3 Committee discussion

The appraisal committee (section 5) considered evidence submitted by Pfizer, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.

The appraisal committee was aware that several issues were resolved or partially resolved during the technical engagement stage:

The company included in its model the therapies people might use after crisaborole or its alternatives: phototherapy and systemic therapies (methotrexate, azathioprine, mycophenolate, ciclosporin).
It is appropriate to base the amount of drug use per application in the economic model on data for people with the same body surface area affected as the licensed indication for crisaborole, that is 40% or less.
It is appropriate to include a health state for severe atopic dermatitis in the economic model.

It recognised that there were remaining areas of uncertainty associated with the analyses presented, and took these into account in its decision making. It discussed the following issues outstanding after the technical engagement stage:

issue 1: what the relevant comparator is for people with mild atopic dermatitis
issue 3: whether to assume only a partial response for therapies used after crisaborole or its alternative treatments
issue 4: how to determine the duration of subsequent therapies
issue 6: whether company network meta-analyses are appropriate.

Experience of people with atopic dermatitis

Atopic dermatitis affects all aspects of a person's life

3.1 Atopic dermatitis is a chronic, recurrently flaring, generalised skin condition that can be life-limiting, debilitating and isolating. It can affect all aspects of life (physical, psychological, social and financial). Severe disease is associated with intolerable itch that disrupts sleep, and there is a higher risk of depression and suicide. The committee concluded that having treatments that improve the condition, and which are associated with few or manageable adverse effects, is important to people with atopic dermatitis.

Assessing atopic dermatitis severity

Symptoms, signs and quality of life determine the severity of atopic dermatitis

3.2 Clinicians assess the severity of atopic dermatitis based on clinical signs and on patient-reported symptoms. These included its effect on sleep and work, and how much topical corticosteroids or systemic therapy people use. The consensus-based Harmonising Outcome Measures for Eczema (HOME) initiative recommends using the Eczema Area and Severity Index (EASI) to assess signs (for example, skin lesions) and the Patient Oriented Eczema Measure (POEM) to assess symptoms (for example, itch). The clinical experts explained that POEM is easier than EASI to administer in practice. NHS clinicians routinely use the Dermatology Life Quality Index (DLQI) to assess quality of life in other skin conditions. However, they do not use the Investigator's Static Global Assessment (ISGA) score, which formed the basis of the company's trials (see section 3.5). The committee concluded that the EASI, DLQI and POEM are appropriate for assessing the severity of atopic dermatitis in NHS practice.

Positioning of crisaborole in the treatment pathway

Crisaborole would be used after emollients and topical corticosteroids

3.3 The marketing authorisation for crisaborole is for mild to moderate atopic dermatitis in people 2 years and older when 40% or less of their body surface area is affected. The company positioned crisaborole as a second-line treatment for people with mild to moderate atopic dermatitis that has not been controlled by topical corticosteroids, or when there is a serious risk of adverse effects from topical corticosteroid use. The clinical experts explained that there is not a group of people with mild atopic dermatitis for whom topical corticosteroids are contraindicated or not effective, and that mild disease can be adequately controlled using emollients and topical corticosteroids. There are several different strengths of topical corticosteroids that people can use safely, and which are effective with the right education. The committee concluded that crisaborole would not be used as a treatment for mild disease or for first-line treatment. The committee further concluded that the appropriate place in the treatment pathway for crisaborole would be for adults and children with moderate atopic dermatitis that is not controlled with optimised treatment with emollients and topical corticosteroids.

Comparators

Topical calcineurin inhibitors are a relevant comparator in the NHS for crisaborole in people with moderate atopic dermatitis

3.4 The company indirectly compared crisaborole with the topical calcineurin inhibitors pimecrolimus and tacrolimus. NICE's technology appraisal guidance on pimecrolimus and tacrolimus for atopic eczema recommends both drugs for moderate disease. The clinical experts explained that topical calcineurin inhibitors are rarely used for mild to moderate atopic dermatitis, and are used only to prevent flares or on delicate areas such as the face. The committee concluded that topical calcineurin inhibitors are a relevant comparator for crisaborole in people with moderate atopic dermatitis on delicate areas such as the face or to prevent flares. It further concluded that crisaborole would be used in a similar way to topical calcineurin inhibitors.

Clinical evidence

The key clinical evidence for crisaborole in AD‑301 and AD‑302 is not generalisable to UK practice

3.5 The company provided evidence from 2 double-blind randomised vehicle-controlled trials for the efficacy of crisaborole: AD‑301 and AD‑302. The trials compared topical crisaborole in vehicle with topical vehicle alone. Both trials were carried out in the US, lasted 4 weeks and included people 2 years and older with an ISGA score of 2 (mild atopic dermatitis) or 3 (moderate atopic dermatitis) and dermatitis affecting 5% or more of the body surface area. The primary outcome was the proportion of people in whom ISGA was defined as a 'success', that is, a score of 0 (clear) or 1 (almost clear) and at least a 2‑grade improvement from baseline at day 29. ISGA success occurred in a higher proportion of people randomised to crisaborole (AD‑301 33%, AD‑302 31%) than vehicle (AD‑301 25%, AD‑302 18%). The clinical experts explained that clinicians in the UK do not use ISGA scores to assess atopic dermatitis. They consider it to be an unreliable subjective measure because results can vary widely depending on the investigator. The committee recalled having heard (see section 3.2) that EASI and POEM are the most appropriate tools for assessing severity in atopic dermatitis. This is because they incorporate quality of life and symptoms, and are the most widely used in UK clinical practice. Therefore, although the clinical trials reported a marginal improvement in ISGA severity with crisaborole in vehicle compared with the vehicle alone, it was not possible to tell whether the results were clinically significant to clinical practice in the UK. Furthermore, the population of the trials was not generalisable to the company's proposed population because only 43% had had previous treatment for atopic dermatitis. The committee concluded that the trial population and results were not generalisable to UK clinical practice.

There are no head-to-head studies comparing crisaborole with relevant treatments

3.6 The key trials compared crisaborole dissolved in vehicle ointment with vehicle ointment alone. The vehicle was not a true placebo because some of the individual ingredients had emollient properties, which could have improved atopic dermatitis. Also, the ingredients in the vehicles for crisaborole and topical calcineurin inhibitors differ, so their emollient benefits may differ. The company did a network meta-analysis to estimate the efficacy of crisaborole compared with the topical calcineurin inhibitors pimecrolimus and tacrolimus. All trials in the network compared active treatment in vehicle with vehicle ointment alone, and used different vehicles. Therefore, the company adjusted its network meta-analysis for the size of the response to vehicle treatment alone. The ERG explained that, by adjusting for a vehicle effect in a network meta-analysis, the assumption is that the vehicles are the same. These alternative approaches were also considered:

The ERG presented a simple unadjusted network meta-analysis.
The company presented a matching adjusted indirect comparison (MAIC).

The ERG explained that, if the vehicles are different, any network meta-analysis would be disconnected, so the MAIC should have been used for the company's base case instead. The committee acknowledged that it was difficult to determine whether one of the network meta-analyses or the MAIC was the most appropriate. However, it considered that, even if the vehicles in the trials were different, the network meta-analyses may have been valid if:
the effectiveness of the active drugs (crisaborole or topical calcineurin inhibitors) and vehicle combined was the same as the sum of the effectiveness of active drug and vehicle individually
there was some interaction between the vehicle and active ingredient (meaning that it was more or less effective when combined than if the benefits were additive), but the baseline risk was adjusted for.

The company's network meta-analysis adjusted for baseline risk of atopic dermatitis in the control arm of each trial (because of a placebo effect or other differences between the studies), and used an average baseline risk across the trials in the economic model. However, the ERG noted that, because different vehicles were used for the different treatments, using an average baseline risk for each treatment was not appropriate. Although there seemed to be some evidence that models adjusting for baseline risk fitted the data better, this was uncertain because there were few datapoints (that is, trials on which to base the adjustment). The committee recognised that there are several methodological limitations with a MAIC because it is not possible to tell if all confounding factors have been adjusted for. It also recognised that the results of the analyses (based on network meta-analyses or the MAIC) may have been biased either in favour of crisaborole or in favour of calcineurin inhibitors, whichever approach was taken. The committee concluded that it was not possible to tell whether crisaborole was more effective than topical calcineurin inhibitors based on the evidence.

There are uncertainties associated with the clinical-effectiveness evidence

3.7 The committee recognised that there were issues with the clinical evidence about whether crisaborole was more or less effective than current options in the NHS. These included that:

no trial directly compared crisaborole with drugs used in the NHS (see sections 3.5 and 3.6)
outcomes of the main crisaborole trial were not reliable or relevant to UK clinical practice (see section 3.5)
only 43% of people in the main crisaborole trial reflected the relevant population, in that they had had previous treatment for atopic dermatitis (see section 3.5)
there was a high degree of uncertainty in the relative effect estimates of crisaborole compared with calcineurin inhibitors produced by the network meta-analysis and MAIC (see section 3.6).

Overall, the committee was concerned about the quality of the available evidence in both the vehicle-controlled crisaborole trials. This was because neither the comparator nor the outcome measures were relevant to clinical practice. It was also concerned about methodological issues when indirectly comparing crisaborole with calcineurin inhibitors (see section 3.6). This meant that it could not recommend crisaborole as an effective treatment for the NHS.

Cost effectiveness

The structure of the cost-effectiveness model is suitable

3.8 The company revised its Markov model in response to technical engagement. The model included 5 health states: controlled (ISGA score 0 or 1), mild flare (ISGA score 2), moderate flare (ISGA score 3), severe flare (ISGA score of 4) and death. Disease could resolve in a proportion of children. The committee agreed that the structure of the model was appropriate for decision making. However, it concluded that there were problems in how the model dealt with sequencing of subsequent therapies after second-line treatment (see section 3.9).

Therapies third line and beyond are a large driver of cost effectiveness in the company's model and are not modelled adequately

3.9 The committee recognised that subsequent treatments after second-line treatment with crisaborole or calcineurin inhibitors were a large driver of cost effectiveness in the model. If a person's atopic dermatitis responded to treatment at 4 weeks in the model, the company assumed no further treatment was needed. However, if it did not respond to treatment, people had subsequent therapy with phototherapy followed by systemic treatment. Using the company's preferred network meta-analysis comparing crisaborole with topical calcineurin inhibitors adjusted for differences in baseline risk (the prevalence and severity in the vehicle only arm of the trials), the model predicted that crisaborole would reduce the cost of treatment by avoiding the need for subsequent therapy. The ERG explained that the company had not adequately modelled subsequent therapies. This was because the model estimated that a high proportion of people with mild and moderate disease go on to have treatment with multiple lines of treatment with long-term systemic therapy, despite their condition not responding when they had previously had systemic therapy. The ERG considered that this lacked face validity. The committee also noted that the model did not include dupilumab after systemic treatment, despite a NICE technology appraisal recommending dupilumab for moderate atopic dermatitis that has not responded to a systemic therapy. The committee concluded that the costs in the model were unlikely to be accurate. It added that it was important that subsequent therapies were modelled accurately because they had driven the differences in costs.

The economic results are sensitive to changes in the data source

3.10 Differences in the clinical effectiveness of crisaborole compared with calcineurin inhibitors from the network meta-analyses and MAIC determined the movement of people through the modelled health states. Because response to treatment was determined by the ISGA, which is not used in the UK (see section 3.7), the committee was unable to determine whether gains in the quality-adjusted life years (QALYs) predicted by the model would apply to clinical practice. Modelled differences in the costs and QALYs for crisaborole compared with calcineurin inhibitors were very small. The results were sensitive to changes in the model assumptions, for example, the dosing regimen of crisaborole compared with calcineurin inhibitors. The cost-effectiveness results varied depending on how they were calculated. Crisaborole dominated calcineurin inhibitors (that is, cost less and was more effective) using the company's adjusted network meta-analysis or MAIC. Calcineurin inhibitors dominated crisaborole in scenarios that used the ERG's simple (unadjusted) network meta-analysis. The committee concluded that crisaborole was not a cost-effective treatment option compared with calcineurin inhibitors.

Crisaborole cannot be recommended as a cost-effective use of NHS resources

3.11 The committee recognised the clinical uncertainty in the clinical benefit of crisaborole compared with the vehicle ointment in the pivotal clinical trials (see section 3.5), and of crisaborole compared with topical calcineurin inhibitors in the indirect comparisons (see section 3.10). Also, the cost-effectiveness results of the model were particularly sensitive to the method used for indirectly comparing the clinical-effectiveness data. Differences in the incremental costs and QALYs for crisaborole were small, making the incremental cost-effectiveness ratio (ICER) sensitive to changes in the model assumptions (for example, the dosing regimen for crisaborole compared with calcineurin inhibitors). Also, the ICERs for crisaborole compared with topical calcineurin inhibitors varied widely, reflecting the high degree of uncertainty in crisaborole's clinical effectiveness compared with treatments currently offered in the NHS. The committee stated that it would need more evidence of the clinical benefit of crisaborole because having crisaborole as another treatment option would delay patient access to dupilumab. This is particularly important because NICE's technology appraisal guidance on dupilumab recommends that the drug has proven efficacy as an option for treating moderate to severe atopic dermatitis if the disease has not responded to at least 1 other systemic therapy. The committee acknowledged that it is unlikely that these uncertainties would be reduced through revised modelling because the uncertainties caused by trial data would remain. The committee agreed that the current cost-effectiveness results were unreliable because of the clinical uncertainty, so it could not identify a most plausible ICER for crisaborole. It concluded that crisaborole could not be recommended as a cost‑effective use of NHS resources.

Innovation

Crisaborole is not innovative

3.12 The committee was aware that crisaborole is a non-steroidal compound and is a first-in-class topical PDE4 inhibitor. Also, it has not been associated with the serious adverse events reported with oral PDE4 inhibitors, such as nausea, vomiting, emesis and headache. However, the committee did not consider this relevant because oral PDE4 inhibitors are not second-line treatment options for moderate atopic dermatitis. The company noted that trials showed that crisaborole improves pruritus, a symptom of atopic dermatitis responsible for a significant proportion of disease burden. However, this was not adequately captured by the EQ‑5D results. Also, the committee did not see evidence for pruritis as an outcome when comparing crisaborole with calcineurin inhibitors. It concluded that crisaborole is not innovative, but that there may be some benefits of treatment that were not adequately captured by the QALY.

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Crisaborole for treating mild to moderate atopic dermatitis in people 2 years and older