Aguas superficiales

Despite differences in inclusion criteria, the relative lack of younger children in the adalimumab and etanercept trials meant that the median age of children across the three trials did not differ greatly. Similarly, measures of disease duration and the component measures of severity did not appear to differ markedly between the three trials. Few participants in any trial had previous experience of biological treatment.

The biologics and their respective comparators in the relevant RCTs in children and young people are summarised inTable 34.

There were no head-to-head comparative data available for the three biologics. In addition, although the etanercept and ustekinumab trials had a placebo as a common comparator, the adalimumab trial used methotrexate as a comparator.

Table 35shows the relative effects for all three biologics from the three RCTs. However, an implicit comparison is not useful for the purposes of the decision-analytic modelling required for the economic evaluation.Chapter 4therefore describes a formal evidence synthesis to inform the relative efficacy of these interventions.

TABLE 33 Survival of first biologic in the BADBIR

Biologic

Drug survival

1 year 2 years 3 years

Adalimumab (n=1879) 0.79 0.67 0.59

Etanercept (n₌1098) 0.70 0.51 0.40

Infliximab (n=96) 0.65 0.50 0.35

Ustekinumab (n₌450) 0.89 0.82 0.75

TABLE 34 Summary of the biologics and their comparators based on RCTs

Treatment Class of therapy Dosage Comparator

Adalimumab Anti-TNF-α Standard (0.8 mg/kg) Methotrexate

Half-standard (0.4 mg/kg)

Etanercept Anti-TNF-α Standard (0.8 mg/kg) Placebo

Ustekinumab Anti-IL-12/-IL-23 Standard (0.75 mg/kg) Placebo Half-standard (0.375 mg/kg)

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TABLE 35 Relative risks of PASI outcomes for biological therapy trials in children and young people

Trial

PASI outcome, RR (95% CI)

PASI 50 PASI 75 PASI 90

Adalimumab vs. methotrexate (M04-717) (16 weeks)

Standard dosage (0.8 mg/kg) Confidential information has been removed

1.79 (1.04 to 3.06)a _{1.34 (0.61 to 2.95)}

Half-standard dosage (0.4 mg/kg) Confidential information has been removed

1.34 (0.75 to 2.42)a _{1.42 (0.65 to 3.08)}

Etanercept vs. placebo (20030211) (12 weeks)

Standard dosage (0.8 mg/kg) 3.26 (2.26 to 4.71) 4.95 (2.84 to 8.65)a _{4.10 (1.88 to 8.95)}

Ustekinumab vs. placebo (CADMUS) (12 weeks)

Standard dosage (0.75 mg/kg) 2.99 (1.79 to 4.97) 7.5 (2.9 to 19.1) 11.0 (2.8 to 43.5) Half-standard dosage (0.375 mg/kg) 2.72 (1.62 to 4.48) 7.3 (2.8 to 18.6) 10.0 (2.5 to 39.8)

a Stated as primary outcome.

DOI: 10.3310/hta21640 HEALTH TECHNOLOGY ASSESSMENT 2017 VOL. 21 NO. 64

© Queen’s Printer and Controller of HMSO 2017. This work was produced by Duarteet al.under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

Chapter 4

Evidence synthesis to inform the

relative efficacy of the interventions

Overview

Randomised controlled trials of the effectiveness of adalimumab, etanercept and ustekinumab for the

treatment of plaque psoriasis in children and young people have been discussed and summarised inChapter 3. The efficacy end point consistently reported across the trials was PASI response rates, which is the key efficacy parameter used in the economic analysis. To determine the relative efficacy of the interventions, it would be ideal to have results from good-quality adequately powered RCTs comparing the active treatments with one another in the population of children and young people. However, the evidence base presents a number of challenges for informing the relative efficacy of the interventions in this population. First, the interventions of interest have not been directly compared in head-to-head RCTs. Second, no common comparator (e.g. placebo) exists across all of the RCTs. Third, the age of the populations included in the trials differs across the RCTs and the interventions of interest have marketing authorisation for different age groups. Fourth, the severity of plaque psoriasis is defined differently in the populations included in the RCTs and the interventions are licensed for different levels of psoriasis severity in children and young people. These challenges mean that a number of assumptions are required to inform the benefits of the active treatments relative to the appropriate comparators and each other.

Meta-analysis using mixed-treatment comparisons enables the estimation of different parameters from several studies with similar comparisons to be combined when direct evidence on comparisons of interest is absent or sparse. The statistical synthesis method of NMA enables the comparison of multiple treatment options using both direct comparisons of interventions from RCTs and indirect comparisons across trials based on a common comparator.95,96_{As suggested by the term, NMA needs a‘network of evidence’to be established}

between all of the interventions of interest. However, with neither direct comparisons nor a common comparator in the evidence base for children and young people from which to derive indirect comparisons of comparator treatments, the evidence base is structured as a‘disconnected network’(Figure 3).

MTX PLB ETA ADA UST 45 CADMUS72 2003021149 M04-71742

FIGURE 3 Network of evidence for children and young people. ADA, adalimumab 0.8 mg/kg, maximum 40 mg/week; ETA, etanercept 0.8 mg/kg, maximum 50 mg/week; MTX, methotrexate 0.1_–0.4 mg/kg/week; PLB, placebo; UST 45, ustekinumab 0.75 mg/kg or 45 mg/week. Trial names are stated when trial evidence informs the network

treatment link.

DOI: 10.3310/hta21640 HEALTH TECHNOLOGY ASSESSMENT 2017 VOL. 21 NO. 64

© Queen’s Printer and Controller of HMSO 2017. This work was produced by Duarteet al.under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

In the following sections we build on the challenges listed above by exploring treatment efficacy by age subgroup and by performing a naive indirect treatment comparison of adalimumab and etanercept, highlighting the limitations of such analysis. Furthermore, a framework of analysis is described that uses different levels of evidence from the adult population to specifically address the issue of having a disconnected network structure.