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Published On: May 13, 2021
Last Updated On: May 17, 2021
The rapidly expanding treatment pipeline for atopic dermatitis (AD) is made possible through a tremendous investment of time, resources and patients participating in clinical trials. Clinical trials are essential for new drug development and approval. AD, like other diseases, can vary greatly across demographic groups1. Therefore, it is critical that trials include as broad a range of patients as possible.
The more diverse people represented in clinical trials are, the more meaningful the results will be for real-world care and treatment. However, it can be difficult to achieve broad representation in clinical trials. Older adults, racial and ethnic minorities, rural residents and individuals of low socioeconomic status are often underrepresented for various reasons2. Pediatric patients in particular have additional considerations that must be adhered to when designing trials3,4. Here we discuss some of the challenges to engaging and recruiting diverse demographics to clinical trials, broadly as well as for AD drugs in development. We also highlight efforts underway to enhance clinical trial recruitment so representation in trials more closely reflects the patient populations affected by AD.
To maximize learning about treatment safety and efficacy (i.e. how well it works), clinical trials are conducted in four phases (see below), and are often undertaken initially in adults, even for diseases such as AD, that affect both adults and children. Each clinical trial phase builds on findings from the previous phase, or ceases further testing if the drug fails to demonstrate improvement in pre-determined disease outcomes, or there are concerning safety signals.
For each clinical trial, researchers calculate the total number of people required to participate to reach statistically meaningful conclusions (called “powering the experiment”). Without enough patients participating, the study can be underpowered, jeopardizing the validity of the overall results and perhaps stopping a drug from moving forward. Dr. Aaron Drucker, MD, of Women’s College Hospital in Toronto, ON explained that, if a trial didn’t find enough participants that meant “all the resources put into the trial – patient time, investigator time and money – may be wasted.” While achieving the desired number of patients in all phases of clinical trials is important, it can also be problematic if the patients are too demographically similar.
In general, to be representative of the broader population, clinical trials should enroll people in percentages similar to their overall representation in the population. While this may seem straightforward, representativeness can be evaluated by several identity factors for each person including gender, age, race and ethnicity, socioeconomic considerations and geography. In addition, some patient populations may be disproportionately affected by a disease (e.g. children with AD, people of color during the Covid-19 pandemic, older individuals with Alzheimer’s). In these cases, trials would also ideally strive to overrepresent those disproportionately affected compared to their population share. These considerations can make the concept and practicality of achieving representation in all these dimensions complex, though important, toward the goal of clinical trials that can lead to Food and Drug Administration (FDA) drug approvals as well as yield findings that can be applied to the care of many individuals.
For example, if a drug is tested disproportionately in the population (e.g. primarily white race, males 18-65 years old), we may not learn if the drug may differently impact patients not included in the trials (such as older aged females from racial or ethnic minority groups). The wider spectrum of potential side effects and efficacy in these underrepresented groups may not be more fully understood until Phase IV studies and published reports documenting outcomes of use in the real-world. If people are not enrolled in similar percentages to their representation in the population, Dr. Drucker says, “This means that the results of the trial may not apply to those who might ultimately use the intervention. For example, if a trial excludes older adults (e.g., 65 and older), we cannot directly apply the results to older adults. This doesn’t allow older patients to make informed decisions and can cause patient harm.” Dr. Amy Paller, MD, of Northwestern University adds, “This does not mean the drug cannot be used for a broader group with the same diagnosis, but the ‘on-label’ indication may be narrow and that could restrict getting insurance coverage and access.”
There are many incentives for a patient to enroll in a clinical trial. According to Dr. Elaine Siegfried, MD, of Saint Louis University School of Medicine, “benefits of participating in clinical trials can include compensation for each visit, getting a medication for free that otherwise would not be available to you (participation in a long-term study may mean receiving the drug for a long time) and altruistically helping society at large or others also living with symptoms similar to yours. In addition, participation in a clinical trial will allow close monitoring, advice, care and support by a research team of doctors and other health care professionals who are experts in your disease or condition.”
Reported barriers to participation in clinical trials include: the administrative burden of a hospital or center being involved in a clinical trial; the way the trial protocols are written (i.e. may specifically exclude older adults, unique protocols need to be written for clinical trials in children); lack of awareness of appropriate clinical trials; belief that the standard therapy already in existence is best; fear, distrust or suspicion toward research; financial repercussions for taking time off work to participate; or practical obstacles such as lack of access to a trial site or language or literacy barriers5-7.
There is also a need for greater public education about clinical trials including helping patients and caregivers understand what clinical trials are for, what the process is like and what the potential risks and benefits may be. NEA’s new Clinical Trials Information Hub can be a resource to find eczema clinical trials that are enrolling, learn more about the process and what questions to ask as you consider this option2-5,8.
Racial and ethnic minority groups are often underrepresented in clinical trials. For example, African American patients represent 13.3% of the US population but only make up 5% of patients enrolled in clinical trials supporting FDA approval of new drugs9. Several factors may contribute to this. Historic abuse of racial and ethnic minority groups by the medical system and ongoing systemic racism and discrimination may contribute to lack of participation of in clinical trials5,10. People who lack insurance or have confounding health conditions may be explicitly excluded from clinical trials2,10. While true for all people, minority groups may disproportionately experience a lack of awareness and information, prohibitive distance to trial sites, limited flexibility in work and caregiving schedules and lack of access to technology for required monitoring, discouraging clinical trial participation2,11. Additionally, as racial and ethnic minority groups can represent several unique cultures and use of non-English languages, forms such as informed consent documents may not be culturally appropriate or appropriately address language differences and health literacy10.
The National Institutes of Health (NIH) has a policy and guidelines on “Inclusion of Women and Minorities as Subjects in Clinical Research12.” This states that women and minorities of all ages must be included in all NIH-funded clinical research unless there is compelling justification for their exclusion that has been approved by the NIH Director and Institute or Center Director. It also makes clear that cost is not an acceptable reason for exclusion. The research design should include the sex/gender and racial/ethnic composition of the study population and a description of the proposed outreach programs for recruiting these individuals as participants. Both the FDA and the Pharmaceutical Research Manufacturers of America (PhRMA) recently updated their policies about clinical trial diversity to enhance inclusion of groups historically overlooked in clinical trials13-15. Together, studies funded by the NIH or the pharmaceutical industry and all drugs approved by the FDA should be making inclusion of minority groups a priority.
One of the most recent examples of focused recruiting of racial and ethnic minority groups into clinical trials occurred with development of the Covid-19 vaccine. Both Pfizer and Moderna undertook deliberate efforts to include racial and ethnic minority groups in their trials, with Moderna even slowing down recruitment so that more people from different racial and ethnic groups could be enrolled16. Still, diverse racial and ethnic groups were underrepresented in these trials compared to their percentage in the U.S. population. For example, black Americans comprise 13.3% of the population, only 9.8% and 9.7% enrolled in the Pfizer and Moderna trials, respectively10. Asian populations represent 5.9% of the population, but only 4.4% and 4.7% enrolled in the Pfizer and Moderna trials, respectively10.
Dr. Paller says she is hopeful about the future of inclusion of underrepresented minorities in clinical trials because there are “opportunities for developing better structures and mechanisms for engagement. For example, trial centers are incorporating more telemedicine, especially if patients in the trial are not close to the medical center or if access is difficult because of economic barriers or limited transportation. There is rapidly evolving availability of new technologies such as sensors, artificial intelligence and mobile apps. There is more engagement of community leaders to help educate and dispel myths about participation in clinical trials.”
Though AD onset typically occurs in childhood, recent studies have revealed that there is a second peak in incidence after 60 years of age17. However, older adults have been underrepresented in clinical trials to date, particularly for systemic therapeutics for AD. A systematic review on inclusion of older adults in trials of systemic AD drugs found that 34% of trials explicitly excluded older adults17. Less than 5% of participants who received dupilumab for AD in clinical trials were 65 or older17. The average age for trials of other new biologic therapies for AD were 37 years for tralokinumab (range 23-49)18, ~40 years for nemolizumab (range 18-82)19 and ~39 years for lebrikizumab (range not given but standard deviation indicates lack of participation of patients older than 60 years)20. There may be separate, age-specific studies that may be more appropriate for children or older adults to participate in21. Dr. Drucker says, “We need to eliminate upper age restrictions for trials of medications in adults. Additionally, we should minimize exclusion criteria related to comorbidities and polypharmacy (taking multiple medications simultaneously) that preferentially exclude older adults. Finally, trialists should proactively seek older participants.”
The NIH has updated its policy on inclusion of older adults in clinical trials as recently as 2017, stating that individuals of all ages, including children under 18 and older adults must be included in all human subjects research conducted or supported by the NIH. Clinical trials proposals must include plans for including individuals across the lifespan. The FDA provided a history of their stance with regard to inclusion of aged individuals in their recent Guidelines for Enhancing Diversity of Clinical Trial Populations which applies to both government and industry-sponsored clinical trials13. They highlighted a Guideline for Drugs Likely to be Used in the Elderly published in 1989, a 1993 document discouraging maximum age requirements in clinical trials and two publications of further guidance in 2012 and 2014 emphasizing the importance of inclusion of older adults, especially patients 75 and older, in clinical trials13. Clearly despite these guidelines, there is room for improvement with regard to inclusion of aged populations in clinical trials.
Access to study sites can be a major issue for individuals living in rural areas compared to those living in urban or suburban areas. A survey of rural and urban residents in South Carolina indicated that there were no significant differences between the groups in terms of willingness to participate in a clinical trial, but rural residents had limited access to trial sites and less knowledge about clinical trials in their area22. Rural residents needed to commit more time and resources to traveling to appointments for clinical trial participation. Extra effort therefore needs to be made on the part of researchers to reach out to rural communities and compensate all patients for travel, lodging and time commitment22.
There is also a greater need for researchers to use other means of communication to reach rural residents. While urban patients may be recruited largely through the medical system, rural individuals will more likely be engaged by raising awareness among community physicians and organizations, using mass media such as the internet or television, or advertisements on more local radio and print publications22.
Even though AD predominantly affects children, the FDA typically approves indications for a drug in different pediatric age groups after initial approval in adults, if the drug is indicated for this population at all. For example, dupilumab was first approved for adults, then ages 12-17, then ages 6-11, and is now under investigation for ages 6 months to 5 years.
It is crucial that children participate in clinical trials since the prevalence of AD is high in this population, and fewer treatment options may be considered for children — they may stand to benefit considerably from new drugs in development. Children are considered a vulnerable population and therefore there are special considerations and protections for including children in clinical trials. As stated above, the NIH requires individuals of all ages to be included in clinical trials21. However, children are unable to give informed consent. The NIH has stipulated that children over seven years old can give their assent to participate in a trial, while their parents give consent or permission23. It is recommended that a study be designed specifically for children, and that researchers not simply re-use a protocol that was designed for adults4.
In general, participation of children in Phase I trials is discouraged since effects of the drug are not yet known in any population 3. Dr. Paller states, “A topical drug that has a known safety record might be able to be tried at the same time in adults and children. However, a systemic drug with no known safety record is more likely to be sequentially assessed for safety in adults first before decreasing the age – so Phase I and II trials may be delayed for children. If a significant safety issue (or poor efficacy) is noted in older patients, the drug likely will not advance.”
Parents and doctors are often fearful of including children in clinical trials due to the potential for harm in this vulnerable population. Parents are understandably protective and often state that they do not want their children to be guinea pigs. Dr. Siegfried encourages parents to think differently, recognizing that the absence of data from clinical trials means a lot of unknowns when used in the real-world, “The truth is that if we do not have good safety and efficacy data for children then ‘all children are guinea pigs.’ Clinicians might still prescribe the medication to children “off label” (meaning in ways other than the FDA-approved label indicates) because it may in fact be the best treatment option. However, in this case insurance may not cover the drug since it is not specifically indicated for children on the label. Dosing can be difficult as well since dosing studies have not been conducted other than in adults.”
After 20 years of trying and coming up against a multitude of systemic barriers, Dr. Siegfried, along with a consensus committee of experts (including NEA President and CEO Julie Block), recently published guidelines that have been accepted by the FDA for inclusion of children three months to 18 years in trials to develop AD drugs4. She states: “The infrastructure to support pediatric clinical trials now lags behind. There are not enough centers capable of doing pediatric clinical trials. It is not part of the training for clinicians. The administrative burden is higher and there is less economic advantage to doing trials in children.” There are organizations specifically set up to support clinical trials of children including the Institute for Advanced Clinical Trials for Children and the Pediatric Trials Network. These organizations specifically help with the planning and completion of pediatric clinical trials. Still, when a pediatric trial is opened, Dr. Siegfried states that the number of children in trials are only 50% or even 10% of what is common for adult clinical trials.
With the explosion of new possibilities for AD therapeutics currently in the pipeline, it is all the more imperative that clinical trials represent the populations that will be using these treatments. There is room for improvement in recruiting for clinical trials overall, but specifically people from different racial and ethnic minority groups, children, aged adults and people who reside in rural locations. Patients often look to their healthcare providers to inform them of clinical trials7,9, so clinicians should be aware of the clinical trials ongoing for their patient populations and supported to encourage their patients to participate. Many steps are currently being taken to improve access to clinical trials for diverse populations and to reduce the barriers people experience when trying to participate. Recent updates to governance and trial protocol technologies are promising to support broader inclusion of underrepresented populations. However, more work is needed and the lag in enrolling appropriate populations may impact knowledge about the safety and efficacy of the AD drugs in the pipeline for years to come.
Take home points:
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13. Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry. In: Administration USDoHaHSFaD, ed2020.
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18. Wollenberg A, Blauvelt A, Guttman-Yassky E, et al. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br J Dermatol. 2020.
19. Silverberg JI, Pinter A, Pulka G, et al. Phase 2B randomized study of nemolizumab in adults with moderate-to-severe atopic dermatitis and severe pruritus. J Allergy Clin Immunol. 2020;145(1):173-182.
20. Guttman-Yassky E, Blauvelt A, Eichenfield LF, et al. Efficacy and Safety of Lebrikizumab, a High-Affinity Interleukin 13 Inhibitor, in Adults With Moderate to Severe Atopic Dermatitis: A Phase 2b Randomized Clinical Trial. JAMA Dermatol. 2020;156(4):411-420.
21. Revision: NIH Policy and Guidelines on the Inclusion of Individuals Across the Lifespan as Participants in Research Involving Human Subjects. National Institutes of Health Grants and Funding. https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-116.html. Published 2017. Accessed 2021.
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23. Paller A. Brief Cognitive Behavioral Therapy to Treat Itch Rumination “Itch CBT” in Eczema. Clincaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT04486742?term=cognitive+behavioral+therapy&cond=Atopic+Dermatitis&draw=2&rank=2. Published 2021. Accessed 2021.