UK, because it allows simultaneous sampling from defined distribution for those parameters where uncertainty may exist. 21,22 Table 1 Health resource costs included in the economic evaluation Resource item Cost Reference and notes Mesalazine 1 g retention enemas in 100 ml pack Gastroenterologist consultation Sigmoidoscopy (ECCO Guidelines 2008) Prednisolone 40 mg per day Infliximab GP consultations Full blood count (ECCO Guidelines) Electrolytes (ECCO Guidelines) C Reactive Protein (ECCO Guidelines) Microbiological testing (ECCO statement 3G) BNF 2008 (net price 7 enemas) 132 Curtis We assume 50% undergo flexible and 50% undergo rigid. NHS National Tariff 297 flexible, 200 rigid BNF (8 week course) 5 mg, 28-tab, 60p, 8 tablets per day BNF, price per vial. Dosed at 5 mg/kg based on 75 kg individual. 34 per 2.2 visits per year, Curtis 16 visit 3.00 NHS National Tariff 1.00 NHS National Tariff 9.00 NHS National Tariff 7.00 NHS National Tariff Abbreviations: BNF, British National Formulary; NHS, National Health Service; GP, general practitioner; European Crohn's and Colitis Organisation.

4 Economic evaluation of once versus twice daily mesalazine 35 Identified model parameters where uncertainty was likely to exist and the appropriate distributions are described in Table 2. Additionally, to reflect clinical practice and the likelihood that all patients will not undergo sigmoidoscopy at the first signs of relapse a separate analysis was conducted which excluded these costs. To supplement the incremental cost-effectiveness analysis and better to reflect uncertainty in the model, we generated a cost-effectiveness acceptability curve (CEAC) using the net benefit approach. The net benefit method allows for graphical presentation of the proportion of iterations for which each product is more cost-effective relative to the other. 23 The results are presented in a CEAC which expresses the proportion of simulations for each strategy that generates the maximum net benefit across a range of willingness-to-pay thresholds. Consequently the product with the highest net benefit at any willingness-to-pay threshold would be considered the optimal treatment strategy. We applied UK norms for the maximum willingness to pay per QALY of 20, Results Average annual costs per person treated with OD 2 g or BD 1 g mesalazine, including costs of treatment failure were 815 and 971, respectively, with an annual cost-savings when using 2 g OD mesalazine of 156 (Table 3). Average annual treatment costs based on excluding sigmoidoscopy at initial relapse for OD and BD were 750 and 881, respectively, with an annual costsavings of 131. QALYs for each treatment are shown in Table 3, where a small advantage in favour of OD 2 g was observed. The incremental cost-effectiveness analysis indicated that OD 2 g was the dominant treatment option: in other words, improved outcomes at reduced costs. Disaggregated annual treatment costs were higher in the BD 1 g treatment arm for all resource categories. Most notable were cost increases for consultation rates and interventions used for acute treatment of 44 and 75, respectively (Table 4). There was no difference in the annual treatment cost of mesalazine for maintenance therapy in either treatment arm, however the Table 2 Parameters with point estimates and variance with defined distributions applied in the PSA Parameter Point estimate and variance OD 1 year relapse rate (95% CI) ( ) BD 1 year relapse rate (95% CI) ( ) Compliance OD a ( ) Compliance BD a ( ) Clinical consultation rate in relapse period Distribution Reference Range 2 4 Uniform Expert opinion Abbreviations: PSA, probabilistic sensitivity analysis; OD, once daily; BD, twice daily. a Compliance based on weighted compliance over entire study period with +/ 25% variance applied. There was no significant difference between compliance rates. Table 3 Cost effectiveness ratios for OD and BD treatment and incremental cost-effectiveness ratio percentage of annual costs represented 43% and 36% for OD and BD, respectively. The major annual cost difference was observed in costs of acute UC failure where costs of 195 and 270 were observed for OD and BD groups, respectively Sensitivity analysis Cost-effectiveness acceptability curves were generated using the net benefits approach by varying the threshold willingnessto-pay (WTP) from 0 to 20,000 (Fig. 1). Over the range of WTP thresholds OD 2 g was found to deliver a higher proportion of benefits compared with BD 1 g. When the WTP threshold for additional QALYs was zero, the proportion of cases in which OD 2 g was more cost-effective was As the WTP threshold approached the likely UK maximum of 20,000 per QALY the proportion of cases in which OD produced more net benefits was 0.98 compared to BD 1 g. 4. Discussion 2gOD 1gBD Annual treatment costs a (95% CI) 815 ( ) 971 ( ) Incremental cost ( 156) per year (OD BD) QALYs ( ) ( ) Incremental QALYs per year (OD BD) Cost-effectiveness ratios (95% CI) 872 ( ) 1043 ( ) Incremental costeffectiveness ratio Dominant Abbreviations: OD, once daily; BD, twice daily; QALY, qualityadjusted life year; CI, confidence interval. a Annual treatment costs excluding sigmoidoscopy for OD and BD were 750 ( ) and 881 ( ), respectively. A critical consideration in all economic evaluations is the applicability and validity of the clinical outcome on which the economic model is based. The key clinical parameter on which this model was based were from a large randomised clinical trial in which UC patients in remission treated using OD 2 g mesalazine had a lower one year relapse rate compared with those treated BD 1 g. 10 The economic evaluation has shown that OD 2 g is cost-saving compared with BD 1 g achieving an average annual savings of 156 per person. Excluding sigmoidoscopy costs at the first signs of relapse did not dramatically alter the findings in which average annual treatment costs for OD 2 g and BD 1 g were 750 and 881, respectively. Treatment with OD 2 g still offered an annual savings per person of 131. The cost savings identified with OD 2 g were attributed to a reduction in costs associated with treating relapse patients in comparison with relapse rates observed with BD 1 g. This may not seem much, but when a Primary Care Trust representing a population of 100,000, in which there are patients with UC, the annual savings through once daily therapy are of

5 36 M.P. Connolly et al. Table 4 Average annual disaggregated treatment costs per person based on OD 2 g and BD 1 g mesalazine Resource Mesalazine OD Mesalazine BD Incremental Average cost per year % annual costs Average cost per year % annual costs cost Mesalazine maintenance 347 ( ) ( ) 36 ( 3) Consultation costs 189 ( ) ( ) 24 ( 44) Diagnostic exams (sigmoidoscopy, blood tests) 85 ( ) ( ) 12 ( 33) Interventions used to treat active disease (e.g., prednisolone, topical mesalazine, infliximab) 195 ( ) ( ) 28 ( 75) Abbreviations: OD, once daily; BD, twice daily. the order of 31,000. For a District General Hospital serving a Primary Care population of 500 UC patients, cost savings might exceed 70,000, but allowance has to be made for higher costs associated with more refractory disease that is not maintained by mesalazine OD 2 g. Such savings would, however, be applicable to a larger centre which might have 500 patients with UC maintained on mesalazine and another 300 patients with more refractory disease. It is also worth noting that the potential savings discussed here are based on a one year time horizon. Extrapolating these results further into the future would likely improve the observed cost-savings. To test the validity of our conclusions from the primary analysis we explored the impact of parameter uncertainty using probabilistic sensitivity analysis (PSA). The principal parameters that were simultaneously sampled in the PSA included the one year relapse rate, mesalazine compliance and the frequency of clinical consultation rates during relapse. 10 These parameters were identified for inclusion in the PSA because relapse rates influence the primary outcomes (QALYs) evaluated in the model, which can also influence costs attributed to relapse. Since our analysis showed that mesalazine costs and clinical consultations accounted for approximately 60 65% of annual treatment costs in this population, variation in these parameters could influence the cost-effectiveness results; hence justifying their inclusion in the PSA. Using well established sampling methods recommended by national technology appraisal groups such as the National Institute for Health and Clinical Excellence (NICE) in the UK, 25 we varied both the relapse events and cost data without significantly influencing our base case conclusions. The net benefits analysis demonstrated that there is a % probability that OD 2 g provides improved net benefits in comparison to BD 1 g over the entire range of willingness-to-pay thresholds (e.g., 0 to 20,000). The costs of treating steroid-refractory UC in the model were based on treatment with 5 mg/kg infliximab at 0, 2, and 6 weeks. In clinical practice steroid-refractory active UC can also be treated using intravenous 2 mg/kg ciclosporin (CsA) administered in hospital for one week followed by 5 mg/kg oral CsA for three months. The cost of intravenous CsA administered in hospital is approximately 3000 compared with three courses infliximab costing approximately ,27 The proportion of subjects progressing to the steroid-refractory health state ranged from 3 4% in each treatment arm. Since the proportion of patients entering this category were so low, it does not alter the cost-effectiveness of mesalazine OD which is predominantly influenced by the remission rates observed in the trial and success rates achieved using oral plus topical mesalazine and prednisolone for relapse, before reaching the steroidrefractory state. Therefore, substituting infliximab with CsA in the evaluation would not have dramatically influenced the results described by our analysis. On this basis we believe the results presented here are applicable to settings where CsA is predominantly used in steroid-refractory patients. Approximately 40% of annual treatment costs were attributable to mesalazine maintenance therapy. While this may seem an appreciable amount, the costs need to be viewed in light of the benefits of maintaining individuals in remission. Not only does maintaining remission save healthcare resources, but the impaired quality of life associated with relapse is significant and worth avoiding from the patient perspective. 19 The economic estimates provided here may underestimate the societal benefits of remission, since we have not included lost productivity costs attributable to a relapse. In addition to being cost-saving, maintenance treatment with OD 2 g mesalazine was also found to improve outcomes in terms of quality of life indices. The quality of life improvement was estimated by the accepted technique of mapping the UCDAI to the validated quality of life instrument, EQ-5D. The observed differences in scores between OD and BD were small, but the differences were sufficient to establish the superiority of OD 2 g in treatment outcomes. Since the estimated duration of relapse appliedinthemodelwasonly4weeks,whichislikelytobean underestimate of the actual duration of active disease, the economic benefit of maintaining remission is likely to have been underestimated. Had the duration reflected observations in Figure 1 Cost-effectiveness acceptability curve comparing OD 2 g and BD 1 g cost-effective proportions by varying the WTP threshold. Abbreviations: OD, once daily; BD, twice daily; WTP, willingness to pay.

6 Economic evaluation of once versus twice daily mesalazine 37 clinical practice the incremental cost per QALY would have been considerably less. 5. Conclusions British Society of Gastroenterology and ECCO guidelines indicate that treatment regimens for maintaining remission are dependent on tolerability, convenience and cost. We have shown that mesalazine 2 g once daily can satisfy all these criteria and can save healthcare resources when compared with conventional 1 g twice daily dosing. Our analysis took the perspective of the NHS in the UK, focusing on costs attributed to treating UC and relapse. Had a societal perspective been applied in which the costs of lost productivity attributable to relapse were factored into the analysis, the cost savings of 2 g once daily would have been greater. In view of the dominant characteristics of once daily dosing in terms of improved efficacy and reduced costs, this regimen is recommended for maintaining UC remission. Acknowledgements The work described in this paper was funded by an independent research grant from Ferring Pharmaceuticals, St Prex, Switzerland. The study sponsor did not influence the study design or results of the study. They were provided with a final copy of the manuscript to review prior to submission. References 1. Loftus EV. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence and environmental influences. Gastroenterology 2004;126: Shivananda S, Lennard-Jones J, Logan R, et al. Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Gut 1996;39: BassiA,DoddS,WilliamsonP,BodgerK.Costofillnessofinflammatory bowel disease in the UK: a single centre retrospective study. Gut 2004;53: Odes S, Vardi H, Friger M, et al. Cost analysis and cost determinants in a European inflammatory bowel disease inception cohort with 10 years of follow-up evaluation. Gastroenterology 2006;131: Boonen A, Dagnelie PC, Feleus A, et al. The impact of inflammatory bowel disease on labor force participation: results of a population sampled case control study. Inflamm Bowel Dis Nov 2002;8: Reinisch W, Sandborn WJ, Bala M, et al. Response and remission are associated with improved quality of life, employment, and disability status, hours worked, and productivity of patients with ulcerative colitis. Inflamm Bowel Dis 2007;13: Kane SV. Systematic review: adherence issues in the treatment of ulcerative colitis. Aliment Pharmacol Ther 2006;23: Kane SV, Cohen RD, Aikens JE, Hanauer SB. Prevalence of nonadherence with maintenance mesalamine in quiescent ulcerative colitis. Am J Gastroenterol 2001;96: Kane SV, Huo D, Aikens J, Hanauer S. Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis. Am J Med 2003;114: Dignass A, Vermeire H, Adamek R, et al. Improved remission rates from once- versus twice-daily mesalazine (PENTASA) granules for the maintenance of remission in ulcerative colitis: Results from a multinational randomized controlled trialuegw Oral presentation; Abstract OP-G Stange EF, Travis SPL, Vermeire S, et al. European evidencebased Consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. J Crohn's Colitis 2008;2: Travis SPL, Stange EF, Lémann M, et al. European evidencebased Consensus on the management of ulcerative colitis: current management. J Crohn's Colitis 2008;2: Carter MJ, Lobo AJ, Travis SPL, on behalf of the IBD Section of the British Society of Gastroenterology. Guidelines for the management of inflammatory bowel disease in adults. Gut 2004;53:v1 v Bebb JR, Scott BB. Systematic review: how effective are the usual treatments for ulcerative colitis? Aliment Pharmacol Ther 2004;20: Marteau P, Probert CS, Lindgren S, et al. Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomized, double blind, placebo controlled study. Gut 2005;54: Curtis L. Unit Costs of Health and Social Care. University of Kent: Personal Social Services Research Unit; Collins P. Ulcerative colitis: diagnosis and management. BMJ 2006;333: Mortimer D, Segal L. Comparing the incomparable? A systematic review of competing techniques for converting descriptive measures of health status into QALY-weights. Med Decis Mak 2008;28: Poole C, Nielsen SK, Currie CJ. Health related utility among adults with remitting ulcerative colitis maintained with oral mesalazine over the long term: findings from the study. United European Gastroenterology Week; Abstract: P Konig HH, Ulshofer A, Gregor M, et al. Validation of the EuroQol questionnaire in patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 2002;14: Briggs AH. Handling uncertainty in cost-effectiveness models. Pharmacoeconomics 2000;17: Claxton K, Sculpher M, McCabe C, et al. Probabilistic sensitivity analysis for NICE technology assessment: not an optional extra. Health Econ 2005;14: Stinnett AA, Mulahy J. Net health benefits: a new framework for the analysis of uncertainty in cost-effectiveness analysis. Med Decis Mak 1998;18(suppl):S68 S Rawlins M, Culyer AJ. National Institute for Clinical Excellence and its value judgments. BMJ 2004;329: National Institute for Health and Clinical Excellence (NICE). Guide to the Methods of Technology Appraisal; May 2004 (Accessed 8 August 2008: NICE. Infliximab for subacute manifestations of ulcerative colitis. Technology Appraisal Guidance 140 April (Accessed 21 August 2008: TA140Guidance.pdf). 27. Poritz LS, Rowe WA, Swenson BR, Hollenbeak CS, Koltun WA. Intravenous cyclosporine for the treatment of severe steroid refractory ulcerative colitis: what is the cost? Dis Colon Rectum 2005;48(9):