Eczema (chronic) - alitretinoin: appraisal consultation document

NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE

Appraisal consultation document

Alitretinoin for the treatment of severe chronic hand eczema

The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a single technology appraisal (STA) of alitretinoin for the treatment of severe chronic hand eczema and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted by the manufacturer and the views put forward by non-manufacturer consultees and commentators, and by the clinical specialist and patient expert representatives nominated for this appraisal by non-manufacturer consultees and commentators. The Committee has developed preliminary recommendations on the use of alitretinoin for the treatment of severe chronic hand eczema.

This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk). This document should be read in conjunction with the evidence base for this appraisal (the evaluation report) which is available from www.nice.org.uk

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.

The process the Institute will follow after the consultation period is summarised below. For further details, see the ‘Guide to the single technology appraisal process’ (this document is available on the Institute’s website, www.nice.org.uk).

The Appraisal Committee will meet again to consider the original evidence and this appraisal consultation document in the light of the views of the formal consultees.

At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.

After considering feedback from the consultation process, the Committee will prepare the final appraisal determination (FAD) and submit it to the Institute.

Subject to any appeal by consultees, the FAD may be used as the basis for the Institute’s guidance on the use of the appraised technology in the NHS in England and Wales.

The key dates for this appraisal are:

Closing date for comments: 20 May 2009

Second Appraisal Committee meeting: 2 June 2009

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

Note that this document does not constitute the Institute's formal guidance on thisechnology. The recommendations made in section 1 are preliminary and may change after consultation.
1 Appraisal Committee's preliminary recommendations

1.1

 

Alitretinoin is recommended, within its licensed indication, as a treatment option for adults with severe chronic hand eczema that has not responded to potent topical corticosteroids if:

  • the person has severe disease, as defined by the physicians global assessment (PGA) and a dermatology life quality index (DLQI) score of 15 or more, and
  • the disease has not responded to a second-line treatment such as ciclosporin, azathioprine or PUVA (psoralen and long-wave ultraviolet radiation), or the person is intolerant of or has a contraindication to these treatments.

1.2

 

Alitretinoin treatment should be stopped:

  • if the eczema does not show an adequate response (defined as hands clear or almost clear) within 12 weeks or
  • as soon as an adequate response (hands clear or almost clear) has been achieved.
1.3 Only dermatologists with specialist experience in managing severe hand eczema should start and monitor treatment with alitretinoin.
1.4 When using the DLQI, healthcare professionals should take into account any disabilities (such as physical impairments) or linguistic or other communication difficulties that the person may have. In such cases, healthcare professionals should ensure that their use of the DLQI continues to be a sufficiently accurate measure.
   
2 The technology
2.1 Oral alitretinoin (Toctino, Basilea) is indicated for use in adults who have severe chronic hand eczema that is unresponsive to treatment with potent topical corticosteroids. Severe chronic hand eczema is defined using the physician’s global assessment (PGA); that is, marked signs of oedema, fissures or functional impairment.
2.2 The recommended dosage is 30 mg once daily for 12–24 weeks. The dosage can be reduced to 10 mg once daily if there are unacceptable adverse effects. If the person still has severe disease after the first 12 weeks, stopping treatment should be considered. In the event of relapse, further treatment courses may be of benefit.
2.3 Alitretinoin is a derivative of retinoic acid (9-cis-retinoic acid) that binds to and activates intracellular retinoid receptors. These receptors regulate cellular differentiation and proliferation.
2.4 The most frequent adverse effects seen with alitretinoin include headache, dry mouth, anaemia, flushing and erythema. Increases in cholesterol and triglyceride levels (hyperlipidaemia) and asymptomatic changes in thyroid-stimulating hormone concentrations have also been observed. Adverse events are generally dose related and reversible. Alitretinoin is teratogenic and therefore contraindicated in women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme (as outlined in the summary of product characteristics [SPC]) are met. Alitretinoin should not be prescribed if the person’s eczema can be adequately controlled by standard measures, including skin protection, avoiding allergens and irritants, and treatment with potent topical corticosteroids. For full details of side effects and contraindications, see the SPC.
2.5 Alitretinoin costs £411.43 for a pack of 30 × 30-mg capsules (excluding VAT; ‘British national formulary’ [BNF] edition 57). Costs may vary in different settings because of negotiated procurement discounts.
3 The manufacturer’s submission
  The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of alitretinoin and a review of this submission by the Evidence Review Group (ERG; appendix B).
3.1 The manufacturer approached the decision problem by comparing alitretinoin with ciclosporin, oral and topical PUVA (psoralen and long-wave ultraviolet radiation), and azathioprine. The population considered was adults with severe chronic hand eczema that is unresponsive to potent topical corticosteroids. The primary outcome measures outlined in the decision problem were overall severity of chronic hand eczema (as defined by PGA), modified total lesion symptom score (mTLSS), patient’s global assessment of improvement, time to response, time to relapse and a disease-specific quality of life measure, namely the dermatology life quality index (DLQI).
3.2 The primary outcome measure used in the clinical trials was severity of chronic hand eczema according to the PGA, which combined the grading of the disease severity against a photographic guide, with an indication of symptoms (pruritis/pain) and degree of functional impairment. The PGA describes five severity states for chronic hand eczema (clear, almost clear, mild, moderate and severe), of which the combined ‘clear/almost clear’ category was used to define response to treatment in the trials.
3.3 The manufacturer’s submission presented evidence on the clinical effectiveness of alitretinoin from two multinational randomised controlled trials (RCTs): BAP0003, a phase II 12-week trial (n = 319) comparing three doses of alitretinoin (10 mg, 20 mg and 40 mg) with placebo; and BAP00089, a phase III 24-week trial (n = 1032) evaluating 10-mg and 30-mg daily doses of alitretinoin versus placebo. It also presented evidence from BAP00091, an extension of the BAP00089 RCT in which non-responding and responding–relapsing people were followed up for 24 weeks. All people (n = 360) in BAP00091 whose eczema did not respond during BAP00089 or who had disease relapse within 24 weeks of treatment received a further 12- or 24‑week course of either 10 mg or 30 mg of alitretinoin or placebo in the extension trial (people from BAP00089 who had received placebo were assigned to receive placebo again, and people who received alitretinoin were given a further course of treatment or assigned to receive placebo). All trials included people whose eczema had not responded to potent topical corticosteroids. The BAP00089 RCT included people with ‘severe’ eczema as defined by PGA score. The BAP0003 trial included people with either ‘moderate’ or ‘severe’ eczema as defined by PGA score.
3.4 Both RCTs found that alitretinoin treatment resulted in a greater proportion of people with hands clear or almost clear at 12 and 24 weeks compared with placebo, as assessed by PGA score and patient’s global assessment of improvement. The differences were statistically significant (although in the BAP0003 trial only the dose of 40 mg of alitretinoin was statistically significantly different fro placebo). For the BAP00089 trial, 47.7% of people were reported as having clear or almost clear skin by week 24 of treatment with 30 mg of alitretinoin, compared with 16.6% for placebo (p < 0.001). The BAP00089 trial also measured rates of remission and found that among people whose eczema had responded to alitretinoin treatment, 30% treated with 30 mg and 37% treated with 10 mg relapsed during the 24-week follow-up period. The manufacturer explained that in the BAP0003 study, 26% of people whose eczema responded to treatment with alitretinoin relapsed (mTLSS score of 75% of the baseline value) within 12 weeks of the end of the treatment.
3.5 Both RCTs found that alitretinoin treatment resulted in a greater proportion of people with hands clear or almost clear at 12 and 24 weeks compared with placebo, as assessed by PGA score and patient’s global assessment of improvement. The differences were statistically significant (although in the BAP0003 trial only the dose of 40 mg of alitretinoin was statistically significantly different fro placebo). For the BAP00089 trial, 47.7% of people were reported as having clear or almost clear skin by week 24 of treatment with 30 mg of alitretinoin, compared with 16.6% for placebo (p < 0.001). The BAP00089 trial also measured rates of remission and found that among people whose eczema had responded to alitretinoin treatment, 30% treated with 30 mg and 37% treated with 10 mg relapsed during the 24-week follow-up period. The manufacturer explained that in the BAP0003 study, 26% of people whose eczema responded to treatment with alitretinoin relapsed (mTLSS score of 75% of the baseline value) within 12 weeks of the end of the treatment.
3.6 The manufacturer also provided details of subgroup analyses from the BAP00089 trial. Alitretinoin 30 mg resulted in a higher proportion of people with hands clear or almost clear than placebo in people with hyperkeratotic disease (54% versus 12%), pompholyx disease (33% versus 30%), and hyperkeratotic and pompholyx disease together (33% versus 12%). It was not stated whether these differences were statistically significant.
3.7 The manufacturer explained that information on health-related quality of life (HRQoL) was collected only during the phase II BAP0003 study and that 51.4% of people in both treatment groups (alitretinoin and placebo) completed DLQI questionnaires. The median change in HRQoL from baseline was greater with alitretinoin than placebo (–3 [for doses of 20 and 40 mg of alitretinoin] and –2, respectively). The findings were not statistically significant, but the manufacturer pointed out that this may have been because of the lack of statistical power of the study. The manufacturer did not include the DLQI or any other measure of HRQoL in any subsequent trials or analyses.
3.8 The primary source of data on adverse events in the manufacturer’s submission was the phase III RCT (BAP00089). Treatment-related serious adverse events with alitretinoin were rare (an incidence of 1% at a dose of 30 mg). The most common adverse event was headache (20%, 30 mg; 11%, 10 mg) and a small proportion of people had elevated blood triglycerides (3%, 30 mg; 1%, 10 mg) and high total cholesterol (14%, 30 mg; 3%, 10 mg). The number of people who withdrew from the trial because of adverse events was 39 (9.5%) for 30 mg of alitretinoin and 24 (5.7%) for 10 mg of alitretinoin. The number of people who refused to continue treatment for other reasons was 16 (3.9%) for 30 mg of alitretinoin and 24 (5.7%) for 10 mg of alitretinoin.
3.9 The manufacturer pointed out that there were no trials that compared alitretinoin directly with any of the comparators specified in the scope for the appraisal. It explained that subsequent searches were carried out to identify trials that assessed the efficacy of PUVA, ciclosporin and azathioprine for the treatment of chronic hand eczema. This search identified 13 trials of PUVA for the treatment of chronic hand eczema, of which eight met the criteria for inclusion in the review. One trial of ciclosporin and no trials of azathioprine were identified. The manufacturer explained that a mixed-treatment comparison could not be carried out because none of the RCTs using PUVA or ciclosporin had a placebo control arm, and therefore no common link could be established between the trials of alitretinoin, PUVA and ciclosporin.
3.10 The manufacturer submitted a cost-effectiveness analysis from a de novo Markov-based patient-level model using a hypothetical cohort of people with severe chronic hand eczema. The demographic characteristics of the model population reflected those of the participants in the BAP00089 trial, and 15% of the women were assumed to be of childbearing potential. The model had five health states that were defined according to the PGA score: severe, moderate and mild chronic hand eczema, remission (patients whose chronic hand eczema was rated as ‘clear’ or ‘almost clear’ by 24 weeks), and refractory disease (patients whose chronic hand eczema was rated ‘moderate’ or ‘mild’ or had returned to PGA ‘severe’ at 24 weeks). The model was designed to compare oral alitretinoin with PUVA, ciclosporin, azathioprine and best supportive care. The model had a 3-year time horizon, and a treatment course of alitretinoin was assumed to be given for between 12 and 24 weeks at an initial dosage of 30 mg once daily.
3.11 The efficacy estimates for alitretinoin in the model were taken from the phase III clinical trial (BAP00089) for the first treatment cycle, and from cohort A of the phase III extension trial (BAP00091) for subsequent treatment cycles. Estimates of efficacy of the comparators were derived from a panel of seven dermatologists. Data on the number of adverse events and the probabilities of dose reduction or withdrawal from treatment were informed by BAP00089 or by the manufacturer’s assumptions. Time to relapse following remission was informed by the BAP00089 trial in the case of alitretinoin and by clinical opinion for the comparators. For alitretinoin, the estimates of the proportion of people who move to each PGA state after initial treatment was obtained from the BAP00089 trial , and re-treatment estimates were obtained from the BAP00091 trial. The corresponding estimates for the comparator interventions were from expert opinion.
3.12 The utility values for all health states were derived using data collected from the BAP0003 trial to predict DLQI scores that correspond to each PGA state. A published algorithm on the relationship between DLQI and EQ-5D scores in people with psoriasis was then used to predict EQ5D-based utility from DLQI scores. The model applied the utility scores associated with the ‘severe’ PGA state to people whose disease was rated as severe and who were still receiving treatment, and to people whose disease was deemed to be refractory. The ‘moderate’ and ‘mild’ utility scores were applied to people receiving treatment whose disease was rated moderate or mild on the PGA scale. The utility scores for ‘clear’ and ‘almost clear’ were averaged to provide a single utility score that was applied to people whose disease was in remission. The manufacturer also provided a set of alternative utility estimates from an unpublished study by Augustin (the information in the Augustin study is marked as academic in confidence and is therefore not presented in this document). These EQ‑5D scores were predicted from the observed average DLQI score of the people within each PGA state. Adverse events were assumed to have no impact on HRQoL.
3.13 It was assumed that if an adverse event occurred (either headache or hyperlipidaemia), 20% of those with headache and 40% of those with hyperlipidaemia would switch to a lower dose (10 mg of alitretinoin, once daily), whereas for the rest treatment would continue unchanged. It was assumed that those people on the lower dose who experienced a subsequent adverse event had a 20% probability of withdrawal owing to headache and a 40% probability of withdrawal owing to hyperlipidaemia; these people would enter the refractory state and the remaining people would continue treatment unchanged. The costs associated with treatment, monitoring and adverse events were included in the model.
3.14 The manufacturer’s original base case resulted in an incremental cost-effectiveness ratio (ICER) of £8,614 per quality-adjusted life year (QALY) gained for alitretinoin compared with ciclosporin. Alitretinoin dominated PUVA. A comparison of alitretinoin with azathioprine resulted in an ICER of £10,612 per additional QALY gained.
3.15 The manufacturer carried out two subgroup analyses. The first subgroup was people with hyperkeratotic disease. For this subgroup, the manufacturer adjusted the efficacy data for alitretinoin to reflect the improved efficacy that had been observed in the BAP00089 trial predominantly in people with hyperkeratotic disease. The second subgroup analysis was in women of childbearing potential. The efficacy was assumed to be the same in these women as in the base case, but the care of these women was assumed to incur additional costs associated with conception, pregnancy consultation and testing. The consequences of the Pregnancy Prevention Programme not working were not considered.
3.16 The manufacturer’s subgroup analyses for people with hyperkeratotic disease resulted in an ICER of £11,177 per QALY gained for alitretinoin compared with ciclosporin. Alitretinoin dominated PUVA. The comparison of alitretinoin with azathioprine resulted in an ICER of £13,174 per QALY gained. The manufacturer’s subgroup analyses for women of childbearing age resulted in an ICER of £9,109 per QALY gained for alitretinoin compared with ciclosporin. Comparing alitretinoin with PUVA resulted in an ICER of £54 per QALY gained. The comparison of alitretinoin with azathioprine resulted in an ICER of £11,038 per QALY gained.
3.17 In response to a request for clarification from the ERG, the manufacturer submitted a revised model comparing alitretinoin with best supportive care. The manufacturer’s revised base case resulted in an ICER of £12,931 per QALY gained. The ICER was £15,018 per QALY for people with hyperkeratotic disease and £26,013 per QALY for people with hyperkeratotic and/or pompholyx disease.
3.18 The manufacturer undertook a one-way sensitivity analysis of the time horizon of the revised model. Using just a 1-year time horizon resulted in an ICER of £21,562 per QALY gained.

3.19

 

The ERG highlighted a number of problems with the clinical and cost effectiveness information in the manufacturer’s submission, including:

  • the reliability of the efficacy estimates for the comparators
  • the possibility that the population and some assumptions in the model may not reflect clinical practice in England and Wales
  • the high degree of uncertainty because of using derived utility values rather than directly observed HRQoL values
  • errors in the model’s visual basic for applications (VBA) code.
3.20 The ERG regarded the comparisons of alitretinoin with azathioprine, ciclosporin and PUVA in the original manufacturer’s submission to be of limited value. This was because the efficacy data for those comparators were based on expert clinical opinion only. Although the ERG accepted that there was no appropriate clinical trial evidence, it did not think the elicitation process used was sufficiently rigorous. It therefore questioned the validity of the efficacy estimates for the comparators used in the model, and noted the absence of any quantification of the uncertainty around these estimates. The ERG therefore viewed the comparison of alitretinoin with placebo in the revised model to be of greater relevance, and focused its evaluation on this aspect of the model.
3.21 The ERG questioned whether the model population (people with severe chronic hand eczema as defined by PGA score) reflected the population of people with corticosteroid-refractory chronic hand eczema for whom clinicians would aim to provide treatment.
3.22 The ERG was unsure of the validity of some of the model assumptions. These included the assumptions that people would stop treatment as soon as their disease responded, even if this was after only 4 or 8 weeks of treatment; that all people who relapse return to the PGA severe state, even though the time to relapse is informed by trial data that used a definition of relapse based on return to 75% baseline mTLSS; and that people receiving alitretinoin would visit a dermatologist every 4 weeks.
3.23 The ERG viewed the derived utility values used in the model as a major source of uncertainty for the cost-effectiveness analysis. It also considered the utility estimates constructed using the directly observed relationship between PGA state and DLQI score from the Augustin study a more appropriate basis for modelling than the analysis of change in DLQI score calculated based on PGA state from the BAP0003 trial.
3.24 The ERG stated that there were errors in the model’s VBA code. This meant that the first 4 weeks of every treatment cycle except the first cycle were omitted from the model. It also pointed out that adverse events associated with alitretinoin had been removed from the revised model that compared alitretinoin with best supportive care.
3.25 The ERG carried out an additional exploratory cost-effectiveness analysis using the manufacturer’s original model. It explained that the results given by the manufacturer were not fully incremental, consisting of pairwise comparisons between alitretinoin and the comparators. The ERG explained that integrating the supportive care arm from the revised model into a fully incremental analysis was possible because the manufacturer removed adverse events from the revised model and did not report on the adverse-event profile associated with supportive care. The ERG’s incremental analysis found that alitretinoin extendedly dominated ciclosporin, alitretinoin dominated PUVA, best supportive care dominated azathioprine, and the comparison of alitretinoin with best supportive care resulted in an ICER of £12,931 per QALY gained.
3.26 The ERG also conducted exploratory sensitivity analyses using the manufacturer’s revised model (which compared alitretinoin with best supportive care). Using the utility estimates from the Augustin study and the assumption that people (except women of childbearing potential) see a dermatologist once every 6 weeks with alitretinoin and once every 12 weeks with supportive care (rather than once every 4 weeks) resulted in an ICER of £27,997 per QALY gained for alitretinoin compared with best supportive care.
3.27 Using the ERG-modified VBA code so that people whose disease relapsed moved to the appropriate PGA state (30.6% of people with relapsing disease moved to the moderate state and the remainder to the severe state) resulted in an ICER of £29,864 per QALY gained for alitretinoin compared with best supportive care. Reinstating adverse events for alitretinoin resulted in an ICER of £29,200 per QALY gained for alitretinoin compared with best supportive care.
3.28 Using the modifications described in sections 3.25 and 3.26, but keeping the utility data from the original model (taken from BAP0003), resulted in an ICER of £15,084 per QALY gained for alitretinoin compared with best supportive care. Using the modifications described in 3.25 and 3.26 and using the alternative utility data from the Augustin study resulted in an ICER of £30,918 per QALY gained for alitretinoin compared with best supportive care.
3.29 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/TAxxx
4 Consideration of the evidence
  Clinical effectiveness
4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of alitretinoin, having considered evidence on the nature of the condition and the value placed on the benefits of alitretinoin by people with severe chronic hand eczema, 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 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 for people with severe chronic hand eczema that is refractory to topical corticosteroids in the UK. 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- 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.
4.6 Cost effectiveness
  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 treated 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 concluded that the evaluation of the cost effectiveness of alitretinoin compared with azathioprine, ciclosporin and PUVA could not be considered further. 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 the symptoms responded (defined as hands clear or almost clear) or after 12 weeks if the symptoms had failed to respond and were still classed as severe.

4.8

 

The ERG 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 for alitretinoin were reinstated from the original model.
4.9 The Committee then 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 in practice they would begin treatment again before a person’s hands had returned to the severe state – therefore it accepted the ERG’s assumption of re-treating people with moderate or severe chronic hand eczema. Finally, the Committee accepted that the adverse effects of alitretinoin needed to be reinstated in the revised model. The Committee noted that the modelling of the adverse effects 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 only plausible compared 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. In addition, for the same reason the high cost of PUVA had not been included in the economic evaluation.
4.10 The Committee discussed the relative merits and disadvantages of the methods used to estimate utilities 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 status. However, the Augustin study identified a higher utility 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 difference between the severe PGA state and the hands clear or almost clear state in the BAP0003 study than in the Augustin study. The Committee noted that combining all of the modifications suggested by the ERG and using the original utility values (derived from BAP0003) increased the ICER to £15,000 per QALY gained. Using all of the above modifications and 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 in the severe state may have been underestimated in the Augustin study (that is, the DLQI score estimated for the PGA severe state may not accurately reflect 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 health state of severe chronic hand eczema to 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 the more robust measure to use was DLQI score. Based on the information available, the Committee therefore concluded that, in people whose eczema is sufficiently severe to result in a DLQI score of 15 or more (the value applied in the BAP0003 study to the PGA-defined severe state), moving to a hands clear or almost clear state would result in benefits that would represent a cost-effective use of NHS resources.
4.14 The Committee discussed the place of alitretinoin in the pathway of care. It noted that because of the lack of evidence for comparator treatments, the relative cost of alitretinoin could not be considered. However, the Committee heard that the different comparator treatments could be effective in achieving an adequate response in some people with severe chronic hand eczema. Therefore the Committee concluded that people with severe chronic hand eczema who have not responded to high-dose topical corticosteroids should have received a second-line treatment such as ciclosporin, azathioprine or PUVA before alitretinoin can be considered as a treatment option, unless they are intolerant of or have a contraindication to these treatments.
4.15 The Committee further concluded that treatment with alitretinoin should be stopped as soon as an adequate response (hands clear or almost clear) is achieved, or after 12 weeks if the symptoms are still classed as severe (see section 4.9). The Committee also concluded, having heard testimony from the clinical specialists, that only dermatologists with specialist experience in managing severe hand eczema should start and monitor treatment with alitretinoin.
4.16 The Committee agreed that when using the DLQI, healthcare professionals should take into account any disabilities (such as physical impairments) or linguistic or other communication difficulties that the person may have. In such cases, healthcare professionals should ensure that their use of the DLQI continues to be a sufficiently accurate measure.
4.17 In considering the evidence and reaching its conclusions, the Committee was aware of the Institute’s duties under the equalities legislation, and considered whether those duties required the Committee to alter or to add to its recommendations in any way. However, the Committee did not identify any way in which its guidance would have a particular impact on any of the groups whose interests are protected by the equalities legislation. The Committee heard from the clinical specialists that there may be people who will be unable to comply with treatment of severe chronic hand eczema for cultural reasons (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.
   
5 Implementation
5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. The NHS is not required to fund treatments that are not recommended by NICE.

5.2

 

NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [NICE to amend list as needed at time of publication]

  • Slides highlighting key messages for local discussion.
  • Costing report and costing template to estimate the savings and costs associated with implementation.
  • Implementation advice on how to put the guidance into practice and national initiatives which support this locally.
  • Audit support for monitoring local practice.
   
6 Proposed recommendations for further research
6.1 The Committee recommends that phase III trials comparing alitretinoin with ciclosporin, azathioprine and PUVA, in people who have severe chronic hand eczema that is unresponsive to treatment with potent topical corticosteroids, should be conducted.
6.2 The Committee recommends that a study that estimates utilities using directly observed health-related quality of life values (such as EQ-5D scores), in people with severe chronic hand eczema that is unresponsive to treatment with potent topical corticosteroids, is conducted.
   
7 Related NICE guidance
 
  • Frequency of application of topical corticosteroids for eczema. NICE technology appraisal guidance 81 (2004). Available from www.nice.org.uk/TA81
 
  • Tacrolimus and pimecrolimus for atopic eczema. NICE technology appraisal guidance 82 (2004). Available from www.nice.org.uk/TA82
8 Proposed date for review of guidance
8.1 The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.
8.2 It is proposed that the guidance on this technology is considered for review in August 2012. The Institute would particularly welcome comment on this proposed date.
Ken Stein
Vice-Chair, Appraisal Committee
April 2009

 

Appendix A: Appraisal Committee members and NICE project team
A. Appraisal Committee members

The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice chair. Each branch considers its own list of technologies, and ongoing topics are not moved between the branches.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Professor Keith Abrams
Professor of Medical Statistics, University of Leicester

Dr Ray Armstrong
Consultant Rheumatologist, Southampton General Hospital

Dr Jeff Aronson
Reader in Clinical Pharmacology, University Department of Primary Health Care, University of Oxford

Dr Darren Ashcroft
Reader in Medicines Usage and Safety, School of Pharmacy and Pharmaceutical Sciences, University of Manchester

Professor David Barnett (Chair)
Professor of Clinical Pharmacology, University of Leicester

Dr Mark Chakravarty
External Relations Director - Pharmaceuticals & Personal Health, Oral Care Europe

Dr Martin Duerden
Medical Director, Conwy Local Health Board

Mrs Eleanor Grey
Lay member

Mr Terence Lewis
Lay Member, Mental Health Consultant, National Institute for Mental Health in England

Professor Gary McVeigh
Professor of Cardiovascular Medicine, Queens University, Belfast

Dr Ruairidh Milne
Senior Lecturer in Public Health, National Coordinating Centre for Health Technology

Dr Neil Milner
General Practitioner, Tramways Medical Centre, Sheffield

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Dr Stephen Saltissi
Consultant Cardiologist, Royal Liverpool University Hospital

Dr Lindsay Smith
General Practitioner, East Somerset Research Consortium

Mr Roderick Smith
Finance Director, West Kent Primary Care Trust

Mr Cliff Snelling
Lay Member

Professor Ken Stein (Vice Chair)
Professor of Public Health, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Professor Andrew Stevens
Professor of Public Health, Department of Public Health and Epidemiology, University of Birmingham

Dr Rod Taylor
Associate Professor in Health Services Research, Peninsula Medical School, Universities of Exeter and Plymouth

Ms Nathalie Verin
Health Economics Manager, Boston Scientific UK and Ireland

Dr Colin Watts
Consultant Neurosurgeon, Addenbrookes Hospital

Mr Tom Wilson
Director of Contracts and Information Management and Technology, Milton Keynes PCT

 
B. NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Helen Tucker
Technical Lead

Joanna Richardson
Technical Adviser

Jeremy Powel
Project Manager

 
Appendix B. Sources of evidence considered by the Committee

A

 

The Evidence Review Group (ERG) report for this appraisal was prepared by the Centre for Reviews and Dissemination (CRD) University of York:

  • Paulden M, Rodgers M, Griffin S et al., Alitretinoin for the treatment of severe chronic hand eczema, March 2009

B

 

The following organisations accepted the invitation to participate in this appraisal. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I II and III also have the opportunity to appeal against the final appraisal determination.

I. Manufacturer/sponsor:

  • Basilea Medical

II. Professional/specialist and patient/carer groups:

  • British Association of Dermatologists
  • British Contact Dermatitis Society
  • Royal College of Nursing
  • Royal College of Physicians
  • Skin Care Campaign

III. Other consultees:

  • Department of Health
  • Welsh Assembly Government

IV. Commentator organisations (did not provide written evidence and without the right of appeal):

  • British National Formulary
  • Cochrane Skin Group, Centre of Evidence-based Dermatology, University of Nottingham
  • Department of Health, Social Services and Public Safety for Northern Ireland
  • NHS Quality Improvement Scotland

C

 

The following individuals were selected from clinical specialist and patient advocate nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on alitretinoin for the treatment of chronic eczema of the hand, refractory to steroids by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

  • Dr Graham Johnston, Consultant Dermatologist, Leicester Royal Infirmary, nominated the British Association of Dermatologists - clinical specialist
  • Dr Anthony Ormerod, Reader in Dermatology, University of Aberdeen, nominated by the British Association of Dermatologists - clinical specialist
  • Andrew Langford, Chief Executive, the Skin Care Campaign, nominated by the Skin Care Campaign - patient expert
   

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Copyright 2014 National Institute for Health and Care Excellence. All rights reserved.