General Comments The TAR economic model is a complex model that attempts to reflect the multiple treatment options and pathways an RA patient can follow. This model demonstrates that it would be cost effective to administer etanercept to a patient with high HAQ on presentation to a clinician, whether they had received prior DMARD therapy or not. The data as it is presented does not reflect the marketing authorisation of etanercept as it uses a patient population distribution that includes patients with milder disease. The clinical and cost effectiveness case put forward by Wyeth is that patients with a high HAQ, erosions identified by x-ray and are rheumatoid factor positive should receive etanercept therapy. Wyeth have undertaken further subgroup analysis to demonstrate this. The Birmingham TAR Group s model has a major weakness in the choice of baseline input data, which is based on NOAR. In this inception cohort, nearly 50% of patients did not receive treatment with either DMARDs or steroids over a 5-year period. Forty five percent of patients had baseline HAQ scores <1 and 65% <1.5. Patients with HAQ scores <1 would not be considered to have severe disease and therefore would not be candidates for therapy with etanercept. The scope for improvement and therefore the QALYs gained in these patients would be limited. It is not surprising therefore that the ICERs are much higher than those obtained in the 3 company models. Graph 1. below, demonstrates the differences in this distribution. Graph 1. Starting Distribution of HAQ from NOAR Compared to TEMPO Patients Distribution of Starting HAQ 12% 11% 10% 9% MTX ETAN MTX + ETAN Frequency (%) 8% 7% 6% 5% 4% 3% 2% 1% 0% Starting HAQ Page 1 of 10
The background data for this distribution is contained in the following file attachment (CiC) The approved indication for etanercept in patients who have not been treated with methotrexate specifically states severe, active and progressive rheumatoid arthritis. The BRAM therefore has not modelled within the etanercept licence. Appendix 1 outlines the cost-effectiveness, in terms of /QALY for etanercept used either as first, second or third line. The various incremental costeffectiveness ratios (ICERs) are represented for each quartile of patients from the TEMPO study. Starting HAQ, initial HAQ change and medium term HAQ change have been incorporated for each quartile. Please be advised that the following data are soon to be published and are therefore no longer considered commercial in confidence: - Data from the 2-year analysis of the TEMPO study (protocol 881A-308) have been accepted for publication - The 6-month results from the Codreanu study (protocol 881A-309) have been posted on htpp://www.clinicaltrials.gov and have been submitted for publication. Page 2 of 10
Section No. Exec Exec Exec Exec Exec 2.0 Background Section Title Current recommendations and service provision Current recommendations and service provision Direction of evidence and treatment effect Page Reference 17 18 1 st para 19 2 nd bullet Existing economic evaluations 20 Cost effectiveness 20 2.1.9 Current drug therapy 23 3 rd para 28 last para 2.3.2 Etanercept 34-35 Comments The first bullet point should be...used in patients with clinically active disease that has not responded adequately to at least 2 DMARDs including MTX (unless contraindicated). It is stated that there is variable implementation of guidance. This needs to be expanded to give reasons (more details are provided in the body of the report) In the bullet referring to adalimumab, reference is made to radiographic joint damage, which is a key endpoint. No reference is made to this in the bullet referring to etanercept, yet data from 2 studies (TEMPO and ERA) clearly demonstrate a significant effect when compared with MTX. Responders and non-responders can be identified using clinical assessments such as DAS28, as recommended by the BSR. Reference is made to the use of both early and late RA data giving different results. This is an expected result. Early RA data should not be used to model 3 rd line as patients are very unlikely to be early (however defined the studies tended to require <3y, but average was <12m). This should be noted by the TAR group. Guidance stated that etanercept and infliximab should be...used in patients with clinically active disease that has not responded adequately to at least 2 DMARDs including MTX (unless contraindicated). Data from the BSRBR shows that in practice, patients have on average failed 4 DMARDs before receiving these drugs The use of the word commonly for some of the drugs e.g. azathioprine is not appropriate. In the paper by Edwards et al (Rheumatol, 2005) based on the GPRD database, azathioprine was not mentioned, and in 2002 less than 3% of prescriptions were for gold or penicillamine No specific mention is made of use in early disease, only to patients not treated with MTX, whereas, the section on adalimumab refers to early disease. As per the emc, adalimumab is indicated for the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate which is the same as etanercept. Therefore the wording for the 2 drugs should be the same. Page 3 of 10
2.3.4 Special precautions 36 Data for adalimumab are limited but an increased risk has also been shown. Reference should be made to the oral presentation from Abbott at EULAR 05 (Perez et al OP0093. Impact of screening for latent TB prior to initiating anti-tnf therapy in North America and Europe). 2.3.4 Special precautions 36 2.4 Current Guidance 2.4 Current Guidance 2.4 Current Guidance 3.1.1 Search Strategy Clinical Effectiveness 37 1 st bullet 39 1st para 39 1 st bullet 42 last para 3.1.5.2 Approach for meta-analysis 46 3.1.5.2 Approach for meta-analysis 48 "Perez Adalimumab and TB in clinicl trials It should be noted that formal screening for TB was included in most of the adalimumab studies. Screening for TB has not been a requirement of any study with etanercept. Official summary of product characteristics (SPC) and guidance, including proposed guidance from the BSR, British Thoracic Society and the British Society for Gastroenterology recommends screening patients before treatment. The SmPC for etanercept does not recommend screening. The primary objective, for which the registry is powered, is to detect a 2-fold increase in lymphoma..although the veracity of the recorded data is unclear seems overly critical of such a major initiative to assess these drugs in clinical practice. To institute audit etc would significantly impact on the study and increase costs. The report references the issues already experienced with collecting data for the registries. In the BSRBR 41% of patients classified as nonresponders It should be made clear the number of patients who were non-responders, and the % this was of the total, so that the 41% can be put into context. In fact the number is small. Therefore 41% could be misleading. as the previous reported had should read as the previous report had The methodology uses variable periods of follow-up so 3-month results or 2 year results are compared. The authors do accept this as a possible weakness (end of report). They have also looked at results available at fixed periods, 1, 3, 6, and 12 months, but only for ACR20. It could be argued that 40 mg ow of adalimumab and 25 mg ow of etanercept should have been included as they are both approved doses. 2 nd para gives PREMIER as an example study but TEMPO was the 1 st study with this design Page 4 of 10
The order in the tables is not the same as the text. Weinblatt 99 is not described in the text 3.2.3 Etanercept General It would be more helpful if the studies were grouped in the way the meta-analysis was done. Versus conventional DMARD (parallel start) Versus placebo (with or without continued DMARD) Combination parallel start 3.2.3.1 3.2.3.1 Description of included etanercept trials -ERA study Description of included etanercept trials -TEMPO 82 compared with placebo. Should be MTX 83 last para The methodology used was the Van der Heidje modification of TSS However around 42% of patients in each arm of this trial had previously tried methotrexate. It is not at all clear why these individuals discontinued methotrexate in the face of active disease if, as stated in the entry criteria, the drug was not ineffective nor toxic. 3.2.3.1 Description of included etanercept trials -TEMPO 84 1 st para Patients who had previously received MTX in this study took the drug a mean of 2 years previously. The doses were generally low by current standards and MTX was usually discontinued due minor adverse events or lack of efficacy at that low dose. Such patients were considered eligible provided investigator considered the adverse event did not represent significant toxicity or the assessment of lack of efficacy was at a dose that would now be considered a target dose for treatment. Other reasons for discontinuation included personal reasons such as wishing to become pregnant, not wanting regular blood tests and travel. 3.2.3.2 3.2.3.2 Meta-analysis of etanercept trials -Etanercept v conventional DMARD Meta-analysis of etanercept trials -Etanercept v placebo 86 1 st para 98 Table 10 The inclusion of the Codreanu study (protocol 881A- 309) in this section is questionable. In Codreanu patients were all receiving SSZ at baseline but had active disease. Patients were randomised to one of 3 groups. Two groups were treated with etanercept, in one of which SSZ was discontinued and in the other it was continued. The third group received placebo to etanercept and SSZ was continued. This study was therefore of a step-up design. In contrast ERA and TEMPO were parallel start studies of etanercept and MTX Codreanu is correctly included in this section Page 5 of 10
but the clinical relevance is not clear. 3.1.3 TNF inhibitors v DMARDs Direction of effect 138 If this significant, and the case of etanercept + MTX (TEMPO) substantial, effect on radiographic progression is not clear, then it would be also be reasonable to conclude that the clinical relevance of such differences in studies of any DMARD v placebo or a second DMARD are also unclear. It is accepted dogma that slowing of radiographic progression has important long-term benefits on prevention of disability. All three TNF inhibitors, when combined with MTX, showed a trend for increased serious adverse events but again this was not statistically significant. 3.3.3 4.1.5 Combination of TNF inhibitor + MTX versus MTX Health economics- Abbott 142 1 st para 160 para 2 163 1 st para The 1-year TEMPO data shows 10 serous infections in each treatment arm and in year 1 plus year 2 the numbers were ETN; 14 (6%), MTX; 15 (7%) and ETN + MTX; 13 (6%). For serious adverse events excluding infections, the corresponding figures were 35 (16%), 35 (15%), and 40 (17%) respectively. It is incorrect therefore to state that with etanercept there was a trend for increased serious adverse events when combined with MTX. This refers to infliximab not adalimumab The Wyeth carefully presented the general argument that treatment of patients with severe active disease should be with the most effective available options. Evidence from studies with DMARDs have clearly established that use of combination therapy early in the course of RA has long term benefits on both progression of structural damage and disability, even when the combination treatment has been discontinued some time before the end of follow-up. Two such examples are the COBRA and FinRACo studies. It is perfectly reasonable and appropriate therefore to propose that the combination of etanercept and MTX be the option modelled for patients with severe, active and progressive disease. In addition Wyeth do not accept that this weights the results in favour of etanercept as the 1 st drug in the comparator sequence is MTX, and therefore the model compares the incremental benefit of the combination over that of MTX, at least in the situation where etanercept is considered 1 st line. Page 6 of 10
164 1st para However for the purpose of switching thresholds a relationship between HAQ and DAS28 was required and changes in HAQ score were used as a proxy for changes in the DAS28. Perhaps here it would have been more appropriate to use actual switching rates from clinical observation rather than this conversion which potentially introduces more uncertainty into the model. 164 1st para Wyeth are not aware of any source currently available, and therefore took a reasonable assumption based on consultation with our clinical experts. Using a fixed HAQ at start of treatment has limitations and the heterogeneity of response is not taken into account Wyeth does not believe that this would have a large influence on the outcome of the cost effectiveness analysis. If this is deemed to have a very large effect our model can be modified to take this into account. The HAQ change for unspecified DMARD was based on the TICORA trial. This is inappropriate since data for individual drugs is available. 164 2 nd para Specific data were used for drugs specified in the model. The specified drugs were those commonly used in the UK. After these particular DMARDs have been used there is no common pattern of use. Hence it was decided to use non-specific data at this late stage in the model. The standard treatment arm of TICORA represents an average response as patients were treated with a range of treatments at the discretion of the rheumatologist. Page 7 of 10
However, the definition of remission is problematic, and the change in HAQ may have been sufficient to represent remission without assuming further treatment benefits in modelling. It is not explained why the definition of remission is problematic. The clinical remission state has been defined using the criteria developed for DAS that have been widely accepted. 164 2 nd para Additional analyses of the data from the TEMPO study have provided further evidence that the combination of etanercept and MTX has important effects on the relationships between disease activity, disability and joint damage. These analyses support the additional benefits that the remission state has on long term outcome. "ACR308Longitudinal Analysis Final.DOC" "ACR Disconnect Draft 3.doc" 165 1 st para This assumption would be unnecessary if actual data on switching were used and the probability of switching may actually be much higher than a third Wyeth would welcome the use of the BSRBR to provide further information on switching. 165 Table 26 Data on IFN and ADL are included in the Table and yet there is no previous reference in the text to Wyeth including these drugs in the model. Inflating the already increased mortality on the basis of HAQ appears to introduce double-counting and is therefore inappropriate 166 2 nd para There is a clear relationship between HAQ and mortality, which is why mortality was adjusted to take this into account. In any event mortality effects are limited. In the BRAM model, risk of death is related to current HAQ score, age and sex. Page 8 of 10
166 2 nd para This was further adjusted to consider SAEs with a loss of 0.05 for each SAE experienced, but this assumption for a six-month period for someone experiencing a SAE appears to be an underestimate. Wyeth would like further clarification of why the TAR group viewed this as an underestimate. Clinical expert opinion sort by Wyeth deemed this a reasonable assumption. Reflecting observed data, while on any treatment, a patient s condition is assumed to decline slowly over time; this is modelled as periodic increases of 0.125 in HAQ score. 4.2 Economic analysis in this report 173 Last sentence This reflects data available for traditional DMARDs and is the same as used in the Wyeth model. However data that now extends to 8 years clearly demonstrate that for etanercept there is no increase in HAQ over time. Data from TEMPO over a 3 year period show that this is also the case for the ETN+MTX combination. The BRAM does not therefore reflect the observed data for etanercept. The distribution of HAQ scores comes from the NOAR cohort. This is a population based inception cohort of polyarticular inflammatory arthritis. The data used is derived from the population described by Wiles et al. 4.2.2 Data used in the BRAM 185 Table 36 "Wiles Disability over 5y using propensity m The patients were from a group of 761 patients from which included patients with IP, RA or PsA (ie not just RA). All patients however did attend hospital within 12 months of registration. It is important to note that only 48% of the patients were treated with DMARDs or steroids over the 5 year follow-up. Therefore over half the patients were considered to have disease that did not require aggressive treatment. It should be noted that patients with higher HAQ scores were more likely to be treated with DMARDs (Table 4) The HAQ distribution shows that 45.2% of patients had scores <1 and 65.2% <1.5. It is unlikely that patients with scores <1 would be considered for biologics. The model would be greatly improved if only data on patients who received DMARDs or steroids was used. In addition decisions on selection of a biologic should only be made if a HAQ threshold, say >1.5, was reached. This would more closely reflect clinical decision making. Patients on the BSR Biologics Register who were treated with etanercept had a baseline mean HAQ score of 2.1 (SD 0.5). Page 9 of 10
4.2.2 Data used in the BRAM 4.2.2 Data used in the BRAM -HAQ changes on treatment 7.1 Principal Findings 7.1 Principal Findings 185 Table 36 (continued) 195 219 Last bullet 220 TEMPO bullet Given the HAQ distribution it is not surprising that the ICERs are higher than those obtained in the Wyeth model as patients with mild disease with limited room for utility gain would be treated with expensive drugs. This would be particularly true 1 st line. It can be concluded that BRAM did not model the licensed indication for RA patients prior to MTX use, that is patients with severe, active and progressive disease. In addition it should be noted that a standard HAQ progression rate of 0.033 pa has been used but in the NOAR data set, the untreated group did not change over 5 years, and those treated within 6 months had a decline in median HAQ from 1.25 to 0.875. Data on etanercept that now extends to 8 years show that in the long term there is no increase in HAQ, unlike treatment with traditional DMARDs Etanercept alone (at licensed dose) was as effective or slightly more effective than MTX in controlling RA symptoms and retarding joint damage in patients who were naïve to or who had no treatment failure with MTX in the ERA 119 and TEMPO 123 trials. The joint damage data for Etanercept is more than slightly more effective, the 2 year change for Etanercept being 1.3 compared with 3.2 for MTX (p = 0.001) It is commented that it is not clear that the results are generalisable to the UK. This was a multinational, multicentre study involving 19 countries and 92 centres. Three UK centres enrolled 19 patients. This is typical of large studies in RA. 7.1 TNF inhibitors versus placebo 221 Top of page Whilst evidence from Codreanu and ADORE show no benefit of adding etanercept to current DMARDs in patients with active disease, evidence from both the BSRBR and Swedish registries have shown improved outcomes in such circumstances compared with patients receiving Etanercept alone. "van Vollenhoven E+MTX v E alone from "Benefit of Etanercept and Metho Page 10 of 10