Diversity in Clinical Trials

Purpose and Applicability

This guidance provides researchers and the IRB with guidelines for ensuring the research design of clinical trials has adequately addressed the Belmont Principle of Justice, the federal regulatory requirement that selection of participants is equitable, and Chapter 69.78 of the Revised Code of Washington (RCW) ^[20] (UW-specific RCW 28B.20.540 ^[21]) requirement to enroll traditionally underserved populations in clinical trials. Use this guidance to complete the Diversity Plan for Clinical Trials Supplement ^[3].

This guidance was developed based on our evaluation of federal regulatory agency guidance, guidance from the Multi-Regional Clinical Trials (MRCT) Center, and peer-reviewed publications. In addition to following this UW IRB guidance, we encourage researchers to read the many FDA guidance documents referenced throughout and to use the vast resources provided by the MRCT Center. The MRCT Center guidance ^[22] has extensive information about how to design and implement a diversity trial plan. The associated MRCT Center toolkit ^[23] breaks down many of these complicated concepts into easy-to-follow checklists. The MRCT Center Outline of Suggested Recommendations for Incorporating Diversity and Inclusion into a Clinical Research Protocol Template ^[24] is a good place to start.

The Diversity Plan for Clinical Trials Supplement was adapted from the FDA guidance, Diversity Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies ^[25].

HSD was one of five work groups supporting various aspect of the Diversity in Clinical Trials Initiative (DCTI) which is overseen by the UW Medicine Office of Healthcare Equity and led by a Strategic Leadership Committee comprised of interested parties and subject matter experts. Background information about the development of the guidance and a summary of key comments that shaped the guidance ^[26] can be found on our website.

Context – Ethics, Regulations, and Washington State Law

The Belmont Principle of Justice promotes a fair distribution of the burdens and benefits of research at both the individual participant and societal levels. This means that no one group should be either targeted for or excluded from participating in research without valid scientific or ethical justification. No one group should bear the burdens of research and no one group should be excluded from experiencing the benefits.

The federal human subjects regulations at 45 CFR 46 (Common Rule) and 21 CFR 56 (FDA), operationalize the Belmont Principle of Justice by requiring the IRB to determine that the selection of research participants is equitable, particularly when vulnerable populations are being enrolled. A more comprehensive discussion of the importance of equitable selection and how to achieve it can be found on our webpage describing the Belmont Principles ^[28].

Washington State RCW 69.78 (RCW 28B.20.540, specifically) requires the University of Washington to adopt a policy to increase participation of underrepresented demographic groups in clinical trials.

The objectives of RCW 69.78 align with the Common Rule and FDA requirement that selection of research participants is equitable.

Policy – Diversity in Clinical Trials

It is UW policy that a Diversity Plan to improve the enrollment of underrepresented groups within the target study population is required for all research that meets the definition of a clinical trial ^[1] and where UW employees or agents are responsible for or engaged in recruitment or consent activities.

• The target study population must be selected based on the epidemiology and/or pathophysiology of the disease, and the population that the intervention is intended to treat. Any exclusion(s) must be justified by science, ethics, and/or safety.
• Underrepresented groups are defined as a community or demographic group that is more likely to be historically marginalized and less likely to be included in research and clinical trials represented by race, sex, sexual orientation, socioeconomic status, age, and geographic location. This UW policy is specific to underrepresented groups as defined in RCW 69.78. The UW acknowledges that there may be other historically underserved populations, including those defined by FDA and NIH that researchers may want to consider when designing their study. The UW encourages inclusion across all types of diversity.
• In addition, this policy applies:
  • Regardless of where the interventions occur;
  • To UW site(s) being reviewed by an external (non-UW) IRB; and
  • To all sites as a condition of the UW IRB agreeing to review on behalf of non-UW institutions and individuals.

Studies Reviewed by the UW IRB

Researchers must submit the Diversity Plan for Clinical Trials Supplement as part of the Zipline application. This provides the UW IRB with information about how the study population was selected and the operational measures that will be used to enroll and retain underrepresented groups. When UW is the reviewing IRB for a multi-site trial, the requirement for all sites to comply with the policy will be a condition of the agreement for UW to serve as the reviewing IRB.

Studies Reviewed by an External (non-UW) IRB

The requirements differ depending on which external IRB is conducting the review.

Local (WA State) Partners with Established Cooperative Agreements.

Fred Hutchinson Cancer Center, Seattle Children’s, and Washington State IRBs must also comply with RCW 69.78. The UW will defer to the policies developed by these organizations for assessing diversity in clinical trials provided they are applied to the portion of the research engaging UW. UW researchers should follow the requirements of those organizations. UW researchers do not need to complete the Diversity Plan for Clinical Trials Supplement as part of the Zipline request to use any of these external (non-UW) IRBs for review.

Commercial IRBs and Other External IRBs

When the review is conducted by WCG IRB or Advarra. To satisfy the requirement, UW researchers must include the Diversity Plan for Clinical Trials Supplement as part of the UW external review Zipline application and must also provide the supplement to WCG IRB or Advarra as part of their submission.

When the review is conducted by an external IRB that is not WCG IRB, Advarra, or a cooperative partner listed above, UW researchers must include the Diversity Plan for Clinical Trials Supplement as part of the Zipline request to use an external (non-UW) IRB for review. The UW Reliance Team will assess the Diversity Plan for compliance with UW policy. Researchers then incorporate the Plan information into the external IRB’s application materials.

For multi-site trials reviewed by commercial IRBs or other external IRBs, the diversity plan and policy requirements technically only apply to the UW site. However, in most cases it will make sense to discuss the target study population and enrollment goals in the context of the larger study and across sites as discussed in Setting Enrollment Goals ^[11], below.

Exceptions to the Policy

The submission of a Diversity Plan is not required for the following categories of research, however researchers may submit a plan if they wish.

• Phase 1 or earlier trials. Questions about variability in response to treatment should be considered along the timeline of product development and post-marketing data collection and analysis. The eligibility requirements for phase 1 trials are necessarily conservative to minimize risk since only pre-clinical data are available, little is known about safety and efficacy, and variability in response may be high. For these reasons, it may be appropriate to exclude certain groups or for certain populations to be underrepresented from Phase 1. Even when eligibility criteria are justifiably restrictive, it is still important to facilitate access by reducing barriers and burdens as discussed below (e.g., flexibility in location and hours for study visits and providing translation and interpretation to allow participation of individuals with non-English language preference), particularly for studies with a therapeutic aim that may offer the prospect of direct benefit.
• Pilot and feasibility studies. The goal of pilot and feasibility work is not to test hypotheses about the effects of an intervention, but rather to assess the parameters or components of a larger scale study. Given the smaller scope of pilot and feasibility studies, they may not include the range of populations for which the treatment was intended. However, these studies may be used to engage communities at the start of study design and assess the likely rates of recruitment and retention of participants, including underrepresented groups for future later-phase trials.
• Clinical trials involving small populations. There are circumstances in which clinical trials can only be conducted with small populations such that considerations of subgroup differences and/or heterogeneity of treatment effect may not be possible. Some examples include rare diseases, unique study populations (e.g., astronauts), isolated environments, emergency situations, restricted resources coupled with an urgent need, and tailored therapies. In these cases, the populations may be too small to allow for statistical calculation. If you believe that this exception applies to your study, please contact HSD early in the study design/budgeting process for a decision about the applicability of the DCT policy to your clinical trial (hsdinfo@uw.edu ^[29]).

Policy – Enrolling Participants with Non-English Language Preference (NELP)

Inclusion of Participants with Non-English Language Preference

It is UW policy that clinical trials that require submission of a Diversity Plan for Clinical Trials Supplement must have resources in place to include prospective participants with non-English language preference (NELP) unless there is a compelling reason for their exclusion. There is a strong argument for inclusion of participants with NELP when: (1) the research offers a potential for direct benefit that may only be available within the context of the research; (2) their inclusion is necessary for the results to be generalizable to a particular group as a whole; and/or (3) when their inclusion is necessary for the research to ensure adequate representation of a group disproportionately affected by the condition being studied. A lack of resources will generally not be considered sufficient justification for exclusion.

Potential Justification for Exclusion of Participants with NELP May Include:

• The inclusion of participants with NELP would jeopardize their safety or well-being. For example, when it is anticipated that participants may need to access emergency care quickly and there could be insufficient time to arrange for interpreter services.
• Scientific and/or methodological reasons. There may be a lack of appropriate validated instruments, surveys, or assessments. In some situations, use of another language may confound the research results or not permit appropriate analysis of the data, especially when protocols are designed with a small sample size. It is an investigator’s obligation to determine whether there are appropriate alternative assessments, instruments, or surveys that could be used for participants with NELP prior to excluding them. The UW IRB is willing to consider flexibility in these situations regarding which instruments are administered and how they are administered, particularly when there is a prospect of direct benefit. If a study includes administration of a specific instrument, ask the following questions:
  • Is the instrument validated for use in languages other than English? If not, is there another equivalent instrument that can be used to be more inclusive?
  • Is the information you will obtain from the instrument important enough that it would be impossible to skip that procedure for some of the participants and still be able to answer the larger research questions? If not, is it possible to do subgroup analyses for that instrument?
  • Could the instrument be administered orally including the use of an interpreter who can help ensure the participant understands the questions the researchers are asking?

Translation and Interpretation

It is UW policy that:

• When 5% or more of the target population speaks a primary language other than English:
  • The study must have translations of any written materials to be read by participants (e.g. consent forms, recruitment materials, surveys) available at the outset of the research.
  • There must be resources in place to support their inclusion for the duration of the study.
• When less than 5% of the target population speaks a primary language other than English
  • There must be a plan in place to support their enrollment and participation in the research when they are encountered.

When study materials have not been translated in advance, best practice is to wait to enroll the participant until the consent form can be translated into the participant’s primary language. For many languages, UW Medicine Language Access and Cultural Advocacy ^[30] can offer rapid translation and the UW IRB will fast track approval of the modification to add the translated forms. When the only item for review in a modification is/are translated consent form(s), the submission is complete, and the researcher contacts the review team via email ^[31] to alert them to the submission, the IRB will approve the modification within 1 business day. UW Medicine Language Access and Cultural Advocacy is available to all UW researchers, not just those within UW Medicine.

When it is not possible to wait to enroll a participant until the consent form is translated, researchers may consider using the short form consent process and interpreter services to help communicate the content of other written materials. Note that to use the short form process you must get prospective IRB approval, and the full consent form must still be translated and provided to the participant.

Review HSD’s webpage about involvement of participants with non-English language preference ^[32] for guidance about translation and interpretation and for full details about requirements when using the short form consent process ^[33].

Procedure – Planning, Budgeting, and Resources

In the next section, we provide details about what you might include in your Diversity Plan, depending on the subject population and study design. Many of these elements require budgeting and advance planning at the time of writing the research proposal. The UW and some sponsors provide resources for helping you plan and budget for these diversity-related activities and expenses.

ITHS Recruitment Support Service

The ITHS provides a consultation service to investigators, focusing on pre-award and study development, study design, implementation strategy, recruitment and retention planning, and budget development to help researchers attain their enrollment goals. They will be adapting this service to align with the Diversity in Clinical Trials Initiative by providing guidance to support researchers, primarily pre-award, in meeting their representation goals. HSD will update this webpage as more information about this resource becomes available. Researchers who are interested in piloting the service should contact ITHS at recruitmentsupport@uw.edu ^[34].

Translation and Interpretation Services

UW Medicine Language Access and Cultural Advocacy ^[35] has many resources for UW researchers and can provide consultation when you are planning your research study and writing the proposal. These resources are available to all UW researchers, even when the study is not taking place at UW Medicine or Harborview. Interpretation services can be accessed anywhere telephone service or video conferencing are available. You can contact them directly at uwlaca@uw.edu ^[36].

Staffing

Enrollment of some underrepresented groups may require planning and budgeting for additional staffing resources. One example would be planning for evening and weekend staffing hours for participants who may not be able to attend study visits during the workday. Another example would be the additional time it takes to complete an interpreted consent process with participants who have a non-English language preference.

Community Engagement

The research budget must include sufficient funding to support your planned community engagement. This could include the cost of: payment/honoraria for members of a community advisory board; holding recruitment events in community locations (e.g., churches, community events, barber shops/beauty salons); developing or adapting culturally inclusive recruitment materials and research instruments; data collection with potentially increased complexity given additional demographic considerations; training and development for research staff on the topics of cultural humility and competency, anti-racism, race-based medicine in research, and implicit bias; and evaluation and dissemination of results back to the research community

The UW Office of Healthcare Equity (OHCE) ^[37] is leading several initiatives aimed at strengthening our community engagement efforts in research. Information about these initiatives can be found on the Diversity in Clinical Trials Initiative website ^[38]. HSD will update this section as more information becomes available.

Location of Research Procedures

While writing the research budget, carefully consider where in-person procedures will take place and whether alternative locations or methods can be used to increase diverse participation. Consider setting up collaborations with clinics that serve the underrepresented groups you want to enroll in locations other than the main study site (e.g., UW Medicine) to allow for greater access to rural populations. Consider budgeting to hire mobile medical professionals who can make home visits and to allow staffing for evening and weekend clinic visits. Details about including these elements in your plan ^[39] are described below.

Payment for Participation

While writing the research budget, include sufficient funds for reimbursement, compensation, and if you anticipate any of the underrepresented groups you are targeting may be difficult to recruit, incentives for participation. Details about the different types of payment ^[40] are described below.

Electronic Methods

If you plan to use electronic surveys or other remote procedures, consider whether the underrepresented groups you want to recruit may have problems accessing the internet, or if they may not own devices that will allow them to participate. Consider whether you need to budget for providing participants with electronic devices or whether you need to put alternative methods in place (e.g., administer the electronic survey over the phone or in person) to allow for more diversity in participation. Details about using electronic methods ^[41] are described below.

Procedure – Developing a Diversity Plan

Use this section to fill out the Diversity Plan for Clinical Trials Supplement. The Supplement asks you to: (1) set enrollment goals for underrepresented groups; (2) provide a rationale for those goals; (3) describe the strategies you will use to meet the stated enrollment goals; and (4) describe the metrics you will collect to monitor whether you are achieving the stated enrollment goals and actions you will take if those goals are not met. The supplement provides hyperlinks to the relevant sections of this guidance.

Setting Enrollment Goals

Identifying a “diverse” participant population is complicated in that any individual may be characterized along multiple dimensions of diversity which include both demographic (age, race, sex, gender, sexual orientation) and non-demographic (comorbid conditions, disabilities, weight, socioeconomic status, geographic location) factors. Any, some, or all of these factors may contribute directly or indirectly to the treatment outcome. The UW IRB does not expect the Diversity Plan to include all underrepresented groups for any particular clinical trial. The appropriate makeup of a study population depends upon a number of factors, including but not limited to the scientific question(s) being addressed, the prevalence of the disease, disorder, or condition among underrepresented groups, and potential gaps in scientific knowledge [Bierer et. al., 2021].

Considerations for how to identify your enrollment goals are described in the next section, Rationale for Enrollment Goals ^[12].

Available tools for identifying the distribution of underrepresented groups within the study’s target population include:

• Leaf ^[42]. A self-service, free of charge tool that allows UW investigators affiliated with UW Medicine and who have an AMC account to query the UW Medicine electronic health system (EHS) records. Leaf interacts with live data from the EHS and can generate de-identified data sets in real time.
• ITHS Biomedical Informatics ^[43]. For researchers not affiliated with UW Medicine, the ITHS Biomedical Informatics team may be able to provide data sets and cohort discovery services. These services may be fee-based but free of charge consultations can be requested.
• UW Health Sciences Library ^[44]. Librarians are available to assist research teams with identifying underrepresented groups described in PubMed and the ClinicalTrails.gov registry. For clinical trials and studies subject to the DCTI requirements, submit your interest via this DCTI Library Intake form ^[45]. The librarians can assist with non-clinical trial research via the Ask Us feature ^[44].

In multi-institutional research, it is the aggregate population across all trial sites that matters for developing a Diversity Plan [Bierer et al., NIH policy Inclusion of Women and Minorities as Participants in Research Involving Human Subjects]. This means that any one site may underrepresent or overrepresent a given subgroup based on the overall demographics of the geographic area. For example, a site in the Seattle area may overrepresent the overall study goals for enrollment of participants of Asian ancestry but have lower enrollment of African American populations. A site for that same study in Alabama may overenroll African American participants and have low enrollment of Asian participants. The goal is to choose sites carefully so that, as an aggregate, the overall enrollment goals are met.

Industry sponsors may already have a diversity plan. In these cases, you may use the details of the sponsor’s plan to fill in the UW supplement so that the UW Diversity Plan aligns with the sponsor plan. If you plan to make any changes to the sponsor plan in light of the UW Diversity Plan guidance, be sure to first consult with and obtain approval from the sponsor before submitting the Diversity Plan to the UW IRB.

Rationale for Enrollment Goals

Defining the Study Population

The FDA’s guidance on Enhancing the Diversity of Clinical Trial Populations and on Diversity Plans notes that a Plan must include a rationale for the identified enrollment goals of underrepresented groups. They provide the following recommendations for what should be included in that rationale:

• Generally, enrollment goals should be informed by the estimated prevalence or incidence of the disease or condition in the population, including any underrepresented populations, intended to take or use the treatment. In the Diversity Plan, provide an analysis of available data on the pathophysiology of the disease or condition in underrepresented populations. If applicable, include in the analysis any differential application or use of currently available prevention, screening or diagnostic strategies and treatments across populations. When possible, use available resources such as certain registries that are reasonably expected to be demographically representative, publicly available epidemiological surveys, and published literature to obtain information about the estimated prevalences or incidences of the disease across underrepresented groups. The goal is to have an enrollment that reflects the epidemiology of the disease.
• When the clinical trial involves a drug or device, analyze any data that may indicate the potential for a medical product to have differential safety or effectiveness associated with underrepresented populations. For drug development, provide information about any known differences in safety or effectiveness of the drug across underrepresented groups such as possible differences in pharmacokinetic (PK), pharmacodynamic (PD), and pharmacogenetic data. When the data are available, include a description of other characteristics (e.g., socioeconomic status, geographic location) that may have an impact on the clinical outcome. For devices, provide information about any known differences in safety or effectiveness of the device across underrepresented groups. For example, variations in skin pigmentation across a diverse population may affect the performance of certain devices.
• When there are no data that indicate differences in safety or effectiveness across underrepresented groups, it is still appropriate that enrollment reflects the epidemiology of the disease. When it is not possible to leverage existing data sources (e.g., published literature, real world data) to set enrollment goals, it may be appropriate to set the enrollment goals based on demographics of the overall population (e.g., Washington State, King County, UW Medicine patient population) when the treatment is being designed for the general population (e.g., preventive vaccine) or when there are limited to no data for the intended use population.
• Enrolling clinically relevant populations with regard to age, sex, race, and ethnicity. The FDA suggests the following strategies:
  • Differences have been observed in response to medical products across racial and ethnic subgroups and may result from intrinsic factors (e.g., genetics, metabolism), extrinsic factors (e.g., diet, environmental exposure, sociocultural issues), or interactions between the two. Therefore, FDA recommends that for drugs and biologics, there should be a plan to include such clinically relevant populations no later than the end of Phase 2.
  • When considering inclusion of children and adolescents in clinical trials, apply the principle of necessity which is encompassed by the regulatory requirements of equitable selection of participants and minimization of risk. First consider whether enrolling children is necessary to assess the safety and efficacy of a treatment that will be used in children. If efficacy in adults can be extrapolated to children, you may not need to enroll children. When it is scientifically necessary to enroll children, the clinical trial must be very well designed to collect interpretable data to avoid exposing children to unnecessary risks. When it is necessary to enroll children, consider a broader pediatric program early. The arbitrary sequential enrollment of pediatric subgroups by chronological age could delay development of treatments for children and should be justified with a clear scientific rationale. Note also that the Pediatric Research Equity Act (PREA) ^[49] gives the FDA the authority to require pediatric studies in certain drugs and biological products. There are additional regulatory requirements when enrolling children, and researchers will benefit from reading regulatory guidance such as FDA’s guidance on Clinical Investigations of Medical Products Involving Children ^[47].
  • Enroll a sufficient number of individuals who are presumed to differ in biological sex (e.g. male, and female, intersex) to allow detection of clinically significant sex-related differences in treatment response. Keep in mind and account for the impact that hormone replacement therapy, gender affirming treatments, medications, and over the counter supplements may have on the analysis.
• If there are available data to suggest that geographic location, socioeconomic status, or sexual orientation of the population with the disease or condition may impact the outcomes under investigation, consider these characteristics when setting enrollment goals. FDA and NIH guidance on enrolling diverse participant populations is primarily focused on biological determinants of health such as age, race, and sex that are reflected in the epidemiology of the disease under study. Disease epidemiology as a factor of social determinants such as socioeconomic status and geographic location or less-studied biological factors such as sexual orientation may not be as readily identifiable in existing data. If an analysis of disease epidemiology does not allow for consideration of geographic location, socioeconomic status, or sexual orientation, consider focusing on removing or reducing burdens and barriers to participation ^[13] and involving community partners ^[14] to increase enrollment in these groups.

Broadening Eligibility Criteria .

The FDA guidance on Enhancing the Diversity of Clinical Trial Populations and the MRCT guidance on Achieving Diversity, Inclusion and Equity in Clinical Research provide several suggestions for broadening eligibility criteria.

• Carefully consider inclusion and exclusion criteria for each trial individually. Do not adopt criteria from prior trials without considering their applicability to the current study. Be able to justify whether an exclusion criterion is necessary to help assure the safety of trial participants or to achieve study objectives. If it is necessary, do a further analysis of whether it can be modified to maximize inclusion. The example the FDA provides is a study in which exclusion of participants with advanced heart failure is necessary to avoid placing them at unreasonable risk. However, if enrolling participants with milder disease would be appropriate, they suggest defining the specific population of heart failure participants that must be excluded (e.g., New York Heart Association (NYHA) stages III and IV).
• Phase 2 and Phase 3 trials. With completion of each phase, analyze the safety and efficacy data to determine whether justified exclusions in a previous phase can be eliminated or modified to avoid unnecessary limits on the study population. The FDA suggests Phase 2 restrictions based on drug-drug or drug-disease interaction may be able to be lifted or revised for Phase 3 if there is new data (e.g., in-vivo or in-vitro studies) about those interactions. A phase 3 trial should include the range of populations for which the product is intended. Studies that offer a prospect for direct benefit, especially Phase 3 confirmatory trials targeting serious or life-threatening diseases, should generally make the greatest effort to enroll all eligible participants. The fewer the treatment options and the greater the potential prospect for benefit, the more important it is to make the benefit of participation widely available. The risks of including higher risk populations might be mitigated if a trial is conducted at a site where there is expertise in treating these participants.
• Trial design and methodological approaches..
• Consider early characterization of drug metabolism and clearance across populations that may metabolize or clear the drug differently. This can help avoid later exclusions and will allow dose adjustment optimization across populations.
• If there are safety concerns, use an adaptive trial design that starts with a narrow population and then broadens to include a larger population if that is supported by the interim safety data from the trial.
• Enrichment strategies.Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products ^[50].
• Provide language access to participants with non-English language preference. Information about how to overcome barriers associated with recruiting individuals with non-English language preference ^[51] is discussed below.

Meeting Enrollment Goals – Reducing Participation Barriers and Burdens

Researchers and IRBs have long understood that when making a research enrollment decision, prospective participants will consider the purpose of the research, risks and benefits, and how participating in research may differ from the clinical care they might receive. It is now clear that the ability to recruit and retain underrepresented groups requires the research team to also understand the potential barriers and burdens of participating for the target population(s) [Bierer et. al., 2021].

Incorporating community and participant engagement in the study design is important for most effectively identifying the needs of underrepresented populations. Community engagement is important across the life of the study. Details about community engagement ^[14] are discussed in a later section of this guidance.

The MRCT Center provides a Recruitment Strategy Document template ^[54] to assist you in creating a comprehensive plan to target and enroll the underrepresented groups you identify in your Diversity Plan across all sites.

Barriers due to location, scheduling, and frequency of study activities..
When making an enrollment decision, participants will need to consider the logistics of being able to complete the procedures. This includes: (1) location of recruitment activities and study procedures; (2) the days of the week and hours of the day that are available for participation; and (3) the frequency of study visits and total time commitment.

• Choose clinical trial sites, including neighborhood healthcare locations that include higher concentrations of the underrepresented groups you hope to recruit. Consider using claims data and electronic health records to identify these sites, while complying with all applicable regulations.
• Consider using mobile medical professionals such as nurses or phlebotomists or setting up study visits at local clinics for participants who live far from the main study site.
• Diversity in healthcare providers and research staff might make some underrepresented groups more comfortable participating in research. In situations where you can engage community clinics, that trusting relationship may already exist, even if the provider is not part of the same underrepresented group.
• When holding in-person recruitment events, hold them frequently, in non-clinical locations (e.g., places of worship, community centers, festivals, barbershops or beauty salons), and during weekend and evening hours. A meta-analysis of 50 studies conducted by the Howard University Clinical Research Unit from 2001-2012 showed this to be an extremely effective approach in recruiting African American populations for research [Otado et al., 2015].
• Consider alternatives to in-person recruitment events and study visits such as electronic communications (e.g., phone/video conferencing, email, social media), telehealth visits, or other digital health tools.
• Consider limiting the number of in-person visits to the minimum necessary to achieve the aims and appropriately monitor safety and efficacy.
• Consider whether it is possible to offer study visits on weekends or in the evenings for those individuals for whom it is difficult or burdensome to take time off from work or caregiving duties.
• Consider consider the additional burden of completing the research procedures for patients who are already undergoing frequent clinical care visits. Is it possible to conduct the research procedures at the time of already scheduled clinical care appointments? Can blood draws or other clinical care procedures be accessed for the research rather than completing procedures twice?

Financial barriers.
Financial barriers to participation can be significant and the impact will differ depending on the financial means of each participant. Financial barriers may include copayments, deductibles, transportation, lodging, meals, child or elder care, lost wages or paid-time-off, and the expenses of participants’ caregivers (e.g., parents of a pediatric participant, spouse/partner) [Bierer et. al., 2021]. Many of these items are included in an NIH list of Allowable Costs Related to Participant Inclusion Activities ^[55].

Costs of participation and participant payment. .
UW IRB guidance on Designing the Consent Process provides discussion and example language for communicating costs of participation ^[56] and compensation for injury ^[57].

The UW IRB provides extensive guidance on participant payment ^[52]. For the purposes of diversity in clinical trials, it is important to note that there are three main types of payment to consider (reimbursement ^[58], compensation ^[59], incentives ^[60]) when thinking about how to recruit and retain the underrepresented groups identified in your Diversity Plan.
Type and timing of payment are important considerations. Immediate reimbursement or pre-payment is becoming standard practice for many research sites. Considerations for choosing the method of payment ^[61] can be found in the guidance. Be sure you understand how the different options work, including the time necessary to process payment and inform participants during the consent process about those details.

Language barriers..
As a long-standing historical process, research has routinely and explicitly excluded individuals with non-English language preference (NELP) from enrollment in clinical trials. Lack of funding for translated materials and interpreter services has often been used as a justification. This practice contributes to the underrepresentation of certain ethnic groups in research.

Persons with limited English proficiency are a growing demographic group. The 2019 United States Census shows that the U.S. population age 5 years and older includes over 67 million people who speak a language at home other than English. Of those, over 41 million speak Spanish. Individuals who have a limited ability to read, write, speak, or understand English, are considered to be of “limited English proficiency.” Of the more than 41 million Spanish speakers, 38.6% report that they speak English less than “very well”.

Consideration should be given to identifying populations that will require translations based on the epidemiology of the disease/condition being studied in the target population and the region(s) where the study will take place. Sufficient resources must be in place to facilitate communication with participants with NELP throughout their participation in the research and, if applicable, emergency situations. The translations must be of sufficiently high quality to be accurate and facilitate comprehension by using language that is familiar and at an appropriate reading level for the population. UW policy and more complete information about translation and interpretation is described above in the section on Enrolling Participants with Non-English Language Preference ^[9] and in the UW IRB consent guidance ^[32].

Electronic methods..
As discussed above, electronic data collection and communication can help to reduce location, scheduling, and frequency of visit barriers ^[39]. RCW 69.78 requires that electronic consent be available. The e-consent regulatory requirements ^[62], including documentation requirements ^[63], and logistics for using UW e-signature tools ^[64] are discussed elsewhere on our website.

It is UW policy that clinical trials that require submission of a Diversity Plan for Clinical Trials Supplement must make e-consent available as an option, unless there is a justified reason for not including e-consent. Even when e-consent must be made available, it is not required that it be used for every participant enrolled in a clinical trial. There may be some participants for whom using e-consent is a barrier, as discussed in the next paragraph.

Electronic methods as a barrier. A strategic and thoughtful approach to electronic research methods is required to ensure gaps in access are not widened for particular groups. In 2023, the Substance Abuse and Mental Health Services Administration (SAMHSA) identified broadband access as a “super determinant” of health with 19 million Americans lacking access to reliable broadband service. This “digital divide” focuses on rural areas and pockets of segregated urban areas that are also disconnected [SAMHSA 2023]. Further, a 2021 Research Brief from the United States of Care describes barriers that underserved populations experience to a greater degree when accessing virtual clinical care. These underserved populations include households with low socioeconomic status, racial and ethnic minority groups, older adults, people experiencing homelessness, rural populations, people who did not graduate high school, people with disabilities, people with non-English language preference, and immigrants. The barriers they identified are as follows:

• Absence of technology devices
• Unreliable, unavailable, and unaffordable broadband and/or phone data
• Limited digital and health literacy
• Concerns about quality and personalization
• Lack of physical accommodations for setting up devices and hearing or vision accommodations
• Language proficiency barriers
• Privacy concerns

As with all aspects of diversity in clinical trials, the most effective way to overcome barriers related to electronic methods may be to engage with prospective participants and community organizations. Although it may not be necessary in all situations, when working with populations who are likely to experience technological barriers (e.g., older adults or populations with limited access to broadband or devices), understanding the prospective participant population and their particular needs can help anticipate who may benefit from electronic methods, who may view them as a barrier, and who may benefit from them if particular accommodations are made. One article suggests the following strategies to address the challenges of digital technology [Rivera-Romero et al., 2022]:

• Apply principles of social sciences, user-centered design, and participatory design during development of social media interventions
• Tailor content to the user group considering cultural aspects, age, and gender as well as cognitive restrictions
• Use appropriate visualizations for content
• Educate patients as well as health professionals in using digital interventions, particularly their benefits and challenges
• Test acceptability

Access and health literacy.
Access. Some academic literature indicates that some underrepresented groups may be reluctant to participate in research as a result of historical exclusion or exploitation. As reported in the MRCT Center guidance, that concept has been challenged in a paper reporting survey data from 70,000 individuals in the U.S., Europe, Australia, and New Zealand which found no difference between race and ethnicity and willingness to consent [Wendler et al., 2005]. The MRCT Center notes that study participation and the demographics of who participates in research are significantly influenced by who is invited to participate. They suggest that the key to enrolling diverse study populations in clinical trials is to ensure all groups have awareness, knowledge, and access to those trials.

Involving community partners in study design and recruitment efforts can improve the chances that the underserved populations you hope to enroll in the research will be aware that the research exists, understand the purpose of the research, and have access to the trial that you are designing. Note that awareness and knowledge should start with ensuring prospective participants understand the role and function of a clinical trial and clinical research before delving into specifics about a particular trial. Make use of existing resources such as Harvard Catalyst’s Research Participant Resources ^[65] and the Center for Information and Study on Clinical Research Participation’s Clinical Trial Resources ^[66]. Information about engaging community partners is described in the next section.

Health literacy. The WHO defines health literacy as the achievement of a level of knowledge, personal skills, and confidence to take action to improve personal and community health by changing personal lifestyles and living conditions. In the United States, 90 million Americans are estimated to have low health literacy, and these people are four times more likely to report fair or poor health than people with the highest literacy skills. Health literacy is critical to empowerment in healthcare [Rivera-Romero et al]. For information about how to design clear participant communications and using plain language, watch the 7-minute MRCT Center video tutorial on Health Literacy in Clinical Research ^[67].

Meeting Enrollment Goals – Community Engagement, Local Context, and Cultural Humility and Competency

The guidance listed below is taken from the Multi-Regional Clinical Trials (MRCT) Center guidance on Achieving Diversity, Inclusion and Equity in Clinical Research ^[22].

Authentic partnerships between investigators, research teams, sponsors, clinicians, and community partners are necessary for research programs to be responsive to the needs of affected populations and successfully recruit and retain underrepresented and underserved populations. These partners include patients and participants, their caregivers, patient advocacy groups, community-based organizations (e.g., YMCAs, youth centers), cultural and faith-based organizations, places of worship, non-profit organizations, community healthcare providers and social workers. Successful community engagement requires long-term investment of effort, time, and resources by the research enterprise. These relationships are most effective when they are part of a long-term strategy of engagement and dialogue rather than on project-specific needs. Meaningful engagement of underserved and underrepresented patients and their communities requires an openness to their perspectives and values and building trust through mutual respect and support.

The UW IRB anticipates that there will be varying degrees of community engagement and different strategies across clinical trials but expects that, at a minimum, researchers demonstrate that they have made an informed effort to develop an approach to recruitment and retention that is culturally appropriate and takes into consideration the barriers and burdens of the target study population.

MRCT Center Recommendations

Provide research team training in cultural humility and competency which should include an assessment of implicit bias, learning how to facilitate the building of trusting relationships with participants, and providing resources for staff on how to engage with participants from diverse backgrounds and avoid use of cultural generalizations and stereotypes. Self-awareness can promote receptivity to the viewpoints of the people the research ultimately aims to serve.

Make an effort to hire a diverse research team, when feasible. Having a diverse research team, particularly for those who interact with patients on a regular basis, can build trust with participants and increase the likelihood that the team will be able to relate, empathize, and communicate with participants. In situations where you are able to engage community clinics, that trusting relationship may already exist, even if the provider is not part of the same underrepresented group.

Community engagement should begin with the development process and continue though publication of results. Ideally, the clinical protocol would be built with community perspective or input. If engaging with a community directly, it is important that the collaboration be genuine, not a false promise of inclusiveness. The section on Data Collection and Reporting ^[15] includes the recommendation that researchers return aggregate study results to participants and to communities at large.

Crafting patient-facing study materials, including the consent form and consent discussion, with community engagement will help ensure the approach and language are clear and honest. Community collaborators can help design communications that include plain language, numeracy, visualization, design, and cultural humility and competency. Community collaborators can help with testing the accuracy and comprehensibility of translated study documents, including the consent form. They can also assist with plain language summaries for the return of aggregate research results.

Community collaborators can provide feedback about how to identify and then reduce or remove the potential barriers to participation discussed in the section above. This could include providing feedback on the number and location of study procedures, identifying child or eldercare resources, helping the research team understand what reasonable reimbursement and compensation for participation is, and other logistical issues.

MRCT Center Case Study Highlights

The MRCT Center website provides several programmatic case studies ^[74] that illustrate diversity efforts that have been successfully integrated into clinical trial designs. We encourage reviewing all the case studies but would like to highlight several that present strategies that we believe can be employed by UW researchers.

• Diverse Patient Engagement at a Pharmaceutical Company (full case study ^[75]; case study highlights ^[76])
  Sanofi Pharmaceuticals uses Patient Advisory Panels to prioritize the patient perspective and to provide feedback on feasibility and design of clinical trials. Participants in the panels are identified through partnerships with various patient advocacy groups such as the Susan G. Komen Foundation. Some of the successes they report are: reducing the participant burden by reducing the number of procedures and clinic visits; broadening eligibility criteria which enables greater access to research; and including mobile health technologies and home administration when feasible.
• Multiple Sclerosis (MS) Research Mythbusting Series. (full case study ^[77]; case study highlights ^[78])
  Minority populations, specifically Blacks and Latinos, may bear an unequal burden from MS due to both biological and social determinants of health. These populations are severely underrepresented in MS research. In order to combat a potential reluctance from these populations to participate in research, several organizations joined together to create and conduct a “Research Mythbusting Series” of events planned and held across the span of one year. The series was designed to educate and inform people with MS about research participation. Comments during and after the presentations indicated that people with MS belonging to Black and Latino populations support and recognize the value of clinical research to enable future breakthroughs but may not be aware of the issues arising from the lack of diversity in research studies.
• All of Us Research Program. (full case study ^[79]; case study highlights ^[80])
  The All of Us Research Program is a large observational study that serves as a repository for collecting data from a diverse and representative U.S. population and across a variety of health conditions. The mission of the program is to enable and accelerate health research and medical breakthroughs, focusing on participants of every race, ethnicity, sex, gender, and sexual orientation and in both rural and urban settings. In 2019, more than 80% of participants were from groups that have been historically underrepresented in biomedical research. During early planning, All of Us conducted public workshops and administered a survey of U.S. adults to measure support for such a study, the acceptability of various design features, and identify and prioritize concerns. A pilot study was conducted targeting LGBTQI groups, vulnerable groups (sexual and gender minorities) and others to understand their specific concerns.
  They removed the following barriers to enrollment: no health insurance is required; there are no costs to participate; participation is irrespective of nationality or health status; Spanish speaking advisors are provided; no electronic devices are required; there is a one-time payment of $25 for specimen and physical measurement collection; there are strong confidentiality and privacy protections, including a Certificate of Confidentiality.

Enrollment Data Collection and Reporting

UW Diversity Plan Continuing Review Enrollment Reporting

For studies reviewed by the UW IRB, researchers will be required to provide an update on their enrollment targets for underrepresented groups as described in the Diversity Plan for Clinical Trials Supplement. Note that these enrollment goals should reflect the intended distribution across all sites. If targets are not being met, researchers will be asked to provide a root cause analysis and propose new strategies for improvement. The IRB continuing review will focus on education and support (e.g., referrals to University resources) rather than penalization so long as the researcher has followed the Diversity Plan described in the Supplement.

For studies reviewed by an external (non-UW) IRB, we plan to ask researchers to provide an update on enrollment targets using an annual, online survey.

Recommendations from the FDA and MRCT Center

These are not Diversity Plan requirements.

• Standardized collection of demographic and non-demographic data variables is critical for statistical analysis as well as for allowing data aggregation over time and across trials. Chapter 11 of the MRCT Center Guidance provides an in-depth discussion about standards and best practices for collecting the demographic variables of age, race and ethnicity, and sex and gender. They note that social determinants of health such as socioeconomic status are more difficult to standardize but may still be important depending on the disease or condition being studied. They recommend using Clinical Data Interchange Standards Consortium (CDISC) standards ^[83] when available. In the absence of CDISC standards, they suggest collecting data at the most granular level.
• Screening failure and selection bias. The MRCT Center recommends keeping an Eligibility and Enrollment Log ^[81] as well as Screening Failure Log ^[82]. Comparing the logs can help ensure exclusions or screening failures are justified per the protocol exclusions and to identify any selection bias for particular demographic groups when individuals are excluded due to investigator discretion.
• Data collection and analysis in the Diversity Plan for drug investigations. According to FDA guidance, the Diversity Plan should outline the sponsor’s plan to collect data to explore the potential for differences in safety and/or effectiveness associated with race and ethnicity throughout the entire development life cycle of the medical product and not just during the pivotal trial(s) or studies [FDA Diversity Plan Guidance].
• Consider characterizing – in early clinical development – drug metabolism and clearance across populations that may metabolize or clear the drug differently (e.g., older adults and participants with liver or kidney dysfunction). Early characterization of drug metabolism and clearance across groups will help avoid later exclusions and more generally, will allow dose adjustment to optimize effectiveness and safety across different populations. For industry-sponsored studies this may be characterized by the sponsor [FDA Enhancing Diversity Guidance].
• Participant feedback about clinical trial experience can help improve future trials. Asking participants about their experience can provide information about how to improve community engagement, study design, conduct, reporting, or other methods or processes to enhance inclusion. The FDA provides a guidance on Patient-Focused Drug Development: Collecting Comprehensive and Representative Input ^[84]. The guidance provides information about how to define the target population, choosing sampling methods and a sampling strategy, data collection methods, data management, storage, analysis, and results dissemination.
• Communicating aggregate results to participants and the community. Sharing aggregate results, such as whether the overall study results supported the hypothesis, is important for ensuring that participants are informed about the trial results, they know their participation has been respected and appreciated, and they understand the value of their contribution to science and public health. The MRCT Center provides many resources on this topic including guidance ^[85], a toolkit for building the communication ^[86], and 8 principles of returning aggregate results ^[87]. This is different than return of individual research participant results. Review HSD guidance on return of individual participant results ^[88] for information on that topic.

Additional Diversity Strategies

Though the Diversity in Clinical Trials policy is required only for the underrepresented groups named in this guidance, the UW IRB encourages diverse enrollment across many populations. We encourage you to consider the guidance below when enrolling pregnant participants and those with accessibility needs.

Pregnant Participants

Consider the safety and feasibility of including pregnant participants in clinical trials. This includes clinical trials that enroll pregnant participants and those that allowed enrolled participants who become pregnant to remain in the trial. This consideration is important because: (1) pregnant people need safe and effective treatment during pregnancy; (2) failure to establish dosing, safety and efficacy of treatments during pregnancy may compromise the health of the pregnant person and their fetus; (3) in some settings, enrollment of pregnant people in clinical trials may offer the possibility of direct benefit that is unavailable outside the research; and (4) development of accessible treatment options for pregnant people is a significant public health issue. The risk-benefit assessment in these situations is complex and there are additional regulatory requirements when enrolling pregnant participants. Researchers will benefit from reviewing FDA’s guidance on the issue ^[89].

Participants with Accessibility Needs

Recent literature notes that 1 in 4 (67 million) American adults has a disability. Some of the most common disabilities are mobility, cognitive or mental, independent living, hearing, vision, and self-care [Varadaraj et al., 2019]. In 2023 NIH designated people with disabilities as a population with health disparities. It is important to design a study with accessibility needs in mind to be inclusive of persons with disabilities in research.

Location, scheduling, frequency of study activities. The previous discussion of barriers due to location, scheduling and frequency of study activities ^[39] is relevant for people with disabilities. Carefully considering how much you are asking of participants is important when considering the additional effort just completing daily tasks can be for people with certain disabilities. Remote participation options, local study visits, and reduced frequency of study activities can make a significant difference. Facilities in which in-person activities take place should be ADA accessible with elevators, automatic doors, curb cuts, disabled parking spaces, and access for service animals.

Accommodation for participants with impaired decisional capacity. Rather than categorically excluding these individuals, be prepared to conduct a cognitive assessment to determine whether decision-making capacity is sufficient to consent on their own behalf. To enhance understanding, make any necessary accommodations such as allowing for extra time during the consent process and making use of visual aids and repetition of key concepts. Consider also whether including a designated supporter in the consent process, such as a trusted family member or friend, could enhance comprehension about making an enrollment decision. The designated supporter may be an official Legally Authorized Representative (LAR) providing consent on behalf of the participant or, if the participant has the capacity to provide consent on their own, they can provide assistance and counsel for the participant. There may be some situations, such as high-risk clinical research with no potential for direct benefit, in which it might be reasonable to exclude individuals with impaired decisional capacity. The UW IRB consent guidance ^[92] provides more information about assessing capacity for consent, providing accommodations, and use of a LAR.

Accessible technology is vital for participants with vision and hearing impairments. Using images, alternative text, and formatting such as heading structures facilitate the use of screen readers and text-to-speech software. (The UW IRB consent template ^[93] is an accessible design.) Electronic consent is discussed in more detail below but note that it is vital to ensure any electronic consent materials are designed with accessibility needs in mind. UW IT provides guidance and resources for designing accessible technology on its website ^[90].

Invite access needs. Consider adding a statement to your consent form inviting prospective participants to ask for accommodation if they anticipate having trouble with the activities that are described. (e.g., “If you need to complete activities in a different way than I have described, let me know and we will try to make other arrangements.”) For example, you might offer to administer online surveys over the phone if a participant is having technical difficulties or has trouble viewing the online survey due to visual impairment.

Resources. The MRCT Center provides guidance for including participants with disabilities in the Accessibility by Design (AbD) in Clinical Research Toolkit ^[91]. The toolkit includes considerations for planning, implementing, innovating, and upholding accessible accommodation. It also includes several checklists on topics such as planning inclusive eligibility criteria, examples of plain language, and site assessment for accessibility.

Related Materials

SUPPLEMENT Diversity Plan for Clinical Trials ^[3]
UW Consent Templates ^[93]
WEBPAGE Consent Guidance ^[94]
WEBPAGE Designing Consent Guidance ^[95]
WEBPAGE Subject Payment Guidance ^[52]

References

• The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects Research. April 18, 1979.
• Bierer B.E., et al., (2021). Achieving Diversity, Inclusion, and Equity in Clinical Research Guidance Document ^[22] Version 1.2. Cambridge and Boston, MA: Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard (MRCT Center).
• Boston Children’s Hospital IRB Policies and Procedures Manual, Informed Consent with Non-English Speakers ^[96].
• Brelsford et al., Developing informed consent materials for non-English-speaking participants: An analysis of four professional firm translation from English to Spanish ^[97] Clinical Trials 2018 15(6):557.566.
• Center for Information and Study on Clinical Research Participation Clinical Trial Resources ^[66].
• Colina et al., Research Documents for Populations with Limited English Proficiency: Translation Approaches Matter ^[98] Ethics & Human Research. 2022 Jan;44(1):29-39.
• FDA Guidance, Diversity Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies. ^[25]
• FDA Guidance, Ethical Considerations for Clinical Investigations of Medical Products Involving Children ^[47].
• FDA Guidance, Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrollment Practices, and Trial Designs ^[46].
• FDA Guidance, Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products ^[50].
• FDA Guidance, Patient-Focused Drug Development: Collecting Comprehensive and Representative Input ^[48].
• FDA Guidance, Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials ^[89].
• Glickman et al., Perspective: The case for research justice: inclusion of patients with limited English proficiency in clinical research ^[99] Acad Med. 2011 Mar; 86(3):389-93.
• Harvard Catalyst, Research Participant Resources ^[65].
• Washington State RCW 69.78 ^[20]. Diversity in Clinical Trials. Effective Date: July 23, 2023.
• Jacobson et al., Barriers to Virtual Care Access Impacting Already Underserved Communities ^[100] United States of Care Research Brief, March 25, 2021.
• Multi-Regional Clinical Trials (MRCT) Center Return of Aggregate Results Resources ^[101].
• Multi-Regional Clinical Trials (MRCT) Center Toolkit and User Guide for Achieving Diversity, Inclusion and Equity in Clinical Research ^[23].
• National Academies of Sciences, Engineering, and Medicine Improving Representation in Clinical Trials and Research: Building Research Equity for Women and Underrepresented Groups ^[102]. Washington, DC: The National Academies Press 2022.
• NIH News Releases, NIH designates people with disabilities as a population with health disparities ^[103]. September 26, 2023.
• NIH Policy and Guidelines on The Inclusion of Women and Minorities as Subjects in Clinical Research ^[104].
• OHRP Tutorial, Equitable Selection of Subjects ^[105].
• Otado et al., Culturally Competent Strategies for Recruitment and Retention of African American Populations into Clinical Trials ^[106] Clin Transl Sci 2015 Oct; 8(5):460-466.
• Patient-Centered Outcomes Research Institute (PCORI) Equity and Inclusion Guiding Engagement Principles ^[68]
• Patient-Centered Outcomes Research Institute (PCORI) Foundational Expectations for Partnerships in Research ^[69]
• RCW 69.78 Diversity in Clinical Trials ^[20]
• RCW 28B.20.540 UW-specific Diversity in Clinical Trials ^[21]
• Rivera-Romero et al., Social Media, Digital Health Literacy, and Digital Ethics in the Light of Health Equity ^[107] Yearb Med Inform 2022; 31(1):82-87.
• SAMHSA Blog, Digital Access: A Super Determinant of Health ^[108] March 22, 2023.
• Silverman et.al., Supported decision-making can advance clinical research participation for people with disabilities ^[109] Nature Medicine 2022; 28:2250-2253.
• Varadaraj et al., National Prevalence of Disability and Disability Types Among Adults in the US ^[110] 2019, JAMA Netw Open 2021; 4:10:e2130358.
• Wendler et al., Are Racial and Ethnic Minorities Less Willing to Participate in Health Research? ^[111] PLoS Med 2006; 3(2).

Version Table

Open the accordion below for version changes to this guidance.

Keywords: Clinical trials; Continuing review; Diversity; Recruitment