Clinical trials are health and medical studies that test drugs, medical interventions, treatments, and devices using human participants, with the goal of producing new knowledge [5]. Clinical trials follow a specified, standardized protocol. Typically, there are three phases [6,7]:

Depending upon the goal of the study, the type of clinical trial will differ. Types of clinical trials include [6,7,112,148]:

Medical scientists and researchers rely on clinical trials because the experimental research designs are the most rigorous research methods to infer cause and effect. The most basic design involves an experimental (intervention) group (i.e., the group that receives the treatment/medicine), a control group (i.e., the group who does not receive the treatment/medicine), and randomization of subjects to one of the two groups. Many trials include more than one experimental group, if different interventions or doses are being compared. Randomization refers to the process whereby human subjects are randomly assigned to one of the groups; in some cases, neither the researcher nor the subject is aware of the assigned group. The goal of randomization is to guarantee that there is no selection bias, which ensures that the groups are comparable [8]. Using such a design, it is the researcher's goal to determine if there are any statistically significant differences in disease experience between the groups. If there is, the researcher would infer that the intervention caused the difference.

By 1863, placebos were introduced. Austin Flint, an American physician, conducted an experiment to examine a treatment for rheumatism utilizing an herbal extract (the placebo) opposed to the standard treatment [14,176]. By 1923, randomization was implemented into research designs [11]. One of the first examples of randomization was documented in a study of interventions for the treatment of tuberculosis. In this study, the researchers tossed a coin to determine which half of the 24 subjects would go to the intervention group [12,162]. The goal was to produce experimental and control groups that were similar in patient characteristics to reduce bias [162].

In the 1870s, the Comstock Act was signed into law. This Act prohibited the publication of brochures about birth control and deemed the dissemination of contraceptives as obscene. The associated laws made research regarding contraceptives difficult to illegal [57].

Motivations for participation in clinical trials vary. As noted, financial incentives have traditionally been a primary motivator. In a study of 136 healthy subjects who participated in a phase 1 clinical trial, participants indicated that financial benefits were the main reason they decided to participate [19].

Not surprisingly, there was a relationship between income and education and motivation to participate, as those individuals with lower income and education levels valued the financial incentives attached to clinical trials more than individuals with higher income and education levels. Others cited more altruistic motives, such as the hope to help further medical advances and to assist future patients [20,21,22].

As discussed, starting in 1993 the NIH Revitalization Act mandated the inclusion of women, racial/ethnic minorities, the elderly, and other marginalized groups in medical research. Similarly, in 1993, the U.S. Food and Drug Administration (FDA) recommended researchers analyze and report their findings according to sex, age, and race. However, according to a Government Accounting Office report, about one-third of the applications for the study of new drugs did not adhere to these policy recommendations in 2002 [26].

By far, white, married, middle-class, and well-educated men are the largest segment of the population who participate in clinical trials and health-related research [31]. The NIH Revitalization Act of 1993 was implemented with the goal of changing this trend. This law has increased the number of minority participants in NIH-sponsored clinical trials, from approximately 1 million minority research subjects in 1995 to almost 15 million in 2016 [174]. However, this gain is almost entirely the result of greater number of trials and larger trials, as the rate of racial and ethnic minority participation has remained relatively level (36.7% in 1995 compared with 37.2% in 2016) [174]. One study examined the extent to which racial minorities were represented in U.S. vaccine clinical trials between 2011 to 2020 [207]. In total, 230 trials met the inclusion criteria, with a total of 219,555 research subjects. Nearly 78% of participants were White, 11.6% were Hispanic, 10.6% were Black/African American, 5.7% were Asian American, and 0.4% were Native American/American Indian.

By far, white, married, middle-class, and well-educated men are the largest segment of the population who participate in clinical trials and health-related research [31]. The NIH Revitalization Act of 1993 was implemented with the goal of changing this trend. This law has increased the number of minority participants in NIH-sponsored clinical trials, from approximately 1 million minority research subjects in 1995 to almost 15 million in 2016 [174]. However, this gain is almost entirely the result of greater number of trials and larger trials, as the rate of racial and ethnic minority participation has remained relatively level (36.7% in 1995 compared with 37.2% in 2016) [174]. One study examined the extent to which racial minorities were represented in U.S. vaccine clinical trials between 2011 to 2020 [207]. In total, 230 trials met the inclusion criteria, with a total of 219,555 research subjects. Nearly 78% of participants were White, 11.6% were Hispanic, 10.6% were Black/African American, 5.7% were Asian American, and 0.4% were Native American/American Indian.

In summary, clinical trial participation rates among women and racial/ethnic minorities and lack of full adherence to the NIH Revitalization Act should be concerns for all healthcare professionals. These disparities in research participation can lead to an imbalance in the distribution of benefits and opportunities among certain groups, a limited generalizability of scientific findings, and continued trends in health gaps among certain groups [37]. The discussion of whether their exclusion is problematic continues to be controversial.

Those who believe women need not be included in clinical trials argue that men and women are essentially the same. These individuals generally assert that if there are biologic gender differences, they may be attributed to hormones. Because hormones do not necessarily affect the disease or intervention being studied, the gender of participants would not affect the findings [40].

Some with this viewpoint also maintain that race is not an important genetic factor in clinical trials, as inter-racial mixing has diluted any differences [52]. They argue that focusing on differences may lead researchers to reinforce stereotypes. They also argue that biologic differences are not at the heart of the argument; rather, differences are largely due to social issues [215].

Historically, women have been excluded from clinical trials as a means of protection. In particular, women of childbearing age were excluded due to concerns of risks to potential fetuses [142,181]. Some have argued that menstruating women should be excluded from clinical trials so as to mitigate the potential effects of fluctuating hormones on pharmacokinetics and pharmacodynamics [161]. This has continued to be used as a justification to exclude women of all ages [142].

This argument is the opposite of the belief that persons of various genders and racial backgrounds are similar. Some individuals argue there are more differences than similarities among subgroups, which leads to too many variations in studies' findings. From this perspective, the goal is to have a very "clean" study, with a homogenous sample, so any variation can be attributed to the intervention [46,171]. Including women and racial/ethnic minorities in clinical trials would make interpreting the data more of a challenge; subgroups should be studied independently [40].

Some researchers argue that the question of whether there are differences in treatment efficacy between men and women is insignificant [124]. The proportion of treatment to which men and women respond differently is unclear, and it has been suggested that apparent differences may be attributed to other factors, such as gene expression [124,142].

There are some who argue that the benefits of participating in clinical trials are overstated [53]. These individuals believe that it is important to note that participation in clinical trials is not long term and does not provide services or medication after the study is completed. Furthermore, medical care associated with a clinical trial is often not free [53].

Recruiting, enrolling, and retaining women and racial/ethnic minorities in clinical trials can be difficult, and some argue that this can prevent important research from being completed [40]. In order to recruit and retain enough women and racial/ethnic minority participants to ensure there is enough statistical power to analyze, the sample size and resources necessary increase substantially. Some argue that women add complexity to studies, which ultimately increases the cost [142,179]. In one study, adding the analysis of gender and race into the equation would have increased the cost of the study more than tenfold, from $115 million to $1.846 billion [54]. Furthermore, women are more likely to have competing domestic demands and responsibilities (e.g., child care) [182]. This would exacerbate the cost.

In addition to institutional barriers, women and ethnic minorities experience their own barriers to participation in clinical trials. Personal fears and anxiety, mistrust, and cultural values can all affect willingness to enroll in scientific research.

The perceived physical risks associated with injections, needles, and intrusive interventions can impede many from participating in clinical trials. Furthermore, many are concerned that ultimately there will be minimal personal benefits of participation [64]. In a survey of 1,256 research participants, the highest rated barriers involved fear and anxiety. Specifically, the participants feared potential side effects, expense not covered by health insurance, and ineffective treatment or placebo [152]. In a 2007 study, women expressed greater concern about the risks involved in clinical trials than men [65].

One of the prominent images associated with medical research is the research subject becoming a human "guinea pig" [175; 183; 216]. For example, one African American woman who was eligible for a smoking cessation clinical trial study opted not to enroll because she did not want "anyone playing with her mind" [66]. In a 2011 study of African Americans with HIV infection who had participated in a clinical trial, many stated that they were fearful of simply being treated like the subjects in the Tuskegee Study [125]. In another focus group study of Chinese immigrants and service providers, some Chinese immigrants from the community likened clinical trials to "experiments with animals" [67]. In fact, in some languages, the translated word for "clinical trials" is closer to the word "experiment," which unfortunately evokes fear in some patients [68]. This image is also associated with the general belief that certain groups are more vulnerable and more likely to be taken advantage of. In a cross-comparison study with 623 whites, 353 African Americans, and 157 Hispanics, women and racial minorities were more likely to believe that women are taken advantage of in biomedical research [69]. After controlling for socioeconomic status, African Americans were four times more likely and Hispanics were twice as likely as whites to believe that women are taken advantage of in medical research.

One of the prominent images associated with medical research is the research subject becoming a human "guinea pig" [175; 183; 216]. For example, one African American woman who was eligible for a smoking cessation clinical trial study opted not to enroll because she did not want "anyone playing with her mind" [66]. In a 2011 study of African Americans with HIV infection who had participated in a clinical trial, many stated that they were fearful of simply being treated like the subjects in the Tuskegee Study [125]. In another focus group study of Chinese immigrants and service providers, some Chinese immigrants from the community likened clinical trials to "experiments with animals" [67]. In fact, in some languages, the translated word for "clinical trials" is closer to the word "experiment," which unfortunately evokes fear in some patients [68]. This image is also associated with the general belief that certain groups are more vulnerable and more likely to be taken advantage of. In a cross-comparison study with 623 whites, 353 African Americans, and 157 Hispanics, women and racial minorities were more likely to believe that women are taken advantage of in biomedical research [69]. After controlling for socioeconomic status, African Americans were four times more likely and Hispanics were twice as likely as whites to believe that women are taken advantage of in medical research.

Finally, many individuals do not have a full understanding of clinical trials, and this can compound individuals' fears and anxieties. Research indicates that African Americans tend to have less subjective and factual knowledge about clinical trials compared with their white counterparts [184]. Factual or objective knowledge can be measured with questions with a specific answer, while subjective knowledge refers to a person's assessment of their own knowledge. A survey study found that deficits in subjective knowledge tended to predict declining to participate in clinical trials; lack of factual knowledge did not appear to affect participation [184]. In a study conducted in 2006 in an African American community, many participants misunderstood the concept of placebos [70]. Participants in the study conveyed that the use of placebos meant some people would not receive medication. They did not comprehend why the medication or intervention would be denied to patients who needed it for health concerns. This was also reported to be correlated with the atrocities committed in the Tuskegee Study [70].

The way that information is presented to research participants, with the use of technical language and jargon, can impede participation. Use of many unfamiliar technical, legal, and medical terms, for example, can foster anxiety and uncertainty. One study found that the largest barrier to women participating in a clinical trial was how well the study was explained [185]. It is important to remember that medical and legal terms and the many acronyms researchers use in their normal day-to-day professional vocabulary are not part of the language used by laypersons. These "unfriendly" terms end up excluding persons who have not been socialized in the medical profession [71,185]. In a study of 353 breast cancer clinical trial sites, very few offered information in other languages and not all sites offered interpreting services for those with limited English abilities [153]. Minimal supplemental information was provided about the clinical trial. In a qualitative study, the majority of the Latino/a participants argued for materials in Spanish, written in a more reader-friendly manner [154]. For those not proficient in English, use of medical language can be intimidating, which can ultimately create a dichotomy of an "us" and "them" (i.e., researchers and participants) [185].

It is important to note that some terms have cultural connotations. The Spanish word investigaciones, for example, can be misconstrued to mean police investigation in some Hispanic cultures, particularly for those who come from more politically repressive countries [4]. Those who are undocumented may also be concerned enrollment in a clinical trial could trigger investigation of their legal status [217]. Clinical trials and health-related research studies are often conducted at medical centers or academic institutions, which may be more convenient for researchers or sponsors of the research rather than the participants [71]. It is possible that this type of environment reinforces the "doctor culture," which could alienate research participants. Research studies and clinical trials are also based on the notion of medical individualism; however, for many cultural groups, family and social relationships are at the heart of decision-making, including decisions related to health [126]. Furthermore, the logistics and inconveniences associated with traveling to research sites may compound potential participants' fears.

The goal of the consent process is to ensure that research participants understand the nature of the study and are able to make an informed decision whether to participate or not. However, many consent forms, particularly in clinical trials, are not easily comprehensible. Most consent forms are written at a college reading level; the average American reads at a fourth-grade reading level [72]. In one study of 287 adult participants in a clinical trial who had read and signed a consent form, approximately 75% of the participants did not understand the treatment discussed and half could not identify the risks and benefits of the study [73].

Cultural differences in gender roles can compound the difficulties women experience participating in scientific research. Having to balance responsibilities of childcare, household-related tasks, and caring for other family members, ethnic minority women are more likely to not prioritize their own healthcare concerns [87]. Depending on the cultural group, assigned gender roles can play a prominent role in whether women will participate in health-related research. For example, due to a patriarchal culture, Korean men assume positions of authority and key decision making, and husbands or other male figures might "forbid" Korean women to participate in health-promoting activities, such as medical research [88].

Western society tends to place emphasis on medical interventions such as vaccinations, immunizations, and antibiotics. In part, this is a reflection of Western biomedical ethos, which is based on individualism and competitiveness [71]. However, many other cultural groups tend to have a more collectivistic and fatalistic orientation, whereby disease and illness are believed to be natural occurrences, not something to fight [71]. For example, some Americans' strong spiritual and religious convictions can impede participating in clinical trials if they adhere to the belief that healing belongs in the hands of God and that they should trust God's plan [216]. Being aggressive in seeking expensive and time-consuming procedures can be perceived as selfish, drawing attention to oneself and not focusing on the family or extended family system [68,71]. This orientation could impede medical research participation.

Cultural beliefs can also affect an individual's view of specific health practices and treatments. When discussing participation in clinical trials that involve drawing blood, some Native Americans express concern that the blood samples would be saved after the individuals die; consequently, the person's soul would be unable to rest [89]. Similarly, some groups view tissue sampling as a violation of the human body, which is sacred and should remain in its natural state [90]. In Chinese culture, some believe that having blood drawn is a sign of disrespect to one's ancestors [92]. Some Asian cultures also believe that drawing or giving blood depletes the life source or life energy, negatively affecting health and vitality [92].

In 1974, the National Commission for the Protection of Human Subjects was formed. In 1979, the Commission published The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. This report recommended that all institutions receiving federal research funding establish institutional review boards. The Belmont Report laid out three ethical principles to guide researchers to ensure that the rights of research participants are protected: respect for persons, beneficence, and justice.

The principle of respect maintains that all individuals are autonomous and that individuals with limited capacity to make autonomous decisions must be protected [93]. This ethical principle is translated into two practical applications in clinical trials. First, research participants must give informed consent; adequate information about the study must be communicated to participants so they can make an informed decision whether to participate in the study or not. In order to make an informed consent, participants must be able to comprehend the information provided. Researchers and practitioners should keep in mind the following questions:

The term "hard-to-reach populations" has been used to categorize certain groups who are not easily accessed or served due to cultural, economic, and geographic factors. While some groups may be difficult to access, such as those in rural or frontier areas, others just may not have been the subject of outreach on the part of researchers [88]. There are several basic guidelines that might be helpful in recruiting women and racial/ethnic minorities to medical research. The first is having knowledge of the lifestyles of the group being targeted. Experts have emphasized the need for researches to understand the unique cultural and social practices of the group being targeted [88]. For example, when recruiting women to participate in a clinical trial, it may be important to offer evening and weekend hours in order to accommodate childcare needs, household responsibilities, and work schedules.

As noted, clinical trials and health-related research studies frequently take place at medical centers or academic institutions [71]. While these locations may be convenient to the researchers or sponsors, they may not be convenient to participants who are unfamiliar with the area or the local transportation system. The environment may be foreign and could potentially breed institutional distrust [71]. Healthcare professionals can play a vital role in mediating this perceived gap by facilitating access to clinical trials and resources and developing rapport with potential participants so they feel involved in the research process [64]. For example, in a study of Korean immigrants, study sites were located in areas where Korean Americans and immigrants frequented, such as ethnic grocery stores [88].

Word-of-mouth from individuals who are perceived to be trustworthy has been found to be the most effective recruiting method in under-represented groups [100,101]. In a cancer screening study targeted to older Filipino women, personal invitations from people whom the potential participants knew were a crucial factor in decisions to take part in the study [100]. This phenomenon was replicated in recruiting and retaining Hispanic research participants for a longitudinal study [101]. Initially, the researcher mailed flyers and conducted community presentations, but these efforts did not result in enrollment. However, when a community representative approached individuals one-on-one, enrollment increased. Some experts recommend message-mapping to ensure that communication to potential participants are evidence-based, intentional, systematic, and clear, using a variety of communication mechanisms [222]. Scripts are written and analyzed for clarity and comprehension. Key messages, with three to five supporting points, should be clearly communicated.

Creative research partnerships should also be considered. Instead of one-sided research, collaborative projects, with creative or educational results, can be effective. For example, in one such project researchers forged a partnership with an African American sorority to recruit African American women for a genetics study [103]. The goal of this partnership was to educate African American women about the hereditary component of breast cancer and to increase African American enrollment in the national Cancer Genetics Network [103]. Although the partnership yielded very modest enrollment, the authors were confident that the lessons learned could lay the platform to building and improving future partnerships with other sororities. For example, they learned that rapid communication was crucial, as many volunteer organizations have competing interests [103].

Assisting women and racial/ethnic minorities from their stated intention to participate to the actual execution of the decision involves addressing the practicalities and logistics of fitting the participation into day-to-day responsibilities [106]. As discussed, traveling to the research sites on multiple occasions for testing can be a burden, infringing upon research participants' time and finances. Furthermore, childcare is often a logistical barrier to participation, particularly for women. Social workers, nurses, and case managers can advocate for resources to deal with these logistical dilemmas and assist participants to coordinate necessary services, as convenience is key for enhanced research participation [52,64,219]. In some trials, childcare and transportation are provided to help with recruitment and retention of women research participants [134]. In another study of nutritional guidance for low-income mothers, participants were scheduled for follow-up interviews during times when they were already in the medical clinics for scheduled well-baby visits [137].

Compensation for the time spent traveling and engaging in study participation should be carefully considered [106,188]. In one study, a several-phase incentive plan was designed to provide grocery gift cards in stages with gradual increasing amounts [137]. In addition, being culturally sensitive to the form of incentive is also important. In one study conducted in the Khmer community, community informants advised that monetary incentives in the form of checks may not be culturally appropriate because many of the targeted research participants worked primarily for cash [108]. In this case, grocery coupons were identified as more culturally sensitive compensation. At the same time, checks, grocery redemption cards, and any other incentive compensation that requires identification documentation for redemption may not be culturally sensitive, particularly for groups who are concerned about their immigration status [138]. Cash may be optimal, but if the funding agency of the study requires participants' social security numbers for tax purposes, this could be viewed as an impediment for some participants [138].

Informed consent is a vital aspect of the healthcare system and of scientific research. While some immigrants may be reasonably fluent in English for day-to-day activities, they may be less comfortable communicating in English about healthcare issues [95]. Some individuals may sign a consent form without fully understanding the significance due to cultural belief systems about the role of authority figures. For example, a study of Japanese elderly research participants found that 40% had signed the consent form because they simply respected their physicians' authority and deferred to their decision making [83]. Furthermore, they perceived that not signing the form would be disrespectful. Given that loss of respect is a cultural value important to some immigrants, researchers should reiterate to research participants that a signature on the consent form is not binding [94]. In the United States, an individual signs the consent form, signifying he/she understands the information provided to him/her. However, in other cultures, community consent and decision making are advocated [149]. In patriarchal or male-dominated cultures, the male head (e.g., husband) may be the one to give consent for a female research participant [225]. Research that involves Native American Indian tribal groups or indigenous groups, the community leader, elders, grandparents, and/or other relatives provide consent (not the individual) [149].