Appraisal Consultation Document Frequency of application of topical corticosteroids for atopic eczema

Appraisal Consultation Document

Frequency of application of topical corticosteroids for atopic eczema

The Department of Health and the National Assembly for Wales have asked the National Institute for Clinical Excellence (NICE or 'the Institute') to conduct an appraisal of the frequency of application of topical corticosteroids for atopic eczema and to 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 and the views put forward by the representatives nominated for this appraisal by professional organisations and patient/carer and service user organisations. The Committee has developed preliminary recommendations on the frequency of application of topical corticosteroids for atopic 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).

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 Technology Appraisal Process on the Institute's website).

  • 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: Thursday 19 March 2004
Second Appraisal Committee meeting: Wednesday 24 March 2004

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 this technology. The recommendations made in Section 1 are preliminary and may change after consultation.
1 Appraisal Committee's preliminary recommendations
This appraisal relates to the frequency of application of topical corticosteroids in the treatment of atopic eczema. It does not include the use of topical agents that combine corticosteroids with other active agents (for example, antimicrobials, salicylic acid, antibacterials).
1.1 It is recommended that topical corticosteroids for atopic eczema should not be administered more than twice daily.
1.2

The decision to use topical corticosteroids once or twice daily will depend on the following:

  • clinical presentation (including severity of clinical symptoms, site of atopic eczema, age of patient)
  • factors related to concordance with treatment
  • patient choice.
1.3 It is recommended that where more than one alternative topical corticosteroid is considered clinically appropriate, the drug with the lowest acquisition cost should be prescribed, taking into account pack size, frequency of application, potency group and product price.
2 Clinical need and practice
2.1 Atopic eczema (synonymous with atopic dermatitis) is a chronic relapsing skin condition characterised by intense itching, dry skin, redness, inflammation and exudation. It affects mainly the flexor surfaces of the elbows and knees, as well as the face and neck.
2.2 The term 'atopic' refers to the association with atopy (a state of hypersensitivity to common environmental allergens that may be inherited) and differentiates atopic eczema from other forms of eczema such as irritant, allergic contact, discoid, venous, seborrhoeic and photosensitive eczema, which have different disease patterns and aetiologies.
2.3 Estimates of prevalence vary but suggest that the condition may affect as many as 15-20% of school-age children and 2-10% of adults. The majority of people with atopic eczema (over 80%) experience mild disease, whereas only a small proportion (around 2-4%) have a severe form of the disease. Despite the lower prevalence, the presentation of disease in adults is often more severe and chronic in nature.
2.4 In most people with atopic eczema, the condition begins in early childhood - often in the first year of life, when it can be particularly severe. Findings from the National Child Development Study (NCDS), developed from the birth cohort of 1958, suggested an incidence rate of around 50 cases per 1,000 in the first year of life, falling to 5 new cases per 1,000 per year for the rest of childhood. In around 60% of children, the condition clears by the time they reach their teens. However the tendency towards dry and irritable skin generally persists and later recurrences are common.
2.5 The aetiology of atopic eczema is complex and not fully understood. Genetic factors are important but environmental factors, such as house dust mites, pollen, tobacco, air pollution and low humidity, may cause its onset and/or exacerbate existing symptoms. More persistent disease has been consistently linked with early disease onset, severe widespread disease in early life, concomitant asthma or hay fever, and a family history of atopic eczema. The condition is exacerbated by soap and detergents, clothes containing wool or certain synthetic fibres, and extremes of temperature.
2.6 The severity of atopic eczema varies enormously, from an occasional dry, scaly patch of eczema, to a debilitating disease, where much of the body is covered by excoriated, bleeding and infected lesions. Its course may be continuous for prolonged periods or of a relapsing-remitting nature, characterised by acute flare-ups.
2.7 Itching skin (pruritus) is a major symptom of atopic eczema. A vicious itch-scratch circle can occur, where itching and scratching damage the skin and increase inflammation, which in turn increases the itch. Damage to the skin from scratching can cause bleeding, secondary infection and thickening of the skin (lichenification).
2.8 The impact of atopic eczema on quality of life can be considerable and it has been shown to vary according to disease severity. In addition to the burden imposed by daily treatment, studies have shown not only that the condition affects everyday activities such as work or school and social relationships, but also that people with atopic eczema may also experience anxiety, depression and other psychological problems. Sleep disturbance is common, especially during flare-ups, which in turn can lead to problems with irritability and lack of concentration. Severe atopic eczema in children can also have a significant impact on family life, with parents/carers coping with the demands associated with caring for a child with a chronic illness.
2.9

Historically, there have been variations over the clinical definition and diagnosis of atopic eczema. A UK Working Party has developed criteria for use in epidemiological studies, and these are now commonly used, although further validation is required. To qualify as a case of atopic eczema using these criteria, the person must have had an itchy skin condition in the last 12 months, plus three or more of the following:

  • history of flexural involvement (that is, affecting the bends of the elbows or behind the knees)
  • history of a generally dry skin
  • personal history of other atopic disease (in children under 4 years, a history of atopic disease in a first-degree relative may be included)
  • visible flexural dermatitis as defined by a photographic protocol
  • onset below the age of 2 years (not used in children under 4 years).
2.10 There is uncertainty and a lack of standardisation around clinical assessment of disease severity, both in practice and in trial settings. Although a number of scoring systems have been used to categorise the disease as mild, moderate or severe, usually by aggregating scores from a range of symptoms and disease characteristics, none of these scoring systems have been accepted as a 'gold standard' and there remains general debate over their use.
2.11 Atopic eczema in childhood shows a reverse social class gradient with higher rates in socio-economically advantaged groups and smaller families. There is also evidence of variation in prevalence by region, with the highest rates recorded in the South East and industrialised Midlands, and the lowest rates in Wales and Scotland.
2.12 Management of atopic eczema takes place predominantly in primary care, and aims to relieve symptoms and prevent complications such as infections until remission occurs. This management involves the identification and avoidance of exacerbating factors, skin care and anti-inflammatory treatment. Providing people with good quality information about these issues is essential to successfully managing and treating atopic eczema. Referral to secondary care is only advised if the condition is severe and has not responded to appropriate therapy.
2.13 Emollients are a first-line therapy for atopic eczema and aim to retain the skin's barrier function (keeping water in and irritants or pathogens out) and to prevent painful cracking. Frequent and continuous use is recommended even in the absence of symptoms. Preparations available include bath oils, soap substitutes and moisturisers; generally, the greasier the preparation, the better the effect, although people using very greasy products may not consider them acceptable.
2.14 Topical corticosteroids are the first-line treatment for episodic worsening (flare-ups) of atopic eczema. In order to reduce exposure to topical corticosteroids, they are used only intermittently to control exacerbations. Treatment regimens for topical steroids vary with disease severity, with clinicians usually recommending use of the mildest potency products possible to treat the condition, in order to minimise the potential adverse effects. Emollients are used in combination with the topical corticosteroids.
2.15

Other treatments, in no particular order, include:

  • antihistamines
  • wet wraps (when a layer of emollients with or without corticosteroids is applied to the skin and wrapped in wet bandages, followed by dry bandages and left over night), which may be used in an attempt to maximise the effect of treatment
  • tar
  • ichthammol (a type of bitumen), which may be used as a cream, ointment or paste bandages, or can be added to a bath
  • evening primrose oil
  • alternative therapies such as Chinese herbs
  • phototherapy
  • immunosuppressants (that is, cyclosporin and azathioprine).

Secondary bacterial infections are treated with antibiotics orally or in combination with corticosteroid creams.

2.16 Systemic corticosteroids may be used in some cases of severe atopic eczema. However, because of risks of growth retardation in children and adolescents and other adverse effects, this treatment option is avoided whenever possible.
3 The technologies
3.1 Topical corticosteroids have anti-inflammatory and immunosuppressive effects. The mechanism of the anti-inflammatory activity of topical steroids in general is unclear, although various symptomatic components of the inflammatory pathway are known to be suppressed.
3.2 Thirty preparations of topical corticosteroids are included in this appraisal (see Appendix D). Topical corticosteroids are classified according to their potency. This is determined by the amount of vasoconstriction a topical corticosteroid produces and the degree to which it inhibits inflammation (a more potent product increases suppression to the inflammatory pathway). In the UK, four potencies are recognised: mild, moderately potent, potent and very potent. Across the different potencies, products have different formulations and different strengths (for example, 0.025%, 0.1%, 0.5%) and are available in various preparations (for example, ointment, cream, lotion, foam).
3.3 The most widespread side effect of topical corticosteroid treatment is skin atrophy, where the skin becomes thin and may become easily bruised. This is more likely on areas where the skin is already thin, such as the face or flexures, as absorption is greatest in these areas. The skin structure may recover gradually after stopping treatment, although the original structure may never return. However, with excessive amounts or prolonged use of a potent steroid, the dermis will lose its elasticity and stretch marks (striae) will occur, which are permanent. For full details of side effects and contraindications, see the Summaries of Product Characteristics (SmPCs) for the topical corticosteroids.
3.4 Guidelines from the British Association of Dermatologists suggest the best way of using of topical corticosteroids is probably twice daily for 10-14 days when the eczema is active, and this should then be followed by a 'holiday period' of emollients only. The National Prescribing Centre recommends that, in general practice, topical corticosteroids be used in short bursts (for 3-7 days) to treat exacerbations of disease.
3.5 There are varying recommendations about the frequency of application. Although there are few empirical data to assess the patterns of prescribing with respect to frequency of application, it appears that a twice-daily regimen is the most widespread approach to the use of topical corticosteroids in atopic eczema. However, the SmPCs for some of the topical corticosteroids indicate that some are licensed for more frequent use (up to four times a day), and two products are licensed for use only once a day in atopic eczema.
4 Evidence and interpretation
The Appraisal Committee considered evidence from a number of sources (see 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 and 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 to be 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.
Moderately potent preparations
4.1.4 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 reported that the study was small, duration of treatment was 7 days, and that 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
4.1.5 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.
4.1.6 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.
4.1.7 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.
4.1.8 Studies included children and adults, people aged over 12 years or 16 years, or adults only. Subgroup analyses of children aged 12 years or less were reported for two trials.
Response to treatment
4.1.9 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.
4.1.10 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. Overall there was little difference between once-daily and more frequent application. Only one study found a statistically significant difference, where twice-daily application of fluticasone propionate ointment increased the chance of success (as assessed by the physician) by 14% of that in the once-daily group, although the 95% confidence interval (CI) was close to no effect (risk ratio [RR] 0.86, 95% CI 0.75 to 0.99). The increase in the chance of success with twice-daily treatment when assessed by patients in this study was not, however, statistically significant (RR 0.87, 95% CI 0.75 to 1.02).
4.1.11 Six studies reported the number of patients with eczema that was rated as cleared/controlled or excellent after 3 or 4 weeks. In one study, the physician's opinion of clearance of lesions showed a statistically significant difference in favour of twice-daily treatment. Once-daily treatment reduced the chance of clearance of symptoms by 31% of that with twice-daily treatment (RR 0.69, 95% CI 0.52 to 0.91). However, this was not supported by the patient's opinion of clearance of lesions, which did not show a statistically significant difference between once- and twice-daily treatment (RR 0.83, 95% CI 0.64 to 1.07).
4.1.12 One trial reported the number of patients aged over 12 years whose atopic eczema was controlled (absent or mild) after 4 weeks with once- or twice-daily fluticasone propionate cream or ointment. The trial found no statistically significant difference between once- and twice-daily application of cream (80% vs 84%, p = 0.546) or ointment (77% vs 71%, p = 0.249).
4.1.13 Results of another trial also found that a target lesion was rated as cleared or excellent by the physician, after 4 weeks, in a similar proportion of patients who received once- or twice-daily fluticasone propionate cream (69% vs 78%, p = not statistically significant). Although this study found a statistically significant difference at 3 weeks (once-daily 57% vs twice-daily 70%, p < 0.014), the difference was not statistically significant at 1 week (29% vs 39%) or 2 weeks (42% vs 62%).
4.1.14 Subgroup analysis of patients aged 12 years or younger produced similar findings to the main analysis, with success rates (as assessed by the physician) of 77% and 91% at the last visit attended with once- and twice-daily application, respectively (difference 13.5%, 95% CI 0.6 to 26.4, p = 0.048). The patients' assessment of success also favoured twice-daily use (72% versus 91%, 95% CI 5.0 to 32.3, p = 0.011). Conversely, subgroup analysis of patients aged 12 years or younger from another study found no statistically significant differences in success rates between once- and twice-daily application at the last visit attended (86% versus 89%, difference -3%, 95% CI 15.5 to 9.6, p = 0.644), again supporting the main analysis of this study.
4.1.15 Overall, studies found little difference in response to treatment between once- and twice-daily application of potent corticosteroids. Some statistically significant differences favouring twice-daily treatment were identified; however, these were inconsistent between outcome assessors (physicians versus patients) and outcomes selected for analysis.
4.1.16 One study compared success rates between morning and evening application in the once-daily group (67% versus 78%, 95% CI -4.6 to 27.2, p = 0.17). Despite finding a statistically significant difference between once- and twice-daily application, the difference between once-daily evening treatment and twice-daily application was not statistically significant (78% versus 84%, 95% CI -6.6 to 18.4, p = 0.33).
Severity of signs and symptoms
4.1.17 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. 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. However, the Assessment Group stated that these trials were all of poor quality.
4.1.18 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.
4.1.19 One trial found total severity scores to be similar between once- 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 (OR 1.72, 95% CI 1.05 to 2.82, p = 0.033). However, the odds ratio (OR) 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).
4.1.20 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
4.1.21 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.
4.1.22 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.
Very potent preparations
4.1.23 One RCT compared once-daily application of halcinonide cream (0.1%) with three-times-daily application of the same product.
4.1.24 The trial was described as double-blind, although the concealment of allocation was not reported. The duration of the study was a maximum of three 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.
4.1.25 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 response to three-times-daily application, 21% had a better 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.
4.1.26 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
4.1.27 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. 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, 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 was the least costly option on six occasions and twice-daily use was the least costly option on three occasions. The wide range of topical corticosteroid products available and their varied prices means that a large number of possible prescribing scenarios exist. The availability of specifically marketed once-daily topical corticosteroids, which are priced at a much higher level 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 (4.88) once daily is substituted for betamethasone valerate (1.31), betamethasone dipropionate (2.05) or hydrocortisone butyrate (1.97) twice daily, the once-daily regimen would be expected to be more costly 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 of patients' target area of atopic eczema. Consequently, a simple estimate of cost effectiveness was made. This found that 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 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 frequency 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. Based on expert testimony, concordance with once- 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 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 for 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 application 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, if once-daily application of a topical corticosteroid was initially advised, most clinicians would increase the potency of the topical corticosteroid rather than frequency, 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, and that application less frequently would depend on a variety of factors related to clinical presentation including severity of clinical symptoms, site of atopic eczema, age of patient and patient choice.
4.3.7 The Committee concluded that, on the basis of the consideration in paragraph 4.3.6, the product with the lowest acquisition cost (taking into account pack size, frequency of application, potency group and product price) 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.
5 Proposed recommendations for further research
5.1 The trial literature is dominated by comparisons of differing frequency of use of fluticasone propionate (four trials) and comparisons of mometasone furoate with more traditional twice-daily treatment options (three trials). Trials are needed to establish whether once-daily use of the older (twice-daily) products is equivalent to more frequent use. Trials are also required to establish whether once-daily use of the older twice-daily products is equivalent to the once-daily-only products. Trials are required for all the potency classes, in particular for mild potency preparations, as no trials examining frequency of application of topical corticosteroids exist for this group.
5.2 Robust trials are required that report quality of life data and patient preferences.
5.3 Long-term follow-up is required in trials to assess adverse effects such as skin atrophy.
5.4 The experts informed the Committee that there was a lack of support for people with the condition and inadequate information about the management of atopic eczema and the risks associated with the use of topical corticosteroids. Research should therefore be conducted to establish the most suitable method of conveying good quality information to people with atopic eczema.
6 Preliminary views on the resource impact for the NHS
This section outlines the Appraisal Committee's preliminary assessment concerning the likely impact on NHS resources if the recommendations in Section 1 were to be implemented. When guidance is issued, this section is intended to assist NHS planners and managers in its implementation. Therefore the Institute particularly welcomes comments and information from those who would be involved in the implementation of the guidance so that this section can be made as helpful and robust as possible.
6.1 Information is not readily available on current prescribing patterns of topical corticosteroids in patients with atopic eczema. There is also limited information on the quantity of product used per treatment regimen. Consequently, it is not possible, with any certainty, to establish baseline information on which to base estimates of the resource impact of changes in prescribing between preparations of different acquisition costs. Furthermore, such cost savings will be relatively small at the patient level, and issues related to pack size and product waste can easily erode any potential cost saving. However, given the large patient group with atopic eczema, there may be opportunities for significant savings to the NHS on products prescribed. Two illustrative scenarios are explored below, though their likelihood is difficult to predict.
6.2 If a prescribing practice of twice-daily use of a topical corticosteroid were changed to once-daily use of the same product, cost savings have been estimated to range from 300,000 to 1.2 million for a patient group of 100,000 people with atopic eczema, for the most commonly prescribed products. The underlying assumptions are that patients have two to four 'flare-ups' a year, patients throw away any unused products after each 'flare-up', and patients applying topical corticosteroids once daily would use either 50% or 75% of the amount they would use if they were applying the product twice daily. These potential savings assume that all the patient prescription costs are met by the NHS.
6.3 Secondly, where a prescribing practice of one of the newer once-daily-only products can appropriately be altered to twice-daily use of one of the older, cheaper topical corticosteroids of the same potency, cost savings have been estimated to range from 475,000 to 950,000 for a patient group of 100,000 people with atopic eczema. The underlying assumptions are that patients have two to four 'flare-ups' a year, patients throw away any unused products after each 'flare-up', and patients applying topical corticosteroids twice daily would use twice the amount they would use if they were applying the once-daily-only product. These potential savings assume that all the patient prescription costs are met by the NHS.
6.4 These estimates are based on a number of convenient assumptions. Many patients receive only one prescription per year, and pack size will determine the quantity dispensed.
7 Proposals for implementation and audit
This section presents proposals for implementation and audit based on the preliminary recommendations for guidance in Section 1.
7.1 All clinicians who care for people with atopic eczema should review their current practice and policies to take account of the guidance set out in Section 1.
7.2 Local guidelines or care pathways for people with atopic eczema should incorporate the guidance.
7.3 To measure compliance locally with the guidance, the following criteria could be used. Further details on suggestions for audit are presented in Appendix C.
7.3.1
Topical corticosteroids for atopic eczema are not prescribed for use more than twice daily.
7.3.2

The prescribing clinician considers the following in the decision to prescribe topical corticosteroids for once- or twice-daily use:

a. the clinical presentation
b. factors related to the individual's concordance with treatment
c. the individual's choice.

7.3.3
If more than one alternative topical corticosteroid is considered clinically appropriate, the drug with the lowest acquisition cost is prescribed.
7.4
Local clinical audits could also include measurement of compliance with recognised guidelines for the management of atopic eczema and the effectiveness of patient education on use of topical corticosteroids.
8 Related guidance
8.1 The clinical and cost effectiveness of tacrolimus and pimecrolimus compared to topical corticosteroids is currently being appraised by NICE and guidance is due to be published in September 2004.
9 Proposed date for review of guidance
9.1 The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review.
9.2 It is proposed that the guidance on this technology is reviewed in July 2007.
Andrew Stevens
Chair, Appraisal Committee
February 2004
Appendix A. Appraisal Committee members

NOTE 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 twice a month except in December, when there are no meetings.

The Committee membership is split into three branches, with the chair, vice-chair and a number of other members attending meetings of both branches. 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.

Dr A E Ades
Senior Scientist, MRC Health Services Research Collaboration, University of Bristol
Dr Tom Aslan
General Practitioner, Stockwell, London
Professor David Barnett (Chair)
Professor of Clinical Pharmacology, University of Leicester
Professor Rosamund Bryar
Professor of Community & Primary Care Nursing, St Bartholomew School of Nursing and Midwifery
Dr Rodney Burnham
Consultant Physician & Gastroenterologist, Oldchurch Hospital, Romford
Dr Gary Butler
Consultant Paediatrician/Endocrinologist, Leeds Teachning Hospitals NHS Trust
Dr Karl Claxton
Health Economist, University of York
Dr Christopher Eccleston
Director, Pain Management Unit, Department of Psychoogy, University of Bath
Ms Bethan George
Interface Liaison Pharmacist, Mile End Hospital, London
Mr John Goulston
Director of Finance, Barts and the London NHS Trust
Mr Adrian Griffin
Health Outcomes Manager, Johnson & Johnson Medical Ltd
Judith Paget
Chief Executive, Caerphilly Local Health Board
Dr Katherine Payne
Research fellow, Health Economics, University of Manchester
Mrs Kathryn Roberts
Nurse Practitioner, Hyde, Cheshire
Ms Anne Smith
Lay Representative; Trustee, Long-Term Medical Conditions Alliance
Professor Andrew Stevens (Vice-Chair)
Professor of Public Health, University of Birmingham
Dr Cathryn Thomas
General Practitioner, and Senior Lecturer, Department of Primary Care & General Practice, University of Birmingham
Dr Norman Vetter
Reader, Department of Epidemiology, Statistics and Public Health, College of Medicine, University of Wales, Cardiff
Dr Paul Watson
Medical Director, Essex Strategic Health Authority
NICE Project Team
Each appraisal of a technology is assigned to a Health Technology Analyst and a Technology Appraisal Project Manager within the Institute.
Joanna Richardson, Technical Analyst
Kathleen Dalby, Technology Appraisal Project Manager
Appendix B. Sources of evidence considered by the Committee
The following documentation and opinion was made available to the Committee:
A.

The assessment report for this appraisal was prepared by Southampton Health Technology Assessment Centre.

Green C, Colquitt JL, Kirby J et al. Clinical and cost-effectiveness of once daily versus more frequent use of same potency topical corticosteroids for atopic eczema: a systematic review and economic evaluation, November 2003.

B.

The following organisations accepted the invitation to participate in this appraisal. They were invited to make submissions and comment on the draft scope and assessment report. They are also invited to comment on the Appraisal Consultation Document and consultee organisations are provided with the opportunity to appeal against the Final Appraisal Determination.

I Manufacturer/sponsors:

  • Dermal Laboratories
  • GlaxoSmithKline
  • Novartis
  • Pliva Pharma
  • Schering-Plough
  • Stiefel Laboratories (UK)
  • Typharm
  • Waymade Healthcare
  • Yamanouchi

II Professional/specialist, patient/carer and other groups:

  • British Association of Dermatologists
  • British Generic Manufacturers' Association
  • Department of Health
  • Hounslow Primary Care Trust
  • National Eczema Society
  • Primary Care Dermatology Society
  • Royal College of General Practitioners
  • Royal College of Nursing
  • Royal College of Physicians
  • Royal Pharmaceutical Society of Great Britain
  • Skin Care Campaign
  • Welsh Assembly Government

III Commentator organisations (without the right of appeal):

  • NHS Confederation
  • NHS Purchasing and Supply Agency
  • NHS Quality Improvement Scotland
  • Skin Treatment & Research Trust
C.

The following individuals were selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee's deliberations. They gave their expert personal view on the frequency of application of topical corticosteroids for atopic eczema by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the Appraisal Consultation Document.

  • Ms Sandra Lawton, Nurse Consultant Dermatology, Queen's Medical Centre, Nottingham
  • Dr Celia Moss, Consultant Dermatologist, Birmingham Children's Hospital
  • Ms Sue Ward, Information and Education Manager, National Eczema Society
Appendix C. Detail on criteria for audit of the frequency of application of topical corticosteroids for atopic eczema
Possible objective for an audit
An audit could be carried out to ensure the appropriateness of prescription of topical corticosteroids for atopic eczema
Possible patients to be included in the audit
An audit could be carried out on all patients seen for atopic eczema in a reasonable period for audit, for example, 6 months, who are prescribed topical corticosteroids but not those topical agents that combine corticosteroids with other active agents (for example, antimicrobials, salicyclic acid, antibacterials).
Measures that could be used as a basis for an audit
The measures that could be used in an audit of the prescription of topical corticosteroids for atopic eczema are as follows.
Criterion
Standard
Exception
Definition of Terms
1. Topical corticosteroids for atopic eczema are not prescribed for use more than twice daily. 100% of people for whom topical corticosteroids for atopic eczema are prescribed None The diagnosis of atopic eczema is established by the individual having an itchy skin condition in the last 12 months plus three or more of the following: history of flexural involvement (that is, bends of the elbow or behind the knees); history of a generally dry skin; personal history of other atopic disease (in children under 4 years, history of atopic disease in a first-degree relative may be included); visible flexural dermatitis as defined by a photographic protocol; and onset below the age of 2 years (not used in children under 4 years).For a list of preparations of topical corticosteroids, that are relevant for this measure, see Appendix D.

2. The prescribing clinician considers the following in the decision to prescribe topical corticosteroids for once- or twice-daily use:

a. clinical presentation and

b. factors related to the individual's concordance with treatmentthe individual's choice

100% of people who are prescribed topical corticosteroids for atopic eczema None 'Clinical presentation' includes severity of clinical symptoms, site of atopic eczema and the individual's age.Clinicians will need to agree locally on how consideration of the clinical presentation, the individual's concordance with treatment and individual choice will be documented for audit purposes.
3. If more than one alternative topical corticosteroid is considered clinically appropriate, the drug with the lowest acquisition cost is prescribed. 100% of people who are prescribed topical corticosteroids for atopic eczema None Clinicians will need to agree locally on how the lowest acquisition cost is determined for audit purposes, taking into account pack size, frequency of application, potency group and product price.


Calculation of compliance with the measure
Compliance (%) with each measure described in the table above is calculated as follows.

Number of patients whose care is consistent with the criterion plus number of patients who meet any exception listed


X 100

Number of patients to whom the measure applies

Clinicians should review the findings of measurement, identify whether practice can be improved, agree on a plan to achieve any desired improvement and repeat the measurement of actual practice to confirm that the desired improvement is being achieved.

Appendix D. Topical corticosteroids for the treatment of atopic eczema, grouped by potency

BNF Chemical Name
Manufacturer
Product Name
Licence frequency from SPC, where available
Net cost per 30g/30ml* for each strength (does not include dispensing fee)
Mild potency
Hydrocortisone

Alpharma Ltd

BCM Limited

Bell Sons & Co (Druggists) Ltd

Bioglan Laboratories Ltd

Bioglan Pharmaceuticals Ltd

Biorex Laboratories Ltd

Co-Pharma Ltd

Diomed Developments Ltd

Galpharm Healthcare Ltd

Lagap Pharmaceuticals Ltd

Norton Pharmaceuticals Ltd

Novartis Consumer Health UK Ltd

Pinewood Laboratories Ltd

Reckitt Benckiser Healthcare (UK) Limited

Roussel Laboratories Ltd

Thornton & Ross Ltd

Waymade PLC

Generic* hydrocortisone cream/ointment 0.5%, 1% N/A 0.66, 0.74
Hydrocortisone GSK Efcortelan cream/ointment 0.5%, 1%, 2.5% 2-3 times daily 0.66, 0.81, 1.83
Hydrocortisone Yamanouchi Mildison Lipocream 1% 2-3 times daily 2.41
Hydrocortisone Dermal Dioderm cream 0.1% Twice daily 2.69
Fluocinolone acetonide Bioglan/ GP Pharma Synalar cream 1/10, 0.0025% 2-3 times daily 1.15
Moderate potency
Alclometasone dipropionate Dominion/ Pliva Modrasone cream/ointment 0.05% 2-3 times daily 1.69
Betamethasone valerate GSK Betnovate RD cream/oint 0.025% 2-3 times daily 1.08
Clobetasone butyrate GSK Eumovate cream/oint 0.05% Up to 4 times daily 1.94
Desoxymethasone Stiefel Stiedex LP oily cream 0.05% 2-3 times daily 2.73
Fluocinolone acetonide Bioglan/ GP Pharma Synalar cream/oint 1/4, 0.00625% 2-3 times daily 1.22
Fluocortolone Schering Health/ Meadow Ultralanum Plain cream/oint 0.25% N/A 1.77
Flurandrenolone Typharm Haelan cream/oint 0.0125% 2-3 times daily 1.63
Potent
Beclomethasone dipropionate GSK Propaderm cream/oint 0.025% Twice daily 1.74
Betamethasone dipropionate Schering Plough Diprosone cream/oint/ 0.05%, lotion 0.05% 1-2 times daily 2.41, 3.04
Betamethasone valerate GSK Betnovate cream/oint 0.1%, lotion 0.1%, scalp applic 0.1% 2-3 times daily 1.54, 1.57, 1.71
Betamethasone valerate Celltech Bettamousse foam 0.12% Twice daily 2.25
Betamethasone valerate Dermal Betacap scalp applic 0.1% Twice daily 1.27
Betamethasone valerate Dowelhurst Futuna Generic betamethasone valerate cream 0.1%, oint 0.1% N/A 1.54, 1.69
Diflucortolone valerate Schering Health/ Meadow Nerisone cream/oint 0.1%, oily cream 0.1% N/A 1.59, 2.56
Fluocinolone acetonide Bioglan/GP Pharma Synalar cream/ointment 0.025%, gel 0.025% 2-3 times daily 1.74, 2.57
Fluocinonide Bioglan/GP Pharma Metosyn FAPG cream 0.05%, oint 0.05% 3-4 times daily 1.54, 1.52
Fluticasone propionate GSK Cutivate cream 0.05% Once daily 4.59
Fluticasone propionate GSK Cutivate oint 0.05% Twice daily 4.59
Hydrocortisone butyrate Yamanouchi Locoid Lipocream 0.1% 2-3 times daily 2.35
Hydrocortisone butyrate Yamanouchi Locoid cream/oint 0.1%, scalp lotion 0.1% 2-4 times daily 2.24, 2.91
Hydrocortisone butyrate Yamanouchi Locoid Crelo 0.1% 2-3 times daily 2.48
Mometasone furoate Schering Plough Elocon cream/oint/scalp lotion 0.1% Once daily 4.88
Very potent
Clobetasol propionate GSK Dermovate cream/oint 0.05%, scalp applic 0.05% 1-2 times daily 2.82, 3.22
Diflucortolone valerate Schering Health/ Meadow Nerisone Forte oint/oily cream 0.3% N/A 4.18
Halcinonide BMS Halciderm cream 0.1% 2-3 times daily 3.40

* Using largest pack sizes available (for example, where 100g is the largest pack size, the cost is calculated using the 100g price multiplied by 0.3)
N/A - not available

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Accessibility | Cymraeg | Freedom of information | Vision Impaired | Contact Us | Glossary | Data protection | Copyright | Disclaimer | Terms and conditions

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