Optimization of placebo use in clinical trials with systemic treatments for atopic dermatitis: an International Eczema Council survey‐based position statement

Abstract

Background As novel systemic therapeutics for patients with atopic dermatitis (AD) are developed, ethical and methodological concerns regarding placebo‐controlled‐trials (PCT) have surfaced. Objective To guide the design and implementation of PCT in AD, focusing on trials with systemic medications. Methods A subgroup of the International Eczema Council (IEC) developed a consensus e‐survey, which was disseminated to IEC members. Results The response rate was 43/82 (52%). Consensus was reached on 24/27 statements and on 3/11 options from multiple‐selection statements, including: performing monotherapy studies in proof‐of‐concept phases; avoiding concomitant topical corticosteroids or calcineurin inhibitors until a predefined timepoint as rescue (borderline consensus); selection of sites and assessors with recognized expertise in AD clinical trials; clear definition and identification of baseline disease severity; minimizing time and proportion of patients on placebo; using daily emollients with several options provided; instigating open‐label extension studies for enrolment after a predefined timepoint; and including outcomes which set a higher bar for disease clearance. Conclusion Conducting PCT in AD requires balancing several, sometimes opposing principles, including ethics, methodology, regulatory requirements and real‐world needs. This paper can provide a framework for conducting PCT with systemic medications for patients with AD.

Placebo response in phase 2 and 3 trials of systemic and biological therapies for atopic dermatitis—a systematic review and meta‐analysis

“…Of interest, since TCS in clinical trials is often provided by the investigators, this tends to increase adherence to TCS use. 34 Importantly, the use of placebo in clinical AD trials was recently discussed by members of the International Eczema Council, 45 who concluded that several considerations should be made when designing an AD placebo-controlled clinical trial and that monotherapy should be used in proof-ofconcept studies. 45 The comparison of our study results with similar data from clinical trials of psoriasis patients with moderate-to-severe disease highlights important differences between these two inflammatory skin diseases.…”

“…34 Importantly, the use of placebo in clinical AD trials was recently discussed by members of the International Eczema Council, 45 who concluded that several considerations should be made when designing an AD placebo-controlled clinical trial and that monotherapy should be used in proof-ofconcept studies. 45 The comparison of our study results with similar data from clinical trials of psoriasis patients with moderate-to-severe disease highlights important differences between these two inflammatory skin diseases. Psoriasis patients experience fewer disease flares and have a more stable disease, whereas AD patients, in particular those with moderate-to-severe disease, have a strongly fluctuating disease with frequent flares.…”

“…Notably, the clinical assessment of disease severity in AD and psoriasis differ due to psoriasis lesions being characteristically more well defined, while chronic AD lesions are poorly demarcated. This further limits the comparison between the placebo response in AD and psoriasis …”

Expert Perspectives on Key Parameters that Impact Interpretation of Randomized Clinical Trials in Moderate-to-Severe Atopic Dermatitis

“…The length of a washout period may have cascading consequences on various aspects of the subsequent stages of a trial. A longer period (e.g., 4 weeks) reduces the likelihood of a carryover treatment effect, but may result in greater disease severity at baseline, potentially leading to increased rescue treatment use, especially early in a study [ 27 ]. Conversely, a shorter washout period may mean the prior treatment still impacts the patient and may reduce the likelihood that participants will flare prior to randomization or may need rescue treatment (typically TCS) to control disease shortly after randomization.…”

“…Placebo-controlled randomized trials are the gold standard for clinical research and are required for regulatory approval. Considerations around placebo utilization in AD clinical trials and practical suggestions for trial design were recently expertly reviewed [ 27 ]. When attempting to compare active agents from independent placebo-controlled trials, attention must be paid to the response rate to placebo in each trial, which may be influenced by background treatments/rescue therapies.…”