Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jan;23(1):1-11.
doi: 10.1007/s40257-021-00639-y. Epub 2021 Oct 26.

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

Jonathan I Silverberg  1 , Eric L Simpson  2 , April W Armstrong  3 , Marjolein S de Bruin-Weller  4 , Alan D Irvine  5 , Kristian Reich  6
Affiliations

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

Jonathan I Silverberg et al. Am J Clin Dermatol. 2022 Jan.

Abstract

The recent advent of numerous clinical trials for the treatment of moderate-to-severe atopic dermatitis has led to new and emerging therapeutic options for this chronic inflammatory skin disease. With this rapid development has come a lack of consistency in study designs, trial conduct, and statistical analyses. Healthcare providers are challenged to interpret how variations in study parameters may influence clinical trial results. Based on literature review and our experience as clinical trialists, we compiled a list of 22 key study parameters of contemporary clinical trials in moderate-to-severe atopic dermatitis and ranked the top study parameters that may have a significant effect on efficacy results. The top parameters included study comparators, rules for rescue treatment, washout periods for topical and systemic treatments, inclusion criteria such as disease severity by Eczema Area and Severity Index and/or Investigator Global Assessment scores, and the duration of the screening period. We describe considerations for these key parameters, with a focus on between-parameter interactions and effect on efficacy results. This may serve to inform the interpretation of atopic dermatitis clinical trials and raise the profile of the need to harmonize the clinical trial design.

Plain language summary

Atopic dermatitis (AD) is a skin disease characterized by red, itchy skin that is highly burdensome for patients. Patients with moderate-to-severe disease have large, inflamed skin areas with frequent itching. Recently, the number of clinical trials for drugs that treat moderate-to-severe AD has rapidly increased, with differences in how these trials are designed. There is a need for healthcare providers examining results from different clinical trials to understand how trial design factors might influence study outcomes. In this article, we identify key trial design factors that impact study outcomes, detail how these factors can impact clinical trial results, and explore how these factors interact with one another to affect study outcomes. The five most important design factors, as determined via author surveys, were study comparators (a placebo and/or another drug to which the drug being studied is compared); the rules for the use of rescue treatment (a form of treatment given if an enrolled participant has uncontrolled AD symptoms); washout periods (the time before the trial when previous treatments are stopped to allow them to be cleared from a patient’s system); inclusion criteria (that determine which participants are included); and the length of the screening period (the time when patients are assessed to determine if they qualify for participation). By understanding how these key trial design factors impact on study outcomes, healthcare providers may be equipped to better interpret different AD clinical trials. This work also emphasizes the value of harmonizing the AD clinical trial design.

PubMed Disclaimer

Conflict of interest statement

Jonathan I. Silverberg reports honoraria, as a consultant/advisory board member, from LEO Pharma and has acted as a consultant for and/or received grants/honoraria from AbbVie, AnaptysBio, Asana Biosciences, Galderma Research and Development, GSK, Glenmark, Kiniksa, LEO Pharma, Lilly, MedImmune, Menlo Therapeutics, Pfizer, PuriCore, Regeneron, and Sanofi. Eric L. Simpson is a consultant and investigator for AbbVie, Celgene, Dermira, Genentech, GSK, LEO Pharma, Lilly, MedImmune, Menlo Therapeutics, Pfizer, Regeneron, and Sanofi. April W. Armstrong is an investigator and/or consultant for AbbVie, Bristol Myers Squibb, Dermavant, Dermira, Janssen, Lilly, LEO Pharma, Modernizing Medicine, Ortho Dermatologics, Regeneron, Sanofi Genzyme, Science 37, and UCB. Marjolein S. de Bruin-Weller is a consultant/advisor for AbbVie, Lilly, Pfizer, Regeneron, Sanofi Genzyme, and UCB, and has received grant/research support from Regeneron and Sanofi Genzyme. Alan D. Irvine reports personal fees from AbbVie, Dermavant, Lilly, Pfizer, Regeneron, and Sanofi. Kristian Reich is a consultant/speaker/researcher for AbbVie, Affibody, Almirall, Amgen, Biogen, Boehringer Ingelheim, Celgene, Centocor, Covagen, Forward Pharma, Fresenius Medical Care, GSK, Janssen-Cilag, Kyowa Kirin, LEO Pharma, Lilly, Medac, Merck Sharp & Dohme, Miltenyi Biotec, Novartis, Ocean Pharma, Pfizer, Regeneron, Samsung Bioepis, Sanofi, Takeda, UCB, Valeant, and Xenoport.

Figures

Fig. 1
Fig. 1
Conceptual framework of biologic/systemic therapeutic trials in moderate-to-severe AD. Multiple parameters spanning clinical trial design (top), execution (center), and statistical analysis (bottom) may influence efficacy outcomes over the course of a phase III clinical trial for moderate-to-severe AD. AD atopic dermatitis, AEs adverse events, EASI Eczema Area and Severity Index, H2H head-to-head, HSV herpes simplex virus, IGA Investigator Global Assessment, LTE long-term extension, PROs patient-reported outcomes, TCS topical corticosteroids, VZV varicella-zoster virus
Fig. 2
Fig. 2
Efficacy implications of variations in rescue treatment. The duration of prior therapy washout during screening may impact the likelihood of flares, which subsequently impacts the need for rescue treatment in the treatment period. Additionally, residual treatment effects due to a short washout period may mask the true severity of the study population, skewing the participants who may meet the inclusion criteria for the treatment period. During the treatment period, whether or not rescue treatment is permitted has implications for trial discontinuation rates. Those who need rescue treatment may be considered non-responders in some trials; how non-responders are statistically accounted for may influence response rates. Long-term extension trials may also set rules around the inclusion/exclusion of participants who required rescue treatment during the treatment period, which may influence the patient profile in this phase. NRI non-responder imputation, TCS topical corticosteroids
See this image and copyright information in PMC

References

    1. Barbarot S, et al. Epidemiology of atopic dermatitis in adults: results from an international survey. Allergy. 2018;73(6):1284–1293. doi: 10.1111/all.13401. - DOI - PubMed
    1. Langan SM, Irvine AD, Weidinger S. Atopic dermatitis. Lancet. 2020;396(10247):345–360. doi: 10.1016/S0140-6736(20)31286-1. - DOI - PubMed
    1. Silverberg JI, et al. Patient burden and quality of life in atopic dermatitis in US adults: a population-based cross-sectional study. Ann Allergy Asthma Immunol. 2018;121(3):340–347. doi: 10.1016/j.anai.2018.07.006. - DOI - PubMed
    1. Simpson EL, et al. Patient burden of moderate to severe atopic dermatitis (AD): insights from a phase 2b clinical trial of dupilumab in adults. J Am Acad Dermatol. 2016;74(3):491–498. doi: 10.1016/j.jaad.2015.10.043. - DOI - PubMed
    1. Zuberbier T, et al. Patient perspectives on the management of atopic dermatitis. J Allergy Clin Immunol. 2006;118(1):226–232. doi: 10.1016/j.jaci.2006.02.031. - DOI - PubMed

Publication types

LinkOut - more resources