Introduction

Enrollment and individual subject completion rates are arguably the most demanding [1] phases of a clinical trial. One of the most important factors in a trial's success is potential participants' willingness to enroll. Past studies have identified a wide variety of determinants of this factor including, education [2], [3], age [4], means of communication [5], race [6]–[9], language [10], patient preference for a certain treatment [11], and a multitude of other personal reasons [12]. Although this list might seem comprehensive, these factors cannot be generalized to individuals from different cultures with divergent lifestyles, social environments, religious beliefs, and economic conditions. This is especially problematic because large culturally diverse countries such as India are playing a more significant role in global trials. India is increasingly recognized as a site for health research in part because of it's large population and growing research capabilities [13]. However, to our knowledge no previous studies have consistently addressed the main factors affecting willingness to enroll in clinical trials among Indians, a key determinant in a trial's success.

India's prominence as a suitable location for health research has emerged partly because of its potential for enrolling patients in clinical trials [14], [15]. India has one of the largest enrollment rates in the world, with rates as high as ten times greater than the ones in the United States for selected trials [16], [17]. With a large and heterogenous population, an additional advantage in India is that several diseases have incidence rates similar to other developing and developed countries [18]. However, critics have expressed concerns over the ethical nature of these enrollment rates citing widespread poverty, illiteracy, and lack of understanding regarding their local culture and customs. [19].

Although there is an extensive literature [20]–[22] evaluating the factors promoting and precluding participation in clinical trials among various populations, there are a limited number of studies that focus on understanding the specific attitudes and willingness to participate within the Indian population. Extrapolation of conclusions drawn from other populations to Indian subjects is unreliable, since previous studies have consistently demonstrated important differences across different cultural groups [23]. Examples include cultural differences in trial conditions [24] and financial and social support [25]–[27].

Given the significance of specific cultural factors affecting enrollment and the central role of India in global trials, the objective of our study is to conduct a meta synthesis of qualitative studies that evaluated factors contributing to participation of Indians in clinical trials.

Methods

Results

Search Strategy Results

The initial review of the literature yielded 327 study articles. After reading the abstracts of these articles, we excluded 147 of them because of the following reasons: 1. They were not clinical trials, 2. They had no Indian population, 3. As the studies did not have desired outcomes, 4. Other study articles were removed because they dealt mainly with educational/prevention programs, screening programs, or medical service camps. We then retrieved and evaluated the full text for the remaining 180 articles, leading to the further exclusion of 171 articles because 1. There full texts were not available, 2. They had no Indian population, 3. As the studies did not have desired outcomes, 4. Other study articles were removed because they dealt mainly with educational/prevention programs, screening programs, or medical service camps. The final list comprised seven studies matching our inclusion and exclusion criteria. This flow chart is summarized in Figure 1.

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Figure 1. Flowchart with inclusion and exclusion of articles.

https://doi.org/10.1371/journal.pone.0010730.g001

We retrieved three studies by the same author (Hussain Gambles), two of which were published in year 2004, and the third was published in 2006. Since one of these three studies was a combination of two studies [31], we considered combined study for inclusion in the current meta synthesis and excluded the other two individual studies [32], [33]. Hand search did not yield any studies matching our selection criteria. The final list of seven articles, all using a qualitative research design, is listed under Table S1.

Discussion

Our meta analysis retrieved, selected and reviewed qualitative studies that evaluated the factors influencing participation of Indian subjects in clinical trials. The meta synthesis of factors cited by Indian subjects provides a better picture of their mindset by revealing what favors or hampers their decision to participate in clinical trials. The emerging themes from our study broadly fall under two categories: Factors favoring participation and factors restricting participation. The former includes the themes: personal health benefits, altruism, trust of physicians, source of extra income, detailed knowledge about trials and methods for motivating participants. On the other hand the latter category includes: mistrust on trial organizations, concerns about efficacy and safety of trials, psychological reasons, trial burden, loss of confidentiality, dependency issues and language. Our study also tried to derive the quantitative data in terms of percentage of population for each of the themes. Though these figures may not be precise and accurate they do represent the broad percentages and would certainly needs attention as to which of the theme might need more focus in terms of any rectification that might have to be implemented either to eliminate barriers or to encourage participation.

Our study focused specifically on Indian population for the following reasons: 1. India as a part of the BRIC nations is the current hotspot for the conduct of clinical trials. 2. Its huge and diverse (racially and ethnically) population is considered favorable for clinical trial implementation because it ensures rapid enrollment and enhances the generalizability of results. Additionally racial and ethnic groups have their own unique ways of looking at, interpreting and deciding on clinical trial participation on account of numerous factors such as their beliefs, religion, knowledge about experimental studies [40]. Therefore, it is essential to understand and evaluate factors that influence their decisions to participate in clinical trials.

Indians were highly willing (prevalence = 47%) to participate in clinical trials when they were convinced that there were personal healthcare advantages. The influence of personal benefit on important decisions like participation in a clinical trial is a natural human tendency and has been confirmed in all major ethnic groups [40]. It can take a variety of forms such as access to free medicines and latest treatments [41]–[44], possible chance of cure by the trial intervention [20], possible relief by trial intervention [45] and possible protective benefit through vaccine trials are some of the most common forms. On the other hand, personal benefit does not always spur participation in trials as apparent from factors like 'non availability of alternative treatments' cited in previous studies [25], [31]. It is important to note that although personal health benefit is often thought of as an individual driver of participation, it may often be affected by cultural, socio-economic and healthcare conditions prevailing in a country. For example, populace hailing from low socio economic background and with little access to quality healthcare are attracted by the free treatment and financial incentives provided in clinical trials. In contrast to the factor 'personal health benefit,' 43.36% subjects also believed in altruism which is a selfless wish to benefit peers, society and science. For example, a patient may participate not only because they hope to be cured but also because they want others to be cured. Previous studies have also simultaneously encountered these contrasting factors. [41], [42]. Altruistic motivations for participating in trials are evident when healthy volunteers participate in clinical trials with the aim of benefiting ailing patients around the world. This inclination has been noted in a number of ethnic groups [31], [41], [44], [46]–[48] and among HIV patients who are usually influenced by safety and personal benefit concerns [42], [49]–[51]. Apart from these two factors, the theme – ‘trust in physician’ (7.9%) reflects the fact that patients frequently rely on their doctors advice while deciding to participate in clinical trials. Patients consider their physicians as their health guide and frequently trust them blindly either out of respect, feeling of indebtedness or based on the belief that their physician would never misguide them. As a result, when physicians ask their patients to participate in a clinical study, they are unlikely to refuse. Along similar lines, previous studies mention the role of 1. physician recommendation, communication and encouragement and 2. sharing trial information with family physicians [20], [25], [48], [52]–[55]. Previous studies also confirm that a converse relationship (mistrust on physician) has a significant impact on trial participation [20], [56].

Though personal health benefits and altruism were the major influencing factors, monetary gain also emerged as a significant theme in our study. It has also been documented in other similar studies [57]. In a developing country like India where poverty is rampant, participating in trials that offer monetary incentives is an extra source of income. Even when the trial does not offer any monetary compensation, the free care and treatment serves as a strong attraction for patients who otherwise can not afford the cost of treatment. Given the influence of an incentive, its ability to distort potential participants' judgment towards trial participation is significant [58]. As per the metasynthesis, “detailed knowledge” about the objectives and procedures in the clinical trial enhances trial participation. This is empirically achieved through an informed consent sheet and a verbal explanation to rule out possible misconceptions about the trial. Lack of detailed information can raise concerns [20], and lead to non participation, while hiding any information or furnishing incomplete information would amount to violation of the ethical conduct of the trial. Motivational methods like newspaper, tv ads [43], newsletters, mail shots [1] and audio visual media can further enhance recruitment by increasing awareness, clarifying misconceptions if any as well as educating participants about clinical trials. Although it was predominant across all studies, one study made a contrasting observation: complete or partial disclosure of the consent process (where patients are provided detailed trial information) did not alter the number of subjects consenting to participate [24]. Rather subjects relied on the explanation and answers furnished by the researchers. Factors like treating physician, poverty and illiteracy might have led to this observation. Summing up, factors like personal health benefit, altruism and monetary gains being subjective lie in the personal decision making domain. On the contrary themes like trust in physicians and detailed knowledge suggest that physicians play an important role in recruitment and they should be well trained and knowledgeable about the trial.

While trust in physician favored trial participation for 7.9% of the subjects, mistrust on physicians and researchers was also expressed as a barrier by 26.27% of the subjects. Other factors like lack of faith and fear towards the healthcare system [23], [59], [60], the notion of 'guinea pig treatment' [40] and mistrust in clinical research [23], [48], [60]–[63] have been shown to negatively influence subject participation in clinical trials. It is important to note there can be a different effect on trial participation depending on whether the treating physician, trial recruiters or researchers were involved in recruitment. While trial recruiters may not be trusted as much as physicians, they often have more training and time for recruiting potential trial participants. Differences in the perceptions about trust or mistrust on trial organization, researchers or pharmaceutical industries can be due to multiple ethnic variations, previous experience in trial participation, language and literacy [64]–[65]. Promoting trust and identifying other sources of mistrust in the trial organization are possible solutions that can enhance subject trust [66], [67]. A lack of detailed knowledge, motivation methods and proper communication methods can significantly enhance the mistrust of subjects in trials. It can also contribute to the theme – ‘concerns about safety and efficacy of trials’ where unproven efficacy, side effects and health risks of experimental treatment may deter subjects from participating in clinical trials. Similar findings have been documented in the Chinese population [25], in cancer trials [52] and placebo controlled trials [44]. The metasynthesis also identified 'psychological reasons' that deter subjects from trial participation. Some examples were 1. preconceived notions about various aspects of clinical trial participation such as pain and number of tests that they (subjects) would have to undergo and 2. the social stigma involved. This is more pronounced in the case of HIV vaccine trial participation where participants may 1. fear serious adverse health consequences, 2. fear the possibility of getting infected due to vaccination and 3. fear on being denied health insurance coverage [68]. Apart from the misconceptions and preconceived notions, some subjects also found trial participation to be a burden as it requires extra time and effort. Participation often meant that subjects would be required to make additional visits to the doctor, spend more time traveling and consume additional drugs. When this burden is decreased, Indian subjects are more likely to participate in clinical trials. Other studies have noted that living at a distance from the trial site and having to participate in a trial with multiple follow up visits tend to be burdensome for the subject and acts as a barrier to clinical trial participation. [21].

In addition to the factors listed above, 17.08% of Indian subjects expressed 'privacy and the negative impact of loss of confidentiality' as an important concern. Maintainence of confidentiality in order to ensure integrity and privacy of participant information has been emphasized and acknowledged in previous studies [69]. Additionally, confidentiality issues and breach of confidentiality have been a concern in genetic association studies [26] as well as in cancer clinical trials [21]. On one hand when subjects were concerned about the maintenance of privacy and confidentiality, a sizable number (18.65%) seeked advice and were dependant on relatives, peers and friends while making their decision. In India and other parts of Asia, patients frequently discuss health issues with family and friends which contradicts the American culture, where doctors typically do not even discuss or disclose a patient's health information to their family members [25]. The involvement of family members in decisions about healthcare is a cultural factor that has also been identified in studies of Chinese subjects [25]. In contrast, studies of African Americans have shown that healthcare decisions are highly individualized and autonomous and the involvement of family members can actually inhibit, rather than promote participation in clinical trials [8], [70]–[72]. Conveying the right information in a simple and clear manner as well as in a language that they understand is important for ensuring optimal delivery of clinical trial information to subjects. Indian subjects in our meta synthesis confirmed this fact when they expressed language and miscommunication as potential barriers to trial participation. Language has also been identified as a barrier by Chinese subjects [25], older south asian population in UK [31] as well by other populations [73], [74]. In fact, it has been argued that language barrier can lead to mistrust which can negatively influence trial participation. In order to avoid language barriers, several methods have been introduced such as: translation into the local language and the use of translators to converse with potential participants in their local languages. For example, since the primary language of the consent form is usually English, several translations of the consent form are made as per the local requirements. This does facilitate understanding of the study by literate people, although it remains unclear how much they actually understand. It has also been emphasized that consent forms should be written for lay man and avoid highly technical language. However, in practice this is not always possible and the use of specialized terminologies in the consent form may cause confusion for the subjects.

Because results from qualitative studies are conducted with an aim to reach depth rather than external validity, the combination of results needs to be subsequently verified through studies evaluating external validity such as population-based surveys. Also, since India is a very diverse country with a variety of ethnicities, religious beliefs, and cultural heritages, these results might vary across different groups, more granular investigations being required once more studies are made available. One other limitation of our study is non availability of full texts of twenty two articles which we had to omit without any option with us.

Our meta analysis identified factors facilitating trial participation specifically for Indian subjects. In order to maintain its status as a hub for clinical trials, India needs to take steps to ensure adequate trial participation. Insights into the mindsets of Indian subjects in relation to trial participation can guide investigators and sponsors when they plan trials in the future. Non consideration of these factors during the planning stage may lead to delays in the trial enrolment and subsequent implications on trial completion and costs. There are several other reasons and factors associated with the decision to participate in a trial that have been expressed by other subjects belonging to different ethnic groups from various parts of the world. However, they remain specific to the region, ethnicity, the disease under study like HIV, cancer, type of intervention-invasive/non invasive, type of study design-use of placebo or any other.

Supporting Information

Acknowledgments

We acknowledge the use of following material developed by the ‘Research on Research’ group [77], Duke University Health System: templates for writing introduction and discussion sections of the manuscript [75] and Literature matrix [76] while compiling this manuscript.