4 Evidence and interpretation

The Appraisal Committee (Appendix A) considered evidence from a number of sources (Appendix B). The remit given to NICE by the Department of Health/Welsh Assembly Government was to advise on the clinical and cost effectiveness of once-daily use compared with more frequent use of same-potency topical corticosteroids in the treatment of people with atopic eczema. The evidence appraised was restricted to comparisons of topical corticosteroids for atopic eczema within the same potency class.

4.1 Clinical effectiveness

4.1.1 The Assessment Report reviewed data from one systematic review and ten randomised controlled trials (RCTs) that examined frequency of application of topical corticosteroids of the same potency. No RCTs or clinical controlled trials of mild topical corticosteroids were identified. One RCT examined moderately potent corticosteroids, eight RCTs examined potent corticosteroids and one RCT examined very potent corticosteroids.

4.1.2 The study setting was hospital or secondary care for four of the ten trials but was not reported in the remaining studies. The duration of treatment for the trials ranged from 7 days to 4 weeks. Quality of life and patient preference were not reported by any of the included trials.

4.1.3 The Assessment Group concluded the systematic review was of good methodological quality. The systematic review included three RCTs (two trials examining potent topical corticosteroids and one examining very potent topical corticosteroids), all of which were included in the Assessment Report. The authors of the systematic review found that in none of the studies was more frequent application superior to once-daily application. They concluded that point estimates suggest that a small difference in favour of more frequent application cannot be excluded.

4.1.4 The Assessment Group did not consider meta-analysis to be appropriate because of the clinical and statistical heterogeneity of the trials.

Moderately potent preparations

4.1.5 One RCT was identified that examined the frequency of application in moderately potent topical corticosteroids for atopic eczema; the study population was children. The Assessment Report stated that the study was small and the duration of treatment was 7 days; the study did not report the setting, how allocation to treatment groups occurred, blinding of either outcome assessors or patients, or the number of patients responding to the treatment. There was no statistically significant difference in severity of symptoms following treatment with once-daily versus twice-daily application of topical corticosteroids. Adverse effects were not reported.

Potent preparations

4.1.6 Eight RCTs were identified that examined frequency of application in potent topical corticosteroids for atopic eczema. Five of these compared the same active compound administered once and twice daily (four of these trials examined fluticasone propionate [ointment and cream]). Three trials investigating potent topical corticosteroids compared different active compounds; these all compared a once-daily-only product, mometasone furoate, with other topical corticosteroids administered twice daily.

4.1.7 Apart from two trials within this potency class, the Assessment Report considered the quality of reporting and the methodology of the included RCTs to be generally poor.

4.1.8 For four of the studies, the study setting was hospital or secondary care but the setting was not reported in the remaining studies. Duration of treatment in the studies was up to either 3 or 4 weeks. Where reported, the studies included people who had moderate to severe atopic eczema, apart from one study that included adults with mild to moderate eczema. One other study did not report the minimum severity of eczema of the study population.

4.1.9 Studies included children and adults, people aged over 12 years or 16 years, or adults only. Subgroup analyses of children aged 12 years or younger were reported for two trials.

Response to treatment

4.1.10 The studies measured effectiveness of the treatments using a variety of different outcome measures, most of which were subjective assessments by the investigator and/or patient. All studies apart from one reported the number of patients responding to treatment. However, response to treatment was defined in different ways by the studies. Two outcomes were considered in the Assessment Report: the number of patients with at least a good response or 50% improvement, and the number of patients whose eczema was rated cleared or controlled.

4.1.11 Seven studies reported the number of patients with at least a good response, assessed by the investigator and/or patient, or at least 50% improvement by the end of 3 or 4 weeks. Six studies reported the number of patients with eczema that was rated as cleared/controlled or excellent after 3 or 4 weeks.

4.1.12 Overall, studies found little difference in response to treatment between once-daily and twice-daily application of potent corticosteroids. Some statistically significant differences favouring twice-daily treatment were identified, but these were inconsistent between outcome assessors (physicians versus patients) and outcomes selected for analysis. Subgroup analysis of patients aged 12 years or younger produced similar findings to the main analysis.

4.1.13 One study compared success rates between morning and evening application in the once-daily group (67% versus 78%, difference 11.3%; 95% confidence interval [CI] –4.6 to 27.2, p = 0.17). Despite finding a statistically significant difference between once-daily and twice-daily application, when assessed by the physician (but not when assessed by the patient), the difference between once-daily evening treatment and twice-daily application was not statistically significant (78% versus 84%, difference 5.9%; 95% CI –6.6 to 18.4, p = 0.33).

Severity of signs and symptoms

4.1.14 None of the studies reported the use of a validated severity scale, and the clinical relevance of a change in severity is not clear. However, in one study, once-daily use of mometasone furoate, which is a once-daily-only product, was found to result in a greater percentage improvement in total atopic eczema scores than twice-daily betamethasone valerate at each assessment, (p < 0.01). Another study found an improvement in pruritus (p = 0.007) only, following mometasone furoate, compared with twice-daily hydrocortisone 17-butyrate. A third study comparing once-daily use of mometasone furoate with betamethasone dipropionate found no statistically significant differences in percentage reduction of severity for erythema, induration or pruritus. However, the Assessment Group stated that these three trials were all of poor quality because they were described as single-blind (investigators blinded), but the trials did not give details of methods or procedures, or use of placebo treatment in the once-daily group. Two of these trials also failed to report whether comparison groups were similar at baseline.

4.1.15 A greater reduction in severity scores demonstrated at 2 weeks (p = 0.04) for twice-daily compared with once-daily use of hydrocortisone 17-butyrate was not maintained at 4 weeks (p = 0.08) in one trial, and although the twice-daily group showed more pronounced reductions in rating for erythema at 4 weeks (p = 0.03), this was not the case for the other symptoms assessed. No confidence intervals were available for these trials.

4.1.16 One trial found total severity scores to be similar between once-daily and twice-daily application of fluticasone propionate ointment at each visit, although logistic regression analysis of total severity score (adjusting for age and baseline total severity score) favoured twice-daily application at the last visit attended (odds ratio [OR] 1.72; 95% CI 1.05 to 2.82, p = 0.033). However, the odds ratio for the treatment effect in the subgroup analysis of patients aged 12 years or younger was not statistically significant (OR 1.85; 95% CI 0.88 to 3.89, p = 1.03).

4.1.17 None of the other studies comparing potent topical corticosteroids found a statistically significant difference in severity of atopic eczema following once-daily application compared with more frequent applications.

Adverse effects

4.1.18 The quality and extent of reporting of adverse effects was variable among studies. There appeared to be little difference in the frequency or severity of adverse events between once-daily and twice-daily application of topical corticosteroids, although data were limited because of the short duration of the studies.

4.1.19 One study did report potential differences in sleep disturbance, finding sleep to be "as good as ever has been" or better by 37% of patients following once-daily application of fluticasone propionate compared with 55% of patients following twice-daily application. No p value or confidence intervals were available for this outcome.

Very potent preparations

4.1.20 One RCT compared once-daily application of halcinonide cream (0.1%) with three-times-daily application of the same product.

4.1.21 The trial was double-blind, but the concealment of allocation was not reported. The duration of the study was a maximum of 3 weeks, or shorter if complete remission was obtained. The age range of patients, the study setting and the minimum severity of eczema for the included patients were not reported in the study.

4.1.22 The study compared the response of similar lesions on each side of the patient. A better response (slightly superior or markedly superior) was observed following three-times-daily application. Overall, 32% of patients had a better clinical response to three-times-daily application, 21% had a better clinical response to once-daily application, and 47% had an equal response (p < 0.05), but no statistically significant difference was found in the number of patients with at least a good absolute therapeutic response.

4.1.23 The authors of the study stated that the side effects were generally of a mild nature, the most common being burning, pruritus and erythema, with no difference in incidence between once-daily and three-times-daily regimens, and that no systemic effects were observed. However, the Assessment Report pointed out that no data were presented on adverse effects.

Summary

4.1.24 Overall, the Assessment Report did not identify any clear differences for any of the potency classes in outcomes between once-daily and more frequent application of topical corticosteroids. For potent preparations, one study indicated a statistically significant difference in favour of the twice-daily application of fluticasone propionate (ointment) in response rates between the different regimens (at least a good response rate or 50% improvement), when patients were assessed by physicians; however, this was not the case for patient assessment. For a response of cleared or controlled atopic eczema, one trial indicated a significant difference in favour of twice-daily treatment of hydrocortisone 17-butyrate when patients were assessed by a physician. Two studies, considered by the Assessment Group to be of poor quality (as described in Section 4.1.14), favoured once-daily treatment of mometasone furoate over twice-daily use of other products (depending on severity of certain symptoms). The trial of a very potent corticosteroid reported a statistically significant difference in clinical response, favouring more frequent application, but no significant difference in the number of patients with at least a good response.

4.2 Cost effectiveness

4.2.1 The Assessment Group did not identify any published economic evaluations that examined frequency of use of same-potency topical corticosteroids.

4.2.2 No economic evaluations were identified or submitted by the manufacturers or other consultees. No quality-of-life or patient preference outcomes were included in any of the studies in the systematic review.

4.2.3 The Assessment Group concluded that there was no basis to draw firm conclusions over the relative effectiveness of once-daily versus more frequent use of same-potency topical corticosteroids for atopic eczema. Consequently, the economic analysis assumes equivalent effectiveness of once-daily application and more frequent application of topical corticosteroids, and cost-minimisation analysis was undertaken.

4.2.4 The cost per application of topical corticosteroids varies depending on the quantity used per application. Evidence was derived from two of the included RCTs and four additional studies that were identified. The Assessment Group stated that, although it would be reasonable to assume that the actual amount of topical corticosteroid used in a once-daily regimen is less than that used for more frequent applications (especially when referring to the same product), it is not possible to estimate accurately the quantity of medication used according to frequency of application. Another consideration was that topical corticosteroids are applied when people experience flare-ups, rather than continuously over time. Consequently, extrapolation over longer periods of time was not straightforward.

4.2.5 The Assessment Group provided a cost-minimisation analysis for nine of the ten included clinical trials. In this, once-daily use was the least costly option on six occasions and twice-daily use the least costly on three occasions. The wide range of topical corticosteroid products available and their varied prices means that there are many possible prescribing scenarios. The availability of specifically marketed once-daily topical corticosteroids, which are priced much higher than other generic and proprietary products, makes a once-daily regimen more costly when these products are used. For example, where fluticasone propionate cream (£4.59) or mometasone furoate (£4.22) once daily is substituted for betamethasone valerate (£1.31), betamethasone dipropionate (£2.05) or hydrocortisone butyrate (£2.38) twice daily, the once-daily regimen would be expected to cost more than the twice-daily regimen.

4.2.6 The trial examining fluticasone propionate (ointment) showed a benefit associated with twice-daily use in terms of physician assessment (but not for patient assessment) of patients' target area of atopic eczema. Consequently, a simple estimate of cost effectiveness was made. This found the additional cost per treatment success to be £76.50. The assumptions underlying this analysis were generous and a more realistic estimate of the treatment cost per additional successfully treated flare-up would probably be half that value. The Assessment Group concluded that the greater likelihood of treatment success (that is, successfully treated flare-up) would be of sufficient value (in terms of patient benefit, and avoided GP consultations, referrals to specialists or prescribing of more expensive products) to regard twice-daily application as cost effective.

4.3 Consideration of the evidence

4.3.1 The Committee reviewed the data available on the clinical and cost effectiveness of the frequency of application of topical corticosteroids for atopic eczema, having considered evidence on the nature of the condition and the value placed on the benefits of different frequencies of application of topical corticosteroids by people with atopic eczema, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources.

4.3.2 The Committee considered the various factors that might influence the frequency of application of topical corticosteroids for atopic eczema. These included the clinical presentation, factors influencing concordance with treatment, and patient choice. It heard from the experts that the potency of corticosteroid was not a relevant factor in determining the frequency of application.

4.3.3 Additionally, the Committee appreciated that people with eczema may have considerable fear of the use of corticosteroids, and also need to use a number of other measures to manage their condition on a daily basis. On the basis of expert testimony, concordance with once-daily or twice-daily application of topical corticosteroids is not of particular concern to patients because of the fact that they have to apply emollients regularly to manage their condition. The Committee was informed that good-quality patient education on the use of topical corticosteroids was a significant factor in ensuring the success of therapy. The Committee was also informed that there was a clear need for continuing education of healthcare professionals to ensure that correct advice on the use of topical corticosteroids is given to people with atopic eczema.

4.3.4 The Committee reviewed the evidence related to the frequency of application of topical corticosteroids in atopic eczema. It considered that the RCTs available were, in general, of poor methodological quality, and it was advised by the experts that longer follow-up – months, not weeks – would be required of trials to assess fully any potential differences in long-term efficacy and adverse effects between once-daily and more frequent applications of topical corticosteroids. The Committee additionally appreciated that there may be differences in the pharmacokinetics of the individual topical corticosteroids, but it was persuaded that these differences, if of clinical significance, would be reflected in the clinical effectiveness evidence.

4.3.5 The Committee was informed that differences exist in clinical practice, between clinicians, in the prescription of once-daily or more frequent use of topical corticosteroids. However, it was agreed by the experts that, where once-daily application of a topical corticosteroid was initially advised, clinicians would have to increase either the potency or the frequency of the topical corticosteroid, if there was no improvement in the condition. Alternatively, if twice-daily application was advised initially for a flare-up, it would be expected that people would reduce the frequency of application of the same product once their condition began to improve.

4.3.6 Having considered the results from the RCTs, as well as the testimony from the expert witnesses, the Committee concluded that there was no compelling evidence of a clinically significant difference between once-daily application and more frequent application of topical corticosteroids in terms of their effectiveness, patient satisfaction, adverse events, concordance with therapy or the number of follow-up visits required. It was persuaded that current clinical practice would therefore support a recommendation for the use of topical corticosteroids no more frequently than twice daily.

4.3.7 The Committee concluded that, on the basis of the consideration in Section 4.3.6, where more than one alternative topical corticosteroid is considered clinically appropriate within a potency class, the product with the lowest acquisition cost (taking into account pack size and frequency of application) should be used in preference to more expensive alternatives. From the cost-minimisation analysis presented, the Committee noted that because of the acquisition cost of some products licensed solely for once-daily application, in some product comparisons, twice-daily application of other products was less costly than once-daily application.