4 Consideration of the evidence

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of alitretinoin, having considered evidence on the nature of severe chronic hand eczema and the value placed on the benefits of alitretinoin by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

Clinical effectiveness

4.2 The Committee heard from the clinical specialists and patient expert that there is a need for new treatments for people with severe chronic hand eczema that is refractory to topical corticosteroids. This is because treatment options are limited and there are no licensed treatments available. The Committee also heard that severe chronic hand eczema is a very debilitating condition. This is because it can be disfiguring, can result in severe functional limitation and may be associated with depression, anxiety and social stigma.

4.3 The Committee discussed the treatment options currently available in the UK for people with severe chronic hand eczema that is refractory to topical corticosteroids. These are the immunosuppressants ciclosporin and azathioprine, and PUVA. It heard the clinical specialists' concerns about using treatments that work by suppressing the immune system because of potential adverse effects over the longer term, such as re-activation of tuberculosis. For this reason, the clinical specialists stated that they would be cautious in their use of immunosuppressants and that such treatments would be reserved for people with the most severe symptoms. The Committee also heard from the clinical specialists about concerns over the adverse effects of comparator treatments: for example, ciclosporin is associated with an increased risk of lymphoma and skin cancer, and PUVA is known to be carcinogenic. The Committee heard from the patient expert that alitretinoin would be well tolerated by most people, with limited short-term or long-term adverse effects that would be no worse than those of the current treatments. The clinical specialists confirmed that there was an increase in blood levels of triglycerides and cholesterol in some people using alitretinoin, but that these effects would be carefully monitored and medically managed in practice.

4.4 The Committee noted the subgroup analyses provided by the manufacturer for people with hyperkeratotic and/or pompholyx disease. However, it heard from the clinical specialists that it would be impractical to differentiate these subgroups in practice. The clinical specialists also stated that they would expect treatment with alitretinoin for severe chronic hand eczema to be started and monitored by specialist dermatologists with appropriate expertise in managing hand eczema.

4.5 The Committee discussed the clinical effectiveness of alitretinoin in treating severe chronic hand eczema and considered all of the available evidence. It agreed that an RCT comparing alitretinoin with the current treatments for severe chronic hand eczema would have been ideal. The Committee was aware that the alternative treatments for this disease generally lack a robust evidence base, and so the manufacturer was unable to conduct an indirect comparison of alitretinoin with the standard treatments. The Committee noted the trial comparing 10 mg and 30 mg doses of alitretinoin with best supportive care, which demonstrated that alitretinoin was more clinically effective than best supportive care. The Committee therefore concluded that alitretinoin is a clinically effective treatment for severe chronic hand eczema compared with best supportive care.

Cost effectiveness

4.6 The Committee discussed the plausibility of the efficacy estimates for the comparators in the manufacturer's model. The Committee heard from the ERG that using a panel of dermatologists to determine the efficacy estimates for the comparators for the model was appropriate. However, the manufacturer did not provide details of the range of opinions obtained, whether the opinions had been weighted or whether the estimates had been adjusted to exclude the effect of placebo. The Committee therefore agreed that the estimates of efficacy for the comparators in the model should be considered with caution. The Committee also heard from the clinical specialists that the efficacy estimates for the comparators in the manufacturer's model did not reflect experience in clinical practice – in particular, azathioprine is considered to be more clinically effective than best supportive care. The specialists stated that in their experience some people's eczema would respond adequately to one of the available comparator treatments. The Committee noted comments from consultees on the side effects of treatment and the weak evidence base for azathioprine, ciclosporin and PUVA. Overall, the Committee concluded that the evidence base for the potential comparators azathioprine, ciclosporin and PUVA was weak and highly contentious. It agreed that an analysis of the cost effectiveness of alitretinoin compared with azathioprine, ciclosporin and PUVA could not be reliably considered further, given the present state of knowledge. It would therefore only consider the revised economic model comparing alitretinoin with best supportive care.

4.7 The Committee noted that the manufacturer's base case for 30 mg of alitretinoin compared with best supportive care and the corresponding ERG analysis both gave ICER estimates of approximately £13,000 per QALY gained. The Committee noted that this analysis included discontinuing treatment as soon as an adequate response (defined as hands clear or almost clear) was achieved, or after 12 weeks if the symptoms were still classed as severe, or after 24 weeks if an adequate response (hands clear or almost clear) was not achieved.

4.8 The Committee noted that the ERG had explored the following modifications to the manufacturer's model:

  • People (except women of childbearing potential) would see a dermatologist once every 6 weeks with alitretinoin and once every 12 weeks with best supportive care.

  • The VBA code was modified so that people with disease moved to an appropriate PGA state (30.6% of people with relapsing disease moved to the moderate state and the remainder to the severe state).

  • Adverse events associated with alitretinoin treatment were reinstated from the original model.

4.9 The Committee discussed the ERG's assumptions and modifications. Firstly, it considered the assumption in the manufacturer's model that people would stop treatment before 12 weeks if an adequate response was achieved. The Committee heard from the clinical specialists that this assumption did reflect clinical practice in the UK and that people receiving alitretinoin would be seen by a dermatologist every 6 weeks. The Committee therefore accepted this assumption. The Committee then discussed whether people would be treated again only when the condition had relapsed to a severe state. The Committee heard from the clinical specialists that they may find it difficult not to begin treatment again before a person's hands had returned to the severe state. The Committee therefore accepted the ERG's assumption of earlier retreatment in a proportion of people. Finally, the Committee accepted that the adverse events associated with alitretinoin treatment needed to be reinstated in the revised model. The Committee noted that the modelling of the adverse events did not capture all monitoring and treatment related to cardiovascular risk or outcomes related to long-term effects that may result from increased blood lipid levels. However, the Committee acknowledged that, because modelling was plausible only to compare alitretinoin with best supportive care, long-term adverse effects of currently used treatments (such as an increased risk of cancer) were also not included in the modelling. For the same reason, the high cost of PUVA was not included in the economic evaluation.

4.10 The Committee discussed the relative merits and disadvantages of the methods used to estimate utility values in the BAP0003 trial and the Augustin study. The Committee acknowledged that both studies were subject to a high degree of uncertainty, as both estimated utilities indirectly. The Committee noted that the manufacturer did not use the DLQI scores from groups of people defined according to their PGA state directly, although this would have been possible. Instead, the manufacturer used a two-stage process to obtain utility estimates via DLQI scores for PGA states. In comparison, the Augustin study measured DLQI scores directly in groups of people defined according to their PGA state. However, the Augustin study identified a higher utility value for mild disease than for the state of hands clear or almost clear, which the Committee noted was counterintuitive.

4.11 The Committee noted the sensitivity analyses provided by the ERG, and that using some of the ERG's plausible assumptions would lead to small increases in the ICERs. However, it also noted that the major driver of the model was the choice of the utility values, with a much bigger utility gain from moving from the severe PGA state to the hands clear or almost clear state in the BAP0003 study (0.33) than in the Augustin study (0.14). The Committee noted that including all modifications suggested by the ERG and using the original utility values (derived from the BAP0003 trial) increased the ICER for alitretinoin compared with best supportive care to £15,000 per QALY gained. Including all modifications suggested by the ERG and using the utility values from the Augustin study increased the ICER to £31,000 per QALY gained.

4.12 The Committee then noted the concerns expressed by the patient expert and clinical specialists that the likely impact of chronic hand eczema on quality of life for people whose eczema is classified as severe may have been underestimated in the Augustin study (that is, the DLQI score estimated for the PGA severe state may not accurately reflect the impact of eczema in people who would be considered as candidates for alitretinoin in practice). In the absence of more robust data, the Committee agreed that the utility estimate for PGA-defined severe chronic hand eczema in the Augustin study may have underestimated the impact of the condition. The Committee also agreed that the benefits of moving from the state of severe chronic hand eczema to the state of hands clear or almost clear would be considerable.

4.13 The Committee agreed that the uncertainty about the relationship between DLQI score and PGA state was too great to base recommendations on PGA state alone, and that it would be appropriate to include guidance on DLQI eligibility criteria for treatment. The Committee discussed what DLQI score was appropriate to define eligibility for treatment with alitretinoin. The Committee considered concerns raised by consultees that a DLQI score of 15 was too high, but thought that this score reflected the deterioration in quality of life produced by a condition affecting the hands that is severe as defined by the PGA. The Committee noted comments from consultees advocating a DLQI score of 10, in line with the current eligibility criteria for biological treatments for psoriasis. However, the Committee considered that psoriasis and severe chronic hand eczema could have different effects on HRQoL. It also agreed, on the basis of the testimony of the patient expert, that severe chronic hand eczema is likely to be associated with a particularly high DLQI score.

4.14 The Committee discussed the implications for the cost effectiveness of alitretinoin of using different DLQI thresholds. It noted that the benefit of alitretinoin had been established in a population with severe disease for whom the manufacturer had calculated a DLQI score of 15. It concluded that the economic case had therefore been made for this population. The Committee therefore concluded that treatment with alitretinoin for people whose eczema is sufficiently severe to result in a DLQI score of 15 or more would represent a cost-effective use of NHS resources.

4.15 The Committee discussed the place of alitretinoin in the pathway of care. It heard that the different comparator treatments could be effective in achieving an adequate response in some people with severe chronic hand eczema. However, the Committee agreed that it was not appropriate to make recommendations about the place of alitretinoin in the pathway of care because robust cost-effectiveness estimates were not available for alitretinoin compared with any active comparator treatments. It also noted that azothiaprine and ciclosporin, although licensed for related conditions, do not have a marketing authorisation for severe chronic hand eczema. In addition, the Committee noted the concerns of consultees about the adverse effects associated with comparator treatments and the lack of RCT evidence of their effectiveness in treating severe chronic hand eczema.

4.16 The Committee discussed comments from consultees that treatment should not be stopped if the eczema remains severe (as defined by the PGA) at 12 weeks, because a longer time period would be needed to assess a response to treatment. However, it noted that the SPC for alitretinoin specifies that discontinuation of treatment should be considered if symptoms are still classed as severe at 12 weeks, and that such treatment discontinuation was included in the cost-effectiveness analysis. The Committee agreed with the suggestion from consultees to state in the guidance that treatment with alitretinoin should be stopped if an adequate response (hands clear or almost clear) has not been achieved by 24 weeks. The Committee also discussed the suggestion by consultees to provide specific advice about what treatments to give after 24 weeks. It agreed that this level of detail would be outside the remit for a technology appraisal.

4.17 The Committee also discussed whether only dermatologists with specialist experience in managing severe hand eczema should start and monitor treatment with alitretinoin. The Committee noted consultee comments that other clinical staff should be included, as this would enable people to receive treatment more quickly. The Committee acknowledged that specialist nurses could have an important role in the management of severe chronic hand eczema, but agreed that guidance on who should start and monitor treatment with alitretinoin should reflect the marketing authorisation for the drug. Therefore it is recommended that only dermatologists, or physicians with experience in both managing severe hand eczema the use of systemic retinoids, should start and monitor treatment with alitretinoin.

4.18 In considering the evidence and reaching its conclusions, the Committee was aware of NICE's duties under the equalities legislation, and considered whether those duties required it to alter or to add to its recommendations in any way. The Committee was aware that a number of the questions in the DLQI focus on aspects that depend on physical activity, such as shopping, working in the home or garden, or sport. The DLQI would therefore need to be used judiciously in people with a physical disability to take account of their lower baseline level of physical activity. Furthermore, sensory or learning disabilities, or other communication difficulties, could also affect the responses to the DLQI. The Committee agreed that in such cases, healthcare professionals should ensure that the DLQI continues to be a sufficiently accurate measure.

4.19 The Committee additionally heard from the clinical specialists that there may be people who, for cultural reasons, will be unable to comply with some aspects of treatment of severe chronic hand eczema (for example, wearing gloves or not carrying out certain household tasks that expose them to known irritants). However, the Committee noted that the SPC for alitretinoin states that it should not be prescribed if the patient's eczema can be adequately controlled by standard measures, including skin protection and avoidance of allergens and irritants. Therefore it was not possible for the Committee to consider this group separately.

  • National Institute for Health and Care Excellence (NICE)