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Journal of Clinical Oncology, Vol 22, No 4 (February 15), 2004: pp. 730-734 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.03.160 Enrollment of African Americans Onto Clinical Treatment Trials: Study Design BarriersFrom the Cancer Center, Division of Cancer Prevention, Control, and Population Sciences; the Department of Surgery; and the Department of Medicine, Howard University College of Medicine, Washington, DC Address reprint requests to Lucile Adams-Campbell, PhD, Howard University Cancer Center, 2041 Georgia Ave NW, Washington, DC 20060; e-mail: ladams-campbell{at}howard.edu.
PURPOSE: African Americans have the highest cancer mortality rates and poorest survival and are more often uninsured and underinsured compared with other ethnic groups. Minority participation in clinical trials has traditionally been low, with reports ranging from 3% to 20%. The present study systematically assesses 235 consecutively diagnosed African American cancer patients regarding recruitment onto cancer treatment clinical trials at Howard University Cancer Center between January 1, 2001, and December 31, 2002. Our intent is to determine the rate-limiting factors associated with enrolling African Americans onto clinical trials at a historically black medical institution. PATIENTS AND METHODS: Two hundred thirty-five consecutively diagnosed African American cancer patients were assessed for participation in clinical trials at Howard University Hospital and Cancer Center. The study population comprised 165 women and 70 men. RESULTS: The overall eligibility rate was 8.5% (20 of 235 patients); however, among those eligible, the enrollment rate (ie, enrollment among the eligible population) was 60.0% (12 of 20 patients). Comorbidities rendered 17.1% of the patient population ineligible for the trials. Advanced disease stage, associated with poor performance status, premature death, and short life expectancy, made an additional 10% of the patient population ineligible. Respiratory failure, HIV positivity, and anemia accounted for 37.8% of the comorbidities in this population. Cardiovascular diseases and renal insufficiency represented 16.2% of the comorbidities. CONCLUSION: It was evident that study design exclusion and inclusion criteria rendered the majority of the study population ineligible. Among African Americans, comorbidity is a major issue that warrants considerable attention.
There exists an unequal burden of cancer among minorities and the underserved, which is measured by a variety of indicators, such as incidence, mortality, and survival rates [1]. The average annual incidence per 100,000 for all cancer sites during the period of 1992–1998 was 445.3 for blacks, 401.4 for whites, 283.4 for Asian Americans and Americans of Pacific Islander descent, 270.0 for Hispanics, and 202.7 for Native Americans [2]. The mortality rate for all cancers combined is approximately 33% higher in black Americans than in white Americans. Five-year survival rates, another measure of unequal burden, reveal that African Americans have the lowest rates, compared with all other ethnic groups [3]. It is well known that minority recruitment onto clinical trials faces a problem with rates of participation, ranging from 3% to 20% [4,5]. The trials are most likely to be composed of white men and women with high educational backgrounds and socioeconomic status [6-9]. However, it is also evident that there is a significant need, based on disease burden, for enrollment of various minority groups with diverse features related to socioeconomic status, age, and sex, onto clinical trials [1,3]. It is further evident that the number of minorities on clinical trials needs to increase to reduce the inherent selection bias and to address the objectivity of clinical trial design. There have been a host of barriers to clinical-trial enrollment reported among minority populations, particularly African Americans, including lack of physician participation, lack of subject participation, and recruitment costs [4,10-17]. Study design is a major barrier that raises critical issues regarding the restrictive inclusion and exclusion criteria [5-8,18,19]. It has been previously reported that cancer patients in minority populations have not benefited from clinical trials investigating quality of life, increased survival, and improved medical care and access. The purpose of the present study is to systematically evaluate the influence of study design on the recruitment and enrollment of African Americans onto cancer treatment clinical trials at Howard University Cancer Center. In addition, we intend to determine the rate-limiting factors associated with enrolling African Americans onto treatment clinical trials at a historically black medical institution.
Study Population Howard University institutional review board approval was obtained before the commencement of the investigations. The study population comprised 235 African Americans consecutively diagnosed with cancer at Howard University Hospital between January 1, 2001, and December 31, 2002. Patient identification was made using physician referrals, daily surgical-procedure lists, pathology reports, admission records, oncology clinics, and the Howard University cancer tumor registry. A preliminary review of each cancer patient was conducted to determine eligibility for one of the approved treatment trials. An investigator informed each patient's medical oncologist, radiation oncologist, and/or primary care physician of the available trials for the patient. The physician then informed and counseled the patient on the appropriate clinical trial(s).
Clincial Trial Protocols
Clinical Trial Tracking Database A clinical trial tracking database was established to aid in the follow-up and outcome assessment of each identified cancer patient. Clinical research associates enter the following information on a weekly basis: patient identification number, medical record number, race and ethnicity, sex, protocol(s), treatment site, date of diagnosis, stage of disease, eligibility status, patient's decision whether to participate, reasons for ineligibility, and additional comments.
Two hundred thirty-five consecutively diagnosed African American cancer patients constituted the study population. The site-specific cancer distributions by sex are shown in Table 2; they included 165 women and 70 men. The overall eligibility rate was 8.5% (20 of 235 patients), with a conditional enrollment rate of 60.0% (12 of 20 patients). Patient ages ranged from 22 to 97 years.
The overall and disease-specific exclusion criteria for African Americans in clinical trial treatment protocols are shown in Table 2. There were no appropriate protocols selected and available for 24.2% of the patient population. In addition, comorbidities were responsible for rendering 17.1% of the patient population ineligible for the treatment trials. Patients with advanced cancer were considered for the appropriate protocols, but poor performance status and premature death made an additional 10% of the patient population ineligible for these trials.
Disease-specific inclusion criteria resulted in the exclusion of additional patients from the treatment trials (Table 3). One of the inclusion criteria for prostate cancer trial MC0151 required testosterone levels less than 50 ng/dL and Gleason scores
A detailed listing of the comorbidities is presented in Table 4. Respiratory failure, HIV positivity, and anemia accounted for 37.8% of the comorbidities in our cohort. Cardiovascular diseases, including congestive heart failure, renal insufficiency, and coronary artery and cerebrovascular disease, accounted for 16.2% of the comorbidities. Some patients were diagnosed with sepsis, which was unrelated to tumor infections.
The inclusion and exclusion criteria, as well as a lack of available clinical trials opened at our institution, were the primary barriers for African American participation at Howard University Cancer Center. Although African Americans' rates of participation in clinical trials in general are low, our review revealed that study design factors were a significant cause of ineligibility. More specifically, there was an overall eligibility rate of 8.3% in the current study, although 60.0% of the eligible patient population participated in our available treatment trials. The primary cause of exclusion of cancer patients was the lack of an available institutional review board-approved clinical trial. Yet the cancer tumor registry was used to assist with characterizing the patients typically seen at Howard University Cancer Center. Breast cancer, the leading cancer diagnosed at Howard University Hospital, reportedly had more advanced-stage premenopausal breast cancer cases. However, during the study time frame, there was clearly a paradigm shift resulting in earlier stage breast cancer cases. As evident in Table 1, there were no breast cancer protocols available to the patients with node-negative status. Opening numerous clinical trials with low numbers of eligible participants potentially poses a tremendous burden on the Howard University Cancer Center clinical trials staff. However, after reviewing the clinical trials database, we observed that a substantial number of cancer cases were not eligible for enrollment to the available approved clinical trials. This led to the opening of more trials to facilitate more cases seen at Howard University Hospital. It is imperative that Howard University Cancer Center and Hospital investigators design studies that address the comorbidity issues in the African American community. In the meantime, it is essential that we document and report on the experience of our patients treated off protocol. This will enable us to better understand the ways to treat comorbidities among African American cancer patients. Although many of the inclusion and exclusion criteria, particularly related to comorbidity, are continual, it is unlikely that the mere opening of additional clinical trials alone will increase the eligibility rate, as noted in Table 1. Protocols investigating ductal carcinoma-in-situ; lymphomas; multiple myeloma; AIDS; small-cell lung cancer; hepatoma; and rectal, ovarian, and renal cancers, are in the process of being opened. It is possible that this will have a significant impact on enrollment, barring comorbidities and other exclusion criteria. It is evident that the African American population has a disproportionate burden of comorbidities that exclude patients from clinical trials. It is difficult to determine which comorbidities should be eliminated as exclusion criteria. For example, patients with cerebrovascular and cardiovascular diseases are frequently excluded from clinical trials to ensure participant safety. However, the disproportionate incidence of these comorbidities in African Americans reduces their enrollment. Therefore, careful protocol design should consider the specific comorbid characteristics of African American cancer patients. It is critical that more African Americans and other minorities be involved in study design, with specific emphasis on inclusion and exclusion criteria. For example, the phase II prostate cancer treatment trial study MC0151 requires that serum testosterone levels be less than 50 ng/dL. Studies have reported higher testosterone levels in African American men [20]. This observation opens the door to the hypothesis that different cutoff values for castrate levels should be considered. Obviously, the variability in cutoff levels could potentially confound interpretation of outcome. However, there should be consideration of this discrepancy. For example, castrate levels could be standardized by determining a percentage of reduction in total testosterone after androgen deprivation. Although many of the inclusion and exclusion criteria, particularly related to comorbidities, are consistent across protocols, it is unlikely that the mere opening of additional treatment protocols will increase the eligibility rate of the African Americans, as evident in Table 1. It is imperative that Howard University Cancer Center and Hospital investigators design studies that address the comorbidity issues in the African American community. In the meantime, it is essential that we document and report on the experiences of our patients treated off protocol. This will enable everyone to better understand ways to treat comorbidities among African American cancer patients. Our enrollment response of 60.0% reflects an enormous opportunity to address the unequal cancer burden borne by African Americans relating to participation in clinical treatment trials. There is a need to increase the number of protocols available at Howard University Cancer Center so that our patient population will have access to state-of-the-art clinical trials appropriate for their disease states. In addition, considerable attention should be given to inclusion and exclusion criteria that serve as potential deterrents to enrollment of African American patients. We do not intend to imply there is a biologic difference in the cancer disease process but rather to note that it is important to realize that the outcome of the treatments may indeed be affected, positively or negatively, by the well-known comorbidities that exist in the African American population. This issue demands all our attention to seriously address the unequal burden of disease.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Received more than $2,000 a year from a company for either of the last 2 years: Duane Smoot, Merck, Novartis, AstraZeneca.
We are very grateful for the dedicated work of our clinical research associates, Joan Pearson, Dionne Thorne, and Kim Utley.
Supported by grants CA91105 and CA79405-03S1 (L.L.A.-C.). Authors' disclosures of potential conflicts of interest are found at the end of this article.
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5. Swanson GM, Ward AJ: Recruiting minorities into clinical trials: Toward a participant-friendly system. J Natl Cancer Inst 87:1747–1759, 1995 6. Roberson NL: Clinical trial participation: Viewpoints from racial/ethnic groups. Cancer 74:2687–2691, 1994[CrossRef][Medline] 7. Millon-Underwood S, Sander E, Davis M: Determinants of participation in state-of-the-art cancer prevention, early detection/screening, and treatment trials among African-Americans. Cancer Nurs 16:25–33, 1993[Medline] 8. Freeman HP: The impact of clinical trial protocols and patient care systems in large city hospitals. Cancer 72:2834–2838, 1993[CrossRef][Medline] 9. Hunninghake DB, Darby CA, Probstfield JL: Recruitment experience in clinical trials: Literature summary and annotated bibliography. Control Clin Trials 8:6S–30S, 1987 (suppl 4)[CrossRef][Medline] 10. Mouton CP, Harris S, Rovi S, et al: Barriers to black women's participation in cancer clinical trials. J Natl Med Assoc 89:721–727, 1997[Medline] 11. Pinto HA, McCaskill-Stevens W, Wolfe P, et al: Physician perspectives on increasing minorities in cancer clinical trials: An Eastern Cooperative Group (ECOG) Initiative. Ann Epidemiol 10:S78–S84, 2000 (suppl 8)[CrossRef][Medline]
12. McCaskill-Stevens W, Marcus PH, Comis R, et al: Recruiting minority cancer patients into cancer clinical trials: A pilot project involving the Eastern Cooperative Oncology Group and the National Medical Association. J Clin Oncol 17:1029–1039, 1999 13. Holcombe RF, Jacobson J, Li A, et al: Inclusion of black Americans in oncology clinical trials: The Louisiana State University Medical Center experience. Am J Clin Oncol 22:18–21, 1999[CrossRef][Medline] 14. Green BL, Partridge EE, Fouad MN, et al: African-American attitudes regarding cancer clinical trials and research studies: Results from focus group methodology. Ethn Dis 10:76–86, 2000[Medline] 15. Mattson ME, Curb JD, McArdle R: Participation in a clinical trial: The patients' point of view. Control Clin Trials 6:156–167, 1985[CrossRef][Medline] 16. Taylor KM: Integrating conflicting professional roles: Physician participation in randomized clinical trials. Soc Sci Med 35:217–224, 1992 17. Taylor KM, Margolese RG, Soskolne CL: Physicians' reasons for not entering eligible patients in a randomized clinical trial of surgery for breast cancer. N Engl J Med 310:1363–1367, 1984[Abstract] 18. Elks ML: The right to participate in research studies. J Lab Clin Med 122:130–136, 1993[Medline] 19. Haynes MA, Bernard LJ: Drew/Meharry/Morehoue Consortium Cancer Center: An approach to targeted research in minority institutions. J Natl Med Assoc 84:505–511, 1992[Medline] 20. Ross RK, Bernstein L, Judd H, et al: Serum testosterone levels in young black and white men. J Natl Cancer Inst 76:45–48, 1986 Submitted March 25, 2003; accepted December 5, 2003.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
8, excluding 15.6% and 25.0% of our prostate cancer patients, respectively. In our study population, potentially eligible men had testosterone levels that ranged from 68.2 to 207 ng/dL and Gleason scores less than 8 (range, 6 to 7). Among the breast cancer patients who had positive nodes, which were required, they had too few positive nodes (< 6). Also, many of the premenopausal breast cancer patients were predominantly lymph node-negative. 
