What Makes Clinical Research in Developing Countries Ethical? The Benchmarks of Ethical Research

In recent years, there has been substantial debate about the ethics of research in developing countries [1–5]. In general, the controversies have centered on 3 issues: first, the standard of care that should be used in research in developing countries[6–13]; second, the “reasonable availability” of interventions that are proven to be useful during the course of research trials [14–19]; and third, the quality of informed consent. The persistence of controversies on such issues reflects, in part, the fact that existing ethical guidelines can be interpreted in multiple ways, are sometimes contradictory, or rely on unstated, yet controversial, ethical principles [6, 7, 9–11, 13, 20–24]. To provide unified and consistent ethical guidance, we apply a previously proposed ethical framework for clinical research within developed countries to developing countries, explicating a previously implicit requirement for collaboration [25]. More importantly, we propose specific and practical benchmarks to guide researchers and research-ethics committees in assessing how well the enumerated ethical principles have been fulfilled in particular cases. An ethical framework for multinational research should minimize the possibilities of exploitation [25]. A exploits B when B receives an unfair level of benefits or unfair burden of risks as a result of interacting with A [25, 26]. In developed countries, the risk of exploitation of subjects or host communities is minimized, because society funds research to improve health, researchers and research institutions are part of the larger community, and there is an infrastructure, even if imperfect, that translates research results into health-care practices for the benefit of the larger community. Research in developing countries creates a greater risk of exploitation: individuals or communities in developing countries assume the risks of research, but most of the benefits may accrue to people in developed countries [27]. Although poverty, limited health-care services, illiteracy, cultural and linguistic differences, and limited understanding of the nature of scientific research neither cause nor are necessary for exploitation, they increase the possibility of such exploitation [16–20, 26–28]. Furthermore, the regulatory infrastructures and independent oversight processes that might minimize the risk of exploitation may be less well established, less supported financially, and less effective in developing countries. Guidelines for ethical research should minimize the risk of exploitation under these circumstances [28]. Previously, we delineated a framework for ethical research that included 7 principles [25]. However, an ethical framework for research in developing countries must provide more than broad principles. As Macklin notes, underlying the apparent “harmony [on principles] we confront unanswered questions, as well as stark disagreements” [29, page 19]. Accordingly, we add an eighth principle—collaborative partnership—and elaborate these principles through 31 benchmarks that systematically specify practical measures to determine the extent to which the research satisfies the principles (table 1) [30, 31]. This framework of principles and benchmarks is complex, because ethical evaluation of clinical research is complex. A single ethical principle is rarely absolute; most situations implicate multiple principles [32–34]. Consequently, the various principles and benchmarks will compete and must be balanced against each other—a process that inevitably requires judgment [30, 32–34]. Importantly, this framework functions within general ethical values, such as honesty, that are relevant to scientific integrity and avoidance of fraud [30, 31]. In addition, these principles and benchmarks must be specified before there can be any enforcement mechanism. We cannot determine how to enforce until we determine what to enforce. A collaborative partnership between researchers and sponsors in developed countries and researchers, policy makers, and communities in developing countries helps to minimize the possibility of exploitation by ensuring that a developing country determines for itself whether the research is acceptable and responsive to the community's health problems [28]. Moreover,without the engagement of researchers and host communities in the developing country, a study is unlikely to have any lasting impact, and, without the investment of makers of health policies, the research results are unlikely to influence policy making and the allocation of scarce health-care resources. A collaborative partnership also demonstrates awareness of and respect for cultural differences [35]. What constitutes a collaborative partnership? Six benchmarks seem to be essential (table 1). First, it requires partners— representation of parties in the developing country. Second, it requires collaboration—sharing responsibility for assessing the importance of the health problem and the value of the research to the community, for planning and conducting the study, disseminating the results, and ensuring that they are used for health improvements. Third, a collaborative partnership requires mutual respect. This entails recognition of and respect for the host community's distinctive values, culture, and social practices, which should be incorporated into the design and implementation of the study. Importantly, respect does not mean uncritical acceptance of practices that might be oppressive or coercive. Fourth, a true collaborative partnership aspires to minimize disparities between researchers and sponsors from developed countries and the host community, at least disparities related to the research project. This could occur through development of health-care research resources and investment in the health-care sector, such as assistance with training of researchers and health-care workers, development and implementation of standard operating procedures for both clinical research and ethics review, and the establishment of a system for independent ethical review of research proposals. Fifth, the community in which the research is being conducted should receive fair benefits from the conduct and/or results of the research [28]. Such benefits might include employment and training for community members to augment health-care services for the entire community [28]. Sixth, collaborative partnership requires a fair distribution of the tangible and intangible rewards of research among the partners. Very little can generate more resentment, mistrust, and a sense of exploitation than unfair distribution of the benefits of collaboration. This may require agreements on sharing intellectual property rights, royalties, and other sources of financial profit, as well as appropriate authorship and other credit for contributions to the research. It is widely recognized that ethical clinical research must have social value, through generation of knowledge that can lead to improvements in health; without social value, research exposes participants to risks for no good reason and wastes resources [25, 36]. However, the process of translating research results into health improvements is complex, incremental, and haphazard [37]. Typically, early studies are valuable only because the information they generate informs additional research that cumulatively could change health care. Priorities may change while a study is being conducted, and the cooperation of diverse groups is often needed to make changes on the basis of research results. Consequently, determinations of social value are always uncertain and probabilistic, entailing judgments about the usefulness of a sequence of research [37]. Even in wealthy countries with well-established research and health-care infrastructures, research results are imperfectly incorporated into clinical practice. These problems are more complex in developing countries, where health-care infrastructures and funding are less well supported and developed. Consequently, the social value of research for the host community must be explicitly specified and enhanced. Four benchmarks ensure social value. First, it should be determined who will benefit from the research. It is important to delineate the prospective beneficiaries of the research study, specifying whether they include the local community from which research participants will be enrolled, the host country, or people outside the host country. Second, the potential value of the research for each of the prospective beneficiaries should be outlined. Each potential beneficiary may rank the health problem's importance differently. For example, because malaria is a substantially greater health problem for certain developing countries than for developed countries, improvements in interventions for cerebral malaria may be of substantial value to people in developing countries, whereas research on prophylactic medications for malaria will be more valuable for tourists from developed countries, and a malaria vaccine may be of substantial value to everyone. Third, it is important to develop mechanisms to enhance the social value of research. Through collaborative partnerships, strategies should be devised to disseminate results in appropriate languages and formats to key stakeholders, including the local community, health policy makers, health-care providers, and international health-care organizations. This may require not only presentations at scientific conferences and publications in journals but also novel forms of dissemination, such as presentations at community gatherings [35]. Social value can also be enhanced when research is integrated into a long-term collaborative strategy, so that the research project forms part of a more comprehensive research and health-care delivery strategy to address significant health problems. Fourth, the conduct of the research should not undermine the community's existing health-care services. Beyond this minimal requirement, supplementing the existing system through the provision of additional resources, equipment, medications, or training appropriate to the research can enhance value. Science and ethics do not conflict; valid science is an ethical requirement [25, 37]. Unless research generates reliable and valid data that can be interpreted and used by the specified beneficiaries of the research, it will have no social value, and participants will be exposed to risks for no benefits [25, 37]. In addition to the standard requirements for valid research, such as adequate sample size and unbiased measurement of outcome, multinational research should fulfill 3 benchmarks. First, a research study must be designed so that the results will be useful in the context of the health problem in the developing country [29]. Interventions should be selected to ensure that the design is useful in identifying effective or appropriate interventions; implementing socially, culturally, and economically appropriate changes in the health-care system; or providing a reliable foundation for conducting subsequent research. Interventions are selected to ensure that the design will realize social value and that the data are generalizable to the host community [38]. Second, the study design must realize the research objectives while neither denying health-care services that participants are otherwise entitled to nor requiring services that are not feasible to deliver in the context of the country's health-care system [10–12, 37, 39]. Determining entitlement to medical services in studies is challenging, because entitlements differ among countries [40, 41]. Even in wealthy countries, participants are not entitled to every available or effective medical service, because justice necessitates establishing priorities [41, 42]. For instance, it is widely accepted that cardiac research should not be required to include a coronary care unit, because participants would not be entitled to this service under a just distribution of resources [9, 10, 12, 43]. Conversely, in a study evaluating interventions to reduce mortality from cerebral malaria conducted in rural settings where travel to hospitals is impracticable, provision of bed nets may be part of a valid design, even if participants may not otherwise have them [44]. If the study's objective is deemed to be socially valuable, especially to the enrolled participants' community, demands for providingmorecomprehensive interventions beyond those to which participants are entitled or beyond those that are feasible and sustainable may be unethical if they undermine the scientific objectives or make the results irrelevant to the community. Third, the study must be designed to be feasible, given the social, political, and cultural environment in which it is being conducted [12]. Ensuring feasibility might require sustainable improvements to the health-care infrastructure, such as training of personnel, construction of additional facilities, or provision of an affordable drug. Historically, populations that were poor, uneducated, or powerless to defend their own interests were targeted for high-risk research, whereas promising research was preferentially offered to more-privileged individuals [25]. A challenge for research in developing countries is fair selection of target villages, tribes, or city neighborhoods from which individual participants will be recruited. First, at a minimum, the study population should be selected to ensure valid science [25]. Scientific reasons for choosing a particular community might be high prevalence, incidence, or transmission rates of an infection, special drug-resistance patterns, or particular combinations of diseases. Scientific considerations alone will usually under-determine which community or individuals are selected. Second, minimizing risk is essential. For instance, in selecting a target population for an HIV vaccine study, a community that does not discriminate against HIV-infected persons and that can provide treatment for opportunistic infections is preferable. Third, the community should be one in which a collaborative partnership can be developed and in which social value can be realized. Consequently, it is preferable to select communities that have established or that are capable of establishing a system for identifying legitimate representatives and that will share responsibility for planning and conducting the study and ensuring that results are implemented through health system improvements or additional research. Fourth, factors such as familial coercion, social marginalization, political powerlessness, and economic deprivation must be considered, to determine the vulnerability of communities or groups within the community [45]. For instance, if health policy makers suggest a particular tribe, the researchers should determine that the group has been selected for good reasons, such as a high incidence of disease, not because of social subjugation. If a scientifically appropriate population is identified as vulnerable, specific safeguards to protect the population should be implemented, such as ensuring confidentiality and the freedom of potential research participants to decline joining the study. All clinical research should offer participants a favorable risk-benefit ratio, or, if potential risks outweigh benefits to participants, the social value must justify these risks [25, 46]. Only benefits that accrue to participants from the interventions necessary to achieve the research objectives or those deriving from the knowledge to be gained by the research should be used to justify risks to participants [25, 47]. Two benchmarks unique to developing countries apply. First, the risk-benefit ratio for individuals must be favorable in the context in which they live. The underlying risks of a particular disease can vary because of differences in incidence, drug resistance, genetic susceptibility, or social or environmental factors. When participants confront a higher risk of disease, greater potential benefits may justify greater risks in research design [48]. Similarly, the riskbenefit ratio for a particular study may be favorable in communities where the social value of the research is high but may be unfavorable where potential value is lower [25, 51]. Second, the risk-benefit ratio for the community should also be favorable. To make this assessment, the risks and potential benefits for the community, such as increased antibiotic resistance or collection of sensitive information, must be might include the information from the study, services to participants, or improvements in the health of the community. 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