3 The manufacturer's submission

3 The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of adalimumab and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 In its submission, the manufacturer compared adalimumab with etanercept, efalizumab, infliximab, methotrexate, ciclosporin and supportive care. Results are not presented below for comparisons with methotrexate or ciclosporin, to reflect the licensed use of adalimumab.

3.2 The major clinical outcome examined was improvement in PASI score – a measure of disease severity based on body surface area affected and the extent, scaliness, thickness and redness of plaques, with scores ranging from 0 to 72. The DLQI score was also used in the manufacturer's submission. This is a disease-specific quality-of-life measure with scores ranging from 0 to 30.

3.3 The main evidence on efficacy in the manufacturer's submission was derived from three randomised controlled trials (RCTs).

  • M02-528 (n = 147, 12-week duration), a phase II, multicentre, randomised, double-blind, placebo-controlled, dose-ranging trial based in the USA and Canada.

  • REVEAL (n = 1212, 52-week duration), a phase III, multicentre, randomised trial based in the USA and Canada, consisting of a 16-week double-blind, placebo-controlled period, a 17-week open-label period and a 19-week double-blind, placebo-controlled period.

  • CHAMPION (n = 271, 16-week duration), a phase III, multicentre, randomised, double-blind, placebo-controlled trial based in Europe and Canada, which also compared adalimumab with methotrexate.

3.4 The results of the three RCTs showed that a statistically significantly greater proportion of people treated with adalimumab at its licensed dose experienced a 75% or greater reduction in PASI score (PASI 75; a primary endpoint in the trials) compared with those who received placebo. The proportions of people with at least a PASI 75 response, relative to baseline, for adalimumab compared with placebo were: 53% versus 4% (M02-528, 12 weeks); 71% versus 7% (REVEAL, 16 weeks); and 80% versus 19% (CHAMPION, 16 weeks); respectively (p < 0.001 in all comparisons).

3.5 Longer-term data from the REVEAL trial showed that PASI response was maintained and continued to favour adalimumab over placebo. During the open-label period of the trial, 89% of people originally randomised to adalimumab, who achieved at least a PASI 75 response at week 16, had at least a PASI 75 response at week 33. In people originally randomly assigned to placebo, PASI 90 response rates increased from week 16 to weeks 24 and 33. During the re-randomisation period of the trial (week 33 to week 52), the proportion of people for whom an adequate response was lost (a primary outcome of the trial) was statistically significantly higher for people randomly reassigned to placebo (28%) compared with people re-randomised to adalimumab (5%) (between-group difference −23.5%; 95% confidence interval [CI] −16.9 to −30.2; p < 0.001). Loss of adequate response was defined as less than a PASI 50 response relative to week 0 and at least a six-point increase in the PASI score relative to week 33.

3.6 For secondary outcomes recorded in the trials, such as the physician's global assessment (PGA) score, the DLQI score and other health-related quality of life scores, adalimumab showed statistically significant improvements compared with placebo.

3.7 Adalimumab was generally safe and well tolerated. Data from the placebo-controlled study set (n = 1469) show that the incidence of adverse events that might be related to the study drug was statistically significantly higher in the adalimumab treatment group than in the placebo treatment group. The most commonly reported adverse effects in people treated with adalimumab were nasopharyngitis, upper respiratory tract infection and headache. The incidence of severe adverse events was low and comparable in the adalimumab and placebo treatment groups.

3.8 The manufacturer carried out an indirect comparison of adalimumab with etanercept, efalizumab, infliximab, ciclosporin and methotrexate using a mixed-treatment comparison approach within a Bayesian evidence synthesis framework. The approach compared each treatment through common links to placebo, either by means of direct comparison or through comparison with any other active agent compared with placebo. The manufacturer included data from the three adalimumab RCTs described in section 3.3, four RCTs comparing etanercept with placebo, four comparing infliximab with placebo, five comparing efalizumab with placebo, one comparing ciclosporin with placebo and one comparing methotrexate with ciclosporin. The results from the evidence synthesis showed that the mean probability of achieving a PASI 75 response was 67% for adalimumab (95% CI 57 to 74), 81% for infliximab (95% CI 75 to 87), 38% for etanercept 25 mg (the dose recommended by NICE; 95% CI 29 to 47), 52% for etanercept 50 mg (not recommended by NICE, 95% CI 43 to 60), 29% for efalizumab (95% CI 24 to 35) and 5% for supportive care (95% CI 4 to 6).

3.9 The manufacturer based its cost-effectiveness analysis on the York model used in 'Etanercept and efalizumab for the treatment of adults with psoriasis' (NICE technology appraisal guidance 103 [TA 103]). The model was adapted by the manufacturer of adalimumab to incorporate additional evidence, including the results of the mixed-treatment comparison described in section 3.8. The updated model also included new utility data derived from empirical estimates of the relationship between PASI response rates and changes in EQ‑5D from the CHAMPION study and study M02-528.

3.10 Within the model, each person underwent a preliminary period of treatment after which initial response was assessed (this was referred to as the trial period). Continuation of therapy into the next phase (referred to as the treatment period) only occurred if a PASI 75 response was achieved in the trial period. The relevant European marketing authorisations defined the time at which response was measured. These time points were 12 weeks (etanercept, efalizumab), 14 weeks (infliximab) and 16 weeks (adalimumab). The treatment period for each therapy (following a response) was taken from the York model, estimated using an annual drop-out rate of 20% for all patients. The cost and resource use data were taken from the York model, NHS Reference Costs and National Tariff and the BNF edition 53. The Personal Social Services Research Unit (PSSRU) inflation index was used to update costs to 2005−6 if current costs were not available.

3.11 In the manufacturer's base-case analysis, the incremental cost per quality-adjusted life year (QALY) gained for adalimumab compared with supportive care was £30,500. Etanercept given continuously was dominated by adalimumab (that is, adalimumab had greater effectiveness and lower costs than etanercept), and etanercept given intermittently (assumed to be 88% of the cost of continuous etanercept) and efalizumab were ruled out on the grounds of extended domination (that is, the incremental costs per QALY gained were higher than for adalimumab even though either the cost or effectiveness was more favourable).

3.12 The manufacturer's base-case analysis included only people whose psoriasis had a substantial effect on their quality of life, as indicated by a baseline DLQI score greater than 10. The manufacturer conducted a sensitivity analysis for people with milder forms of psoriasis (baseline DLQI less than or equal to 10) and this increased the incremental cost per QALY gained for adalimumab compared with supportive care from £30,500 (baseline DLQI greater than 10) to £80,100 (baseline DLQI less than or equal to 10).

3.13 The manufacturer carried out further sensitivity analyses to test key assumptions in the model. Changing the number of hospital inpatient days assumed to be avoided by using a biological therapy instead of supportive care had a large impact on the results. Changing the assumption used in the base-case analysis (21 hospital inpatient days avoided per year) to 0 days and 39 days was associated with incremental costs per QALY gained of £60,600 and £4800, respectively, compared with supportive care.

3.14 Changing the assumption regarding the cost of intermittent etanercept from 88% of the cost of continuous etanercept to 74% (the figure used in the York model) reduced the incremental cost per QALY gained for intermittent etanercept compared with supportive care from £37,300 to £27,600.

3.15 The manufacturer also carried out a probabilistic sensitivity analysis. This estimated that adalimumab had a 46% probability of being cost effective at a threshold of £30,000 per QALY gained.

3.16 The ERG considered there to be a number of limitations with the evidence in the manufacturer's submission. It noted that very limited descriptions of the comparator trials and the methodological assumptions used in the mixed-treatment comparison were provided by the manufacturer. It was also uncertain about the appropriateness of the mixed-treatment comparison because the manufacturer did not discuss the issue of possible heterogeneity across the trials. The ERG did, however, state that the results for most of the included treatments were broadly similar to those published by the York Assessment Group in their analysis of etanercept and efalizumab (TA 103).

3.17 The ERG also commented that it is uncertain to what extent the trial populations included in the adalimumab and comparator trials match the population specified in the decision problem, in terms of prior treatment with systemic therapy.

3.18 The ERG identified a number of limitations with the manufacturer's model. Because of the limited information provided, the ERG was unclear about the appropriateness of the approach used by the manufacturer to relate changes in PASI scores to EQ-5D data.

3.19 The ERG pointed out the lack of information available on the number of hospital inpatient days that are avoided by use of biological therapy instead of supportive care and that changes to the assumption used in the manufacturer's model (21 days per year) had a large impact on the results for all the biological drugs. The ERG also commented that the baseline DLQI was important in determining the cost-effectiveness results (see section 3.12).

3.20 The ERG was concerned that the manufacturer's base-case assumptions for intermittent etanercept did not seem appropriate and that the dose of intermittent therapy used in the model (88% of continuous therapy) to calculate costs was inconsistent with the dose used to calculate utility gains (68%).

3.21 The ERG ran the manufacturer's model, changing the assumption for the cost of intermittent etanercept to the value used in the York model (74% of the continuous etanercept cost); this resulted in £27,300 per QALY gained for intermittent etanercept compared with supportive care and £36,700 per QALY gained for adalimumab compared with intermittent etanercept. Changing the assumption for the cost of intermittent etanercept did not alter the cost effectiveness results for adalimumab compared with continuous etanercept; adalimumab continued to have greater effectiveness and lower costs than etanercept.

3.22 The ERG performed a probabilistic sensitivity analysis, re-running the manufacturer's model using different assumptions for treatment with intermittent etanercept (74% of the continuous etanercept dose used to calculate costs rather than 88%) and infliximab (three infusions in the trial period rather than four). The ERG found that adalimumab had a 16% probability of being cost effective at a threshold of £30,000 per QALY, compared with 46% estimated by the manufacturer (see section 3.15).

3.23 Full details of all the evidence are in the manufacturer's submission and the ERG report.

  • National Institute for Health and Care Excellence (NICE)