**3. Reasons for the disparity**

of these disparities. Regardless of the cause, the lack of participation of these groups in clinical trials raises important questions about the quality and ethics of clinical research. The goal of this document is to discuss the evidence and reasons behind disparities in clinical trial participation. We also provide a discourse on potential mechanisms to address disparities in clinical trial accrual including the ethical considerations of financial incentives, the impact of a more stringent policy and review process for product approval from the Food and Drug Administration

The composition of minorities in clinical trials has historical been low. Between 1996 and 2002, blacks represented on average 9.3% of the total number of enrollees in cancer clinical trials [1]. That number peaked at 11% in 1996 and steadily declined to 7.9% in 2002 [1]. Similarly, Hispanics on average represented on average 3.1% of the total number of enrollees in cancer clinical trials between 1996 and 2002 [1]. Not only are minorities under-represented in clinical trials, but the overall racial and ethnic composition of clinical trials is not reported at an acceptable rate. Between 1990 and 2000, only 35.1% of treatment studies among cancer clinical trials reported race/ethnicity [2]. This number increased to 51.6% from 2001 thru 2010, but the percentage of blacks included in the analysis for the second decade decreased by 42% [2]. The lack of diversity goes beyond race and ethnicity. Similar trends are found in women, where they only represented 26.5% of the population in prevention studies between 2001 and 2010 [2].

The disparity in clinical trial participation is not limited to cancer clinical trials and the scientific impact can be significant in terms of outcomes. African Americans are disproportionately affected by hepatitis C virus (HCV) in the United States and HCV infection is the leading cause of cirrhosis and hepatocellular carcinoma and the most common indication for liver transplantation in the United States [3]. Although African Americans comprise approximately 13% of the US population, they make up approximately 23% of Americans with hepatitis C [4]. The rate of a positive HCV antibody test was higher in blacks than in whites (3.2% versus 1.5%) and black men had higher rates of infection, with the highest prevalence rate (9.8%) among black men ages 40–49 years [5, 6]. HCV treatment has undergone a rapid evolution in treatment with the first generation protease inhibitors released in 2011 and now multiple

We performed a meta-analysis of clinical trials on hepatitis C treatment between January 2000 and December 2011 [9] to evaluate the participation of African Americans in hepatitis C clinical trials given the tremendous burden of that disease within this population. We reviewed 588 randomized controlled clinical trials on hepatitis C treatment with interferon 2a or 2b between January 2000 and December 2011. Of the 588 reviewed, 314 (53.4%) fit inclusion criteria [9]. This meta-analysis showed that of the 314 RCT's that met search criteria, only 123 (39.2%) actually reported race. We evaluated clinical trials in North American and Europe, and found significant differences. The clinical trials performed in North America were more likely to report racial data than European trials, although racial reporting overall increased

(FDA) including a diversity mandate with an associated population black box warning.

**2. Evidence of disparity among racial/ethnic minorities**

4 Clinical Trials in Vulnerable Populations

direct acting antivirals regimens with amazing outcomes [7, 8].

The persistent disparity in minority clinical trial participation is a result of a combination of historical, demographic, and socioeconomic factors. These complex issues combine to create barriers preventing clinical researchers from reaching communities and barriers preventing communities from engaging in clinical trial research.

Socioeconomic status (SES) is a major contributor to disparities in minority clinical trial participation. The mechanism through which SES impacts minority trial accrual is *primarily* through individual patient level access to resources associated with clinical trial participation. Lower levels of education and income are known to correlate with a lack of insurance and underinsurance. Previous estimates have shown that up to 30% of the US population is underinsured or uninsured [11]. While the "Patient Protection and Affordable Care Act, 2010" will significantly improve access to health insurance, the impact on clinical trial participation will need to be studied given the lack of uniformity in implementation across the individual states in the US. Low SES presents issues with transportation as well [12]. Hence, patients with limited transportation resources are more likely not to be able to logistically make the follow up appointments associated with participation in a clinical trial [1, 12]. The cost of transportation and clinical trial research participation goes beyond typical costs such as fuel and mileage. Many patients of lower SES cannot afford to miss the time from work required for clinical trial visits as well. A lack of education and awareness of cancer and clinical trials has been shown to contribute to reduced participation in clinical trials [12–15] due to a lack of knowledge concerning the cancer diagnosis, treatment options, and precisely what is clinical research. One's SES is often reflected in the neighborhood that they live. Unfortunately, living in lower SES neighborhoods (be they urban or rural) reduces the likelihood of one having access to clinical trial research [12].

Cultural issues related to race and ethnicity also contribute to disparities in clinical trial participation. The race of one's provider can impact access to clinical trials. Under-represented minorities are more likely to receive healthcare from a physician who is also a minority [1, 16]. Few minority physicians are engaged in clinical research and this thus reduces opportunities for the minority populations they serve to be engaged in clinical research. A lack of culturally appropriate educational materials targeting individuals with diverse cultural backgrounds and in whom English is their second language contributes to an inability to recruit individuals of Hispanic and other ethnic backgrounds [12, 17–19].

Provider characteristics also contribute to the lack of diversity within clinical trials. Provider attitudes towards a patients age, comorbidities [20, 21], physician perception of mistrust of researchers [21, 22], and lack of physician awareness of clinical trials [21, 23] all contribute to disparities in clinical trial research. Furthermore, studies targeting under-represented minorities (Hispanics and blacks) have found that provider miscommunication including lack of compassion, lack of respect, and perceived mistrust have all contributed to minorities hesitating to engage in clinical trial research [21]. The legacy of the Tuskegee Syphilis experiment still resonates among blacks in the United States when confronted with issues around clinical trial research. The Tuskegee study involved 400 African American males with syphilis who were systematically denied treatment from 1932 to 1972 even though a known treatment existed [24, 25]. This was the longest nontherapeutic experiment on human beings in medical history [25]. These men were largely illiterate and uninformed about the risks and benefits of this study despite the existence of US policy to protect clinical research subjects [24]. The social and political significance of the US Public Health Service performing unethical research on African Americans following the Civil Rights Movement of the 1960s was monumental and continues to contribute to the mistrust among African Americans for clinical research today [24, 25].

and biological agents [31]. The purpose of these laws was to provide financial motivation for pharmaceutical companies to engage in pediatric clinical research. Children, similar to minorities the elderly, the poor, and women, were a group often not included in clinical trials. In return for their willingness to provide drug labeling information on children and increase delivery of biologics for children to the market, pharmaceutical companies received financial benefits. These laws resulted in critical changes in drug labeling for pediatric patients because unique pediatric dosing is often necessary because of the growth and maturational stages of pediatric patients [31]. Furthermore, since the implementation of these incentive programs, a majority of biologics (vaccines, anti-toxins, and insulin) approved include pediatric informa-

Scientific and Ethical Considerations for Increasing Minority Participation in Clinical Trials

http://dx.doi.org/10.5772/intechopen.70181

7

A major reason for concern with financial incentives for pharmaceutical companies to engage in pediatric clinical research is monetary. There is concern that PHARMA could reap great financial reward from the patent extensions, and many question the ethics of this in return for doing what is deemed to be the morally correct thing to do [28]. Complicating the debate is the fact that the financial data is mixed. Li et al. [28] performed a cohort study of nine drugs granted pediatric exclusivity. They found that exclusivity did not guarantee a financial windfall with the distribution of net economic return for 6 months of exclusivity varying widely [net return ranged from (−)\$8.9 million to (+)\$507.9 million] [28]. However, at times, it appears that the financial incentives provided are disproportionate to the cost of the research being done because the profit ratio for certain blockbuster medications (anti-hypertensives), can be

Within 10 years of implementation of the Pediatric Exclusivity Act in 1997, there were more than 300 studies conducted and more than 115 products with labeling changes to account for pediatric use [31, 33, 34]. However, many of the drugs studied were not considered important targets among the pediatric population [33, 34]. The pediatric exclusivity studies have also tended to focus on more profitable drugs and the drugs most frequently studied are more likely to be important targets for the adult population [33, 34, 36]. The literature also raises important concerns related to the quality of the clinical trials conducted under the exclusivity act [37]. The extensions for patents under the exclusivity act are granted regardless of the quality or outcome of the clinical trial and many of the results of studies done under the

The data on the use of financial incentives to increase clinical trial diversity is mixed with evidence of success in terms of new drug labeling and evidence of failure in terms of poor research quality and financial gains for industry. However, financial incentives to increase diversity in clinical trials may be a viable and aggressive means of eliminating these health disparities if implemented in a thoughtful and ethical way. Men make up more than twothirds of the population in clinical tests of cardiovascular devices [10]. African Americans and Hispanics respectively make up 12% and 16% of the US population. However, African Americans and Hispanics respectively make up only 5% and 1% of clinical trial participants [10]. There are clear benefits and costs associated with the use of financial incentives. These must be carefully considered and weighed when implementing any policy concerning finan-

tion in their labeling [32].

as high as 17:1 [28, 33–35].

exclusivity act are not published [38].

cial incentives to increase clinical trial diversity.
