Advanced Systemic Therapies for Pediatric Atopic Dermatitis and Skin of Color: A Review and Strategies for Improving Trialist Involvement

Data Sources and Search Strategy

We employed a comprehensive search strategy alongside a trained health sciences librarian at Memorial University of Newfoundland using the following databases: PubMed (Medline), EMBASE, and the Cochrane Library (CENTRAL). Search filters^13,14 for clinical trials were imposed to allow for a sensitive yet specific search strategy. The search included relevant studies from inception to the date of the search ( Supplemental 1). We restricted the search to English articles only.

Eligibility Criteria

Our eligibility criteria were defined using the population, intervention, comparator, outcome, and study design structure as follows:

Study Selection

Articles identified from our search were imported into Covidence, ¹⁵ and duplicates were automatically removed. Following our eligibility criteria, study screening and selection were conducted by a single reviewer (R.H.). A senior author (M.P.) was consulted for final decisions in cases of uncertainty regarding study selection. At the full-text stage, articles that reported the same clinical trial and study population were only included if they were the primary study.

Data Extraction

A pre-designed form was used to extract study information. Data related to study characteristics, participant characteristics, interventions, and racial/ethnic counts were extracted. In clinical trials of both adult and pediatric populations, only pediatric data were extracted and reported. Supplementary information was sought for data extraction when the information was not retrievable from the main study figures. Percentages were also calculated manually when the information was not presented in the article.

Literature Search and Study Selection

A detailed PRISMA flow diagram highlighting the study selection process is illustrated in Supplemental Figure 1. Following our search strategy, 1517 studies were imported: 766 from EMBASE, 228 from PubMed, and 523 from the Cochrane Library. Once duplicates were removed, 1017 titles and abstracts and 154 full-text studies were screened. Eleven ongoing clinical trials could not be assessed for their eligibility.

Characteristics of Included Studies

A total of 16 studies comprising 21 clinical trials and 3148 patients were included. Twelve studies were randomized controlled clinical trials, and 4 displayed data from open-label extension trials. Systemic therapies investigated included Abrocitinib, Baricitinib, Dupilumab, Lebrikizumab, Nemolizumab, Tralokinumab, and Upadacitinib. Ten trials investigated a combination of systemic therapy and topical corticosteroids (TCS) in the interventional arm and a placebo group with or without TCS. All trials were multicenter and based in several countries globally. A detailed description of the study characteristics is displayed in Supplemental Table 1.

Race and Ethnicity Participant Characteristics

The racial and ethnic backgrounds of participants were reported in eleven (69%) of the studies, representing 17 clinical trials. Four studies did not provide the racial and/or ethnic demographics of their participant population. Among those, 3 studies were conducted in Japan and included only Japanese participants. The fourth study was completed across Europe, North America, Asia, and Australia, highlighting a potential for diverse participant demographics. Three studies reported the proportion of participants with Hispanic or Latino ethnicity in addition to racial breakdowns. Three studies reported on Indigenous North American demographics, which were represented at 1% of the study population. None of the studies reported involvement of Indigenous participants based in Canada. Multi-racial individuals were reported in 1 study by Cork et al. ¹⁶ Across all studies, White participants were largely represented, ranging from 56.1% to 76% of the patient population investigated. Asian demographics were the next largely represented group, ranging from 7.6% to 33%. Among the articles reporting racial and/or ethnic demographics, Black patients were the minority across 6 of the studies and ranged from 0.02% to 17% of the study population. The baseline racial participant characteristics are illustrated in Supplemental Table 2.

Racial and Ethnic Disparities in Atopic Dermatitis

The prevalence of AD continues to increase yearly and disproportionately affects racially diverse populations. In a large population-based survey conducted in the United States, the odds of AD were 1.7 times higher among Black patients when compared to White patients. ⁸ Another study found that Black, Hispanic, and Asian patients with AD were less likely to be prescribed systemic therapies for their conditions. ¹⁸ Similar results were shown in the United Kingdom, where Black Caribbean children displayed a disproportionate prevalence of atopic dermatitis even when confounders were accounted for Williams et al. ¹⁹ Asians and Pacific Islanders with atopic dermatitis in the United States and England were also more likely to visit their physician compared to White patients. ²⁰

Other disproportionately affected demographics include Indigenous populations in Canada and Native Americans in the United States (US). A 2008/2010 First Nations Regional Health report ranked AD as 1 of the leading chronic conditions among Indigenous youth in Ontario, with a reported prevalence of 10.4%. ²¹ In the First Nations reserve of the Natuashish, Labrador, rates in Indigenous children were as high as 16.5%, with approximately 67% living with moderate to severe levels. ²² Despite the pronounced impact, Indigenous populations in Canada and America represented less than 1% of participants in atopic dermatitis clinical trials between 2013 and 2023. ²³

In general, reporting of the racial and ethnic makeup of study participants has increased over the past few decades.^24,25 This may be attributable to the engagement of regulatory bodies and research funders, including the US Food and Drug Administration and the National Institutes of Health, which emphasize the inclusion of children, women, and racial minorities in research.^26,27 In pediatric US-based clinical trials, reporting of participant racial and ethnic backgrounds increased by 50% between 2007 and 2018. ²⁴ American dermatology trials also increased reporting of race and ethnicity by 12.1% between 2010 and 2015 and 2015 and 2020. ²⁵ However, prevalence of non-White participants throughout this 10-year period has remained relatively stagnant. ²⁵ Some may argue that these rates are representative of the general population; however, they do not reflect the disproportionate burden of disease in minoritized demographics.^24,28 Representation of participants in clinical trials should therefore strive to echo prevalence rates and enable sufficient sample sizes for racial/ethnic subset analysis to achieve generalizability of results across varied patient demographics. ²⁸

Challenges Experienced by Skin of Color and Caregivers

Challenges related to clinical trial participation within ethnoracial communities stem from (1) mistrust in the medical research ecosystem,^29-31 (2) language barriers,^30,31 (3) lack of study awareness and accessibility,^29-31 and (4) logistical barriers.^29,31 Regional and historical context, in addition to modern-day biases against racialized communities in society and medicine, may explain the longstanding distrust in the medical research community.^32,33 In the United States, African American involvement in research trials has been historically low. ³³ In a survey of Black patients residing in the US, Harris et al ³³ report that limited involvement of these groups in research involved a lack of knowledge about study recruitment, distrust in the medical profession, and financial limitations. Parents of children presenting to academic dermatology clinics revealed that Black caregivers were slightly less trusting of clinical trials compared to White caregivers. ³⁴ These parents were also 3-times more likely to believe their child would be “treated like a guinea pig.” ³⁴ As authors Shaw et al ³⁴ hypothesize, historically notorious events, such as the Tuskegee Syphilis Trials of the 1930s, which experimented on African American patients unaccompanied by true patient consent, ³³ may explain these perceptions of medical research several decades later.

Language barriers emerging from research jargon and terminology used in recruitment strategies can exacerbate challenges experienced by potential participants.^30,31 Focus group discussions among ethnically underrepresented adults with inflammatory skin conditions revealed mistrust in research when objectives, methodology, and safeguards were not adequately understood. ³⁰ Furthermore, concerns surrounding limited English language proficiency among ethnic minorities may contribute to this barrier.^30,35 Notably, Hispanic/Latino and Asian/Pacific Islanders were more likely to participate in pediatric research when adequate translation was provided than not. ³⁵ Lastly, various studies found that individuals from marginalized communities were largely unaware of ongoing clinical trials and/or of their significance.^29-31

Conducting clinical trials in children and adolescents adds another layer of complexity into addressing involvement in AD studies. Parental consent is an important pillar of trial involvement and is influenced by a myriad of factors, including perceived degree of interventional risk ³⁶ and concerns regarding overmedicalization (eg, repeated lab work). ³⁷ Interviews of parents with children participating in clinical trials reinforced previously mentioned themes surrounding trust building and research transparency. ³⁷ Parents wanted to feel that trials prioritized their child’s safety and were willing to engage in trials with minimal or absent risk even if disruptions to daily routines were a result. ³⁷ Other logistical challenges experienced by parents and caregivers include transportation to study sites ³⁷ and lack of time. ³⁸

Strategies to Enhance Involvement

A multistakeholder approach to enhancing skin of color trialist involvement has previously been described^29-32 and was used to summarize strategies in this review (Supplemental Figure 2). Involving stakeholders with longstanding and trusted relationships with ethnoracial groups, including dermatologists, community-based groups and leaders, and patient partners during the study initiation phase can set up a successful participant recruitment and retention strategy.^29,30,32 Dermatologists and health professionals working closely with multiracial pediatric populations are encouraged to collaborate with study investigators before the study interventional phases to ensure research objectives are patient-centered and inclusive of the populations they serve. ³² As part of a 4-pronged framework for enhancing diversity in dermatologic clinical trials, Asabor et al ³⁹ emphasize involvement of communities in shaping research priorities, a process which should take place prior to trial commencement. To address transparency and language barriers, study investigators should use inclusive, culturally sensitive, and clear language that can be understood by individuals from varied educational backgrounds, ³⁰ prioritize the safety and well-being of child participants, ³⁷ and translate study materials as needed.^30,32

During study recruitment, patients and caregivers can be approached and recruited through health professionals and community-based organizations with established relationships with the participants. Studies have consistently shown that patients and caregivers with skin of color feel more comfortable when trial invitations come from a healthcare provider they are familiar with.^30,32,40 Interviewed adults from racially diverse backgrounds preferred being approached by a member of their healthcare team, more so than being approached by strangers of the same ethnic background. ³⁰ Partnerships with community groups and leaders can also help reach target demographics and highlight the value of trial involvement through educational sessions.^29-32 This approach can help address barriers related to a lack of trial awareness and social stigma associated with the disease.^29,30 Study investigators and recruiters also hold responsibility during this phase to ensure full transparency with potential participants regarding benefits and risks posed by interventions, ³⁷ utilizing language translation services where needed. ³⁰

Dermatologists involved in clinical trials are encouraged to ensure that trial investigators are providing adequate follow-up with patients and caregivers regarding study updates, as per The Skin of Color Society’s recommendations from the Meeting the Challenge Summit in 2022. ³² Addressing logistical barriers through caregiver support, including flexible scheduling^32,40 and selecting locally accessible clinics as study sites ³⁰ may offer more practical solutions for families.

Finally, dissemination of study results to the community is crucial for maintaining continued trust and increasing the likelihood of participants continuing to participate in trials. ³¹ In a focus group study, members from racial and ethnic minority groups expressed the importance of dissemination of findings following the conclusion of the research, with some participants hoping “something tangible” may follow from their involvement. ³¹ As part of a participant retention strategy, Choy et al ³⁰ recommend that study investigators seek and provide feedback from study subjects at the end of each study. One participant in this study noted that the dissemination of results, along with recognizing the benefits at an individual and societal level, was a “big driver” to continue participation in research. ³⁰

Study Limitations

There are some study limitations that should be addressed. First, the study screening and selection were conducted by a single author, which could introduce selection bias to the articles included in this study. However, a predefined full protocol was followed in efforts of minimizing bias where possible. In addition, studies examining clinical trials of both pediatric and adult populations were excluded if baseline race/ethnicity characteristics were not separated for the pediatric population. This could eliminate potentially eligible clinical trials from our pooled assessment. Non-English studies were excluded for the purposes of this rapid review, potentially eliminating more diverse demographic data. While newer advanced topical therapies, including Roflumilast 0.15% and Roxulitinib 1.5%, have recently been approved for children in Canada, they were excluded to minimize clinical heterogeneity among included studies.

Despite these limitations, our study still provides critical evidence toward the representation of historically underrepresented and excluded demographics in research and calls for increased efforts to ensure skin of color demographics are adequately represented in pediatric literature for atopic cutaneous diseases.