Trials are meaningful for clinical decision making only when their endpoints are valid and comparable
Authors: J. Schmitt
Journal: British Journal of Dermatology (2015)

Clinicians and their patients with atopic eczema (AE) are free to choose from several different topical and systemic therapies. Although most of these treatment options have been investigated in clinical trials,1, 2 evidence-based comparisons of such trials are almost impossible, as trials in the field of AE have typically used different outcome measurement instruments. In 2003, a systematic review identified 56 different instruments to measure clinical signs of AE in 93 AE trials, and 31 different descriptions of clinical signs.3 Because most of the instruments that are available to measure the clinical signs of AE have unclear or even inadequate validity and reliability, systematic reviews that aim to compare the efficacy of interventions for AE have concluded that trial results cannot be pooled in a meta-analysis due to the high heterogeneity in the efficacy endpoints used.2, 4 To respond to this challenge, the Harmonising Outcomes Measures for Eczema (HOME) initiative5 set out to critically appraise, validate and recommend a core outcome set (COS) of efficacy outcome measures for all AE trials involving patients, clinical experts, other health professionals, journal editors, regulators, methodologists and manufacturers on an international level. Any person interested in contributing to the HOME initiative is welcome and should contact the HOME project manager (HOME@nottingham.ac.uk). A COS is an evidence-based and consensus-derived minimum set of valid and reliable outcome measures, for use in clinical trials, that allows direct and indirect comparisons of trial results to be performed, and thus contribute to guideline development and clinical decision making.6 COSs are currently being developed throughout medicine for various indications and different settings, for example clinical trials, effectiveness studies and quality assurance. Informed by a Delphi exercise7 including clinical experts and patient representatives from Europe, North America, South America, Asia and Australia, the HOME group identified symptoms of AE, health-related quality of life, clinical signs and long-term control of AE flares as the core outcome set of domains that should always be measured in AE trials.8 Following the guidance of the HOME roadmap,9 the next step after identifying such domains is to identify the most valid, reliable and feasible measurement instruments to measure each core outcome domain. With regard to clinical signs, a systematic review found that the Eczema Area and Severity Index (EASI)10 and objective Severity Scoring of Atopic Dermatitis (oSCORAD)11 are currently the best measurement instruments to assess the clinical signs of AE.12 EASI and oSCORAD both have adequate validity, internal consistency and sensitivity to change. EASI also has adequate intraobserver reliability and intermediate interobserver reliability, suggesting that the same investigator should perform the EASI scoring in a longitudinal study. The oSCORAD has adequate interobserver reliability and unclear intraobserver reliability.12 Based on this systematic review and following extensive group discussion,13 the international HOME group recommended EASI as the core outcome measurement instrument to be used in all future AE trials.14 Reasons for this broad international consensus among all stakeholders in favour of EASI included difficulties in selecting a representative site for each sign, as requested by the oSCORAD, and the disproportionately high relative weight of the intensity of signs compared with low weight of the extent of skin lesions in the oSCORAD formula.13 Unidimensional measurement instruments [i.e. instruments that assess only a single outcome domain such as EASI for clinical signs or the Patient-Oriented Eczema Measure (POEM) for symptoms] offer important advantages over composite scores to inform patient-centred, individualized clinical care of patients with chronic skin diseases. From psoriasis we know that a mismatch of objective and subjective disease severity as assessed by the physician and the patient is a strong predictor for psychiatric comorbidity15 that offers valuable information for routine patient care.16 SCORAD is a composite score that includes an assessment of clinical signs by the physician and an assessment of the AE symptoms pruritus and sleeping problems by the patient.17 This makes interpretation of specific SCORAD scores difficult as it remains unclear what proportion of the total score is explained by the objective and subjective parts of SCORAD. In the current issue of the BJD, Leshem et al.18 present a feasibility study that closes the last remaining validation gaps of the EASI.12 In addition to the classic psychometric properties of validity and reliability, feasibility is another critically important feature of outcome measurement instruments.19 Feasibility includes interpretability, in other words providing clinically meaningful information for defined score ranges. Other aspects of feasibility are ease of use, availability, cost, practicability and time to administer.19 Leshem et al.18 assessed both EASI and the six-point gestalt Investigator Global Assessment (IGA) in a cohort of 170 children and adults with different degrees of AE severity. Stratifying EASI score ranges by the corresponding IGA scores, the authors identified the best-fitting EASI bandings for each IGA category. According to their findings, EASI scores of 1·1–7 represent mild AE, scores 7·1–21 moderate AE, scores 21·1–50 severe AE, and scores > 50 very severe AE. The study fulfils the current methodological standards as suggested by the COSMIN (Consensus-Based Standards for the Selection of Health Measurement Instruments) guidelines.20 On average, trained investigators needed 6 min to perform the EASI,18 which is similar to the time to administer reported for the objective SCORAD previously.12 For clinical trials, 6 min to undertake an accurate clinical assessment is probably acceptable, but too long for tracking clinical progress in routine clinical practice, where other patient-reported symptom scores like POEM21-23 may be more appropriate, easier and more useful. In summary, the study by Leshem et al.18 strengthens the recommendation to use the EASI score as the preferred instrument to measure the core outcome domain of the clinical signs measure in all future clinical trials on AE, to make trials comparable and meaningful for guideline development and clinical decision making. The recently introduced EASI app (www.easicalc.uk) may help to further increase the feasibility of this instrument. Typically, in previous trials mean changes in EASI from baseline have been calculated and compared between treatment groups. Recently, 50% improvement in EASI (EASI 50) response rates have been reported in a study investigating dupilumab for AE.24 Dichotomizing EASI changes into EASI 50 or EASI 75 response rates offers the advantage that trial results can be interpreted easily by patients and physicians as the chance for a certain benefit in the severity of AE signs. However, such dichotomization loses a lot of valuable information, and mean changes in the EASI score from baseline should also be reported in trials to allow comparisons with previous trials in meta-analyses. Patient-reported outcome measures such as health-related quality of life have been used only rarely as outcome measures in AE trials; only one in 10 AE trials conducted between 1985 and 2010 assessed quality of life.25 The HOME initiative is dedicated to change this situation and to make AE trials more patient relevant. Three of the four core outcome domains for AE trials are patient-reported outcome measures.8 Currently, systematic reviews are under way to summarize the evidence on the psychometric properties of measurement instruments for AE symptoms, quality of life and long-term control of AE flares. These reviews will serve as the evidence base for group discussion and consensus voting to identify the best instrument for these patient-reported core outcome domains. All investigators conducting AE trials are certainly free to choose additional outcomes beyond and in addition to those included in the COS, as long as the COS is considered in the trial design. This will help to overcome the current situation in which trials are not comparable and are therefore of only limited use for clinical decision making. The consistent use of patient-relevant, valid, reliable, feasible and comparable outcome measures in AE trials is of particular relevance in the current situation with several new biological treatments being developed for AE. This is critically important, as choosing inappropriate outcomes may lead to ‘wasted resources or misleading information that overestimates, underestimates, or completely misses the potential benefits of an intervention.’26 J.S. is a member of the international HOME initiative. He has received research grants for investigator-initiated studies from Novartis, Pfizer, MSD, ALK and Sanofi, and has consulted for Novartis, Abbott, Sanofi and Regeneron.