4 Consideration of the evidence
4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of infliximab for the treatment of adults with psoriasis, having considered evidence on the nature of the condition and the value placed on the benefits of infliximab 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 discussed the nature of moderate to severe psoriasis and how it affects patients, including the variability in the extent and nature of skin manifestations over time. In particular, the Committee understood that the effect of psoriasis on patients' quality of life is related both to the degree of skin involvement and to the body sites affected. It understood that the PASI is primarily a measure of severity estimated on clinical examination and that the DLQI is a patient-estimated measure of quality of life.
4.3 The Committee considered the cost-effectiveness estimates for the all-patient group (PASI of 10 or more and DLQI of more than 10). The Committee was persuaded that under all scenarios presented the ICERs compared with best supportive care, etanercept and efalizumab were greater than £35,000. Therefore the Committee concluded that in this all-patient group infliximab could not be considered a cost-effective use of NHS resources.
4.4 The Committee understood that in the pathway of care, infliximab may have a particular role in the treatment of patients in whom the disease is very severe or potentially life threatening, and who need a rapid response to treatment. It noted from the British Association of Dermatologists and the Royal College of Physicians that patients with very severe psoriasis could be defined as those with a PASI score of 20 or more and a DLQI score higher than 10.
4.5 The Committee considered how the population with very severe psoriasis could be defined. The Committee observed that the manufacturer's submission for this appraisal had focused on a subgroup of patients with psoriasis with a particularly poor quality of life, as defined by the highest 25% of DLQI scores at baseline in the EXPRESS trial (DLQI greater than 18), that is those in the 4th quartile. Taking this into account, as well as the considerations in section 4.4, the Committee considered that the combination of a PASI of 20 or more and a DLQI of more than 18 would be an appropriate definition for very severe psoriasis, which could reasonably be expected to represent those whose psoriasis requires a rapid response or is so severe in some circumstances as to be potentially life threatening.
4.6 The Committee considered what the appropriate comparator technologies were for infliximab in the treatment of severe psoriasis. The Committee thought that the principal comparator should be etanercept, given intermittently in line with NICE guidance (TA103). The Committee also accepted that in very severe psoriasis etanercept given continuously would probably be considered by clinicians as a treatment option, because recurrence of very severe psoriasis between cycles of intermittent etanercept would be likely to significantly affect quality of life. The Committee was therefore persuaded that continuous etanercept was also an appropriate comparator in the subgroup of patients with very severe disease even though it was not currently NICE guidance. The Committee also accepted that in the absence of RCT evidence demonstrating any clinical difference between intermittent and continuous etanercept, it was reasonable to assume for the purposes of cost-effectiveness analysis, that there was no difference in clinical outcomes between continuous and intermittent treatment.
4.7 The Committee discussed the RCT evidence for infliximab compared with placebo in the treatment of psoriasis and concluded that the evidence supported a clinically important effect on both the extent and severity of skin disease (reduction in PASI score) and the quality of life of patients with moderate to severe psoriasis in comparison with best supportive care. The Committee considered that, given the evidence presented by the manufacturer, the clinical benefit of infliximab in the 4th-quartile DLQI group could be assumed to be equivalent to its benefit, measured by improvement in PASI score, in the all-patient group defined on the basis of a PASI of 10 or more and a DLQI greater than 10.
4.8 The Committee discussed the clinical effectiveness of infliximab compared with etanercept or efalizumab, taking into account the indirect comparison presented by the manufacturer and the information presented by the clinical specialists and patient experts. The Committee considered that the heterogeneity among the trials included in the indirect comparison could result in uncertainty around the conclusions. Therefore, the Committee could not conclude definitely that infliximab had a statistically significantly greater clinical effectiveness than intermittent etanercept and efalizumab. However, it heard from clinical specialists and patient experts that in clinical practice infliximab is associated with a higher response rate and a more rapid and longer-lasting response than other therapies with a comparable adverse effect profile, particularly in patients with very severe disease.
4.9 The Committee considered that the approach adopted by the manufacturer for the economic modelling was appropriate because it captured the main aspects of the presentation and course of the disease. However, the Committee expressed concerns over the validity of main input parameters in the model and subsequent analyses.
4.10 Particularly, the Committee considered that the manufacturer's approach to the mapping of SF-36 quality of life data to EQ-5D scores using an unvalidated and unpublished algorithm was not appropriate. The Committee would have preferred it if the SF-36 data had been converted to values appropriate to calculate QALYs with a validated instrument, such as SF-6D (short form 6 dimensions, a utility instrument). The Committee did not accept the manufacturer's reasons for using an unvalidated instrument. However, the Committee considered that the utilities presented by the manufacturer along with those from the York report could be accepted as a plausible range for estimating the cost effectiveness of infliximab.
4.11 The Committee also discussed the range of alternatives presented by the manufacturer for the costs of administering infliximab. The Committee considered that it would be difficult to estimate with any certainty the precise infusion costs given the variations within the NHS in clinical practice, local circumstances and interpretation of costing codes. The Committee therefore concluded that, given the methods behind the calculation of reference costs, the base-case figure of £65.02 and the figure of £124 used in sensitivity analysis represented a plausible range for these costs.
4.12 The Committee discussed the ERG's concerns over the drop-out rate for patients being given infliximab and the various inpatient costs. The Committee noted that the ERG's analysis had assumed a 50% drop-out rate over 12 months whereas the rate suggested by the manufacturer was 20% based on the York report. The Committee considered that the appropriate drop-out rate was likely to lie between these two estimates, particularly because the majority of drop-outs would occur in the first 6 months. Therefore it accepted that the values adopted by the manufacturer were appropriate.
4.13 The Committee next considered the cost-effective use of infliximab in the subgroup of patients identified by the manufacturer as those in the 4th quartile of baseline DLQI values among those with a PASI of 12 or more. The Committee noted that these patients would be treated with intermittent etanercept according to NICE guidance (TA103). The ICERs provided by the manufacturer of infliximab compared with intermittent etanercept in this group ranged from £33,000 to £44,000, whereas the ICERs compared with continuous etanercept ranged from £26,000 to £35,000 for the various utilities and costs presented. The Committee was persuaded by the clinical experts' view, as explained in section 4.6, that for people with very severe disease the appropriate alternative to infliximab is more likely to be etanercept given continuously, even though this is not recommended by TA103. The Committee was therefore persuaded that the use of infliximab in the subgroup of patients with very severe disease was a cost-effective use of NHS resources. The Committee further concluded that the definition of very severe psoriasis, as discussed in section 4.5, of a PASI of 20 or more combined with a DLQI of more than 18 would ensure that infliximab was appropriately targeted at those patients who were most likely to benefit from this treatment.
4.14 The Committee considered the appropriate duration of treatment. It noted that the principal endpoint in the infliximab trials was a PASI 75 response at 10 weeks, and that in the manufacturer's economic modelling it had been assumed that treatment would be discontinued if this response were not achieved at 10 weeks. The Committee thought it appropriate for treatment to be continued beyond 10 weeks only in people whose psoriasis has shown a PASI 75 response to treatment within 10 weeks. In addition the Committee was persuaded that for consistency the response criteria should be defined in a similar way to TA103 (including a 50% reduction in the PASI score and a five-point reduction in the DLQI) except that the assessment should made at 10 weeks after initiation of therapy.
4.15 The Committee was aware that there may be some circumstances in which DLQI is not a clinically appropriate tool to inform a clinician's conclusion on the severity of plaque psoriasis, for example, because of a patient'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 the infliximab.