Comments from Wyeth on the Assessment Report for the appraisal of adalimumab, etanercept and infliximab for the treatment of Ankylosing Spondylitis

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1 1. Introduction Wyeth are concerned by the conclusions reached by the Assessment Report as they do not reflect the weight of evidence on the clinical and cost-effectiveness of TNF-targeted therapies in ankylosing spondylitis (AS). It is surprising that the report does not mention the ASAS/EULAR recommendations for the management of AS which were published on-line in August and in paper format this year 2. These recommendations were supported by a systematic literature review 3, 4. The Wyeth model was developed by an independent academic unit (ScHARR). We believe that, as with previous etanercept models, the structure is sound, and with the exception of a few minor errors (which have now been corrected) makes appropriate use of the available clinical data. We have taken into account some of the suggested alternative inputs and present a revised base case ICER of 22,704 over a 25 year time horizon. We have however found it particularly difficult to respond to many of the points relating to the Wyeth data as they have been hidden as Commercial in Confidence (CiC). Wyeth had previously informed NICE that any data relating to the 314 study and any information on the economics and costing contained in the main body of the submission could be disclosed. Since then additional information on the economics has become public. Copies of the posters are included with this response. We have attempted to understand why the Liverpool model differs substantially from all other models submitted to NICE, including those developed independently from pharmaceutical companies. This has proved particularly difficult, as the use and presentation of the Individual Patient Data (IPD) has been hidden from scrutiny, as it is CiC. We have however identified a number of issues that need to be carefully reconsidered, as we believe they are in error and will have significant impact on the end results. Wyeth does not believe that the Assessment Report, as it stands, can form the basis for decision making with these drugs. 2. Clinical evidence As set out in the Wyeth submission, AS is a chronic disabling disease with usual onset in the 3 rd decade of life, with males affected more often than females. The outcome of the disease is variable, but in severe cases is progressively disabling. Until the advent of the TNF-targeted therapies treatment was limited to symptomatic alleviation with NSAIDs and use of physical therapy. Consequently the level of research into the disease was significantly less than, for example, RA. A systematic review of evidence was undertaken by ASAS- EULAR as part of the development of recommendations for the treatment of AS 3, 4. The Assessment Report does not acknowledge this comprehensive review, although it was referenced in the Wyeth submission. The recommendations for the treatment of AS that was based on this review were developed in accordance with the EULAR procedures and were published electronically in and in paper format in The Assessment Report makes no reference to this authoritative document when discussing the treatment of AS. Page 1 of 30

2 The report, particularly in the economic section, places undue weight on a paper that describes patient experiences of disease exacerbations and flares, which typically last no more than a month 5. However, such flares are against a background of ongoing disease. Data from Truro 6 in which annual assessments were undertaken showed that, over a five year follow-up period, approximately one third of patients had BASDAI scores that were 4 on every occasion, that is had severe active disease. The authors then suggest that, based upon their analysis and interpretation of the data, that drugs that inhibit TNF may do no more than treat flares. In this respect they have assumed that the behaviour of patients treated with placebo injections equates to the normal pattern of behaviour of such patients, whereas it is well known that inclusion in a trial will modify patient expectations. In the study used by Liverpool the availability of active escape therapy for patients doing badly at 12 weeks would clearly lead some patients to report worsening disease activity to ensure they received active treatment. This data therefore cannot be used to model the pattern of disease under normal clinical conditions. There is also inconsistency between the interpretation of the clinical evidence in the economics section which is exemplified in section Summary and in the clinical section. The consideration of cost-effectiveness of anti-tnfα treatments for AS is overshadowed by the unfortunate absence of evidence concerning both the dynamics of the disease as experienced by patients at different stages in the progression of the condition, and the mode of action of the anti- TNFα agents. In particular, it is far from clear whether we should expect benefits in any or all of these aspects of AS: - providing immediate relief of symptoms, especially pain; - altering the normal level of disease activity; - accelerating recovery from flare episodes; - reducing the severity of flare episodes; - reducing the frequency of flare episodes; - preventing or delaying long-term disease progression. In addition there is no substantive RCT evidence of the performance of anti-tnfα agents when used sequentially (or even in combination). This means that the models submitted by the industrys are based on a large number of assumptions, and framed in structures which are unlikely to apply in practice, and which tend to present the new products in a favourable light. This contrasts with the clinical summary, and also with the evidence on the individual drugs set out in the clinical section of the report, particularly in relation to the first 2 points. The report makes no attempt to put the efficacy of these drugs into the context of the efficacy of other available therapies, for example by estimating effect size, as has been done by Levy et al 7, who reported an effect size on spinal pain for NSAIDs of 0.38 (95% CI 0.16, 0.60), compared with 3.67 (95% CI, 3.31, 4.02) for the TNF targeted treatments. This shows these drugs have substantial effects on pain, far greater than current treatments. Similar effect sizes were reported for BASFI. The evidence from the ASAS/EULAR systematic review reinforces this, the results of which are tabulated below (Table 1), and which were included in the Wyeth submission. Clearly the first two points in section are in contradiction to the available evidence. Page 2 of 30

3 Table 1 Effect size estimates from ASAS/EULAR systematic review 4 Outcome Spinal pain (effect size, 95% CI) Function (effect size, 95% CI) Non-selective NSAIDs 1.11 (0.96,1.26) 0.62 (0.26, 0.97) Coxibs 1.05 (0.88, 1.22) 0.63 (0.47, 0.80) SSZ (-5.78, -1.03) 0.20 (-0.77, 1.18)` MTX (-0.48, 0.36) 0.02 (-0.40, 0.45) ETN 2.25 (1.02, 2.59) 2.11 (1.81, 2.41) IFX 0.90 (0.66, 1.14) 0.93 (0.69, 1.17) The three points made regarding effects on flares are valid, but probably overplay the importance of flares as they tend to be of limited duration, and for most patients are relatively infrequent. The effect on flares has not been assessed since, unlike studies with NSAIDs, as flare designs were not thought appropriate. Evidence on long-term function as a measure of disease progression is limited as studies with these agents in this disease only began a few years ago. Wyeth presented 2 year data in the submission. This has now been extended to 3 year data, and data on a limited number of patients for 4 years is available. The results show that in patients who respond and remain on therapy (the withdrawal rate is very low), the initial improvements in BASFI and spinal mobility are maintained. The body of evidence clearly demonstrates the substantial improvements in clinical and patient outcomes that these agents bring to patients with AS compared to other treatment options, but this is not reflected in the clinical section of the report and this is further downplayed in the economic section. Page 3 of 30

4 3. Economic modelling 3.1. Evaluation of the Wyeth model Utility relationship The Assessment Report is critical of the choice of the utility relationship, which is central to the economic model and suggests that an SF-6D based relationship might be preferable. The Guide to the Methods of Technology Appraisal [NO515 NICE, 2004] states that for economic evaluations: the most appropriate choice in the UK appears to be the EQ-5D and the institute would ideally wish that all appraisals used the same system. In addition, as stated in the Wyeth economic submission document, it is believed that the EQ-5D is the preferred preference based instrument for measuring HRQoL in patients with AS who would be eligible for anti-tnf treatments i.e. those with severe disease. The decision to use the EQ-5D model as opposed to the SF-6D model was based on the findings of the analyses of the HRQoL data (ScHARR economic evaluation report). The analyses demonstrate that there is a possible floor effect in the SF-6D with a wide range in EQ-5D scores corresponding to low SF-6D scores. For patients scoring below 0.5 on the SF-6D the corresponding EQ-5D scores have a mean of 0.11 with a range 0.02 to This is consistent with findings of other studies comparing preference based utility measures derived using the EQ-5D and the SF-6D instruments 8. The consequence of this is that the EQ-5D should discriminate better between patients at the severe end of the disease spectrum again, concurring with the finding of a recent study in AS patients 8. Therefore the choice of EQ-5D based utilities is appropriate BASDAI and BASFI Comments regarding the generation of baseline BASDAI and BASFI values have been carefully considered and an alternative approach has now been adopted. Data on a subset of patients with BADAI 4 were utilised. Modifications have been made to the modelling techniques used to predict the changes in BASDAI and BASFI measurements. The data is split into the four subsets defined according to the BSR criteria: placebo non responders (PNR), placebo responders (PR), etanercept non responders (ENR) and etanercept responders (ER). Using transformed data, changes in BASDAI at week 12 and 24 are now calculated using baseline BASDAI and/or week 12 BASDAI measurements, while changes in BASFI at week 12 and 24 are now calculated using baseline BASFI and/or week 12 BASFI for each of the four subgroups. The Liverpool group has reported that patients in the Abbott model with high BASDAI at baseline may have a more limited response to treatment. This has been evaluated in the Wyeth data. Plotting BASDAI at baseline against the percentage improvement in BASDAI at week 12 (Figure 1), the data suggests that there is a possible relationship between disease severity at the start of treatment and the effect of treatment. However, the association is not strong and there is a much larger variation in the magnitude of effect for patients at the very severe end of the disease scale. For patients with baseline BASDAI greater than 90, the observed week 12 measurements range from 5 to 75.5; whereas for patients with baseline BASDAI between 40 and 50, the corresponding 12 week measurements range from 0.3 to 29. The results are summarised in Table 2. Page 4 of 30

5 Figure 1 Responders to etanercept (study 314): Baseline BASDAI plotted against % change at week Percentage reduction in week Baseline Table 2 Observed changes in BASDAI measures subgrouped by patients BASDAI score at baseline Observed BASDAI Reduction at week 12 baseline week 12 absolute percentage The errors identified in the Report regarding gender and age range have now been corrected but had little effect on the results generated by the original model Life expectancy The Report also claimed that life expectancy had been wrongly calculated. This is incorrect as it was calculated using a nested lookup function. The function is a conditional formula based on the age and thus the cumulative probability of survival of the patient at baseline. In essence, the function uses the fact that the patient has survived up to baseline age and randomly samples how long they will survive after this age. The lifetable used gives the cumulative probability of death. The cumulative probability of death for each patient is calculated by randomly sampling from the cumulative probabilities of deaths for ages greater than the baseline age, subject to the probability that the patient has survived to the baseline age. The cumulative probability of death, and hence the age of death, is calculated as shown in the example for a female aged 44 years at baseline, the cumulative probability of death at age 44 is (see Table 3) Page 5 of 30

6 Table 3. Calculation of cumulative probability of death for 44 year old female Random number: *(1-0.5*(1- cumulative p(death) ) ) *( ) lookup cumulative p(death) age of death with calculated cumulative p(death) The formula used also includes an appended function that randomly assigns the death to one of four quarters in the year Progression The Report is critical of the choice of progression rate used in the basecase. The economic evaluation was based on patients with severe AS who would potentially be eligible for anti-tnf agents in the UK. As stated in the economic evaluation, the disease progression rate for this subgroup of patients is uncertain. The limited data that is published is based on all patients with AS, not patients who are potentially eligible for treatment of TNF-targeted therapy. As was discussed, if BASFI is used as an indication of disease severity, then based on the patient characteristics of the etanercept RCT cohorts, patients eligible for anti-tnf agents would be at the extreme end of the Truro disease spectrum. Thus their disease progress could potentially be very different. The uncertainty surrounding the evidence chosen was discussed and a total of 11 sensitivity analyses, including allowing no progression at all for any patients in the model (s.a. 5.1), were performed to explore the impact of varying the values used. Patients included in Bath analyses 9 also included the full spectrum of BASDAI and BASFI values and therefore the annual progression rate of 0.07 (scale 0-10) for BASFI may not reflect the more severe patients likely to receive these drugs. Despite these reservations Wyeth have now chosen to use the 0.07 value for BASFI and to exclude BASDAI from the progression rate Costs In response to the comments received on the cost data used in the Wyeth submission we recognise that the use of different models on cost data can produce a variation in the predicted costs and acknowledge that the methodology used will yield a model of the geometric as opposed to the arithmetic mean. A number of possible models were explored with various combinations of independent variables. The appropriateness of the methodologies and techniques used to model costing data is an ongoing debate with advocates both for 10 and against the method that was used in the Wyeth evaluation, hence the assertion that the approach is fundamentally flawed is not justified. Page 6 of 30

7 The final model used in the Wyeth submission was chosen for simplicity and transparency. Both the BASDAI and BASFI were independently significant predictors of the transformed costs with both BASDAI and BASFI driving costs across the full spectrum of disease severity. Hence both were included in the final model. We disagree strongly that the choice of model would in any way increase the apparent cost savings from using the treatment. On the contrary, if it is acknowledged that the model used potentially underestimates disease costs for patients at the severe end of the disease scale (which is the implication of using the geometric as opposed to the arithmetic mean), this is a conservative approach, as the potential costs offset from responding to treatment are reduced. The Assessment Report implies the model used was selected as it yields less extreme cost values for high BASFI scores which will tend to reduce the apparent cost savings from using the treatment (page 87 of the assessment report). If the Wyeth cost model is compared with the model used in the Liverpool evaluation, it is clear that the Wyeth model is conservative as the cost offsets using the Wyeth model are far smaller than those accrued when using the Liverpool model (Table 4). Page 7 of 30

8 Table 4: The difference in cost offsets due to changes in BASDAI/BASFI when using the Liverpool or Wyeth model Start BASDAI/BASFI End BASDAI/BASFI Liverpool Start-End Wyeth Start-end Cost offset Liverpool Cost offset Wyeth ,615 2, ,940 2, ,187 1, ,958 2, ,283 1, , ,578 1, ,566 1, , ,428 1, , , , , , , , As stated in the Wyeth submission document / economic report (page 38), the cost data used to inform the costing study was obtained directly from patients hospital records. Hence the assertion made by the Assessment Report that the data relies on patients long-term memory recall is incorrect. It is believed that the hospital records used provide an accurate account of health care resources consumed by typical AS patients in the UK. A model was produced from the Stoke data using the Liverpool preferred functional form (Cost=a*exp(b*BASFI)). Annual costs generated using this model are similar to the values predicted using the original sample using the BASDAI and BASFI model (Table 5). Page 8 of 30

9 Table 5: Annual cost predicted using the Liverpool, original and revised Stoke models Liverpool Wyeth original CIC Wyeth CIC Model x exp( x BASFI) Exp( *BASDAI+0.016* BASFI) *exp( *BASFI) Bd/Bf 0 1, , , , , ,962 1,066 1, ,759 1,330 1, ,715 1,661 1, ,865 2,074 1, ,245 2,589 2, ,902 3,233 2, Sensitivity analyses The Assessment Report asked why the Wyeth submission presented a sensitivity analysis using the SF-6D data but excluded it from tornado diagram. As stated in the Wyeth economic report (page 37), the literature suggests utility values (and thus corresponding ICERs) generated using different instruments are not directly comparable 11. Indeed the authors of the Guide to the Methods of Technology Appraisal state: results from the use of different systems cannot always be compared as different classification systems do not give consistent utility values to the same health states [NO515 NICE, 2004]. However, the authors also suggest that those submitting data should indicate whether they have any evidence that will help the Committee to understand to what extent, the choice of instrument will have impacted on the QALYs gained [NO515 NICE, 2004]. Based on this, a sensitivity analysis was performed to explore the impact on the QALYs gained if the SF-6D utilities were used as opposed to the recommended EQ-5D utilities. It was not thought appropriate to include the results from this sensitivity analysis in the tornado diagram as inclusion would imply that these results are directly comparable with the basecase results generated using the EQ-5D data, which is not the case Revised model results Using the revised regressions for BASDAI and BASFI variables, the revised annual progression rates of BASDAI = 0, BASFI = 0.7 (scale 0-100) and the original Stoke cost model, the revised results using different time horizons are shown in table 6. Page 9 of 30

10 Table 6: Revised central estimate using different time horizons Years Average discounted QALY per patient ETN Com Inc Average discounted cost per patient ETN 7,440 13,042 26,390 41,574 51,415 57,996 62,517 Com 1,403 2,890 7,109 13,313 18,596 23,001 26,538 Inc 6,037 10,152 19,281 28,260 32,819 34,995 35,978 Incremental cost per QALY 36,972 27,594 23,649 22,702 22,580 22,638 22,704 Sensitivity analyses exploring the impact of varying the annual rate of BASFI progression are shown in Table 7. Table 7: Results demonstrating the impact of varying the disease progression rates for the BASFI variable Treatment Comparator Time horizon Annual progression rate (scale 0-100) BASDAI BASFI BASDAI BASFI ,020 24,112 24,281 25, ,986 23,782 23,066 23,544 Basecase ,972 23,649 22,580 22,704 Including progression for responders to treatment ,972 23,722 22,907 23, ,986 23,834 23,307 23, ,986 23,887 23,553 24, Evaluation of the Liverpool model Critical evaluation of the Liverpool model has been significantly hindered by the amount of information that has been blacked out as CiC. This is particularly important as the results reported are substantially different from the company models and other published models 9, 12. The significant impact of the TNF targeted therapies on clinical outcomes and health related quality of life of patients in a disease with limited therapeutic options does not appear to have been appreciated by the authors of this report. This would appear to have a significant influence on the approach to the modelling and the selection of modelling inputs Utility model When critiquing the Wyeth choice of model the Assessment Report states: Using the EQ-5D utility model leads CiC. If this is conceded then either the BASDAI/BASFI models are not appropriate in the long term, or the SF6-D utility model may be more realistic. It is unclear from the text what is to be conceded or why the author believes the SF-6D model may be more realistic. The concerns expressed in this section are not reflected in the Liverpool model, which used utilities, derived from EQ-5D data without reference to this particular issue. Page 10 of 30

11 The utility model used in the Wyeth submission is derived from patients participating in an anti-tnf RCT. The data used to inform the utility model used by Liverpool is derived from a cross-sectional survey with few if any patients receiving anti-tnf agents. Ideally the utility measures should be obtained from patients who are receiving the intervention being researched. As with all surveys of this nature, there are issues concerning response and recall bias. The Liverpool authors do not discuss the potential impact these may have had on the results, or if any analyses were performed in the original study to address these issues BASDAI and BASFI The relationship between BASDAI and BASFI that has been derived by Liverpool is substantially different from that observed in the etanercept studies (see Table 8) which is likely to have a significant impact on the results. In addition the application of lower response with higher baseline BASFI, (which was not seen in the Wyeth data) will impact on the utility gains. Table 8 Relationships between BASDAI and BASFI Impact of age Wyeth Liverpool BASDAI BASFI BASDAI BASFI The Assessment Report states the absence of age as a predictor prevents any considerations of the long term modifying effects of ageing and growing co-morbidities on patient utilities, which must be important when projecting outcomes for 3 decades. This implies the author believes there is a negative correlation between age and utility i.e. as age increases, utility decreases due to comorbidities. The impact of comorbidities is potentially more relevant for patients with AS as they are at greater risk of, for example, cardiovascular disease, than the general population. However, the model the Liverpool modellers elected to use has a positive coefficient for age. This describes a converse relationship as an increase in age will increase the predicted utility measure. It is possible that patients with AS adapt to the disease as they age. It is also possible that the impact on HRQoL from co-morbidities is cancelled out by patients adaptation to the disease. However, there is currently no published evidence to support either of these hypotheses or to suggest that age is significantly associated with utility in AS patients Cost model Justification for the choice of AS disease related costs used by the Liverpool model may be open to question. The cost data used to inform the Liverpool evaluation is taken from published data based on non-uk health systems 13. We feel strongly that the UK cost data used in the Wyeth submission is the preferred source to inform an economic evaluation for AS patients in the UK. Table 9 below summarises the main concerns with the use of the European data and compares these with the Stoke data used in the Wyeth submission Page 11 of 30

12 It would appear that the costs for the comparator arm of model have been miscalculated. In Table 7-4, page 128/187, the annual treatment costs for the conventional treatment arm is given as 213, whereas applying the Liverpool cost equation ( 1, x exp( x BASFI) gives a value of 4171 for a baseline BASDAI of This error, if not typographical, will have substantial impact on the incremental costs and hence the ICERs. Page 12 of 30

13 etanercept and infliximab for the treatment of Ankylosing Spondylitis Table 9: Comparison of data sources for costs Liverpool Wyeth Preferred data for a UK based costeffectiveness evaluation Setting 4 centres in France, Belgium and the Netherlands UK As results will be used to inform UK policy decision makers UK sources should be used where possible Date 1999 & 2002 Resource use: Liverpool uses PPI and inflates which Health care system Non NHS: France, Belgium, Netherlands, potentially very different in each country. Resources European: The treatments and resources may reflect practice in the respective studies but may differ from current practice in the UK. Costs Data collection Data France, Belgium Netherlands; costs for corresponding interventions differ between countries. These may not be directly transferable. Questionnaires every 6 months over 2 years Published aggregate costs weighted by the number of grouped observations costing data 2005 NHS: The patients in the UK are in the NHS system and receive NHS treatment. UK: The treatments and resources reflect current practice in the UK UK: authoritive UK sources Hospital records over a period of 12 months Individual patient level data introduces more uncertainty Health care systems differ between countries. As the results are to inform UK policy decision makers costing data on patients within the NHS system should be used if it is available. Health care practice differs across countries. The type and frequency of resources consumed by a patient with AS in the UK is likely to differ from a similar patient in a different country. UK data is preferred for a UK based evaluation. Health care practice differs across countries. The cost of an intervention is likely to differ widely between countries. UK cost data is preferred for a UK based evaluation. Using retrospective data is preferred to using repeated economic questionnaires. The later relies on patients co-operation and is subject to response bias. Individual patient level data will provide a more accurate model on which to base costs. Page 13 of 30

14 4. Impact on NHS It is interesting to note that considering the different approaches used by Wyeth compared to LRiG the budget impact to the NHS is very similar for the first year. Comment is made on the robustness of the epidemiological data available for AS. This is addressed earlier in the Wyeth response. The central estimates used by LRiG are similar to those used in the Wyeth model; incidence 6.9 per 100,000 versus 7.3 per 100,000 and prevalence 0.15% versus 0.14%. We believe we have taken a pragmatic approach which reflects the current clinical management of these patients and takes into account eligibility criteria from the BSR, UK patient data on severity of disease and expert clinical opinion. The LRiG model assumes a response rate of 40% at 12 months. Based on the clinical efficacy data for etanercept we have used a 44% response rate at 3 months, resulting in 54% failing to respond and discontinuing therapy. Wyeth also assume a further 10% of those patients remaining on treatment, will drop out each year due to the development of side effects, lack of compliance or other reasons contributing towards natural attrition. The fundamental difference in the two budget impact models is the failure of LRiG to take into account the long term benefits of the TNF targeted treatments in maintaining a clinical response and suggesting that they should be used for short-term management of AS. This is not reflective of current clinical practice and the weight of evidence. This has a major influence on the cost impact after the initial year of treatment. For completeness the budget impact scenarios from the Wyeth model are presented below in Table 10. Table 10: Wyeth Budget Impact Model Year 1 Year 2 Year 3 Wyeth base case Total 61,474,599 62,946,994 65,933,430 Wyeth base case with uptake split over 3 years Total 20,148,651 42,012,957 63,878,283 Based on expert clinical opinion and uptake split over 3 years Total 10,115,263 21,091,133 32,067, Summary and Conclusions The Assessment Report appears to have taken a view of AS that differs from experts in the field, suggesting that the guidelines developed by the BSR (and therefore indirectly those developed by ASAS) may not be valid. The substantial efficacy of the TNF-targeted drugs in comparison with other available therapies appears to have been ignored. It is suggested that these agents may only be treating flares. This appears to have been translated into the economic modelling leading to ICERs much greater than that reported by the other models. Page 14 of 30

15 Wyeth has carefully considered the points made in the report regarding the submitted economic model (as far as possible given the large amount of CiC data). Changes have been made to the model, which now gives a basecase ICER of 22,704 at 25 years. The overall weight of evidence is in favour of recommending etanercept for NHS patients with AS who meet BSR criteria for eligibility. Page 15 of 30

16 Section No. Section Title Page Reference Disease 2/ Epidemiology Assessment Assessment of response to therapy Criteria for treatment Prognosis Burden of disease Anti-TNFα Drugs Comments Up to 60% of patients have an inflammatory bowel disease similar to Crohn s disease with symptoms of variable intensity. This figure is incorrect as only 7% have Crohn s disease. A higher percentage may have evidence of bowel inflammation on biopsy but without symptoms 14 (see submission) It is important to acknowledge that epidemiology studies in AS are difficult to undertake as it requires that all subjects identified from a population with signs and or symptoms suggestive of inflammatory back pain should have an X-ray as part of the diagnostic process. In the Wyeth submission, the prevalence of diagnosed AS has been estimated from the GPRD database to be 0.104%. Using a UK prevalence of HLA B27 of 8% (Calin and data from the review of Gran and Husby 15 on the relationship between HLAB27 prevalence and the prevalence of AS, gives an estimate of 0.38% No mention is made of the increasing use of MRI as a means of evaluating acute and chronic spinal changes in AS, for which OMERACT have established the preferred methods 16. The derivation of the ASAS criteria is inappropriately referenced and described. The reference to the development of the criteria is Anderson et al 17 which proposes the ASAS20 as it discriminated between active NSAID and placebo. The validation of ASAS20 and the performance of ASAS50 and ASAS70 was described by Stone et al 18. At this point in the report it would seem appropriate that other treatments that are used in AS should have been reviewed so that the subsequent sections on the interventions that are subject of the assessment can be put into context. The text in this section is not referenced and therefore it would appear that these are the recommendations of the authors. In fact these are a reproduction of the BSR recommendations 19 and should be introduced as such (although in Box 2 the appropriate reference is used). No reference is made to the internationally developed ASAS recommendations 20, 21. This section also appears to be out of order and would be more appropriate at the end of section 2.1 or at the beginning of 2.2 With treatment, symptoms can usually be relieved or controlled so that the patient can lead a normal, productive life. Contradicts the statement in the executive summary Currently, there is no standard (or effective) therapy for AS and is at odds with the body of evidence on the impact of the disease (see section 2.4 of Wyeth submission) However, ninety percent of individuals suffering from AS remain fully independent or minimally disabled in the long term The reference is from the Prodigy guidelines but this does not give a primary source for this data which conflicts with evidence on the 22, 23 impact on UK patients Etanercept is now licensed at both 25 mg twice weekly and 50 mg once weekly Page 16 of 30

17 3.3.1 Inclusion criteria Patient population Scope of review Selection of evidence 19 It is unclear why the inclusion criteria for etanercept and infliximab differ from those for adalimumab. Enbrel is followed by whereas should be used, as with the other drugs. For resource reasons, other non-rcts, which could not be linked with an included RCT, were not considered further within the timeframe of the assessment means that not all the available evidence was considered Selection of evidence Study characteristics NICE were informed prior to the report being issued that 314 is no longer CiC No reason is given for not including the 50 mg once weekly dose in the review. NICE had been informed that a licence had been applied for. (Were they informed it was granted?) By not including 50 mg data from 314 in the meta-analyses not all the available evidence was considered. It should be noted that at the time of these analyses adalimumab was not licensed and if the logic for excluding the 50 mg data is followed then none of the adalimumab data should have been included! Study characteristics 20 In a number of places it states that certain information was not available. This would have been provided on request Participant characteristics Comparability of AS patients in the RCT evidence base and those in clinical practice 22 It is noted that patients enrolled in studies may not have met BSR criteria. However the criteria were derived from the ASAS recommendations which were developed after the majority of these studies had been started and when many had already been published. It is not surprising therefore that the entry criteria and BSR recommendations are not the same. It should be noted that Clinical Study Reports were not requested by Liverpool, which would have included much of the data noted as N/A. Journals often limit the space available to individual publications so that not all available data can be included. Other Assessment Groups have either requested the CSRs or asked whether the data is available Approach to analysis 26 3 rd para We were not aware that patients in the adalimumab ATLAS trial were offered escape medication with etanercept Indirect comparisons of ant- TNFα agents 32 Table 4.2 The table reports values for ASAS 40 whereas Davis et al 24, Calin et al 25 and Study 314 all reported ASAS Longitudinal metaanalysis Role of LMA Open label studies 37 It would be unethical to have conducted placebo controlled studies longer than 24 weeks in a progressive disabling disease In chronic disease, open label studies are an important source of information on the longer term risks and benefits of treatment albeit on a selected sub-group of patients who completed the controlled studies. They are essential evidence to inform economic modelling inputs and therefore must be considered in the assessment of these drugs. Page 17 of 30

18 Discussion Limitations 39 Discussion 40 2 nd para 4.8 Summary 41 5 Economic Review Whole section 5.2 Table Submitted models Table While we are confident that we have included all appropriate RCTs, not all data collected in these studies are presented within trial reports. Available evidence on the effects of anti-tnfα therapy is reported in a variety of detail and format. Both these issues may mean that not all data on the effects of anti-tnfα agents have been presented in our review or included in our summative analysis. The authors of the assessment report misuse the term trial reports as they are referring to published manuscripts. The authors should have requested access to company Clinical Study Reports or asked for specific information for the assessment of these agents to be considered comprehensive. This has been the case with other technology appraisals of etanercept. Many of the trials selected ASAS 20 as principle outcome. Although appropriate for the statistical powering and conduct of the trials, 20 percent improvement may only confer a modest change in a patient s overall wellbeing However ASAS, an international group of experts, have recommended ASAS 20 as a meaningful improvement that in particular discriminates between treatments (based on NSAID studies) Importantly the criteria used for continuation of treatment in the BSR Guideline is a 50% improvement in BASDAI or a decrease of 20 mm. Pavy et al 26 have reported that the MCID for the BASDAI is 10 mm or 22.5% so the BSR recommendations substantially exceed these criteria. In addition, BASDAI 50 was an endpoint in all of the studies as the % responders by this criteria were always significantly greater in the etanercept treated patients than placebo. Little suitable long-term data were available of analysis across trials or anti-tnfα agents. However such data were rejected (4.5) This section is extremely difficult to assess as much of the key data on derivation of inputs and the inputs themselves are CiC. Consequently it is impossible to undertake a critical appraisal of the Liverpool model. This is particularly important given the results which are very different 9, 12 from the 3 industry models and the independent models Incomplete. Does not include all drugs eg celecoxib, etodolac, SSZ, MTX etc. Why is indometacin not included as a standard NSAID? Etanercept is also licensed for 50 mg once weekly All the models are narrowly focused on the limited clinical trial data associated with their own product, and none attempt to make direct or indirect comparisons to other anti-tnfα agents. According to the scope issued, under the section other considerations, the recommendation is that comparisons between adalimumab, etanercept and infliximab will be undertaken, if the evidence allows. As Wyeth does not have access to the clinical data on competitor products it is not feasible or reasonable for Wyeth to undertake comparative analysis. CiC should not be blacked out Page 18 of 30

19 6.2.2 Resource use Resource use Resource use 80 Current practice suggests that all patients be screened for TB before commencing anti-tnfα therapy (personal communication RM). However, no specific costs of tuberculosis screening are included in the model. Although the Enbrel SmPC doesn t require clinicians to specifically conduct a chest x-ray prior to initiating treatment we have incorporated the cost of an initial chest x-ray as this in now recommended by the British Thoracic Society Guideline 27. The inclusion of a second X-ray in the costs is inappropriate as this is only required in patients who develop respiratory symptoms in the first 3 months of treatment. The rate of developing TB during treatment with etanercept is low. Data from the BSRBR based on over 10,000 patient years of follow-up is 0.5 per 1000 patient years (95% CI: 0.2, 1.2). The impact of adding this to the model would be minimal There are several differences between the patients in the costing study and in the RCTs; for example, the patients in the costing study have substantially lower BASDAI and BASFI scores, patients are approximately 10 years older and the average time since diagnosis is longer. There is a further comment in section The model uses patient data from two RCTs and one open-label extension study. Patients in these clinical trials differ from UK patients in two ways. Firstly, UK patients have lower BASDAI/BASFI scores (i.e. these patients have less severe AS). Secondly, the duration of disease in patients in the UK studies appears to be longer. This raises two issues, firstly due to the lack of clinical effectiveness data of Enbrel in AS the use of clinical outcomes based on phase III RCTs is appropriate and secondly as the costing study is done on what the TAR group considers representative UK patients, this data is entirely appropriate as the basis for costs in a UK environment. Costs in the model are influenced by the withdrawal rate used. As etanercept is a relatively new drug, there is very little evidence on long-term withdrawal rates. In the base case, the withdrawal rate is set at 10% per annum. In support of this figure, the authors quote the results of a Swedish study of rheumatoid arthritis patients taking etanercept for 24 months. Data from Sweden now extend to over 3 years 28 and is supported by recently published data from Spain 29 based on over 1500 patients with SpA and over 4000 with RA showed that continuation of treatment with anti-tnf drugs was significantly in SpA over a follow-up time of 3 years. The hazard ratio for discontinuation compared with RA was 0.66 (95% CI ). Drug survival for AS is summarised below with 95% CI: I year 2 years 3 years 0.88 ( ) 0.82 ( ) 0.74 ( ) Data presented at EULAR 2006 from Norway also shows greater retention for AS than RA (Heiberg et al OP0091) with 82% of 211 patients with AS remaining on treatment at 1 year, very similar to the results from BIOBADASER. Page 19 of 30

20 6.2.3 Health outcomes Specifying the patient cohort Gender 83 Age Range 83 Duration of disease 83 BASDAI/BASFI values 83 Correlation Response rate 84 The EQ-5D regression was chosen for the base case analysis on the grounds that it encompassed a wider range of utility values, though there is no further justification for this choice. In the Wyeth submission (section 7.4.9) the issues with using SF-36 are discussed in detail, reinforcing the appropriateness of EQ-5D for utility values in the base case. The Guide to the Methods of Technology Appraisal [NO515 NICE, 2004] states that for economic evaluations: the most appropriate choice in the UK appears to be the EQ-5D and the institute would ideally wish that all appraisals used the same system. It appears that the sex of patients has been mislabelled in the model, so that the model generates predominantly female patients This has been corrected The model produces a very wide range of patients age, with several hypothetical patients under the age of 10 in the cohort This has been amended but made little difference to the results.. The age and duration of disease for hypothetical patients are generated independently within the model, despite the obvious connection. This leads to glaring anomalies, The model has been revised with a new regression model, which does not include disease duration, so this comment is now redundant. The range of BASDAI and BASFI baseline values in the model cohort is very restricted and does not represent patients with BASDAI > 4.0 A revised methodology has now been adopted which corrects this issue. Baseline values for BASDAI and BASFI are generated **************************************************** **************************************************** **************************************************** **************************************************** ************************************************ It is not possible to respond The assumed response rate to treatment is considered to be ******************************************************************************** ******************************************************************************** ******************************************** It is likely that this omission will overstate the impact of etanercept in patients in the worst condition at baseline and may thereby bias economic results in favour of etanercept. It is not possible to respond Page 20 of 30

21 6.3.3 Disease Progression 84 In the company submission, disease progression rates are based on a Finnish study of only 65 patients followed for 3 years. This is preferred over the main published and authorative reference 30 on disease progression in AS based on data from 1100 UK patients over 8-10 years, and validated by 3 year data from a further 493 patients. They also quote and then dismiss another UK study carried out at Truro on 257 patients over 5 years. In both of these papers the estimated annual progression rates in BASFI are much lower than those in the Finnish paper. In addition the Truro study showed no significant progression in BASDAI scores over 5 years, whereas the authors have adopted the same strong progression rate for BASDAI as for BASFI, again on the limited evidence of the Finnish paper. We do not believe that these are credible assumptions The economic evaluation was based on patients with severe AS who would potentially be eligible for anti-tnf agents in the UK. As stated in the economic evaluation, the disease progression rate for this subgroup of patients is uncertain. The limited data that is published is based on all patients with AS not patients who are potentially eligible for ETN. As was discussed, if BASFI is used as an indication of disease severity then based on the patient characteristics of the etanercept RCT cohorts, patients eligible for anti-tnf agents would be at the extreme end of the Truro disease spectrum. Thus their disease progress could potentially be very different. The uncertainty surrounding the evidence chosen was discussed and a total of 11 sensitivity analyses, including allowing no progression at all for any patients in the model (s.a. 5.1), were performed to explore the impact of varying the values used. Patients included in Bath analyses 9 also included the full spectrum of BASDAI and BASFI values and therefore the annual progression rate of 0.07 (scale 0-10) for BASFI may not reflect the more severe patients likely to receive these drugs. Despite these reservations Wyeth have now chosen to use the 0.07 value BASFI and to exclude BASDAI from the progression rate in the amended model. The impact of varying the progression rates used for the responders to treatment has also been explored in some detail. Treatment Comparator Time Annual progression rate (scale 0-100) Horizon BASDAI BASFI BASDAI BASFI 25 years , , , , , ,236 Page 21 of 30

22 6.3.4 Regression models for BASDAI and BASFI Utility model Regression models of AS costs Choice of predictors 87 Model structure Life expectancy 87 Following the comments in the report a revised model has been developed. The data is split into the four subsets defined according to the BSR criteria: placebo non responders (PNR), placebo responders (PR), etanercept non responders (ENR) and etanercept responders (ER). Using transformed data, changes in BASDAI at week 12 and 24 are now calculated using baseline BASDAI and/or week 12 BASDAI measurements, while changes in BASFI at week 12 and 24 are now calculated using baseline BASFI and/or week 12 BASFI for each of the four subgroups. We cannot respond to key points in this section as it has been blacked out as CiC. Critically, under Choice of model it states, immediately after a section that is CiC If this is conceded then either the BASDAI/BASFI models are not appropriate in the long term, or the SF6-D utility model may be more realistic. As we do not know what the point is we can neither concede or refute it. The limitations of the SF-36 derived utilities is discussed in detail in the Wyeth submission (section 7.4.9) As with the utility model, the selected AS costs model uses both BASDAI and BASFI values to model long-term costs, despite the regression coefficient for BASDAI being clearly insignificant for inclusion. The issues that the Report has with the cost model adopted by Wyeth are covered in the overview and appendix The use of a single compendium cost model is questionable, particularly as use of a log-normal model necessarily involves producing biased cost estimates. It is often more reliable (and certainly easier to explain) if an attempt is made to sub-divide costs on the basis of cost-driving events (e.g. via a 2-part conditional model) rather than resorting to a logarithmic transformation just because of skewness. The issues that the Report has with the cost model adopted by Wyeth are covered in the overview and appendix. The estimation of life expectancy from life tables appears to have been wrongly calculated, failing to condition expectancy on the attained age of patients. This would tend to distort the balance of patients in the long-term projection period, and may contribute to erroneous results Life expectancy is calculated correctly using a nested lookup function. The formula used also includes an appended function which randomly assigns the death to one of four quarters in the year Page 22 of 30

23 7.1.3 Intermediate outcomes 106 It is disappointing that the Bath metrology index (BASMI) has not been more widely used, and correlated with the other indices and with direct observations of morbidity and cost, though this is presumably because of the additional time and cost involved in carrying out the clinical measurements required by the BASMI. Using the BASMI would facilitate an objective measure of physical deterioration. BASMI consists of 5 measures of spinal mobility Modified Schober s Cervical rotation Tagus to wall Lumbar flexion Intermalleolar distance In the etanercept studies three measures of spinal mobility were included Modified Schober s Chest expansion Occiput to wall These were significantly improved compared to placebo in the short term and the improvement was maintained in the longer term. (see section of Wyeth submission). Data are now available out to 3 years of open label treatment showing that the initial improvement in these measures is maintained over that time Continuous or intermittent therapy 106 The three submitted models all assume that patients will continue on anti-tnfα therapy indefinitely unless withdrawn due to loss of efficacy or adverse events. This is a very optimistic basis on which to evaluate cost-effectiveness Expert opinion is clearly of the view that as there are no other effective therapies available then these drugs will be used continuously, as when they are stopped relapse occurs quickly 32. Page 23 of 30

24 7.2.1 Inherent variability in the BASDAI Long-term continuation involves a second implicit objective; that of prophylaxis against subsequent symptomatic relapse. The use of the term prophylaxis shows a complete misunderstanding of the progressive nature of the disease. Patients may experience periods of worse disease but this is against a background of continuing disease activity. Indeed the understanding that NSAIDs are mainly used intermittently to treat such flares appears to be lacking. The Truro data 6 may be useful in this respect showing for example that around one third of patients continually have BASDAI scores above 4. There must therefore be serious concerns about whether the BSR criteria for anti-tnfα therapy are meaningful or practical as a means of distinguishing those patients most likely to benefit, either in deciding whether to commence treatment, or whether to discontinue treatment for non-response. The BSR Guideline 19 and the essentially similar ASAS recommendations 20, 21 were developed by UK and international experts in the field of AS and used recognised methodology for guideline development and yet these are dismissed by the Report Non-linearity in outcome gains 109 All Wyeth and Schering-Plough submitted models adopt an average measure of benefit in terms of reduction in BASDAI score, which is independent of the initial condition of the patient. This is a crude assumption and does not take account of the closed nature of the BASDAI scale which imposes non-linearity on the measured scores through floor and ceiling effects, resulting in important deviations from linearity in the vicinity of the extreme values (0 and 10). Using the beta distribution as an analogy for a double-bounded stochastic process, we reasoned that in the vicinity of a boundary, relationships between measurements separated in time should be approximately quadratic in form. We are unable to determine whether the Liverpool approach is valid Spontaneous resolution without anti-tnf therapy 111 We are unable to determine whether this approach is valid Pragmatic criteria for withdrawal from long-term therapy 113 We are unable to determine whether this approach is valid Profiling the heterogeneity in AS patients 114 We are unable to determine whether this approach is valid Page 24 of 30

25 Recently published data from Spain 29 based on over 1500 patients with SpA and over 4000 with RA showed that continuation of treatment with anti-tnf drugs was significantly in SpA over a followup time of 3 years. The hazard ratio for discontinuation compared with RA was 0.66 (95% CI ). Drug survival for AS is summarised below with 95% CI: Long term effectiveness 119 I year 2 years 3 years 0.88 ( ) 0.82 ( ) 0.74 ( ) Disease-related treatment costs Health-related utility estimation Data presented at EULAR 2006 from Norway also shows greater retention for AS than RA (Heiberg et al OP0091) with 82% of 211 patients with AS remaining on treatment at 1 year, very similar to the results from BIOBADASER The use of 15% as the annual withdrawal rate would appear to be an overestimate. Unfortunately this approach is fundamentally flawed as a basis for modelling disease-related costs over the full spectrum of patient experience. Issues relating to criticisms of the Wyeth cost model are dealt with in the overview and appendix. It is incorrect to state that the approach is fundamentally flawed as other authors support the approach used in the Wyeth submission 10. In addition, retrospective data collection over an extended period (12 months in this case) is also very likely to underestimate resource use, especially where it relies on patients long-term memory to recall multiple health professional contacts. Data was collected from hospital and departmental records so no patient recall was involved The OASIS data should be considered a more reliable source than either Stoke or Bath, being prospective and over a longer time period. Although prospective in nature, the data on resource use is collected in health care systems outside the UK. UK cost data should be used where possible. We have chosen to adopt the Schering-Plough utility model on the grounds that it draws on a much larger sample of UK AS patients, and because the formulation incorporates age and gender variables, allowing a wider exploration of alternative scenarios. As mentioned previously there is a full discussion in the Wyeth submission concerning the validity of adopting EQ-5D to derive health related quality of life. Page 25 of 30

26 Effect of discontinuing treatment and the disease process It is disappointing that no attempt is made to base model assumptions on a reasonable assessment of the behaviour of the disease, and responses to clinical events. A study of AS patients experiences is instructive here. Group discussions involving 214 patients (25 years average duration of disease) suggested that normal experience consists of periods of relative stability interrupted by unpredictable flares of disease activity lasting from a few days to a few weeks. The dominant symptom of all flares was reported to be severe pain. Two types of flare were identified - localised flares affecting one or more specific areas, and general flares involving the whole body. All patients experienced the former at frequencies of 1-5 per annum, whereas only 40% of patients reported experiencing general flares at less frequent intervals. In either case, resolution was reported to be sudden, with return to the pre-existing condition. If the symptoms persisted for months it was suggested that this indicated a progression in disease severity rather than a flare. The authors of the Assessment Report appear to have misinterpreted this data. Patients who participated in this study were attending the RNHRD in Bath for 2 weeks of intensive physiotherapy 5. Therefore they should be considered to have severe active disease. The patients describe their experiences of flares. It should be noted that the duration of the flares was days or weeks. Any flare lasting longer than a month was thought to be a general worsening of the disease. When the flare subsided the patient returned to baseline disease activity in 75% of cases. That is the flares are short term exacerbations on the background of ongoing active disease, which obviously requires effective treatment. Therefore the intermittent treatment of flares with anti-tnf drugs would be inappropriate given the chronic nature of active disease in these patients This raises some important issues affecting the way anti-tnfα drugs are used, and the way treatment is modelled. The notion of loss of efficacy may be wrongly assigned in some cases on the basis of an isolated transient event breaching an arbitrary threshold. The use of baseline measurements to establish the normal experience of AS patients may be flawed, since it is more likely that patients recruited into trials are suffering the effects of an abnormal flare event. This calls into question the nature and magnitude of the true treatment effect of anti-tnf-α treatment, which may be rather less than appears in trial results. It is then unclear to what extent rebound of patient scores should be included in AS models; it may be that the primary benefit of these drugs for some patients is to accelerate the recovery time from flare events rather than to alter the normal quiescent condition of the patient. Moreover, if this is the case then continuation of treatment for extended periods may not be appropriate unless it can be shown to reduce the frequency or severity of subsequent flare events. It should be noted that unlike studies with NSAIDs in AS, where treatment is stopped and only patients who flare are enrolled (so called flare design), in studies with the anti-tnfs current treatment was continued and flares were not required for randomisation. It is incorrect therefore to presume that it is more likely that patients recruited into trials are suffering the effects of an abnormal flare event Page 26 of 30

27 127 For the long-term increase in BASFI scores we have adopted the survey estimate used by Kobelt of per annum for the conventional treatment comparator and this is applied for all periods after week 20 in the model. In the baseline analysis we have used the same value in the intervention arm adjusted pro-rata to the proportion remaining of the maximal excess response seen at 12 weeks. In effect this implies that patients withdrawn from treatment are assumed to incur an increase in functional score which returns them to the trajectory of non-responders. An alternative option is also considered in which the size of this long-term increase can be scaled-down to provide an enduring benefit to responders. This rate has now been chosen as the basecase rate in the revised Wyeth model Most striking is the range of variation in utility gains obtained when the baseline BASDAI/BASFI scores are varied from the eligibility threshold for anti-tnfα treatment (BASDAI = 4.0) up to more severe disease activity levels (BASDAI = 8.0). (CiC) and suggests counterintuitively that treatment may be less cost-effective for patients with the most severe symptoms at initiation, presumably because in these circumstances there appears to be a greater probability of early natural improvement independent of anti-tnfα treatment Analysis of the Wyeth RCT data shows that the relationship between baseline BASDAI and response is weak. 7.4 Exploratory economic modelling: shortterm model Table Percentage reduction in week Baseline It would appear that the costs for the comparator arm of model have been miscalculated. In Table 7-4, page 128/187, the annual treatment costs for the conventional treatment arm is given as 213, whereas applying the Liverpool cost equation ( 1, x exp( x BASFI) gives a value of 4171 for a baseline BASDAI of This error, if not typographical, will have substantial impact on the incremental costs and hence the ICERs. Page 27 of 30

28 7.5.6 Sub-groups Summary 142 Unfortunately, the evidence submitted by the industrys does not provide any basis for distinguishing between patients; it seems that success for a particular patient treated with a particular agent is akin to a random lottery with the present state of knowledge. In Wyeth s opinion this emotive language is inappropriate in a review of this nature. In medicine it is rare that factors can be identified that determine the likelihood that an individual patient will respond to treatment. In the case of etanercept baseline factors associated with ASAS 20 responses have been analysed but the predictive value was low 33. The consideration of cost-effectiveness of anti-tnfα treatments for AS is overshadowed by the unfortunate absence of evidence concerning both the dynamics of the disease as experienced by patients at different stages in the progression of the condition, and the mode of action of the anti-tnfα agents. In particular, it is far from clear whether we should expect benefits in any or all of these aspects of AS: - providing immediate relief of symptoms, especially pain; - altering the normal level of disease activity; - accelerating recovery from flare episodes; - reducing the severity of flare episodes; - reducing the frequency of flare episodes; - preventing or delaying long-term disease progression. In addition there is no substantive RCT evidence of the performance of anti-tnfα agents when used sequentially (or even in combination). This means that the models submitted by the industrys are based on a large number of assumptions, and framed in structures which are unlikely to apply in practice, and which tend to present the new products in a favourable light. There is clear evidence to support the beneficial effects of etanercept and the other TNF-targeted therapies, in particular the results of two independent meta-analyses that reported effect sizes substantially higher than any other treatment for the disease. As stated elsewhere in this document the emphasis of flares as a target for treatment shows a misunderstanding of the nature of this disease. 8.1 Incidence, Prevalence and Patient numbers Incidence Prevalence 145 It should be acknowledged that because of the requirement for subjects to have an X-ray to confirm a diagnosis of AS, population based epidemiology studies are difficult to undertake The report criticises the validity of the data from Rochester and yet the results are almost identical to the study from Finland preferred by the authors: Rochester 7.3 ( ) per 100,000 person-years Finland 6.9 ( ) per 100,000 person-years It is understood that there are no recent studies on the prevalence of AS in the UK. The report does not make use of the extensive review in the standard textbook, Rheumatology 15. The authors do not fully explain why they prefer the data from Finland to the other potential sources of information. The Finnish estimate doses however fall around the mid-point of the range quoted in the BSR guidelines. An estimate from the GPRD gives a figure of 0.104% (Mines, unpublished). Page 28 of 30

29 References 1. Zochling, J. et al. ASAS/EULAR recommendations for the management of ankylosing spondylitis. Annals of the Rheumatic Diseases doi: /ard (2005). 2. Zochling, J. et al. ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 65, (2006). 3. Zochling, J., van der Heijde, D., Dougados, M. & Braun, J. Current evidence for the management of ankylosing spondylitis a systematic literature review for the asas/eular management recommendations in ankylosing spondylitis. Annals of the Rheumatic Diseases doi: , ard (2005). 4. Zochling, J., van der Heijde, D., Dougados, M. & Braun, J. Current evidence for the management of ankylosing spondylitis: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis. Ann Rheum Dis 65, (2006). 5. Brophy, S. & Calin, A. Definition of disease flare in ankylosing spondylitis: the patients' perspective. Journal of Rheumatology.29(5):954-8 (2002). 6. Mascerenhas, R. F., Davis, M. J. & Robertson, L. P. Eligibility for anti-tnf therapy in ankylosing spondylitis: what's the real situation? Rheumatology 43 (Supplement 2), ii126-abstract 319 (2005). 7. Levy, S., Smith, C. M. & Choy, E. H. A systematic review of treatment options in ankylosing spondylitis (AS). Rheumatology 44 (Supplement 1), i116-abstract 279 (2005). 8. Brazier, J., Roberts, J., Tsuchiya, A. & Busschbach, J. A. A comparison of the EQ-5D and SF-6D across seven patient groups. Health Economics 13, (2004). 9. Kobelt, G. et al. The burden of ankylosing spondylitis and the cost-effectiveness of treatment with infliximab (Remicade ). Rheumatology 43, (2004). 10. Barber, J. & Thompson, S. Multiple regression of cost data: use of generalised linear models. Journal of Health Services & Research Policy 9, (2004). 11. McDonough, C. M. et al. Comparison of EQ-5D, HUI, and SF-36-derived societal health state values among spine patient outcomes research trial (SPORT) participants. Quality of Life Research.14(5): (2005). 12. Boonen, A. et al. Markov model into the cost-utility over five years of etanercept and infliximab compared with usual care in patients with active ankylosing spondylitis. Annals of the Rheumatic Diseases 65, (2006). 13. Boonen, A. et al. Direct costs of ankylosing spondylitis and its determinants: An analysis among three European countries. Annals of the Rheumatic Diseases 62, (2003). 14. Barkham, N., Kong, K. O., Fraser, A., Tennant, A. & Emery, P. The impact of ankylsoing spondylitis on quality of life and ability to work. Rheumatology 43 (Supplement 2), ii123-abstract 307 (2004). 15. Gran, J. T. et al. in Rheumatology e-edition (Mosby, 2003). 16. van der Heijde, D. M. F. M. et al. Application of the OMERACT filter to scoring methods for magnetic resonance imaging of the sacroiliac joints and the spine. Recommendations for a research agenda at OMERACT 7. Journal of Rheumatology 32, (2005). 17. Anderson, J. J., Baron, G., Van Der, H. D., Felson, D. T. & Dougados, M. Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis. Arthritis & Rheumatism 44, (2001). 18. Stone, M. A., Inman, R. D., Wright, J. G. & Maetzel, A. Validation exercise of the Ankylosing Spondylitis Assessment Study (ASAS) group response criteria in ankylosing spondylitis patients treated with biologics. Arthritis & Rheumatism.51(3): (2004). 19. Keat, A. et al. BSR guidelines for prescribing TNF-alpha blockers in adults with ankylosing spondylitis. Report of a working party of the British Society for Rheumatology. Rheumatology.44(7): (2005). 20. Braun, J. et al. First update of the international ASAS consensus statement for the use of anti-tnf agents in patients with ankylosing spondylitis. Annals of the Rheumatic Diseases 65, (2006). 21. Braun, J. et al. International ASAS consensus statement for the use of anti-tumour necrosis factor agents in patients with ankylosing spondylitis.[see comment]. [Review] [48 refs]. Annals of the Rheumatic Diseases. 62, (2003). 22. Barkham, N. et al. The unmet need for anti-tumour necrosis factor (anti-tnf) therapy in ankylosing spondylitis. Rheumatology.44(10): (2005). 23. Barlow, J. H., Wright, C. C., Williams, B. & Keat, A. Work disability among people with ankylosing spondylitis. Arthritis & Rheumatism.45(5):424-9 (2001). 24. Davis, J. C., Jr. et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis & Rheumatism. 48, (2003). Page 29 of 30

30 25. Calin, A. et al. Outcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitis. Annals of the Rheumatic Diseases 63, (2004). 26. Pavy, S., Brophy, S. & Calin, A. Establishment of the minimum clinically important difference for the bath ankylosing spondylitis indices: a prospective study.[see comment]. Journal of Rheumatology.32(1):80-5 (2005). 27. British Thoracic Society Standards of Care Committee. BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-tnf-a treatment. Thorax 60, (2005). 28. Kristensen, L. E., Saxne, T. & Geborek, P. The LUNDEX, a new index of drug efficacy in clinical practice: results of a five-year observational study of treatment with infliximab and etanercept among rheumatoid arthritis patients in southern Sweden. Arthritis & Rheumatism 54, (2006). 29. Carmona, L., Gomez-Reino, J. J. & Group, a. o. b. o. t. B. Survival of TNF antagonists in spondyloarthritis is better than rheumatoid arthritis. Data from the Spanish Registry BIOBADASER. Arthritis Research & Therapy 8 (2006). 30. Kobelt, G. et al. The burden of ankylosing spondylitis and the cost-effectiveness of treatment with infliximab (Remicade). Rheumatology 43, (2004). 31. Sieper, J. et al. Long term efficacy and safety of etanercept in patients with ankylosing spondylitis: 148 to 160 week analysis from an ongoing trial. EULAR Annual Meeting FRI0508 (2006). 32. Brandt, J. et al. Six-month results of a double-blind, placebo-controlled trial of etanercept treatment in patients with active ankylosing spondylitis. Arthritis & Rheumatism. 48, (2003). 33. Davis Jr, J. C. et al. Baseline factors that influence ASAS 20 response in patients with ankylosing spondylitis treated with etanercept. Journal of Rheumatology.Vol.32(9)()(pp ), 2005., (2005). Page 30 of 30

31 The cost-effectiveness of etanercept in patients with severe ankylosing spondylitis in the UK Ara RM 1, Reynolds A 2, Conway P 2, Brennan A 1. THU University of Sheffield, UK; 2 Wyeth Pharmaceuticals, UK. Introduction Ankylosing spondylitis (AS) is a lifelong disease which causes irreversible skeletal damage. Typically presenting in young males, long term prognosis is poor with some patients experiencing severe loss of physical function, high levels of pain and large reductions in health related quality of life (HRQoL). The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI) are validated and established measures in AS patients and have been shown to have strong associations with both AS disease costs and utilities. Anti-TNF agents such as etanercept (ETN) are effective alternatives for patients whose current treatment is symptomatic relief in the form of NSAIDs and physiotherapy. The aim of this study is to explore the costs and benefits associated with ETN in patients with severe AS in the UK under BSR criteria. [1] BSR guidelines [1] Eligibility: diagnosed using Modified New York Criteria for AS and failure of 2 or more NSAIDs taken sequentially at maximum tolerated dosage, and BASDAI 4cms (scale 0-10, 10 = worse) and spinal VAS 4 units. Response: defined as a reduction of BASDAI to 50% of the pre-treatment value (or a fall of 2 units) and a reduction of the spinal VAS by 2 units. Methods A patient level simulation model (written in Excel 2005) estimates the costs and benefits associated with ETN plus NSAIDs compared with NSAIDs alone. Placebo data used to inform comparator arm as 88% of patients received NSAIDs in RCTs [2-3] Proportion who respond to ETN (placebo): wk 12 = 67% (24%); wk 24 = 55% (16%) [2-3] Efficacy of treatment measured by changes in BASDAI & BASFI at weeks 12 and 24) [2-3] Initial efficacy data supported by additional 72 weeks open label data [4] Direct AS healthcare costs (including NSAIDs costs) estimated using the relationship: Annual direct costs = exp(0.006*basdai * BASFI ) [see poster THU0523] ETN dose: 2 x 25mg/week; 3 month cost (ETN plus monitoring): 2,343 plus 71 start-up cost Quality adjusted life years (QALYs) estimated using the relationship: Utility (EQ-5D) = * BASFI * BASDAI [see poster THU0522][2] Costs and quality of life benefits discounted at 3.5% per annum in keeping with NICE recommendations Time horizon: 25 years, reflecting the chronic progressive nature of AS Incremental cost-effectiveness ratios (ICERs) presented for shorter horizons Univariate sensitivity analyses used to explored the impact of varying individual key parameters Discrete event simulation techniques were used to synthesise the evidence and overall uncertainty was examined using a Monte-Carlo approach. Model Assumptions Natural disease progression: BASDAI & BASFI measurements increase at 0.3 units per annum [5] For responders to ETN, BASDAI & BASFI measurements remain constant at 6 month values observed in RCTs On withdrawal from ETN, BASDAI & BASFI measurements revert to baseline instantaneously and subsequently follow natural disease progression 10% annual withdrawal from ETN due to lack of efficacy/adverse events [6] Mortality risk assumed equal in both arms: age and sex related lifetables adjusted by a relative risk of 1.5 [7] A small proportion of patients will receive ETN for the full 25 years Basecase Results Over a 25 year horizon, ETN with NSAIDs gave 2.4 more QALYs when compared to NSAID treatment alone at an additional cost of 31.4k. This equates to a central estimate of 13.2k per QALY. Table 1: Basecase results: mean discounted costs and QALYs per patient at different points in time Horizon 2 years 5 years 15 years 25 years Incremental QALYs Incremental Costs 10.3k 19.1k 29.8k 31.4k ICER 30.8k 22.8k 15.0k 13.2k Results (Costs & benefits) The mean annual treatment and disease costs for the ETN cohort decreased from 7.3k to 2.6k over the 25 years as patients withdraw from treatment. Over the same period, the mean annual undiscounted costs for the comparator arm increased from 1.2k to 2.4k reflecting the increase in cost intensive resources associated with disease progression such as hospital care. The mean utility in the ETN cohort decreased from 0.63 to 0.11, while the mean utility for the comparator arm decreased from 0.49 to 0.07 over the 25 years. Figure 1: The mean annual AS disease costs and utilities in the ETN and comparator cohorts over 25 years (undiscounted) Mean annual AS disease cost 8, ,000 6,000 5,000 4,000 3,000 2,000 1, Results (Univariate( sensitivity analyses) The tornado diagram shows that the three variables that have the largest impact on the 25 year results are: 1) the costs directly attributable to AS; 2) the values used to represent HRQoL; 3) disease progression. When using the lower confidence interval (95%) for disease costs ETN becomes cost saving; while allowing no disease progression in either arm increases the ICER by 86% to 24.6k per QALY. Figure 2: Tornado diagram showing the parameters which have the largest impact on the results Disease costs (CI) No disease progress Quality of life (CI) Ceiling BASDAI/BASFI Disease progress (CI) Discounting Initial response Annual withdrawal s t s t Time (years) East West North 0 5,000 10,000 15,000 20,000 25,000 Cost per QALY East West North ETN Cost Comp Cost ETN Utility Comp Utility Mean utility (scale 0-1) Conclusion With a baseline ICER of 13.2k per QALY, this study provides evidence of the potential cost effectiveness of long term (25 year horizon) use of ETN. When allowing no disease progression for any patients in the model, and assuming patients revert to baseline BASDAI and BASFI measurements instantaneously on withdrawal from treatment, the ICER increases to just 25k which is viewed as cost effective under NICE thresholds. Monte-Carlo Results Using a 25 year horizon all estimates fall between 10k and 20k per QALY thresholds while the corresponding cost effectiveness acceptability curve shows that ETN is 88% likely to be cost effective at 15k. The 25 year ellipse is substantially larger than the earlier ones demonstrating the increase in uncertainty in the extrapolated data. However, as the time horizon increases the ICER decreases reflecting the potential increase in benefits and costs offset by prolonged ETN treatment. Figure 3: Cost effectiveness plane over 2, 5, 15 and 25 years 50,000 40,000 30,000 20,000 10,000 0 Future research into: Disease progression: the most appropriate variable to use the magnitude of natural disease progression halt/delay disease progression for responders to anti-tnf agents BASDAI & BASFI: further explore relationship to disease costs (adj R 2 = 0.24) further explore relationship to utilities (adj R 2 = 0.54) Anti-TNF agents: are they efficacious in patients with BASDAI < 40 do they halt/delay disease progression if prescribed early in the disease do they impact on work days lost /early retirement identify patients for whom it is most efficient to prescribe anti-tnf agents Develop prognostic algorithms to identify patients at highest risk of debilitating AS References 30,000 per QALY 20,000 per QALY Incremental Benefits 10,000 per QALY 2 year 5 year 15 year 25 year 1. Keat A, Barkham N, Bhallla A, Gaffney K, Marzo-Ortega A. BSR guidelines for prescribing TNF-alpha blockers in adults with ankylosing spondylitis. Report of a working party of the British Society for f Rheumatology. Rheumatology 44(7):939-47, , Final Report: A randomized double-blind, blind, placebo controlled trial evaluating safety and efficacy of o etanercept 50 mg once weekly compared with 25 mg twice weekly in subjects with ankylosing spondylitis. Protocol number 0881A EU.CSR Davis JC, van der Heijde D, Braun D, Dougados M et al. Recombinant tumor necrosis factor receptor (etanercept( etanercept) ) for treating ankylosing spondylitis. Arthritis and Rheumatism, 2003; 48: Davis JC, van der Heijdw,, Braun J. Sustained durability and tolerability of etanercept in ankylosing spondylitis for 96 weeks. 2005; Annals of the Rheumatic Diseases. 64(11): Heikkila S, Viitanen JV, Kautiainen H, Kauppi M. Functional long-term changes in patients with spondyloarthropathy. Clin Rheumatology(2002) 21: Tahir H, Moore S, Ehrenstein MR. Comparison of Anti-TNF therapy in daily practice. Poster abstract, BSR Simmonds DPF. Mortality in ankylosing spondylitis. Rheum in Europe 1996, 24;

32 The direct healthcare resource costs associated with Ankylosing Spondylitis patients attending a UK secondary care rheumatology unit THU0523 Ara RM 1, Packham JC 2, Haywood KL 3 1 University of Sheffield, UK; 2 Staffordshire Rheumatology Centre, Stoke on Trent, UK; 3 Royal College of Nursing Institute, Oxford, UK. Introduction Anti-TNF inhibitors such as etanercept (ETN), are now licensed for treating patients with severe Ankylosing Spondylitis (AS) (defined as BASDAI > 40, scale where 100 is severe). These treatments have larger cost implications than previously available therapies and comprehensive economic evaluations of these novel treatments in individual disease areas are increasingly requested by policy decision makers to inform reimbursement decisions. The objective of the current study was to explore the direct healthcare resources utilised by AS patients attending a UK secondary care rheumatology unit to inform an economic evaluation of ETN in AS patients. A secondary objective was to establish if resources, and thus health care costs, vary by disease severity (as classified using the Bath AS Disease Activity Index (BASDAI) and the Bath AS Functional Index (BASFI) variables). Methods The medical records (obtained December 2003 to June 2004) on 147 sequential AS patients (diagnosed using the New York criteria) attending the Staffordshire Rheumatology Centre, were examined retrospectively to assess the direct healthcare resources used over the previous 12 months. Costs were assessed using a micro-costing approach starting with a detailed inventory and measurement of resources consumed by the patient. Unit cost multipliers were applied to the quantity of each type of resource consumed. The mean cost per patient is estimated using the total cost divided by the total number of patients included. Resources included: NHS physiotherapy, outpatient appointments; inpatient days, laboratory based tests (FBR, ESR, LFT, U&E), X-rays, scans, prescribed medications. (Note: No patients were receiving anti-tnf therapies during the study period) Demographic features The mean (range) age was 51 (21-78) years and the mean disease duration 18 (0.5-63) years. 87% of the sample were male. The mean (sd) were 42.5 (23) and 44.4 (29) for BASDAI and BASFI respectively. Over 56% of the cohort had a BASDAI 40. Table 1 shows the proportion of patients sub-grouped by disease severity as characterised by disease activity (BASDAI) or functional disability (BASFI). Table 1: Distribution of patients across the disease spectrum BASDAI group < >70 Proportion 33% 10% 16% 16% 13% 12% Corresponding mean BASFI BASFI group < >70 Proportion 35% 13% 4% 14% 10% 24% Breakdown of resources used The three most relevant cost domains were: 1) Physiotherapy (accounting for 33% of total costs) 30 patients incurred a total of 1,127 NHS physiotherapy appointments 2) Hospitalisation (accounting for 21% of total costs) Total number of inpatient days was patients incurred inpatient costs 1 patient had an inpatient episode of 68 days Mean length of stay was 14.6 days 3) Medication (accounting for 19% of total costs) Mean annual disease costs The mean total annual costs is estimated to be 1,837 (s.d. = 2,764; median = 772). The total annual costs range from 101 to 18,012 with an asymmetric distribution (just 11/147 patients have annual costs concentrated beyond 7,000). The mean annual cost per patient is correlated with both measures of disease activity (BASDAI) and functional disability (BASFI) as seen in Figure 1. Figure 1: The mean annual costs by levels of disease activity and functional disability Mean annual cost 4,000 3,500 3,000 2,500 2,000 1,500 1, The difference in mean costs associated with BASDAI and BASFI scores over 60 ( 3,507 v 1,296 and 3,628 v 942) is due to the increases in the number of physiotherapy sessions and hospitalisations required by patients with severe disease (Table 2). Table 2: Mean (proportion) annual costs by resource type and disease severity Physiotherapy Hospitalisation BASDAI mean annual cost BASFI mean annual cost BASDAI median annual cost BASFI median annual cost < Disease severity (disease activity (BASDAI) or functional disability (BASFI)) BASDAI < ; 22% 303; 23% BASDAI > 60 1,575;45% 785; 23% BASFI < ; 13% 243; 26% 4,000 3,500 3,000 2,500 2,000 1,500 1, BASFI > 60 1,547; 43% 779; 22% Median annual cost Using BASDAI & BASFI to predict AS disease costs Both the BASDAI and BASFI measurements were moderately correlated with the log transformed annual costs (Pearson correlation = 0.40 and 0.48 respectively; p < 0.001). The model # with the best predictive ability was : Annual direct costs = exp(0.006*basdai *BASFI ) # Adj R 2 =0.24 hence BASDAI and BASFI only partially account for the variability in costs. For hypothetical patients with BASDAI, BASFI scores of 10, 10 (100, 100) the annual AS disease costs are estimated to be 439 ( 3,233). A 10 unit increase in both BASDAI and BASFI measurements incurs an increment of approximately 130 for scores of 40 and below; and an increment of approximately 480 for scores of 70 and above. Comparison with published evidence on AS costs With the exception of patients at the severe end of the disease spectrum, the results are comparable with those generated by a cross sectional survey conducted on AS patients in Bath [1]. For individuals with BASDAI and BASFI scores of 20 (50, 80) the annual costs estimated using the Stoke data are 546 ( 1.1k, 2.0k). Using the direct costs only (hospital and medication costs), we estimate the Bath annual costs to be in the region of 600 ( 1.4k, 3.0k) #. Table 3: Comparing the estimated annual disease costs Stoke (linear regression) Bath (estimated using published data)[1] # Annual costs estimated from data provided in Figure 4 & Table 3 in study by Kobelt et al.[1] # Discussion / Future research Disease severity (BASDAI, BASFI score) 20 1,056 1,400 # 2,043 3,000 # The results of this costing study give an indication of the range of direct healthcare costs associated with patients who have AS and are eligible for anti-tnf treatments in the UK. Due to time constraints only readily accessible data such as clinical visits; inpatient care, technical procedures including radiographic examinations, prescribed medications, and physiotherapy appointments were included. The study would benefit from inclusion of additional information such as the number of GP visits. Further research into the most (cost)-effective provision of physiotherapy to patients with AS would be constructive. As AS is a progressive debilitating disease, it may be appropriate to include nonmedical resources such as aids and appliances or formal household care and paid productivity losses such as absence from paid work Corresponding mean BASDAI BASDAI and BASFI scores were correlated (R 2 =0.77). Medication Outpatient/tests 315; 24% 397; 31% 479; 14% 668; 19% 225; 24% 351; 37% 615; 17% 688; 19% References 1. Kobelt G. Andlin-Sobocki P, Brophy S. Jonsson L. Calin A, Braun J. The burden of ankylosing spondylitis and the cost effectiveness of treatment with infliximab (Remicade( Remicade). Rheumatology 2004;43:

33 THU0522 Mapping generic quality of life measurements to disease specific variables in patients with Ankylosing Spondylitis Ara RM 1, Brazier J 1. 1 University of Sheffield, UK Introduction The disease specific instruments the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) are frequently used to measure disease progression and response to treatment in patients with ankylosing spondylitis (AS)[1,2]. However, economic evaluations demand health related benefits to be measured in terms of quality adjusted life years. These require utility measurements which can be generated using generic instruments such as the EQ-5D or the SF-6D (derived from the SF-36)[3,4]. While it has been reported that the SF-6D can be more responsive to changes in health state, there is a floor effect suggesting it may be more applicable for measuring utility in mild to moderate diseases [4]. Patients with AS who are eligible for anti-tnf treatments are at the extreme end of the disease spectrum, with severely impaired health related quality of life (HRQoL). Hence the EQ-5D is potentially a more appropriate instrument to measure changes in their quality of life (QoL). As the choice of instrument used to measure utility can have a large impact on results of economic evaluations, it is important that the most appropriate instrument is used. Objective The primary objective of this study was to identify which QoL instrument (EQ-5D or SF- 6D) is the most appropriate to measure health state utility values in patients with AS. A secondary objective was to derive a relationship between BASDAI and BASFI variables and the preference based index. Methods Data on the disease specific (BASDAI and BASFI) and HRQoL (EQ-5D and SF-36) variables were collected during a multi-centre European etanercept (ETN) RCT (n=356) [5]. Differences in the utility scores resulting from the two measures were explored through graphical methods (box and scatter plots). Data was analysed using STATA (version 8) and SPSS (version 12) with significance set at P < Linear regressions were used to explore a possible relationship between BASDAI, BASFI and health state utility values. Data The majority of the 356 patients were male (73%), with a mean age of 40.5 years (range 18-66), and a mean disease duration of 9.3 years (range 0-40). The mean (sd; range) BASDAI and BASFI measurements were 30.9 (22.9; ) and 34.8 (25.6; ). QoL tariffs (mean (sd; range)) for SF-6D and EQ-5D were 0.70 (0.087; ) and 0.65 (0.268; ) with utility scores available on 89% and 100% of the sample respectively. All four variables were significantly correlated (Pearsons correlation coefficient significant at P < 0.001). Table 1: Correlations between the SF-6D, EQ-5D, BASDAI and BASFI Variable Correlation SF-6D- EQ-5D 0.699* SF-6D- BASDAI * SF-6D- BASFI * EQ-5D- BASDAI * EQ-5D- BASFI * BASDAI- BASFI 0.836* Direct comparison of the SF-6D and EQ-5D scores While the SF-6D and EQ-5D preference based indices are correlated (correlation coefficient: 0.699; p<0.001); the pattern is not linear. There is a large amount of variation in scores across both measures with the EQ-5D producing the largest range. The EQ-5D has placed individuals in health states that are worse than death (i.e. <0) whereas the lowest score on the SF-6D scale is For the 10 lowest EQ-5D scores of ; the corresponding mean SF-6D score is 0.58 with a range of 0.45 to There are 50 EQ-5D scores indicating full health (i.e. utility = 1) and the corresponding mean (sd) SF-6D score is 0.78 (0.06) with a range of 0.61 to The current results (Figure 1) emulate those presented by Brazier et al. [6]. Figure 1: Scatter plot of paired SF-6D and EQ-5D utility scores * the possible floor effect in the SF-6D was shown to be caused by the proportion scoring on the lowest possible levels for physical functioning and role limitation in comparison to the mobility and usual activities in the EQ-5D (24.6% 39.4% versus 0.2% and 10.5%) [6]. Comparing dimensional scores results are not linear a ceiling effect in the EQ-5D data where a wide range in SF-6D indices correspond to EQ-5D = 1 a possible floor effect in the SF-6D* where a wide range in EQ-5D indices correspond to low SF-6D indices (for SF-6D < 0.5; EQ-5D mean = 0.11 range to 0.29) the EQ-5D indices cluster with gaps in a number of places, including between EQ-5D = 1 and those < 1, and around EQ-5D = 0.45 (caused by the N3 term) [6]. There is evidence of correlation between similar dimensions: mobility with physical function; and pain/discomfort with body pain. The lowest correlations are observed between self care with both mental health and vitality. All patients reported 1 for the anxiety/depression question on the EQ-5D questionnaire. Table 2: Correlations between the 8 overall dimensional scores in the SF-36 (scale where 0 is worse) and the 5 scores from the EQ-5D (scale 1-3 where 3 is worse) SF36/ EQ5D PF SF BP MH VT RE RP GH M SC UA PD EQ-5D dimensions: M = mobility; SC = self care; UA = usual activities; PD = pain/discomfort. SF-36 overall dimensional scores: PF = physical functioning, SF = social functioning; BP = bodily pain; MH = mental health; VT = vitality; RE = role emotional; RP = role physical; GH = global health. Predicting health state utility values The correlations between the BASDAI and BASFI and EQ-5D utility measurements are reasonably strong at and respectively. Using the BASDAI and BASFI as the independent variables and the EQ-5D as the dependent variable in a linear regression; the disease specific measurements explained 52% of the variance in utility. The model predicts health state utility values over the range 0.09 to 0.92, corresponding to BASDAI and BASFI measurements of 100 and 0 respectively. Utility = *BASFI *BASDAI (p<0.001; MAE=0.13) Figure 2: Using BASDAI & BASFI to predicted health state utility values Utility (scale 0-1) Conclusion/Discussion BASDAI & BASFI (scale 0-100)... There are large differences in the EQ-5D and SF-6D health state utility values The differences in the health state utility values are comparable with other results [6] The EQ-5D health state utility values differ from those observed by Maetzel et al. [7] but are similar to those reported by Kobelt et al. [8] and Boonen et al.[10] The SF-6D suffers from a floor effect in severe AS and so underestimates the magnitude of improvement in quality of life for patients starting at the lower end of the scale The EQ-5D may be more sensitive to changes in patients with severe AS and thus may be the most appropriate instrument for measuring HRQoL in these patients References 1. Garrett S, Jenkinson T, Kennedy LG et al. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatology 1994;21(12): Calin A, Garrett S, Whirelock H et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol. 1994;21: EuroQol Group. EuroQol: a new facility for the measurement of health-related quality of life. Health Policy 1990; 16: Brazier J, Roberts J, Deveill M. The estimation of a preference-based measure of health from the SF-36. J Health Econ 2003; 21(2): Final Report: A randomized double-blind, placebo controlled trial evaluating safety and efficacy of etanercept 50 mg once weekly; compared with 25 mg twice weekly in subjects with ankylosing spondylitis. Protocol number 0881A3-314-EU.CSR Brazier J, Roberts J, Tsuchiya A, Busschbach J. A comparison of the EQ-5D and the SF-6D across seven patient groups. Health Economics : Maetzel A, Boonen A et al. US and UK EQ-4D Scoring algorithms result in different utility estimates: results from an etanercept open-label extension trial in ankylosing spondylitis. EULAR 2006 Poster THU Kobelt G, Andlin-Sobocki P, Brophy S. et al. The burden of ankylosing spondylitis and the cost-effectiveness of treatment with infliximab (Remicade ). Rheumatology 2004:43: Kobelt G, Andlin-Sobocki P, Maksymowych WP. Costs and Quality of Life of Patients with Ankylosing Spondylitis in Canada. J Rheumatol 2006;33: Boonen et al. The SF-6D differentiates less in the lower ranges of the patient s utility when compared eith the EQ-5D but has better reliability and sensitivity to change. Ann Rheum Dis 2005;64(Suppl III):390