The Nuts and Bolts of Successful Recruitment and Retention: Success Stories/Work in Progress

Delgado | Cargill | Fleckenstein | Mildvan | Mitchell | Discussion

Dr. Hernandez introduced the panel discussion on successful recruitment and retention, which included success stories and work in progress. Dr. Jane Delgado, who moderated the panel of distinguished scientists, is the president and chief executive officer of the National Alliance for Hispanic Health, the Nation's largest and oldest organization of providers serving Hispanics. The National Alliance for Hispanic Health was previously called COSSMHO (National Coalition of Hispanic Health and Human Services Organizations); it serves more than 12 million Latinos annually. Dr. Delgado is a practicing clinical psychologist and the author of many books, including Salud: A Latina's Guide to Total Health, the first health book written by and for Latinos.

Jane Delgado, Ph.D., M.S., President and Chief Executive Officer, National Alliance for Hispanic Health, Washington, DC

Dr. Delgado affirmed the commitment of the National Alliance for Hispanic Health to clinical trials and facilitating the participation of Hispanics in clinical trials. She described a recent incident in which one of her friends was admitted to an intensive care unit at a local hospital. Shortly after being treated for a heart attack, he was asked to sign a consent form for participation in a clinical trial and he was subjected to an uncomfortable echocardiogram. Dr. Delgado noted that the content of the consent form was acceptable but that the context in which it was used was questionable. She stated that her friend's informed consent experience made her question the informed consent process, specifically, when and how the process is begun.

Victoria A. Cargill, M.D., MSCE, Director of Minority Research, and Director of Clinical Studies, Office of AIDS Research, NIH

Dr. Victoria A. Cargill stated that, regarding clinical trials, stereotyping and decisions are based more on the power of distribution in our society than on scientific reasons for excluding certain key populations. She explained that clinical trials can fail to meet the needs of marginalized populations. A proof of concept might be interesting to a researcher, but it is not interesting to a woman with a viral infection and two sick babies who has to take four buses to get to a study location. In addition, clinical trials sometimes do not address issues of importance to the community. They end up being done to the community instead of with the community; they can be characterized as "drive-by" research.

Given these circumstances, how can recruitment and retention be successful? Dr. Cargill remarked that successful recruitment and retention will occur within the community when researchers "think outside the box," expand their horizons, and allow the community to be their teachers. She stated that researchers must be user friendly for the potential participant, not for themselves. She reported on a clinical trial targeted to women with HIV infection. By definition, most of the eligible women were women of color, many of them single mothers with limited income. The recruitment for the study was slow at first. Not surprisingly, the study was conducted in a place with fixed hours, no transportation provided, and no "perks." Dr. Cargill pointed out that the study should have expanded its hours to include nights and weekends and should have addressed challenges such as providing onsite childcare. To operationalize a study, the study planners must respect the barriers. For example, taxicab vouchers can offset transportation barriers. In addition, Dr. Cargill suggested providing something in return to the participants--either additional education, clinical trial buddies, or town hall meetings to share the study results with the community.

Dr. Cargill commented on the need to reduce structural barriers, including institutional racist barriers. Stereotyping must be eliminated, and the needs and challenges of the target population must be learned. A balance also must be struck between coercion and respecting time commitments. In addition, one strategy cannot work for all participants. Recruitment must be targeted to individuals.

As Dr. Cargill explained, thinking outside the box means acting outside the box, including taking the following steps:

• Addressing individual barriers involves identifying issues, reducing or modifying them when possible, and including staff members who reflect the patient population at all levels. Dr. Cargill pointed out that the target population often has no one to speak for them in an authentic way and that they are beset with genuine fear, mistrust, and a disinclination to speak up on their own behalf. She affirmed that community-based organizations and what they can provide are often overlooked.
• Reducing structural barriers involves taking action on providing childcare, transportation, and study buddies.
• Creating unique collaborations and partnerships might involve a technical specialist who provides a voice mailbox to participants and links it to a call-in computer that acts as an advice-giver.
• Realizing that special populations are not aliens means recognizing individuals' core desires and needs.

Dr. Cargill concluded by citing a Chinese proverb: "Study without reflection is a waste of time; reflection without study is dangerous." She referred to a pharmacokinetics study involving pregnant women. The study involved several blood draws done in a hospital over a protracted period of time. Dr. Cargill credited NIAID with providing transportation, childcare, and a person to explain the various aspects of the study to the participants. As a result, the women had the opportunity to learn about HIV and pregnancy. Many of the women have remained much more engaged in their care than they were before. This win-win situation can be replicated elsewhere.

Jaquelyn Fleckenstein, M.D., Associate Professor of Medicine, University of Tennessee, Memphis, Tennessee

Dr. Jaquelyn Fleckenstein stated that she is participating in a NIAID U-19 Cooperative Hepatitis C Research Center project titled "Racial Differences in HCV/Host Interactions." The principal investigator (PI) is Dr. Caroline Reilly, Dr. Fleckenstein is the project leader, and Ms. Anne Madey is the study coordinator. The substudy is titled "The African American Response to Therapy for Hepatitis C." Dr. Fleckenstein remarked on the unusual circumstance of having two minorities run this project and mentioned that Dr. Reilly is one of the few female PIs in the Hepatitis C Cooperative Centers.

One of the major health issues today, hepatitis C infects about 3.8 million Americans. The prevalence in African American men between the ages of 40 and 49 is 10 percent. In 1997, Dr. Fleckenstein and her colleagues carried out a multicenter study looking at treatment for hepatitis C with interferon and ribavirin, which at the time was the best therapy available. They enrolled a total of 341 patients, including 34 African Americans, which is very small amount, particularly because of the high prevalence of hepatitis C in the African American population. Dr. Fleckenstein noted striking differences in response rates between Caucasians and African Americans. Caucasians had a 49-percent overall response rate, whereas African Americans had a 4.8-percent response rate. This difference sparked the researchers' interest, and they submitted an application for funding to study the phenomenon.

The current study entails treatment with pegylated interferon and ribavirin, which is now the standard treatment. The enrollment goal for this small, single-center study is 75 African Americans and 50 Caucasians. The enrollment process will probably take 2 months, followed by 48 weeks of labor-intensive treatment and 6 months of followup. The therapy involves a multitude of side effects. The data on response rate indicate that the African American subjects probably have a 20-percent chance of a cure and the Caucasians have a 50- to 60-percent chance of a cure. Enrollment for this 4-year study began in 2001. Thus far, 78 patients have been enrolled--46 African Americans and 32 Caucasians. Of the 46 African Americans, 31 are female and 15 are male. Dr. Fleckenstein remarked that African American men are the least likely to participate in clinical trials because they have the greatest sense of mistrust. On the other hand, of the 32 enrolled Caucasians, 18 are males and 14 are females.

The researchers' initial efforts were focused on recruitment. Retention has not been a problem because of the study design. The clinical research center provides easy access, parking, and scheduling. The participants see the same study coordinator each visit, the same physician is always available, and the physicians often help participants with their other medical problems. The clinical research center includes a large proportion of minority providers; in fact, a popular African American phlebotomist helped retention dramatically. In addition, the study coordinator is very helpful to the researchers, and the clinical research center helps provide food stamps and transportation.

Recruitment efforts for the study included physician referral letters, advertisements in resident clinics, and volunteering in local clinics such as the Church Health Clinic, which provides care to the working class who have no insurance. In return for being able to see the patients with hepatitis C, the researchers also agreed to provide liver care for anyone, on request. Dr. Fleckenstein stated that she also recruited at the VA hospital, where the prevalence of hepatitis C is 10 percent for all patients. The researchers also participated in health fairs and screenings, increased their participation in a local hepatitis support group, and created a branch of the American Liver Foundation in Memphis. In addition, they established outreach programs in community health clinics.

In assessing all these strategies, Dr. Fleckenstein noted that the physician referral letters were completely ineffective. Also, the clinic advertisements were not at all beneficial. In addition, although the health fairs and screenings have not provided any additional patients, they have increased awareness in the community and provided access to testing for patients. The biggest disappointment was in the VA recruitment. Dr. Fleckenstein also noted the complete lack of success in obtaining IRB approval for the study, not because of risks related to the treatment, but because of the use of genetic testing and banking specimens.

The successful strategies related to the "African American Response to Therapy for Hepatitis C" study included volunteering at the Church Health Clinic, which began in 2001. Referrals from the clinic's minority providers began to be very frequent beginning in the past year. The researchers' continued input and their willingness to treat all patients made their participation in the clinic a successful recruitment strategy. Another successful strategy involved using nursing support staff at resident clinics and community health clinics. Nurse practitioners helped outreach efforts. Providing open access for patients and direct contact with doctors' offices was another strategy. If a patient was referred, he or she would be seen immediately. Likewise, direct contact between a minority nurse practitioner and minority physicians' offices resulted in referrals. The hepatitis support groups, after a period of many months with regular participation, also proved fruitful for recruitment. The 50-percent African American population of Memphis was another key factor in the successful recruitment for the study.

Donna Mildvan, M.D., Chief, Division of Infectious Diseases, and Principal Investigator, AIDS Clinical Trials Unit, Beth Israel Medical Center, New York, New York

Dr. Donna Mildvan presented information about a work in progress--the Adult AIDS Clinical Trials Group (AACTG), the largest HIV clinical trials organization in the world, which has played a major role in setting the standard of care for HIV treatment. In collaboration with academia throughout the world and with industry, AACTG has been responsible for designing and conducting trials that have led to the licensing of the now 19 available agents for the treatment of HIV disease as well as anti-opportunistic infection and malignancy therapies. Moreover, AACTG is composed of leading clinical scientists in HIV/AIDS therapeutic research.

The focuses of AACTG are (1) pathogenesis-based therapeutic interventions, (2) treatment strategies to limit replication of HIV-1 and improve disease-free survival among infected individuals, (3) rapid development of agents that prevent or delay the complications of HIV-related disorders, (4) HIV-1 pathogenesis through advanced laboratory investigation, (5) recruitment and retention of clinical trial participants who reflect the changing demographics of the AIDS epidemic, and (6) therapeutic approaches that improve quality of life for persons with HIV-1 infection. Beginning with its inception in the late 1980s, AACTG has been committed to recruiting participants from at-risk populations for the clinical trials process. AACTG has had impressive successes in the treatment of HIV disease commensurate with its understanding of these populations. With AACTG's understanding that single agent treatment was going to fail and that therapy had to be directed toward multiple targets in the HIV life cycle, and with the introduction of protease inhibitors, dramatic declines in mortality began to occur.

The declines in mortality, however, have not necessarily been reflected to the same degree across all the populations affected by HIV. CDC data through the year 2001 show no leveling off of the AIDS incidence curve among black and Hispanic individuals in this country. The devastation of AIDS continues in U.S. cities. In the 2001 data, of the 816,000 AIDS cases reported to the CDC, blacks and Hispanics accounted for 57 percent of the total cases, for 78 percent of all women who had been reported to CDC, for 79 percent of all heterosexuals, and for 82 percent of all children diagnosed with AIDS by 2001. Confronted with these statistics, some like-minded individuals proposed the formation of a small working group within AACTG to focus on the changing face of the epidemic. AACTG endorsed the formation of the Underserved Populations Working Group, whose goal was to develop proposals designed to increase minority representation in clinical trials. The question asked was "Were there issues around the design of clinical trials themselves that would enable an increase in the diversity of their patient populations?"

Dr. Mildvan and her colleagues wanted to increase the critical mass of individuals who were committed to this goal by inviting PIs, senior investigators, and past and present Minority AIDS Training Program (MATP) fellows to join the working group. Dr. Mildvan and her colleagues also invited individuals from the community constituency group and the patient care committee. This year, the working group conducted the first review for selection of the 2003 MATP fellow, who has joined the working group. Dr. Mildvan presented the list of members. The cochair, Kimberly Smith, is a graduate of the MATP fellowship program. Another member, Toyin M. Adeyemi, is also a graduate of the MATP fellowship program and is very committed to the goal of the working group. Other fellows include William King from UCLA, Donna DeFreitas from California, and the newest member, Obiamiwe Umeh. The diversity within the working group illustrates the group's universal commitment to the common goal.

The Underserved Populations Working Group had its first conference call around the same time that an article by Gifford and colleagues in the New England Journal of Medicine⁵ pointed out the important discrepancy between nationwide AIDS demographic information and participation in NIH clinical trials. The working group took that information very personally because figure 2 in the article was a bar graph referring to AACTG clinical trials. The group also thought that the timing was perfect because it raised the awareness of disparity in the AIDS clinical trials program and increased interest in its goal.

The white, not Hispanic proportion of the AIDS population represents a minority of AIDS cases in the United States but a majority of participants in clinical trials and an impressive majority of individuals to whom experimental medication has been given. Dr. Mildvan stated that the presented data reflect a period of time between 1996 and 1998; she and her colleagues wanted to ask the question, "What do our data look like now within the AACTG?" She pointed out that they collected very good data from all 35 AIDS Clinical Trials Units (ACTUs) around the country, and each ACTU has its own very well-documented accrual rates for the four populations of interest. In addition, once a year, each of the sites must present its regional demographics to NIH; therefore, the ratio between the particular site and the regional demographics could be calculated to determine which sites are overperforming compared with their expected regional demographics.

The target is a ratio of accrual to regional demographics greater than or equal to 1.0. Such a ratio would indicate a site that was successful in recruiting a particular patient population. For the 2001-2002 evaluation year, 41 percent of the participating sites around the country met or exceeded the target for women. For blacks, only 17 percent of the ACTUs met or exceeded the target. For Hispanics, 44 percent met the target, and for injecting drug users, only 19 percent met the target. For the entire AACTG accrual over the national statistics, the ideal would be a ratio of 1.0; that ratio was not approximated for many of the populations of interest.

For the current evaluation year, 2002-2003, the data show improvement in every category in the proportion of sites that achieved or exceeded the accrual compared with the regional demographics. Dr. Mildvan explained that her group also wanted to identify other possible successful strategies that the overperforming sites might have developed. In addition, they wanted to ascertain whether the year that a particular study was conducted and the type of study question contributed to successes in accrual of minority populations.

Dr. Mildvan described an ongoing study that will yield very important information. The same Dr. Gifford who published the New England Journal of Medicine article that was the wakeup call for many is now conducting a comparative study across two protocols to examine recruitment and retention in trials as a function of baseline factors in patients: reasons for trial enrollment, attitudes and beliefs about retention, depressive symptoms and perceived stress, social demographics and social support systems, and alcohol and substance use. In addition, descriptive site surveys were conducted within AACTG to share best-practice information. A document was distributed in 1997 and updated in 2002 by the Patient Care Committee. The Underserved Populations Working Group wants to take the next step in data gathering. It created the Questionnaire Focus Group led by the MATP investigators, who are developing a questionnaire to link the site performance data to site investigator attitudes and beliefs regarding recruitment and retention. It is expected that the statistical analysis resulting from the survey will be very informative.

Dr. Mildvan described two exploratory proposals that are works in progress. These proposals are looking for models for potential export from successful sites to the entire group and for development of clinical trial curricula that are culturally sensitive and specific. Dr. Mildvan explained that she envisions developing partnerships with AIDS service organizations and working with community-based organizations. In addition, the benefit or effect of a clinical trial could be shown. This phenomenon has been well described in the cancer literature; that is, participants in clinical trials--even in the conventional arm--do better than individuals who do not participate in clinical trials. The same could be the case in HIV disease. Finally, can trials be designed that answer questions relevant to the targeted population? For example, anemia and HIV-associated nephropathy occur at much higher rates in African Americans than in whites. A case-controlled study is needed to investigate genetic polymorphisms in HIV/AIDS. Regarding drug-using populations, of all the thousands of subjects enrolled in AACTG studies, fewer than 100 subjects were on methadone; therefore, a focus group will look at PK interactions with methadone. A lead-in study is possible, to go through the steps of awareness and understanding before enrollment into a clinical trial. Finally, a trial is needed to examine pharmacogenomics to determine why different individuals handle the complicated HIV regimens differently.

Dr. Mildvan concluded her presentation by referring to the shared vision of her colleagues in the Underserved Populations Working Group and their desire to make inroads in the problem of getting at-risk populations into clinical trials.

Herman E. Mitchell, Ph.D., Senior Research Scientist, Rho Federal Systems Division, Inc., Chapel Hill, North Carolina

Dr. Mitchell presented information about the NIAID inner-city asthma study, one of the most intense efforts ever undertaken to study a chronic disease among inner-city children aged 4 to 9 years old. In the late 1980s, several investigators documented the rapidly increasing prevalence of asthma, especially among minority children in the inner city. Congress mandated funds to NIH to study the problem. Dr. Mitchell and his colleagues have studied more than 4,000 inner-city children over 15 years.

Dr. Mitchell's presentation focused on the first intervention study, in which 93 percent of the families were African American and Hispanic. He commented on the changing definition of target populations, including terms such as "minority population," "underprivileged," "disadvantaged," "underserved," and now "health disparities." Dr. Mitchell and his colleagues redefined the population under study as "inner city" because that was the language used by Congress. The definition of inner city is "contiguous census tracts in an urban area where 20 to 40 percent of the population is below the Federal guidelines for poverty." The inner-city population does not necessarily consist of minorities, but by definition the population is poor. The caretakers of children in this population were 96 percent female, and 62 percent of the children with asthma in the study were males.

In 1993, when the study was undertaken, 52 percent of the families included a household member with a job and 55 percent had incomes below $15,000, which was the Federal poverty level for a family of three. In 1999, with welfare-to-work programs, 74 percent of the families had jobs, but 60 percent of them were below the Federal poverty level. It was harder to recruit the families; they were now out working but not making any more money. Recent data show that, although poverty decreased for 24 years in this country, it has increased in the past 2 years, especially among African Americans.

The first notion was to do a broad-based epidemiologic study to identify factors related to asthma morbidity. The study found that many factors (access to care, insurance, continuity of care, family issues, compliance with care, cockroach sensitivity, psychosocial factors) are involved in the problem and there is no "silver bullet." Faced with all these factors, the researchers struggled with intervention design, specifically the question of whether to use nurse case managers or social workers. They ultimately decided to use social workers because it was easier to teach a social worker how to do asthma care than it was to teach a nurse how to do social work.

The issue involves "the signal-to-noise ratio." As Dr. Mitchell explained, with so many things going on in the lives of inner-city families, when a physician or a nurse says, "You have to take your meds three times a day, and you have an appointment next Thursday at 5 o'clock," that message is drowned out. The system has to be changed; the noise must be reduced so that the message can be heard.

Study design considerations included an ethnographic committee and focus groups with the target population. During the focus groups, the participants suggested using the term "asthma counselors" instead of "social workers" and "program" instead of "research." Cultural consultants taught the researchers about the target populations. Experienced population researchers, project staff from the population, and pilot testing also became part of the design considerations.

Data collection bias included the social desirability response. A highly unlikely 96-percent medication adherence rate was reported, but subjects had difficulty with appointments. As a result, the clinics were opened at night and on the weekends. The study participants had needs that ranged from financial to health care to social support to legal, and the study had to find ways to meet those needs. Operational considerations included problems with safety for home visits. The researchers met with police to identify high-risk areas. Two home visitors were always sent out together, with a cell phone but without reimbursement money, and they always called right before the visit.

Other study design considerations included recognizing and designing to the population's needs. Reminders for appointments were necessary 2 weeks in advance, 2 days in advance, and on the same day. Transportation was provided. Flexibility in scheduling and rescheduling was necessary because 30 percent of visits were missed. Such flexibility applied to both staffing availability and design flexibility. A classroom setting is awkward for this type of asthma education, and 8 hours of education is too long. Therefore, the study resorted to 2 hours of education over two group sessions to introduce the study, followed by individual, one-on-one learning. In addition to transportation, babysitting was provided along with entertainment for siblings, incentives, and reimbursement. Participants were treated with kindness and respect. The number one reason participants continued in the study was that they liked the staff. After 2 years, the study had a retention rate of 96 percent.

The Inner-City Asthma Study, developed in the 1990s, had a strong, significant effect on asthma morbidity, an effect that continued through the following year. The study is now being implemented in 24 cities around the United States and is going on currently with thousands of families.

Discussion

The panel discussion raised the following issues and questions:

• A participant asked about the "thinking outside the box" idea expressed by Dr. Cargill and why in 2003 researchers still struggle to get people enrolled in clinical trials. Dr. Delgado pointed out that Dr. Zerhouni, in his Reengineering the Clinical Research Enterprise, stated that full participation in clinical trials is good science. Dr. Cargill pointed out that the problem with getting minorities into clinical trials occurs in the context of a larger issue--so-called "macrostructural forces." Investigators want a "clean" population to facilitate publishing papers in order to keep their jobs. Community-based organizations do not have the support to be able to document their work. Getting minorities into clinical trials requires that people work together to get past some of their own barriers. In addition, minority investigators must be trained, and that is an investment.

• Dr. Sidney McNarry, associate director of research infrastructure at the National Center for Research Resources at NIH, called the participants' attention to an untapped resource in this Nation in terms of recruiting and retaining minority participants in clinical research, namely, minority medical schools. Minority medical schools have credibility, faculty, and resources, and they should be offered membership on external advisory committees and boards. Dr. Delgado commented that everyone agrees with this assertion, but the people who need to hear it are not present.

• A participant from Beth Israel Hospital in New York remarked that the increase in the poverty level coincided with 9/11, when the economy dipped, and asked about the association between the two events. The participant also asked Dr. Fleckenstein whether biopsies were required in the hepatitis C study. When Dr. Fleckenstein said yes, the participant asked whether the biopsy requirement was a hindrance to accrual and whether patients were compensated. Dr. Fleckenstein responded that the biopsy requirement was not a hindrance to accrual because of the extreme efforts taken to provide free biopsies. The patients were not compensated, but the medicine and visits were free. Travel was not provided for patients, but childcare was offered. The participant also asked whether the Underserved Populations Working Group would include deaf people, disabled people, transgender people, and Asian Americans in addition to people of color and Hispanics. Dr. Mildvan responded that the community constituency group has asked that another member be added to the Underserved Populations Working Group from one of the mentioned populations that are at risk for HIV. The participant suggested that the study staff and PIs might want to play-act at joining a trial so that they can discover what it is like to be a patient participating in a study. A panel member reported that a number of community-based organizations have asked whether they can undergo mock participation in a clinical trial, and that activity has been initiated.

^5.Gifford AL et al. Participation in research and access to experimental treatments by HIV-infected patients. N Engl J Med 2002;346(18):1400-2.