Appraisal Consultation Document: Tacrolimus and pimecrolimus for atopic eczema

Appraisal Consultation Document

Tacrolimus and pimecrolimus 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 tacrolimus and pimecrolimus for atopic eczema compared to current standard treatments and provide guidance on their 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 use of tacrolimus and pimecrolimus.

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).

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 (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: 28 April 2004
Second Appraisal Committee meeting: 13 May 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

1.1	Topical tacrolimus is recommended as an option for the second-line treatment of moderate to severe atopic eczema that has not been controlled by adequate use of appropriate potency topical corticosteroids and where there is a serious risk of important adverse effects from further topical corticosteroid use, particularly irreversible skin atrophy.

1.2	For the purposes of this guidance, atopic eczema that has not been controlled by adequate use of appropriate potency topical corticosteroids refers to disease that has not shown an adequate clinical response to the maximum strength and potency of topical corticosteroid that is appropriate for the patient's age and the area being treated.

1.3	It is recommended that treatment with tacrolimus be initiated only by physicians (including general practitioners) with a special interest in the treatment of atopic eczema, and only after careful discussion with the patient about the potential risks and benefits of all second-line treatment options.

1.4	Pimecrolimus is not recommended for the treatment of atopic eczema.

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, developed from the birth cohort of 1958, suggested an incidence of around 50 cases per 1000 in the first year of life, falling to 5 new cases per 1000 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 (scratched and abraded), 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 of daily treatment, studies have shown not only that the condition may affect everyday activities, such as work or school, and social relationships, but also that people with atopic eczema may 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 at younger than age 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 infection 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 form a standard part of skin care and aim to retain the skin's barrier function (keeping water in and irritants or pathogens out) and prevent painful cracking. Frequent and continuous use is recommended even in the absence of symptoms. Preparations include bath oils, soap substitutes and moisturisers.

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. Emollients are used with the topical corticosteroids.

2.15	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).

2.16	Treatment regimens for topical corticosteroids 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.

2.17	One of the potential long-term effects of topical corticosteroid treatment is permanent skin atrophy, whereby the skin becomes thin and loses some of its function. This is more likely to occur in areas where the skin is already thin, such as the face and flexures. Although reversible in the short-term, prolonged exposure can lead to permanent damage. Signs of atrophy include telangiectasia (abnormal dilation of capillary vessels and arterioles), increased transparency and shininess of the skin, and the appearance of striae (stripes or lines in the skin distinguished from surrounding tissue by colour, texture or elevation).

2.18	Systemic adverse effects with topical corticosteroids are rare but include suppression of the pituitary-adrenal axis (which may restrict growth).

2.19	Absorption of topical corticosteroids is higher at certain sites such as the face and flexures, and potent topical corticosteroids are generally avoided in these areas. The more potent topical corticosteroids are also contraindicated in infants younger than 1 year and are avoided in children or used with great care and for short periods. A potent or moderately potent topical corticosteroid may be appropriate for severe atopic eczema on the limbs, but for 1-2 weeks only, followed by a weaker preparation as the condition improves.

2.20	Treatments of last resort in resistant severe cases include systemic corticosteroids, phototherapy and systemic use of immunosuppressants, such

3	The technologies

	Tacrolimus and pimecrolimus are members of a new class of topical immunomodulators and belong to the class of immunosuppressant drugs known as calcineurin inhibitors. The way in which these drugs work differs from the way in which topical corticosteroids work: the topical immunomodulators work mainly by reducing inflammation through the suppression of T-lymphocyte responses. The use of emollients in conjunction with the topical immunomodulators is generally recommended. Although they have similar mechanisms of action, tacrolimus and pimecrolimus are licensed for different indications: pimecrolimus is licensed for first-line use in mild to moderate atopic eczema, whereas tacrolimus is licensed for second-line treatment of moderate to severe disease.

*3.1*	*Tacrolimus*

3.1.1	Tacrolimus ointment (Protopic, Fujisawa) is available in two strengths (0.1% and 0.03%), both of which are licensed for the treatment of moderate to severe atopic eczema in adults who have not adequately responded to, or are intolerant of, conventional therapies. The Summary of Product Characteristics currently recommends that adults should be treated with 0.1% tacrolimus for the first 3 weeks and should subsequently use the 0.03% strength. The lower strength is also licensed for the treatment of moderate to severe atopic eczema in children aged 2 years and older whose condition has not responded adequately to conventional therapies.

3.1.2	The Summary of Product Characteristics currently states that tacrolimus should 'only be prescribed by dermatologists and physicians with extensive experience in the treatment of atopic dermatitis with immunomodulating therapy'.

3.1.3	The Summary of Product Characteristics states that tacrolimus should be applied as a thin layer to affected areas of the skin twice daily and may be used on any part of the body, including the face, neck and flexural areas. It also states that the treatment of each affected region of the skin should be continued until the area is clear, and then be discontinued. In children, the frequency of application should be reduced to once a day after a maximum of 3 weeks and, in adults, an attempt should be made to reduce the frequency of application if the clinical condition allows. Tacrolimus can be used for short-term and intermittent long-term treatment. The net price is £21.60 for 30 g and £41.04 for 60 g (0.1% tacrolimus) and £19.44 for 30 g and £36.94 for 60 g (0.03% tacrolimus) (British National Formulary, 46th edition). Costs may vary in different settings because of negotiated procurement discounts.

3.1.4	Side effects include a burning or tingling sensation, pruritus, erythema, folliculitis, herpes simplex, acne, increased sensitivity to hot and cold, and alcohol intolerance. Lymphadenopathy has also been reported. When taken orally for other indications, tacrolimus has a number of well-recognised adverse effects, including renal toxicity and blood vessel narrowing effects. The potential long-term adverse effects of the topical use of tacrolimus on the skin, the immune system and other systems are not yet clear. For full details of the side effects and contraindications, see the Summary of Product Characteristics.

3.2	Pimecrolimus

3.2.1	Pimecrolimus cream 1.0% (Elidel, Novartis) is licensed for the first-line treatment of mild to moderate atopic eczema in adults and children aged 2 years and older, for short-term treatment of signs and symptoms and intermittent long-term treatment to prevent flare-ups.

3.2.2	Pimecrolimus is applied as a thin layer to affected skin twice daily and may be used on all skin areas, including the head, face, neck and intertriginous areas (an area where opposing skin surfaces touch and may rub, such as skin folds of the groin, axilla and breasts). The treatment of each affected region of the skin is continued until the area is clear and is then discontinued. Due to the low level of systemic absorption, there are no restrictions on the total daily dose applied, the body surface area that can be treated or the duration of treatment. The net price is £19.69 for 30 g, £37.41 for 60 g and £59.07 for 100 g (British National Formulary, 46^th edition). Costs may vary in different settings because of negotiated procurement discounts.

3.2.3	Side effects include a burning sensation, pruritus, erythema, skin infections (including folliculitis, herpes simplex and zoster, impetigo and molluscum contagiosum), papilloma (rarely) and local reactions such as pain, paraesthesia, peeling, dryness, oedema and worsening of eczema. Long-term effects on local immune response in the skin or on skin cancer incidence are not clear. For full details of the side effects and contraindications, see the Summary of Product Characteristics.

4	Evidence and interpretation

	Ten randomised controlled trials (RCTs) of tacrolimus and eight RCTs of pimecrolimus for the treatment of atopic eczema were considered. In most of the studies, comparators were topical corticosteroids or vehicle (a placebo consisting of the base cream or ointment without the active ingredient).

	Effectiveness was assessed in different ways across the trials but common measures included the following. Changes in severity using the Eczema Area Severity Index (EASI) or modified Eczema Area Severity Index (mEASI), which are well established and validated assessment tools that account for individual symptoms and disease severity in four predefined regions of the body. The Investigator's Global Assessment (IGA), a physician rating scale based on interpretation of signs of eczema, which does not appear to have been validated and has been criticised for having vague categories. The Physician's Global Evaluation (PGE) of treatment success, which estimates the percentage change in the condition since the person was last seen but does not appear to have been validated. The physician's evaluation of reduction in affected body surface area (BSA). Patient-based measures such as number of flare-ups, pruritus and use of alternative treatments, such as topical corticosteroids.

	The main quality-of-life measure used in the trials was the Dermatology Life Quality Index (DLQI), which is a 10-item self-administered questionnaire that is designed to measure the impact of skin diseases on patients' lives over the previous week.

4.1.1	Tacrolimus

4.1.1.1	Of the ten RCTs of tacrolimus, four were conducted in children and six in adults, all in populations with moderate to severe disease, reflecting the licensed indications.

4.1.1.2	Two of the studies in children compared tacrolimus with mild topical corticosteroids (n = 374 and n = 417) and two compared it with vehicle (n = 180 and n = 352). Results were considered for 0.03% tacrolimus only, as 0.1% tacrolimus is not licensed for use in children. No trials in children have compared tacrolimus to potent or moderately potent topical corticosteroids.

4.1.1.3	Three of the RCTs in adults used potent topical corticosteroid regimens as a comparator (n = 181, n = 570 and n = 975) and three used vehicle (n = 14, n = 215 and n = 632).

4.1.1.4	For children, a pooled analysis of two studies that compared 0.03% tacrolimus with mild topical corticosteroids showed 0.03% tacrolimus to be more effective at 3 weeks, as measured by an improvement of at least 90% ('cleared' to 'excellent' improvement) in the PGE (Relative Risk [RR] = 2.56, 95% Confidence Interval [CI] 1.95 to 3.36). On the basis of the median improvement in mEASI score, both studies also showed 0.03% tacrolimus to be significantly more effective than mild topical corticosteroids.

4.1.1.5	Both of the studies in children that compared 0.03% tacrolimus and vehicle found tacrolimus to be more effective using the PGE categories of 'cleared' to 'marked improvement' (69% vs 38% in the larger study [p < 0.001] and 56.5%% vs 15.7% in the smaller study [p < 0.007] for 0.03% tacrolimus vs vehicle). Statistically significant differences were also demonstrated for a number of other measures, including changes in EASI score, pruritus score and patient reports of 'feeling better'. Loss to follow up was higher in the vehicle arms of the trials (56% vs 17% in the larger study and 15.9% vs 8.1% in the smaller study).

4.1.1.6	For adults, a pooled analysis of two studies (n = 181 and n = 570) comparing 0.1% tacrolimus and potent topical corticosteroids found no statistically significant difference in the proportions of people with an improvement of at least 75% on the PGE ('cleared' to 'marked improvement') at 3 weeks (RR = 1.08, 95% CI 0.97 to 1.21).

4.1.1.7	The pooled analysis did not include the largest study (n = 975), which compared 0.1% tacrolimus with mild topical corticosteroids on the face and with potent topical corticosteroids on the body. This study found (without available results differentiating face and body) a greater improvement with tacrolimus (62.9% vs 40.7% at 3 months, difference = 22.2%, 95% CI 16.1% to 28.4%). This study reported other statistically significant differences favouring tacrolimus compared with a topical corticosteroid regimen. This included a higher proportion of people achieving an improvement in mEASI by at least 60% at 3 months (the primary outcome), a greater median improvement in mEASI (83.3% vs 76.9% at 3 months, p < 0.001; also statistically significant at 4 and 6 months, 95% CIs not stated), a greater reduction in the affected BSA, and a greater proportion of people 'feeling better'. However, there was a high loss to follow up (25.5% with tacrolimus and 42.1% with topical corticosteroids).

4.1.1.8	The other two studies that compared 0.1% tacrolimus and potent topical corticosteroids in adults did not report any statistically significant differences, although the larger of the two (n = 570) found smaller improvements in median mEASI score with 0.03% tacrolimus compared with potent topical corticosteroids (71% vs 83%, p < 0.05). Loss to follow up in this study was 11.5% with tacrolimus and 9.1% with topical corticosteroids.

4.1.1.9	Compared with vehicle, treatment of adults with tacrolimus was shown to be statistically significantly more effective using a number of outcome measures, including the PGE categories of 'cleared' to 'marked improvement', reduction in BSA affected, and improvement in EASI score. Loss to follow up was noticeably high in the vehicle arms of the trials (68.4% vs 26.7% and 38.9% vs 13.2% in the two largest trials).

4.1.1.10	Quality of life measures were reported by one study with an active comparator (n = 975) and one vehicle-controlled study (n = 985) in which participants were drawn from subsets of the largest studies of adults and children. Both studies measured quality of life using the DLQI. Compared with a topical corticosteroid regimen (potent topical corticosteroid on the body and mild topical corticosteroid on the face), greater percentage improvements were found with 0.1% tacrolimus (66.7% vs 58.5% at 3 months and 74.3% vs 69.2% at 6 months, significance levels were not reported), although the results for the different dimensions of 'quality of life' were not reported separately. Compared with vehicle, both strengths of tacrolimus were associated with greater improvements across all measurement dimensions in adults (symptoms and feelings, daily activities, leisure, work/school, personal relations, treatment [p = 0.0001]). In children (using the Children's DLQI [CDLQI] completed by children with help from parents/guardians), greater improvements were found with 0.03% tacrolimus than with vehicle across all measurement dimensions except one (the personal relationships dimension [p < 0.0001 to p = 0.02]) and across all dimensions for toddlers (using the CDLQI for toddlers completed by parents/guardians [p < 0.0001 to p = 0.001]).

4.1.1.11	For adverse effects, pooled analyses showed no statistically significant differences in skin infection rates between tacrolimus and topical corticosteroids. However, there was more skin burning in children with 0.03% tacrolimus compared with mild topical corticosteroids (RR = 1.97, 95% CI 1.25 to 3.11) and in adults with 0.1% tacrolimus compared with potent topical corticosteroid regimens (RR = 4.17, 95% CI 3.36 to 5.18). Withdrawal due to adverse effects was similar with tacrolimus and topical corticosteroids (1.6% to 3.9% of the tacrolimus group vs 1.6% to 3.3% of those using topical corticosteroids) but was consistently higher in the vehicle arms of the trials (between 4.5% and 12.3% with vehicle vs 2.9% to 5.7% with tacrolimus).

4.1.1.12	Overall, tacrolimus is more effective in treating moderate to severe disease in adults and children than is vehicle alone. In children, a number of measures of treatment effect suggest that tacrolimus is also more effective than mild topical corticosteroids but no trials have compared it with more potent topical corticosteroids. In adults, compared with topical corticosteroids, 0.1% tacrolimus was statistically significantly more effective in one study (n = 975) but not statistically significantly different in the other two studies (n = 570 and 181).

4.1.2	Pimecrolimus

4.1.2.1	Of the eight RCTs of pimecrolimus, three were conducted in children and five in adults. Three of the studies were provided by the manufacturer as commercial in confidence (two studies in adults and one study in children).

4.1.2.2	None of the RCTs in children compared pimecrolimus with topical corticosteroids. Two studies used vehicle as a comparator (n = 403 and n = 713) and one compared pimecrolimus with 0.03% tacrolimus (provided in confidence by the manufacturer [n = 141]).

4.1.2.3	Two of the RCTs in adults used potent topical corticosteroids as a comparator (n = 260 and n = 658); the larger of these two RCTs was provided in confidence by the manufacturer. Three studies used vehicle as a comparator (n = 34, n = 192 and n = 260). A further vehicle-controlled study was provided in confidence by the manufacturer [n = 200].

4.1.2.4	One of the studies in children (n = 713) and one in adults (n = 192) permitted the use of moderately potent topical corticosteroids to treat flare-ups in the treatment and control groups.

4.1.2.5	Three of the studies in adults were conducted in people with moderate to severe disease, which does not match the licensed indication (see Section 3.2.1). They were included in the review for pragmatic reasons, firstly, on the basis of expert advice that there is considerable overlap between categories of eczema severity and, secondly, because of the limited evidence available from studies comparing pimecrolimus with an active treatment.

4.1.2.6	Compared with potent topical corticosteroids, evidence from the smaller study suggests that pimecrolimus is less effective in treating moderate to severe atopic eczema. This study included four strengths of pimecrolimus (0.05%, 0.2%, 0.6% and 1.0%) but only the results for 1.0% pimecrolimus are presented, reflecting the product licence (see Section 3.2.1). Fewer people treated with pimecrolimus were judged to have 'clear' or 'almost clear' eczema at 3 weeks using the IGA score (11.1% vs 50%, difference = 38.9%, 95% CI 21% to 56%). The study also reported a smaller percentage reduction in EASI for those using pimecrolimus (47% vs 78%, significance levels not reported) and that fewer people treated with pimecrolimus had mild or absent pruritus (46.7% vs 81%, difference = 34.3%, 95% CI 15.5% to 53.1%, p < 0.05). The risk of skin burning was greater with pimecrolimus (RR = 5.26, 95% CI 1.97 to 14.0). However, almost a quarter of participants were lost to follow up (23.5%).

4.1.2.7	Compared with vehicle, pooled analyses of studies in children with mild to moderate disease and in adults with moderate to severe disease showed that treatment with pimecrolimus resulted in better IGA scores at 3 and 6 weeks (RR = 4.47, 95% CI 1.40 to 14.27 [3 weeks] RR = 1.87, 95% CI 1.26 to 2.76 [6 weeks]) and fewer flare-ups at 6 months (RR = 1.78, 95% CI 1.10 to 2.86). People using pimecrolimus were less likely to use additional treatment with topical corticosteroids (RR = 1.82, 95% CI 1.51 to 2.21) and pruritus was more often absent or mild at 3 and 6 weeks among the pimecrolimus group (RR at 3 weeks = 1.99, 95% CI 1.53 to 2.58).

4.1.2.8	Results from individual studies showed that pimecrolimus was statistically significantly more effective than vehicle using other measures of treatment effect, such as changes in EASI score and reduction in BSA affected.

4.1.2.9	Quality of life for people treated with pimecrolimus was reported by one comparison with vehicle in adults (n = 192) and for a subset of participants from the smaller study in children (n = 241). The study in adults reported changes in two quality of life measures (the Quality of Life Index - Atopic Dermatitis [QoLIAD] and the DLQI) and found greater improvements among patients using pimecrolimus compared with those using vehicle for both measures (25.6% vs 7.4%, p = 0.002 and 22% vs 6.7%, p = 0.01). The study in children, which used the Parent's Index of QOL in Atopic Dermatitis, also reported a higher quality of life with pimecrolimus (p = 0.023).

4.1.2.10	For adverse effects, a pooled analysis showed no statistically significant differences in rates of bacterial infection and skin burning between pimecrolimus and vehicle, but there was a greater risk of viral skin infection with pimecrolimus (RR = 1.97, 95% CI 1.21 to 3.19).

4.1.2.11	Overall, studies found pimecrolimus to be more effective at treating atopic eczema in adults and children than was vehicle alone. There is limited evidence on the effectiveness of pimecrolimus compared with topical corticosteroids.

*4.2*	*Cost effectiveness*

	The Committee considered economic analyses submitted by the manufacturers of both products and a model developed by the Assessment Group. There was only one relevant published economic analysis and this was conducted from the perspective of the US healthcare system and had methodological problems that limited its value. The Assessment Group analysis consisted of eight separate models, each relating to different cohorts of people with atopic eczema.

4.2.1	Tacrolimus

4.2.1.1	For the analysis of cost effectiveness in children, the Assessment Group model was run over 14 years to incorporate the possibility of disease resolution. All patients were assumed be aged 2 years on entering. The results of this model estimated that the costs per additional quality-adjusted life year (QALY) of first- and second-line treatment of eczema on the body were £9100 and £14,200, respectively, relative to standard practice of using topical corticosteroids alone. For eczema in sensitive areas (on the face or in areas such as the armpits or groin where the treatment options are more limited because of concerns about skin atrophy), the costs per additional QALY were higher. First-line treatment cost £35,700 per additional QALY and second-line treatment was dominated by topical corticosteroids (that is, tacrolimus was both less effective and more costly than topical corticosteroids).

4.2.1.2	In adults, the cost per additional QALY of first-line treatment of eczema on the body with tacrolimus was £68,400 relative to standard treatment with topical corticosteroids, and second-line treatment with tacrolimus was dominated by topical corticosteroids. For eczema in sensitive areas (see Section 4.2.1.1) the cost per additional QALY of first-line treatment with tacrolimus was £11,900, and second-line treatment with tacrolimus was dominated by topical corticosteroids.

4.2.1.3	Using a lower estimate of the amount of tacrolimus ointment used (2.3 g per day rather than 6.8 g per day) for adults reduced the incremental cost effectiveness ratio (ICER) for the treatment of 'body' eczema with tacrolimus (first line) to £30,300 per QALY. Second-line treatment of 'body' eczema with tacrolimus was shown to cost less than topical corticosteroids alone but also conferred fewer QALYs. The ICER for first-line treatment of eczema in sensitive areas (see Section 4.2.1.1) was also lower (£7000 per QALY) but tacrolimus as a second-line treatment continued to be dominated by topical corticosteroids.

4.2.1.4	Overall, tacrolimus (first- and second-line) was estimated to be more costly than topical corticosteroids alone in all cases except one (second-line treatment of 'body' eczema with tacrolimus in adults assuming a lower amount of agent used) whilst absolute differences in QALYs were very small. The Assessment Group also performed probabilistic analyses. The base-case results of all the Assessment Group's models were shown to be associated with considerable uncertainty.

4.2.1.5	The manufacturer provided a cost-effectiveness analysis, in terms of disease-controlled days (DCDs), and compared treatment with tacrolimus (0.1% in adults, and 0.1% and 0.03% in children) after topical corticosteroids (potent topical corticosteroids as comparator for 0.1% tacrolimus, mild topical corticosteroids as comparator for 0.03% tacrolimus) with treatment with tacrolimus before topical corticosteroids in a hospital outpatient setting. The model adopted a semi-Markov approach, organised in four arms (topical corticosteroids in moderate or severe disease and tacrolimus in moderate or severe disease), and each one included four states of progression of atopic eczema (cleared or virtually cleared, moderately controlled, uncontrolled and flare-up). Each arm was run for 27 weeks (adults) or 15 weeks (children), corresponding to the duration of follow up in the RCTs from which the effectiveness estimates were derived (scenario 1). In a second scenario, the model was run for 51 weeks on the basis of effectiveness estimates obtained from experts, and ciclosporin was included as a comparator for adults with severe eczema. A modified NHS and Personal and Social Services perspective was adopted, including work days lost.

4.2.1.6	The results were presented as average cost effectiveness ratios rather than ICERs. The Assessment Group calculated ICERs using the data provided by the manufacturer.

4.2.1.7	For children with moderate disease, results from scenario 1 showed that 0.03% tacrolimus was dominated by both topical corticosteroids and 0.1% tacrolimus (that is, it produced fewer DCDs and was more costly than topical corticosteroids and 0.1% tacrolimus) and that 0.1% tacrolimus produced more DCDs than topical corticosteroids but was also more costly (the cost per additional DCD with 0.1% tacrolimus relative to topical corticosteroids was £16.40). By contrast, for children with severe disease, 0.1% tacrolimus was dominated by 0.03% tacrolimus and topical corticosteroids, and 0.03% tacrolimus produced more DCDs than topical corticosteroids but was also more costly (the cost per additional DCD with 0.03% tacrolimus relative to topical corticosteroids was £18.10). In scenario 2, where the model was run over 51 weeks, the cost per additional DCD with tacrolimus relative to topical corticosteroids was £3.30 (moderate eczema) and £16.10 (severe eczema). Overall, differences in the costs and effectiveness of tacrolimus compared with topical corticosteroids were very small and the results were sensitive to a number of cost and effectiveness variables.

4.2.1.8	For adults, results from scenario 1 showed that tacrolimus dominated topical corticosteroids in those with moderate or severe atopic eczema. In scenario 2, where the model was run over 51 weeks, tacrolimus produced more DCDs compared with topical corticosteroids but was also more costly; the cost per additional DCD with tacrolimus was £6.20 (moderate eczema) and £26.80 (severe eczema). However, patients with severe atopic eczema treated with ciclosporin achieved more DCDs than did those treated with tacrolimus, although ciclosporin was more expensive; the cost per additional DCD with ciclosporin was £4.80. These patterns were reflected in further analyses excluding work days lost. The results were sensitive to a number of variables.

4.2.2	Pimecrolimus

4.2.2.1	The Assessment Group's base-case results showed that, compared with topical corticosteroids, first-line use of pimecrolimus costed more and conferred slightly fewer QALYs for children and adults with atopic eczema both on the body and in sensitive areas (see Section 4.2.1.1). Using pimecrolimus as a second-line rather than a first-line treatment was less expensive but was still dominated by topical corticosteroids. However, the probabilistic analyses showed that these results were associated with considerable uncertainty.

4.2.2.2	The Assessment Group developed subsidiary models (one for adults and one for children) to evaluate the cost-effectiveness of pimecrolimus compared with emollients, with moderately potent topical corticosteroids used as a 'rescue therapy' for all patients with uncontrolled 'problem' eczema. The basic structure of these models was the same as that of the models used to compare active treatments, although no distinction was made between eczema on sensitive areas and eczema on the rest of the body. Compared with emollients alone, the ICERs for treatment with pimecrolimus were £9700 per QALY in children and £16,600 per QALY in adults. Again, the results were associated with uncertainty.

4.2.2.3	The manufacturer developed a cost-utility model comparing pimecrolimus with emollients. A Markov approach was used, based on four states of progressive severity (remission, mild, moderate and severe). The use of topical corticosteroids was permitted as a rescue therapy in patients with severe disease. The model was run for 1 year. An NHS perspective was adopted and 2003 was the base year for estimating costs.

4.2.2.4	For all parts of the body, the estimated cost per additional QALY was £24,500 in children and £27,400 in adults and, for head and neck only, £4668 in children and £21,766 in adults. The results were sensitive to a number of variables. Probabilistic analyses of the model for children showed that, when £30,000 is considered to be an acceptable amount to pay for an additional QALY, the probability of pimecrolimus being most likely to be cost effective is 60%, the probability that it will dominate vehicle is 20% and the probability that the cost for an additional QALY will be greater than £100,000 is 17%. In patients with mainly head and neck atopic eczema, the probabilities were 75%, 35% and 20%, respectively. Probabilistic analyses were not presented for adults.

*4.3*	*Consideration of the evidence*

4.3.1	The Committee reviewed the evidence available on the clinical and cost effectiveness of tacrolimus and pimecrolimus, having considered evidence on the nature of the condition and the value placed on the benefits of tacrolimus and pimecrolimus 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 was persuaded that tacrolimus and pimecrolimus have both been shown to be effective in treating atopic eczema when compared with vehicle. They noted, however, that vehicle is not the most appropriate comparator in the majority of cases.

4.3.3	The Committee observed that no studies had compared 0.03% tacrolimus in children with moderate to severe disease with potent or moderately potent topical corticosteroids, but that there was evidence from two RCTs of greater effectiveness compared with mild topical corticosteroids. It also noted that the two largest RCTs in adults that compared tacrolimus and potent topical corticosteroid regimens had produced inconsistent results: 0.1% tacrolimus was statistically significantly more effective than topical corticosteroids in the larger study, whereas no statistically significantly differences were reported in the smaller study, although potent topical corticosteroids were found to be more effective than 0.03% tacrolimus. Possible explanations for this were considered, including the fact that the trial favouring tacrolimus had included mild topical corticosteroids as a comparator on the face, and reported its results without distinguishing comparators. The Committee concluded that the available evidence suggested that tacrolimus may be similar in effectiveness to topical corticosteroids for the treatment of moderate to severe atopic eczema.

4.3.4	The Committee noted that there is limited evidence on the effectiveness of pimecrolimus compared with topical corticosteroids. No studies had compared pimecrolimus with topical corticosteroids in children, and the evidence base for adults included a proportion of people with severe disease for which the product is not licensed. The Committee concluded that the limited evidence available did not suggest that pimecrolimus is as effective as topical corticosteroids in treating atopic eczema.

4.3.5	Consideration was given to the results of the three economic models developed by the Assessment Group and the manufacturers of tacrolimus and pimecrolimus. The Committee noted that the Assessment Group's base-case results suggested that, in children, compared with topical corticosteroids, the costs per additional QALY of first- and second-line treatment of 'body' eczema with tacrolimus were in the range likely to be considered cost effective, whereas this was not the case for treatment of eczema on sensitive areas such as the face. For adults, the reverse was the case: on sensitive areas, the cost per additional QALY of first-line treatment was in the range likely to be considered cost effective but this was not the case for treatment with tacrolimus on other parts of the body. These inconsistencies may be the result of the necessity to estimate a number of parameters in the model in the absence of good-quality evidence, and of the need to combine treatment and disease states in order to address the different potential uses of the new immunomodulators. A further anomaly was that, in both children and adults, the costs per additional QALY were generally lower for first-line treatment than for second-line treatment with tacrolimus, but tacrolimus is only licensed for second-line use.

4.3.6	The Committee acknowledged that probabilistic analyses had shown that the base-case results of the Assessment Group's model were associated with very considerable uncertainty. It further acknowledged that the probabilities of any of the treatment options being the most likely to be cost effective (topical corticosteroids alone, tacrolimus first line and tacrolimus second line) were broadly similar at values generally considered as acceptable amounts to pay for an additional QALY. The Committee concluded that, because of the significant parameter uncertainty and some counter-intuitive results, the base-case ICERs could not, in themselves, inform a decision. It was agreed, however, that similar benefits accrue with tacrolimus but at greater cost compared with topical corticosteroids.

4.3.7	The Committee considered that the Fujisawa economic model of tacrolimus did not provide any evidence to override this conclusion. It was also limited in providing an analysis in terms of DCDs rather than QALYs; and it only compared treatment with tacrolimus after topical corticosteroids with treatment with tacrolimus before topical corticosteroids, and not with topical corticosteroids alone.

4.3.8	On the basis of the Assessment Group's model of pimecrolimus compared with topical corticosteroids, the Committee agreed that pimecrolimus was not cost effective. Although the Assessment Group's model and the manufacturer's model suggested that pimecrolimus was cost effective relative to emollients, the Committee was not convinced that this was the most clinically appropriate comparator in the majority of cases.

4.3.9	The Committee heard from the clinical experts that topical corticosteroids provide effective first-line management of atopic eczema and that, due to the higher cost of topical immunomodulators and their potential unknown long-term adverse effects, the experts would not recommend tacrolimus or pimecrolimus as first-line treatments.

4.3.10	The Committee was concerned by the possibility that immunomodulators might increase the risk of malignancy in the long term, particularly skin malignancy, and that there is some evidence that tacrolimus may reduce the time to development of ultraviolet-induced tumours in experimental animals. It is known that systemic use of tacrolimus and related drugs is associated with the development of skin cancers. For this reason, the Committee believed that topical immunomodulators should not be used without careful discussion of the potential risks and benefits with the patient.

4.3.11	The Committee heard from the clinical experts that topical immunomodulators are useful in cases where continual use of potent topical corticosteroids is required and there is a serious risk of skin atrophy. The experts also agreed that topical immunomodulators are useful alternatives to systemic treatments in severe resistant atopic eczema.

4.3.12	The Committee heard from the clinical experts that the risk of skin atrophy and concern about other long-term adverse effects causes significant anxiety about the use of topical corticosteroids. The clinical experts were in agreement, however, that anxiety around steroid use should not be an indication for treatment with topical immunomodulators, but that this anxiety should be addressed through effective patient information and education.

4.3.13	Taking into account the evidence on the cost and effectiveness of topical immunomodulators, and the views of the clinical experts, the Committee agreed that topical immunomodulators should not be recommended as first-line treatments for atopic eczema. The Committee did however recognise the need for second-line treatments in patients with moderate to severe disease who need ongoing treatment with potent topical corticosteroids, and are thus at serious risk of skin atrophy. The Committee also acknowledged the need for second-line treatments in patients with moderate to severe disease who do not achieve an adequate clinical response to the maximum strength and potency of topical corticosteroid that is appropriate for their age and for the area of the body being treated. The Committee therefore concluded that tacrolimus should be recommended as a second-line treatment for moderate to severe atopic eczema in these circumstances.

4.3.14	Consideration was given to the relative benefits of pimecrolimus compared with tacrolimus and to the role of pimecrolimus as a second-line treatment in patients with mild to moderate atopic eczema. The Committee noted the stronger evidence base for tacrolimus. In addition, the Committee considered that safety concerns over continual and high-dose topical corticosteroid use were relevant to the moderate and severe end of the disease spectrum for which tacrolimus is available. No comparative trials were available to suggest that pimecrolimus was to be preferred to tacrolimus. The Committee therefore concluded that tacrolimus should be the recommended second-line treatment and that pimecrolimus should not be used.

4.3.15	Finally, the Committee considered how and by whom tacrolimus should be prescribed. Given the uncertainties around its long-term effects, the Committee agreed that it would be appropriate to recommend that tacrolimus should be initiated only by physicians (including general practitioners) with a special interest in the treatment of atopic eczema, and only after careful discussion with the patient of the potential risks and benefits of all second-line treatment options.

5	Proposed recommendations for further research

5.1	Given that 0.03% tacrolimus in children with moderate to severe atopic eczema has only been compared to mild topical corticosteroids, the Committee recommends that high-quality studies be undertaken using moderately potent topical corticosteroids as a comparator.

5.2	The Committee recommends that high-quality RCTs of pimecrolimus compared with appropriate potencies of topical corticosteroids be undertaken in children and adults with mild to moderate atopic eczema.

5.3	The Institute notes that there are ongoing head to head studies of tacrolimus and pimecrolimus to enable further direct comparisons of efficacy to be made.

5.4	The Committee emphasises the need for careful and long-term surveillance for adverse effects of tacrolimus, including skin and other types of malignancy.

5.5	To achieve greater consensus among researchers and clinicians on how to measure treatment success in studies of atopic eczema, the Committee recommends that further research be conducted into the reliability of methods of measurement.

5.6	The Committee recommends that observational studies be conducted to provide basic information about the treatment patterns and health service utilisation by people with atopic eczema in England and Wales.

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	Estimating the impact of using tacrolimus as a second-line treatment of moderate to severe atopic eczema that has not been controlled by adequate use of appropriate potency topical corticosteroids is hindered by uncertainties surrounding the number of children and adults who suffer from atopic eczema (see Section 2.3) and the proportion of topical corticosteroid use that would be replaced by tacrolimus.

6.2	It is thought that the guidance will affect only a small proportion of atopic eczema sufferers who are estimated to have moderate or severe forms of the disease (see Section 2.3). It is not clear what proportion of people with moderate to severe disease currently experience an inadequate clinical response to the maximum strength and potency of topical corticosteroid that is appropriate for their age and the area being treated and who are at serious risk of developing important adverse effects such as permanent skin atrophy. It is therefore unclear what proportion of people with moderate to severe atopic eczema would be eligible for tacrolimus under this guidance.

6.3	The cost per gram of topical corticosteroids (3-14p) is small compared with the cost per gram of tacrolimus (62-68p). By varying estimates around the cost of topical corticosteroids and the quantity used, a crude calculation suggests that the additional cost per year per patient treated with tacrolimus compared with topical corticosteroids would lie between £538 and £1192. However, this assumes that all other treatment costs, such as the quantity of tacrolimus and topical corticosteroids required, the number of visits to physicians and the incidence of adverse effects such as infections, would remain the same.

6.4	Using the above estimates, the Assessment Group calculated the additional spending in a Primary Care Trust with a population of 150,000 people, assuming different levels of tacrolimus uptake. The calculations assumed that the point prevalence of atopic eczema is 13.4% (based on a prevalence study in the UK in 1996) and that 9% of people with atopic eczema have moderate to severe disease. On the basis of these assumptions, the estimated additional annual spending in a PCT this size would be: between £19,368 and £42,912 if it is assumed that 2% of people with moderate to severe disease switch to tacrolimus between £48,420 and £107,280 if it is assumed that 5% of people switch to tacrolimus between £97,378 and £215,752 if it is assumed that 10% of people switch to tacrolimus. Given the number of assumptions involved in the calculations, these estimates should be interpreted cautiously.

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 tacrolimus is considered as an option for second-line treatment of moderate to severe atopic eczema that has not been controlled by adequate use of appropriate potency topical corticosteroids, where there is a serious risk of important adverse effects from further topical corticosteroid use, particularly irreversible skin atrophy.

7.3.2	Treatment with tacrolimus is initiated only by a physician with a special interest in the treatment of atopic eczema.

7.3.3	Treatment with tacrolimus is initiated only after careful discussion between the prescribing physician and the patient of the potential risks and benefits of all second-line treatment options.

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 the use of treatments for atopic eczema.

8	Related guidance

8.1	The frequency of application of topical corticosteroids for atopic eczema is currently being appraised by NICE and guidance is due to be published in July 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 September 2007.

Andrew Stevens

Chair, Appraisal Committee

March, 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 two 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 Darren Ashcroft
Senior Clinical Lecturer, School of Pharmacy and Pharmaceutical Sciences, University of Manchester

Mr Bryan Buckley
Lay representative, Vice Chairman, InContact

Professor John Cairns
Professor of Health Economics, Health Economics Research Unit, University of Aberdeen

Professor Mike Campbell
Statistician, Institute of General Practice & Primary Care, Sheffield

Dr Mark Chakravarty
Head of Government Affairs and NHS Policy, Procter and Gamble Pharmaceuticals (UK) Ltd, Egham, Surrey

Dr Peter I Clark
Consultant Medical Oncologist, Clatterbridge Centre for Oncology, Wirral, Merseyside

Dr Mike Davies
Consultant Physician, University Department of Medicine & Metabolism, Manchester Royal Infirmary

Professor Jack Dowie
Health Economist, London School of Hygiene

Professor Gary A Ford (Vice Chair)
Professor of Pharmacology of Old Age/Consultant Physician, Newcastle upon Tyne Hospitals NHS Trust

Dr Fergus Gleeson
Consultant Radiologist, The Churchill Hospital, Oxford

Ms Sally Gooch
Director of Nursing, Mid-Essex Hospital Services NHS Trust, Chelmsford

Professor Trisha Greenhalgh
Professor of Primary Health Care, University College London

Miss Linda Hands
Clinical Reader in Surgery, University of Oxford

Professor Peter Jones
Professor of Statistics & Dean, Faculty of Natural Sciences, Keele University

Professor Robert Kerwin
Professor of Psychiatry and Clinical Pharmacology, Institute of Psychiatry, London

Ms Joy Leavesley
Senior Clinical Governance Manager, Guy's and St Thomas' NHS Trust

Ms Ruth Lesirge
Lay Representative, previously Director, Mental Health Foundation, London

Ms Rachel Lewis
Staff Nurse (Nephrology), Hull Royal Infirmary

Dr Ruairidh Milne
Senior Lecturer in Public Health, National Coordinating Centre for Health Technology Assessment, University of Southampton

Dr Neil Milner
General Medical Practitioner, Sheffield

Dr Rubin Minhas
General Practitioner with a Special Interest in Coronary Heart Disease, Primary Care CHD Lead, Medway PCT & Swale PCT

Mr Richard Devereaux-Phillips
Public Affairs Manager, Medtronic Ltd

Mr Miles Scott
Chief Executive, Harrogate Health Care NHS Trust

Mr Malcolm Stamp
Chief Executive, Addenbrookes NHS Trust, Cambridge

Dr Ken Stein
Senior Lecturer, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Professor Andrew Stevens (Chair)
Professor of Public Health, University of Birmingham

Professor Mark Sculpher
Professor of Health Economics, University of York

NICE Project Team

Each appraisal of a technology is assigned to a Health Technology Analyst and a Technology Appraisal Project Manager within the Institute.

Zoe Charles

Technical Lead, NICE project team

Dr Sarah Cumbers

Project Manager, NICE project team

Appendix B. Sources of evidence considered by the Committee

A	The assessment report for this appraisal was prepared by Peninsula Technology Assessment Group.

	Garside R, Stein K, Castelnuovo E, Pitt M, Ashcroft D, Dimmock P, Payne L, Peninsula Technology Assessment Group, The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema, January 2004.

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 ACD and consultee organisations are provided with the opportunity to appeal against the FAD. I Manufacturer/sponsors: Fujisawa Ltd Novartis Pharmaceuticals Ltd II Professional/specialist and patient/carer groups: British Association of Dermatologists Department of Health Kensington and Chelsea Primary Care Trust National Eczema Society Royal College of General Practitioners Royal College of Nursing Royal College of Physicians Royal Pharmaceutical Society Skin Care Campaign Welsh Assembly Government III Commentator organisations (without the right of appeal): British National Formulary NHS Confederation NHS Purchasing and Supplies Agency NHS Quality Improvement Scotland Centre of Evidence-based Dermatology, University of Nottingham 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 tacrolimus and pimecrolimus for atopic eczema by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD. Ms Margaret Cox, Chief Executive, National Eczema Society, nominated by the National Eczema Society. Dr John English, Consultant Dermatologist, Queens Medical Centre, Nottingham, nominated by the Centre of Evidence-Based Dermatology. Professor John Harper, Consultant Paediatric Dermatologist, The Hospital for Sick Children, Great Ormond Street, nominated by the British Association of Dermatologists. Dr Celia Moss, Consultant Dermatologist, Birmingham Children's Hospital, West Midlands NHS Trust, nominated by The National Eczema Society and The Centre of Evidence-Based Dermatology. Dr Catherine H Smith, Consultant Dermatologist, Lewisham University Hospital, nominated by the British Association of Dermatologists.

Appendix C. Detail on criteria for audit of the use of tacrolimus and pimecrolimus for atopic eczema

Possible objectives for an audit

An audit could be carried out to ensure the following. Tacrolimus is prescribed appropriately. Pimecrolimus is not prescribed for atopic eczema.

Possible patients to be included in the audit

An audit could be carried out on all patients seen for moderate to severe atopic eczema in a reasonable period for audit, for example, 6 months.

*Measures that could be used as a basis for an audit*

The measures that could be used in an audit of the appropriateness of prescription of tacrolimus and pimecrolimus for atopic eczema are as follows.

Criterion	Standard	Exception	Definition of Terms
1. Topical tacrolimus is considered as an option for second-line treatment of moderate to severe atopic eczema if the individual's atopic eczema has not been controlled by adequate use of appropriate potency topical corticosteroids and where there is a serious risk of important adverse effects from further topical corticosteroid use, particularly irreversible skin atrophy	100% of people with moderate to severe atopic eczema	None	Clinicians will need to agree locally on how to identify people with moderate to severe atopic eczema and how to document that topical tacrolimus has been considered as an option, for audit purposes. 'Atopic eczema that has not been controlled by adequate use of appropriate potency topical corticosteroids' refers to disease that has shown an inadequate clinical response to the maximum strength and potency of topical corticosteroid that is appropriate for the patient's age and the area being treated. Irreversible skin atrophy includes telangiectasia, increased transparency and shininess of the skin and the appearance of striae. Clinicians will need to agree locally on what constitutes adequate use of appropriate potency topical corticosteroids, for audit purposes, but steroid anxiety alone should not be considered an indication for treatment with tacrolimus.
2. Treatment with tacrolimus is initiated only by a physician with a special interest in the treatment of atopic eczema	100% of people who are prescribed tacrolimus	None	'A physician with a special interest in the treatment of atopic eczema' can be a physician or a general practitioner.
3. Treatment with tacrolimus is initiated only after careful discussion between the prescribing physician and the patient of the potential risks and benefits of all second-line treatment options	100% of people who are prescribed tacrolimus	None	Clinicians will need to agree locally on how the discussion with the patient is documented, for audit purposes. Risks of topical tacrolimus include side effects including a burning or tingling sensation, pruritus, erythema, folliculitis, herpes simplex, acne, increased sensitivity to hot and cold, alcohol intolerance and lymphadenopathy. The discussion should make clear to the patient that the potential long-term adverse effects of topical tacrolimus on the skin, immune system and other systems are not yet known and that it is possible that topical immunomodulators might increase the risk of malignancy in the long term, particularly skin malignancy. Second-line treatment options, in addition to tacrolimus, include systemic corticosteroids, phototherapy and systemic use of immunosuppressants such as ciclosporin. Clinicians will need to agree locally on the risks and benefits of second-line treatment options that are discussed with the patient, for audit purposes.
4. Pimecrolimus is prescribed for the treatment of atopic eczema	0% of people with atopic eczema	None

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.

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