Commentary
Ethical issues for collaborative research in developing countries1,2
Benjamin Caballero
INTRODUCTION
Whereas human experimentation can be traced back several
centuries, organized efforts to protect human subjects participat-
ing 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 com-
munity and led to the universal adoption of the principle of inde-
pendent, individual informed consent. However, effective protec-
tion 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 col-
laboration 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 pro-
vide assistance to less-developed countries have resulted in the
increasing involvement of scientists from developed countries in
research performed in less-developed countries. International enti-
ties such as the World Health Organization and the Food and Agri-
culture Organization and national agencies such as the US Agency
for International Development, the Agency for Technical Cooper-
ation 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 coun-
tries. 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 transpor-
tation 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 interac-
tion is another important development. Corporations from devel-
oped 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 cor-
porations may have an important influence on the prevailing
research practices in many less-developed countries, considering
their economic power and flexibility.
Am J Clin Nutr 2002;76:717–20. Printed in USA. © 2002 American Society for Clinical Nutrition
BASIC PRINCIPLES
In a recent report, the US National Bioethics Advisory Com-
mission (NBAC) noted that there are more than 90 documents
from government, nongovernment, and international organiza-
tions 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:
1) The research plan must receive prior review by an independent
ethics review committee.
2) Efforts must be made to minimize the risk to research participants.
3) The research must involve a reasonable risk-benefit ratio.
4) Adequate plans for the care and compensation of participants
for injuries directly related to the research must be presented.
5) Individual informed consent must be obtained from all participants.
6) All participants must receive equal consideration and care.
7) There must be an equitable distribution of the burden and the
benefits of the research.
For research performed in less-developed countries by scien-
tists 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
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@jhsph.edu.
Received December 17, 2001.
Accepted for publication March 21, 2002.
717
718 COMMENTARY
TABLE 1
Constraints for the application of ethical principles in less-developed countries (LDCs)
Ethical guideline
1) Prior review of research plan by an ethics review committee
2) Minimization of risk to research participants
3) Reasonable risk-benefit ratio
4) Adequate plans for the care and compensation of participants
for injuries directly related to the research
5) Individual informed consent from all participants
6) Equal regard for all participants
7) Equitable distribution of the burden and benefits of the research
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 substan-
tial 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 organi-
zations 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 fac-
tors, others may be a reflection of more fundamental philosoph-
ical differences between developed and less-developed countries.
For example, although Western culture, largely centered on indi-
viduality, lends itself well to the idea of individual, independent
informed consent, this concept may not be as evident for cul-
tures that give preeminence to the group (tribe, clan, or family)
or to land or nature and not to the individual. Some of these dif-
ferences 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 com-
mittees (Table 2).
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 independ-
ence. 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 allo-
cation through a peer review system. In contrast, public funding
for research is limited and unstable in many less-developed coun-
tries, and even full-time researchers in the public sector may
depend on additional private funding. This weakens the political
Constraint to application in LDCs
Lack of experienced, independent institutional review boards
Population already living under high-risk health conditions
Assessment of risk-benefit ratio may be biased by prevalent conditions
Participants may not be aware they are entitled to compensation and may not report
adverse events or injuries
Low literacy and other cultural constraints may prevent truly independent consent
Cultural or political restrictions to participation of women or members of certain
social groups
Incentives may draw participants disproportionately from poorest segments of the
population
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. Simi-
larly, 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 sev-
eral organizations have questioned the use of placebo in such tri-
als (2). This view is supported by a recent revision of the
Declaration of Helsinki (3), which states that a new treatment or
TABLE 2
Two special situations for obtaining informed consent1
Collective consent
In some settings, it may be appropriate to obtain group or community
approval for individuals’ participation in a study. This usually means
that permission must be obtained from the local authorities prior to
approaching individuals in the population. It should not be construed as
a substitute for individual consent, which must still be obtained from
each participant upon enrollment in the study.
Consent by women
Some cultures may require that the husband give permission for his
wife’s participation in a research study. This would be acceptable under
the following conditions:
1) It would be impossible to perform the study without obtaining
husbands’ permission.
2) Failure to conduct the research would deprive women of its
potential benefit to their health care.
3) Measures to protect the woman’s autonomy to consent to
research are undertaken to the greatest extent possible.
4) In no case may a competent adult woman be enrolled in a study
solely upon the consent of her husband. Her individual consent is
always required.
1
From a statement by the National Bioethics Advisory Commission (1).
 COMMENTARY
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 pre-
vailing 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. How-
ever, other scientists and organizations, including the International
Conference on Harmonization of Technical Requirements for Reg-
istration 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 with-
holding of a proven treatment as long as it does not pose a “risk of
irreversible harm” to participants and that all other ethical require-
ments 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, includ-
ing 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 nutri-
ent supplementation to a chronically deficient population depends
on many factors, of which nutritional status for the nutrient in ques-
tion 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 defi-
ciency, for example, may be difficult to define because an adequate
vitamin content in the diet is not equivalent to an “effective treat-
ment” 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 dif-
ficult 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 curricu-
lum at the undergraduate and graduate levels, 2) support for capac-
ity 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
719
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 train-
ing, the approval process can become an integral part of the capac-
ity-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 indi-
rect costs, but this is rare in less-developed countries. If the costs
of ethical reviews cannot be included in the indirect cost, alterna-
tive sources should be available, perhaps from pooled contribu-
tors 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-stand-
ing 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 lim-
ited 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 indi-
vidual 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 pro-
cedures, is not common practice, but it should be considered rou-
tinely. 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 Path-
ways obesity prevention study (9), in which American Indian rep-
resentatives with full voting rights were included in the scientific
steering committee of the study, has been very positive. Participa-
tion 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 scien-
tists’ 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 investiga-
tors 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 com-
pliance, 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.
720 COMMENTARY
REFERENCES
1. National Bioethics Advisory Commission. Ethical and policy issues in inter-
national research: clinical trials in developing countries. 2001. Internet: http:
//bioethics.georgetown.edu/nbac/pubs.html (accessed 10 June 2002).
2. Angell M. The ethics of clinical research in the Third World. N Engl
J Med 1977;337:847–8.
3. World Medical Association. Declaration of Helsinki: ethical princi-
ples for medical research involving human subjects. September 1989.
Internet: http://ohsr.od.nih.gov/helsinki.php3 (accessed 16 June 2002).
4. International Conference on Harmonization of Technical Require-
ments for Registration of Pharmaceuticals for Human Use (ICH):
ICH guideline for good clinical practice. Geneva: ICH, 1996.
5. Koski G, Nightingale SL. Research involving human subjects in
developing countries. N Engl J Med 2001;345:136–8.
6. Emanuel EJ, Miller FG. The ethics of placebo-controlled trials—a
middle ground. N Engl J Med 2001;345:915–8.
7. Shapiro HT, Meslin EM. Ethical issues in the design and conduct of
clinical trials in developing countries. N Engl J Med 2001;345:
139–41.
8. Strauss RP, Sengupta S, Quinn SC, et al. The role of community advi-
sory boards: involving communities in the informed consent process.
Am J Public Health 2001;91:1938–43.
9. Davis CE, Hunsberger S, Murray DM, et al. Design and statistical
analysis for the Pathways study. Am J Clin Nutr 1999;69:760–3.