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1 From the Center for Human Nutrition, Johns Hopkins Bloomberg School of Public Health, Baltimore.
2 Address reprint requests to B Caballero, Center for Human Nutrition, Johns Hopkins Bloomberg School of Public Health, Room W 2041, 615 North Wolfe Street, Baltimore, MD 21205. E-mail: bcaballe{at}jhsph.edu.
INTRODUCTION
Whereas human experimentation can be traced back several centuries, organized efforts to protect human subjects participating in experiments started only 50 y ago. In 1947, the Nuremberg Code banned forced experiments in humans, setting the basis for the Declaration of Helsinki a few years later. These landmark statements received general support from the international community and led to the universal adoption of the principle of independent, individual informed consent. However, effective protection of human subjects continues to vary widely across countries, and the increasingly multinational nature of research activities has underscored some of these differences, particularly when the collaboration involves a developed country and a less-developed country. This brief commentary outlines some of the ethical issues involved in that collaboration from the perspective of scientists from developed countries doing collaborative research in less-developed countries.
Over the past decades, national and international efforts to provide assistance to less-developed countries have resulted in the increasing involvement of scientists from developed countries in research performed in less-developed countries. International entities such as the World Health Organization and the Food and Agriculture Organization and national agencies such as the US Agency for International Development, the Agency for Technical Cooperation in Germany, the Canadian International Development Agency, and many others have provided continuing opportunities for scientists from developed countries to work on and indeed to specialize in research questions specific to less-developed countries. More recently, the global AIDS epidemic has been another factor that has increased the interest and support for research in less-developed countries by scientists from developed countries. Finally, the dramatic advances in communications and transportation have expanded exponentially the opportunities for scientific exchange between developed and less-developed countries.
The increasing participation of the private sector, particularly the pharmaceutical and food industries, in this scientific interaction is another important development. Corporations from developed countries may promote and fund research in less-developed countries for a variety of reasons. In some cases, they may be responding to regulatory demands for local data; in others it may be simply an opportunity to enhance the corporate image within the local scientific community. There may also be cost advantages to performing some of the research and development work in less-developed countries rather than in developed countries. Large corporations may have an important influence on the prevailing research practices in many less-developed countries, considering their economic power and flexibility.
BASIC PRINCIPLES
In a recent report, the US National Bioethics Advisory Commission (NBAC) noted that there are more than 90 documents from government, nongovernment, and international organizations that provide ethical guidelines for human research (1). It may be difficult to ascertain how much input less-developed countries have had on the elaboration of those documents, but it is likely that they reflect primarily the beliefs and principles prevalent in the developed world. In any case, it seems that there is considerable consensus on at least 7 principles, as enumerated by the NBAC:
For research performed in less-developed countries by scientists from developed countries, another fundamental principle is relevance to the local situation: the study must address a problem of importance for the local population and thus must have the potential to benefit it. Thus, research aimed at developing and testing therapies that will never be available or affordable for populations in less-developed countries may not be ethically appropriate.
Another issue to be considered in the collaboration between developed and less-developed countries is that of service to the community. This is distinct from the potential benefit that research results may eventually have for the community. Instead, it refers to activities by investigators, usually parallel but unrelated to the research plan, aimed at providing a direct and immediate benefit to the community from which volunteers are recruited. These benefits include free immunization, screening for endemic diseases, building basic health care facilities, and assisting in the planning of local or regional health interventions. Note that this is also distinct from benefits to the study participants, who may receive specific compensation or benefits commensurate with their involvement. Many investigators from developed countries working in less-developed countries already offer some form of community service voluntarily by donating their time for health care or by using their research infrastructure to support health care activities. In cases in which the specific health needs of the community require substantial funding, investigators may not be able to fulfill them from their research budget but may be able to assist in formulating a proposal and advocating for its funding. Involvement of community organizations in these activities is obviously crucial.
IMPLEMENTATION OF ETHICAL GUIDELINES IN LESS-DEVELOPED COUNTRIES
Research ethics in less-developed countries are affected by cultural, social, and economic conditions affecting both researchers and the population. Some of the difficulties in implementing the guidelines enumerated by the NBAC are summarized in Table 1. Although it seems clear that some of these difficulties may be primarily related to educational or verbal communication factors, others may be a reflection of more fundamental philosophical differences between developed and less-developed countries. For example, although Western culture, largely centered on individuality, lends itself well to the idea of individual, independent informed consent, this concept may not be as evident for cultures that give preeminence to the group (tribe, clan, or family) or to land or nature and not to the individual. Some of these differences may be misinterpreted as educational limitations and may be compounded by language barriers. The process of obtaining informed consent may be particularly affected, and some special circumstances have been defined by expert committees (Table 2).
View this table:
TABLE 1 . Constraints for the application of ethical principles in less-developed countries (LDCs)
View this table:
TABLE 2 . Two special situations for obtaining informed consent1
Other constraints to implementation concern the investigator. To be a strong and unbiased advocate of the ethical process, an investigator must have a good measure of intellectual independence. In developed countries, the scientific autonomy of the researcher is sustained in part by the fact that a large proportion of the research budget comes from public funds and by their allocation through a peer review system. In contrast, public funding for research is limited and unstable in many less-developed countries, and even full-time researchers in the public sector may depend on additional private funding. This weakens the political standing of scientists in general and may often result in conflicts of interest.
Another factor affecting investigators from less-developed countries may be limited training and expertise in the area of research ethics. As discussed above, limited domestic funding for research generates limited demands for its ethical review. Similarly, an environment in which financial and political corruption may be common, as exists in some less-developed countries, may also jeopardize the building of a strong ethics tradition among young scientists. Nevertheless, a few initiatives and institutions—including the Strategic Initiative to Develop Ethical Review, the Fogarty International Center of the National Institutes of Health, and the World Health Organization—have begun targeting ethics training in less-developed countries.
PLACEBO-CONTROLLED STUDIES
The nature of control treatment in randomized trials in less-developed countries has generated some controversy, because several organizations have questioned the use of placebo in such trials (2). This view is supported by a recent revision of the Declaration of Helsinki (3), which states that a new treatment or technique "should be tested against the best current prophylactic, diagnostic or therapeutic method." This signifies that the use of placebo would be acceptable only when no effective treatment exists. Furthermore, the NBAC has interpreted "standard of care" as a generally recognized therapeutic modality and not as the prevailing form of care available in the country where the research is to be performed. Thus, lack of access to antibiotics does not make "no treatment" the standard of care for a bacterial infection. However, other scientists and organizations, including the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (4), scientists from the US Department of Health and Human Services (5) and the National Institutes of Health (6), and the NBAC itself (1,7) have proposed a less rigid criteria for placebo use. This criterion allows the withholding of a proven treatment as long as it does not pose a "risk of irreversible harm" to participants and that all other ethical requirements are met. In addition, "...any study that would not provide the control group with an established effective treatment should include a justification for using an alternative design.... Ethics review committees must assess the justification provided, including the risk to participants, and the overall ethical acceptability of the research design..." (1). Because this approach hinges on the interpretation of "irreversible harm," in many cases there will be a great deal of uncertainty about whether any harm could result, and if so, what the potential long-term consequences may be.
Most of these considerations apply to nutrition research, with the caveat that the gray area of uncertainty may perhaps be wider. For example, the potential risk posed by temporarily withholding nutrient supplementation to a chronically deficient population depends on many factors, of which nutritional status for the nutrient in question may not be the most important. Thus, it is more difficult to determine the risk of irreversible harm. Similarly, the standard of care for a population living in an area with an endemic vitamin deficiency, for example, may be difficult to define because an adequate vitamin content in the diet is not equivalent to an "effective treatment" of the deficiency. The great need for independent, qualified institutional review boards and safety monitoring committees is again emphasized, because the ultimate decision on potential harm and the cost-benefit ratio would be in their hands.
SOME OPTIONS
Efforts to strengthen the application of ethical principles in research should focus on the underlying conditions that make it difficult to achieve a sustainable ethical climate in less-developed countries. Some of the tasks that should be considered as priorities include 1) training in research ethics as part of the science curriculum at the undergraduate and graduate levels, 2) support for capacity building in research ethics, and 3) community involvement.
Training in research ethics as part of the science curriculum at the undergraduate and graduate levels
Many graduate programs already include ethics courses as a requirement, and programs focusing on international work should address specifically the ethical issues of research in less-developed countries.
Support for capacity building in research ethics
Although the research initiatives of many developed countries in less-developed countries include efforts to build local capacity in areas such as laboratory or data analysis, few such efforts are directed toward building a research ethics infrastructure. Helping to establish independent, well-trained institutional review boards should be as valuable a legacy of collaboration as leaving a well-equipped research laboratory. With adequate resources and training, the approval process can become an integral part of the capacity-building component, essential to the collaboration between developed and less-developed countries.
Success in this effort will require specific funds for research ethics capacity building. In the United States, research institutions are expected to support their institutional review boards from indirect costs, but this is rare in less-developed countries. If the costs of ethical reviews cannot be included in the indirect cost, alternative sources should be available, perhaps from pooled contributors from the private and public international sectors. These funds might be used to defray the cost not only of protocol approval but also of training and sustainment of research ethics activities.
Community involvement
Community involvement is fundamental in 2 areas: in the approval process and in the research enterprise itself. A long-standing principle of the approval process is that consent should be given by an individual, acting on his or her own volition, and not by proxy though an organization or group. However, in the social and cultural context of most less-developed countries, the ability of individuals to provide independent consent may be far more limited than in developed countries. As noted above, some cultures may place a higher value on communal rather than on individual decisions and on the opinion and advice of their leaders. Thus, whereas approval by the community should in no way replace individual consent, it may constitute an additional collective consent and strengthen the protection of individuals from research risks (8).
The second aspect of community participation, involving the community in the development of the research plan and study procedures, is not common practice, but it should be considered routinely. The principles of participatory research are not new and have been primarily implemented in studies aimed at effecting cultural or behavioral changes in the community. Our experience in the Pathways obesity prevention study (9), in which American Indian representatives with full voting rights were included in the scientific steering committee of the study, has been very positive. Participation of members of the community ensures that the research goals remain relevant to the problems of the community, that intervention components are culturally appropriate, and that justifications and adverse events related to study procedures are presented promptly and in the most clear and relevant way. Community involvement also helps bridge the gap between the population’s and the scientists’ expectations and perceptions about the research effort.
RESEARCH ETHICS AND RESEARCH QUALITY
Although sound research ethics certainly do not ensure good research quality, poor ethical practices more often than not may affect the quality of scientific results, perhaps because investigators who are willing to cut corners on ethical procedures may be more apt to do the same with research protocol procedures as well, and also because a lack of ethical considerations in the research plan may result in biased subject selection, poor compliance, and other factors that may complicate the interpretation of data. Furthermore, research results that cannot be ethically defended are unlikely to be embraced by the community they are supposed to benefit.
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