The IDEAS Initiative

In order to narrow disparities and strengthen our healthcare system, it is important to increase women and minority participation in clinical research studies to ensure that effective drugs are available for everyone, regardless of race, gender, or age. To facilitate the inclusion of women and minorities in clinical studies, the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) implemented legislation to require the inclusion of women and minority populations in clinical studies. These new policies would affect research funding, support, or approval by the institutions.

The lack of access to medical care for minorities, along with a combination of other social factors such as socioeconomics and lifestyle, have led to higher incidence, and oftentimes, higher mortality rates for several diseases, including HIV/AIDS,^{1, 2, 3} cardiovascular diseases,^{3, 4} diabetes,^{5, 6, 7, 8, 9, 10} and cancer.^{11, 12, 13, 14, 15}

The NIH Revitalization Act of 1993 was instituted to turn existing policies urging the inclusion of women and minorities in clinical trials into law and was established to ensure four major efforts:

• The inclusion of minorities and women in all human subject research.

• An adequate number of minorities and women included in all Phase II clinical trials for legitimate analysis of racial/ethnic and gender differences in intervention effects.

• To state that cost was not an acceptable reason for excluding minorities and women from clinical trials.

• To initiate NIH-funded programs and support for outreach efforts in the recruitment and retention of minorities and women as participants in clinical research studies.

Under the FDA Modernization Act of 1997 (FDAMA), the FDA instituted a new policy stating that women and men should be included in clinical trials if both would receive the drug once marketed. The policy also states that a gender analysis should be performed. The FDA also lifted its 1977 ban on including women of child-bearing potential in the early phases of clinical studies.

The FDA also consulted with the NIH as well as representatives of the drug manufacturing industry to review and develop guidance on the inclusion of minorities and women in clinical trials. The Center for Drug Evaluation and Research was assigned implementation responsibility and established the "FDAMA Women and Minorities Working Group" with representation from the FDA and NIH. This new policy expanded upon existing guidance emphasizing the importance of including analysis of demographic data in New Drug Applications (NDAs).

In 1998, the "Final Rule on Investigational New Drug Applications (INDs) and New Drug Applications (NDAs)" regulation required that analysis of effectiveness and safety data for gender and racial subgroups be submitted to NDAs. Enrollment of subjects into clinical studies for drugs and biologics must also be reported by age group, gender, and race subgroups in IND annual reports.

Despite the legislation and guidelines set forth by the NIH and FDA, minority and women participation in clinical trials has traditionally been low.¹⁶ As an example of disproportionate trial participation, approximately 40% to 45% of HIV/AIDS cases are diagnosed among Blacks, and approximately 15% to 18% among Hispanic/Latino, however the participation rates for these demographics in HIV/AIDS trials are much lower (Table 1). Similarly, the prevalence of hypertension is approximately 40% among Blacks and 25% among Hispanic/Latinos with a large discrepancy in clinical trial participation. Typically, minority participation in clinical research ranges from 3% to 20%.^{1, 17, 18} Based on survey data, those who are black and middle income were less likely to participate in a clinical trial. Those who are black were also less likely to be approached to be in a clinical trial.¹⁹ Studies from the cancer literature have reported that those in cancer studies in the past were mostly educated white men with high economic status.^{1, 20, 21, 22, 23} There is a significant need for the enrollment of various, diverse minority groups related to socioeconomic status, age, and sex in clinical trials based on disease burden.

Recent literature has shown that drug safety and/or efficacy varies among racial or ethnic groups (Table 2). Although some of the differences are positive, the lack of minority representation in clinical research studies poses a real long-term problem for the pharmaceutical industry, as several drugs have been shown to have negative effects in minorities versus their majority counterparts.

The difficulties of recruiting and retaining minority subjects in clinical trials are well-documented. Recruitment and retention barriers that have been identified and discussed in the literature and include mistrust of research and or the medical community,^{,24, 25} lack of access to research,²² lack of information about research,^25,27 and fear of tests and procedures.^{27, 28} Features associated with successful recruitment of a minority population into cancer clinical trials were primarily related to study design. Namely, the inclusion criteria mirrored the disease status of the target population (i.e., more advanced disease).²⁹ A second successful recruitment strategy involved direct contact and visits to churches and community events by culturally linked study staff who were bilingual, if needed.³⁰ Despite these studies addressing issues and potential solutions, there are currently little comprehensive resources or roadmaps which have combined available data that provide strategies on how to effectively recruit and maintain women and minority subjects throughout the life of a clinical research study.

The Eliminating Disparities in Clinical Trials Project (EDICT) from Baylor College of Medicine, in collaboration with the Intercultural Cancer Council, published findings on the major deficiencies in the design and funding of clinical trials.³¹ The review cited that the exclusion and/or under-representation of minorities, women, elderly, disabled, and rural populations exist within the vast majority of all research studies conducted in the United States. In addition to flawed clinical trial design that enable disparities by using research protocols that do not include all affected populations from the beginning of the study, numerous factors, including behavioral, social, economic, medical, and policy-related issues also contribute to clinical trial deficiencies. Towards eradicating clinical trials disparities, the EDICT project made policy change recommendations using input for the public, private, and nonprofit sectors.³² The primary recommendations from the EDICT project team were to: foster community collaborations and involvement in clinical trials, enhance clinical trial population disparity education among healthcare professionals and researchers, enhance community clinical trial education, deliver clinical trial navigation services, and assure insurance coverage for costs associated with clinical trials.³² The primary continuing activities of EDICT are to support two ongoing projects, namely :

• To facilitate adoption into clinical trials the National Standards on Culturally and Linguistically Appropriate Services developed in 2000.

• To compile and make available projects, programs, and best practices related to eliminating disparities in recruitment and retention on the EDICT website.³³

Using the EDICT recommendations as a guide, the Improving Diversity Education, and Advancement in Studies (IDEAS) Initiative, co-sponsored by Legacy Healthcare Solutions, Inc. and Campbell University Clinical Research Center, was formed. The goal of IDEAS is to provide guidance on how to successfully include and retain women and minorities into clinical research studies through community engagement.

IDEAS objectives

IDEAS main objective is to produce the first operational guide to assist the inclusion of underrepresented minorities and women into clinical trials. This guide will assist pharmaceutical companies, clinical research organizations (CROs), universities, or any other institution that conducts clinical trials in successfully recruiting and retaining women and minority subjects in their research throughout the life of the study. The specific goals are to:

• Develop a guide for how to recruit women and minority populations in clinical trials.

• Develop and test effective educational recruitment and retention materials that support women and minority population participation in clinical trials throughout the life of the study.

• Develop evidence-based models that aid in retaining minority subjects in clinical studies.

• Work with public, private, nonprofit, and industry sponsors of clinical trials to develop effective women and minority recruitment and retention strategies while conducting clinical trials.

Initiative milestones

The IDEAS steering group identified three major milestones to reach in order to produce an effective and accurate guide providing strategies and solutions for the inclusion of women and minority populations in clinical trials. These milestones are:

• Identify and define subject and physician (including sub-investigators, clinical research coordinators, etc.) recruitment barriers by obtaining stakeholder (community and researchers) feedback and identify solutions to those barriers.

• Develop a guide on the inclusion of women and minorities in clinical trials.

• Publish the guide for use by pharmaceutical industry, CROs, biotech companies, academic institutions, nonprofit agencies, and IRBs.

Recruitment barriers and potential solutions

Several recruitment barriers were discussed based on previous data sources and further identified by the steering group. These were:

• Lack of motivation and subject knowledge of clinical trials

• Subject accessibility and availability to participate in clinical trials

• Mistrust of clinical trials

• Lack of support from family members

• Transportation and too much time required to participate

• Language barriers

• Financial burdens

Lack of motivation and knowledge of studies. The group identified that many eligible women and minorities decline to participate in clinical research studies because of their lack of knowledge about clinical trials. If trials are not explained, subjects may not fully understand the individual and/or global benefits of participation. Providing physicians with effective tools used to educate minority and women populations may help to increase recruitment and retention in clinical trials. While one common fear of using drugs not approved by the FDA is the risks of negative side effects, communicating the facts that FDA-approved drugs (including the medication that potential subjects are currently using) have undergone the same clinical trial process and were approved with known side effects may increase a patient's willingness to participate in clinical research.

Subject accessibility. The lack of accessibility to clinical trials is also a limiting factor in minority recruitment. Based on the location of large research universities and institutions, patient populations are limited to those living in, or who have access to, major cities. More research sites are needed in smaller, more rural areas to eliminate the lack of transportation as a reason for declining to participate in clinical research studies.

Mistrust. The stigmas of instances such as the Tuskegee Syphilis Experiment have added to mistrust of the medical system and of clinical trials within minority communities.^{17, 34} Providing tools to identify "cultural brokers" to assist with recruiting minority populations can help to eliminate this barrier.

Transportation, time required, and family support. For some potential subjects who can access clinical trials, availability to participate may be a factor in declining to enroll. Specifically, many patients who are paid hourly are unable to regularly take time off of work for office visits. Or, if the patients are older and rely on family members for transportation to the doctor's office, they may have difficulty finding transportation for the increased number of visits.

Language barriers. The language used to describe a clinical study in the informed consent form may be too difficult to understand and is often written at higher than eighth grade level. Further, the language may be inadvertently offensive to certain cultures and can discourage participation. For example, usage of the word "trial" versus "study" may produce a negative reaction and could dissuade a person from participation.

Financial barriers. Participating in clinical trials may also have a financial burden that discourages research participation. Although the insurance company may pay for the visit, out-of-pocket expenses, or co-payments, are still incurred. Increased office visits have a direct financial impact. Individuals without insurance coverage have an even greater financial burden and are less likely to receive routine care, let alone participate in clinical research and accumulate extra cost in care.

Physician recruitment barriers and solutions

Many physician recruitment barriers were discussed at the first meeting, particularly in these key areas:

• Decreased minority physicians conducting clinical trials.

• Decreased minority patient pool and lack of referrals.

• Availability and willingness to participate in clinical trials.

• Lack of staff to support participation.

• Lack of education for non-minority physicians to deal with culture-specific issues to improve upon recruitment.

• Lack of training for minority physicians.

Minority physicians. Centers successful in recruiting minority participants in research studies attribute success to minority staff and recommend increasing the number of minority health care professionals in clinical trials.³⁵ Patients may be more willing to participate following recommendation from a doctor that is currently providing their medical care. Further, patients who use English as a second language (ESL) may prefer and seek doctors who speak their native tongue.

Minority patient pool. Physicians have a decreased potential minority subject pool since ethnic minorities generally appear to visit the doctor less often. In addition, doctors are reluctant to refer patients to other doctors for participation in a clinical trial for fear of losing that patient, thus negatively impacting them financially.

Availability and willingness to participate. Clinical trials are time consuming and physicians are not always in a position to take on a clinical trial in addition to their daily responsibilities. Those physicians who do participate in clinical trials often participate in competing trials, which restricts the pool of participants.

Lack of staff support and lack of education. Clinical trial conduct requires an infrastructure consisting of both equipment and trained personnel. Many physicians lack proper training and knowledge of clinical trials, which results in lack of study participation. Including physicians from rural areas and those with private practices will increase the potential of minority participants as well. Educating physicians on how regulatory agencies work may help to eliminate the fear of regulatory authorities for potential audits and fines and may increase participation in research studies. Culture sensitivity training for physicians and their staffs may also increase minority recruitment and retention in clinical trials. Training should be provided to non-minority physicians on how to speak to minority patients about clinical trials, health disparities, and access issues.³⁵

Key implementation strategies

The IDEAS Initiative has also identified key elements for improvement and has begun developing implementation strategies. The key elements identified are:

• Social marketing utilizing a culturally sensitive grass roots strategy and development of long-term relationship with community leaders to promote clinical trials.

• Informed consent documents.

• Protocol inclusion/exclusion criteria.

• Providing investigator training to increase the number of competent and culturally sensitive clinical researchers.

Social media marketing. Social marketing in the context of clinical trial recruitment is applying marketing principles to achieve social behavioral goals, namely clinical trial interest, for the social good of enrolling a clinical trial. We can immediately improve upon our efforts by examining past successes and failures. Areas needing improvement are in the way we use media outlets such as radio, newspapers, special language TV channels, and magazines to target women and minority populations. One way to improve these venues is to use local community groups to advertise to ethnic communities as well as using recruitment agencies with a large patient database. Researchers should use culturally sensitive, easy to understand language, and inclusion of trusted community members to relay messages in neighborhood gathering locations.

Informed consent documents. Improving the language on the informed consent form for the general public is an essential key element that would help eliminate recruitment barriers. While it is required that informed consent forms be at an eighth-grade reading level, the inclusion of medical jargon complicates the document, making it difficult to read and understand. One proposal is for a medical writer or someone experienced in relaying medical information to the general public participate in drafting the ICF template to ensure easier readability.

Physicians and other study staff members involved in consenting patients should be adequately trained on how to have an effective conversation with the potential subject. An in-depth discussion about the trial, benefits, and risks may help the patient feel more comfortable about the study and consider participation. Lastly, because the informed consent documents are lengthy, providing potential participants with an informed consent form summary to take home and review before making a decision may help clarify any questions and support the patient's decision to participate. Other ideas include giving potential subjects a comprehensive test to ensure they understood what was told to them. This tool would aid the physician in measuring comprehension and in determining questions to be addressed. It also helps to encourage the potential subject to ask questions freely.

Protocol inclusion/exclusion criteria. Ensuring the protocol inclusion/exclusion criteria can accommodate women and minority participation in clinical trials is also an essential key element. One proposal is to invite local PIs to provide input on typical minority baseline lab ranges during the protocol development phase, and not exclude minority participation.

Investigator training. Investigators should be better trained to explain the purpose, pros and cons, and importance in participating in clinical trials to all potential subjects, including minorities. Knowing how to identify what resources are needed to gain access to key players within a community to increase the participation of women and minorities in clinical trials will also be a valuable skill. Suggestions included targeting smaller churches in addition to larger churches; focusing on other targets, such as barber shops and hair salons to expand to those who do not attend church. Other potential solutions are to assign navigators to guide participants through the entire clinical research process.

Summary and future directions

Increasing minority and women recruitment and retention in clinical trials is critical in obtaining drugs that are safe and effective for the entire population. The IDEAS Initiative has been formed to help those involved in clinical research implement strategies to overcome these barriers. In order to communicate these strategies, the initiative's goals are to develop a guide with an action plan of how to recruit women and minority populations in clinical trials; develop effective educational materials that support women and minority participation in clinical trials throughout the life of the study; and work with public, private, nonprofit, and industry sponsors of clinical trials to develop effective women and minority recruitment and retention strategies while conducting clinical trials.

The next step towards accomplishing our goal will be to recruit additional experts from the community to provide input for educational training and guide development. We will also seek to engage individuals in the pharmaceutical industry to assist in identifying critical issues and to provide input in the planning process. Once educational components have been identified and designed, we will also conduct field tests with local community groups.

The Patient Protection and Affordable Care Act (PPACA) was signed into law by President Barack Obama on March 23, 2010. Although healthcare reform will unfold incrementally, this law has immediate impacts on specific pools of potential clinical trials participants. Individuals considered high-risk who have been uninsured for at least six months will have access to affordable insurance through a temporary, subsidized high-risk pool. Thus, those who were denied or dropped from coverage due to preexisting conditions will immediately have access to coverage and could potentially participate in clinical trials.

The PPACA provision mandates that no group health or health insurance plan may deny participation in a clinical trial, deny (or limit or impose additional conditions on) the coverage of routine patient costs for items and services furnished in connect with participation in the trial, nor discriminate against an individual on the basis of participation in a clinical trial. As healthcare reform continues to unfold to the ultimate goal of every United States citizen being required to carry health insurance (2014), more minorities and women will have the financial burden of clinical trial participation eased and more may potentially participate in clinical trials through the duration of the study.

Dionne R. Glast, PhD, Mae Huang, Ph.D, and Sumit Rawal, PhD, were Clinical Research Fellows at the Campbell University College of Pharmacy & Health Sciences Department of Clinical Research and Clinical Research Center, Buies Creek, NC at the time this article was written. Entrane Harvey, is CEO at Ethos Clinical Group, LLC, Cary, NC. Brenda Jamerson,* PharmD, is Associate Professor and Director, Clinical Research Center at Campbell University College of Pharmacy and Health Sciences and Research Pharmacist at Veterans Administration Medical Center, Geriatric Research Education and Clinical Center,, Durham, NC, e-mail: [email protected].

*To whom all correspondence should be addressed.

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