4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of adalimumab for the treatment of psoriasis in adults, having considered evidence on the nature of the condition and the value placed on the benefits of adalimumab by people with psoriasis, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.

4.2 The Committee considered that the RCTs identified in the manufacturer's submission showed the clinical effectiveness of adalimumab compared with placebo in people with moderate to severe plaque psoriasis. The Committee, however, also noted that the inclusion criteria for the studies did not fully reflect the population for which this technology is licensed because the psoriasis of the participants in the trials had not necessarily failed to respond to systemic therapies. However, the Committee was reassured by the views of the clinical experts that adalimumab is as effective for people who have not responded to other available treatments as for those who are otherwise treatment naive.

4.3 The Committee noted that there are no head-to-head studies comparing adalimumab with the current standard treatment for people who have not responded to systemic therapies, in particular other biological treatments that are used in UK clinical practice as recommended in TA 103. The Committee heard from the clinical experts that, from clinical experience, when anti-TNF is considered an appropriate treatment for a person with severe psoriasis, adalimumab could provide greater clinical benefit than etanercept. The Committee also noted the results of the mixed-treatment comparison conducted by the manufacturer, which suggested a higher probability of response after treatment with adalimumab than with etanercept. It was aware, however, that the ERG had expressed concerns about this analysis and that the robustness of the results was uncertain. For example, very limited descriptions of the comparator trials and the methodological assumptions used in the mixed-treatment comparison were provided by the manufacturer, and the issue of possible heterogeneity across the trials was not discussed. Therefore the Committee was persuaded that, although there is some evidence to suggest that adalimumab may be more effective than etanercept in some circumstances, clinical superiority of adalimumab over etanercept has not been firmly established in the treatment of severe psoriasis.

4.4 The Committee heard from the clinical experts and patient representatives that adalimumab is generally easier to use than etanercept because of the self-injection dosing regimen every other week.

4.5 The Committee discussed the results of the economic analysis conducted by the manufacturer. It considered that the overall approach adopted by the manufacturer was appropriate but that there was uncertainty in the estimates of cost effectiveness. A crucial assumption in the model is that 21 hospital inpatient days are avoided by using a biological therapy compared with using supportive care without biological therapy. The Committee noted the lack of data available to inform this assumption. It heard from the clinical experts that 21 days of inpatient treatment is an appropriate estimate for people in this group with severe psoriasis who do not receive biological treatment, and that this view is supported by recently published, multicentre audit data. The Committee was also aware that this assumption had been accepted in TA 103 and, in the absence of any strong evidence to the contrary, agreed that this represented the most appropriate estimate.

4.6 The Committee noted that in the manufacturer's base-case analysis using indirect comparisons, etanercept given continuously was dominated by adalimumab (that is, adalimumab had greater effectiveness and lower costs) and etanercept given intermittently (assumed to be 88% of the cost of continuous etanercept) was ruled out on the grounds of extended domination (that is, the incremental cost per QALY gained was higher even though either the cost or effectiveness was more favourable).

4.7 The Committee noted that the manufacturer's base-case analysis included an estimate of utility for the use of intermittent etanercept that assumed a disutility related to the associated 'gaps' in therapy. The Committee was concerned, however, that the dose of intermittent therapy used to calculate costs (88% of the continuous etanercept dose) was estimated from US data and was inconsistent with the dose assumed in TA103 (74%).The Committee noted that assumptions regarding the yearly dose for etanercept based on an intermittent dosing schedule had a large impact on the results, and it agreed that the assumptions used should be consistent with those applied in TA103. It also noted the manufacturer's sensitivity analysis, where the assumption regarding the cost of intermittent etanercept was changed to 74% of the cost of continuous etanercept (as in TA103); the resulting incremental cost per QALY gained for intermittent etanercept compared with supportive care (£27,600) was consistent with the value calculated by the ERG (£27,300) in its re-analysis of the manufacturer's model. In addition, the Committee noted that the ERG had also estimated the incremental cost per QALY gained for adalimumab compared with intermittent etanercept, which was £36,700.

4.8 The Committee considered whether the appropriate comparator for adalimumab should be etanercept given continuously or given intermittently, in line with TA103 and as indicated in the marketing authorisation for etanercept. It heard from the clinical experts that people with severe disease are either not treated with intermittent therapy or have a very small gap (often no more than 1 week) between courses of treatment if the disease flares up very quickly. The Committee was therefore persuaded that, for some people with severe psoriasis, the periods of time between courses of intermittent treatment with etanercept could often be very short. The Committee therefore agreed that, for people with severe psoriasis, the incremental cost per QALY gained for adalimumab compared with etanercept that reflected clinical practice should take into account the results calculated by the ERG for both intermittent etanercept and continuous etanercept (that is, £36,700 per QALY gained and dominating [greater effectiveness and lower costs for adalimumab], respectively). Although the precise value was not known and would depend on the assumptions regarding the length of time between courses of etanercept, the Committee accepted that it would be likely to be within a range consistent with that which it had previously considered to be a cost-effective use of NHS resources.

4.9 The Committee was aware that the manufacturer's base-case analysis (and the ERG's re-analysis of this described in section 4.6) only included people whose psoriasis had a substantial effect on their quality of life, as indicated by a baseline DLQI score greater than 10. The Committee noted that the manufacturer had conducted a sensitivity analysis on the base case for people with milder forms of psoriasis (baseline DLQI less than or equal to 10) and that 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). The Committee therefore agreed that the use of adalimumab for people who have moderate disease with a DLQI less than or equal to 10 would not be a cost-effective use of NHS resources.

4.10 The Committee considered how the population with severe psoriasis could be defined. It heard from the clinical experts that a combination of DLQI and PASI is routinely used in clinical practice and agreed that it would be appropriate to define severe disease as a PASI of 10 or more and a DLQI of more than 10 in line with TA 103.

4.11 The Committee concluded that adalimumab should be recommended as a treatment option only for people with severe plaque psoriasis when standard systemic therapies have failed. Owing to the limitations of the clinical effectiveness data and the uncertainty around the cost-effectiveness results, the Committee further concluded that it could not recommend adalimumab in preference to etanercept and that clinicians would need to exercise their clinical judgement in choosing between the two treatments.

4.12 The Committee considered the appropriate duration of treatment. It noted that the principal endpoint in the phase III adalimumab trials was a PASI 75 response at 16 weeks and that this was the time‑point at which response to treatment was assessed in the cost‑effectiveness analysis. Therefore, the Committee concluded that it would be appropriate for treatment to be continued beyond 16 weeks only in people whose psoriasis had shown a PASI 75 response to treatment within 16 weeks. In addition, the Committee agreed that the response criteria should be defined in a similar way to TA 103 and should include an additional alternative criterion of a PASI 50 response and a five-point reduction in the DLQI from start of treatment.

4.13 The Committee was aware that there may be some circumstances when the DLQI is not a clinically appropriate tool to inform a clinician's conclusion on the severity of plaque psoriasis, for example, because of a person's disabilities (such as physical impairments) or linguistic or other communication difficulties. The Committee concluded that in such cases healthcare professionals should ensure that their use of the DLQI continues to be a sufficiently accurate measure. The same approach should apply in the context of a decision about whether to continue the use of adalimumab.