What Makes Clinical Research in Developing Countries Ethical? The Benchmarks of Ethical Research
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PERSPECTIVE
What Makes Clinical Research in Developing Countries
Ethical? The Benchmarks of Ethical Research
Ezekiel J. Emanuel, David Wendler, Jack Killen, and Christine Grady
Department of Clinical Bioethics, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland
(See the editorial commentary by Kuritzkes, on pages 794–5.)
In recent years, there has been substantial research-ethics committees in assessing may be less well established, less supported
debate about the ethics of research in de- how well the enumerated ethical principles financially, and less effective in developing
veloping countries [1–5]. In general, the have been fulfilled in particular cases. countries. Guidelines for ethical research
controversies have centered on 3 issues: should minimize the risk of exploitation
first, the standard of care that should be under these circumstances [28].
MINIMIZING EXPLOITATION
used in research in developing countries [6–
13]; second, the “reasonable availability” of An ethical framework for multinational BEYOND PRINCIPLES
interventions that are proven to be useful research should minimize the possibilities TO BENCHMARKS
during the course of research trials [14–19]; of exploitation [25]. A exploits B when B
and third, the quality of informed consent. receives an unfair level of benefits or unfair Previously, we delineated a framework
The persistence of controversies on such burden of risks as a result of interacting for ethical research that included 7 prin-
issues reflects, in part, the fact that existing with A [25, 26]. In developed countries, ciples [25]. However, an ethical frame-
ethical guidelines can be interpreted in mul- the risk of exploitation of subjects or host work for research in developing countries
tiple ways, are sometimes contradictory, or communities is minimized, because so- must provide more than broad principles.
rely on unstated, yet controversial, ethical ciety funds research to improve health, As Macklin notes, underlying the apparent
principles [6, 7, 9–11, 13, 20–24]. researchers and research institutions are “harmony [on principles] we confront un-
To provide unified and consistent ethical part of the larger community, and there answered questions, as well as stark dis-
guidance, we apply a previously proposed is an infrastructure, even if imperfect, that agreements” [29, page 19]. Accordingly,
ethical framework for clinical research translates research results into health-care we add an eighth principle—collaborative
within developed countries to developing practices for the benefit of the larger com- partnership—and elaborate these princi-
countries, explicating a previously implicit munity. Research in developing countries ples through 31 benchmarks that system-
requirement for collaboration [25]. More creates a greater risk of exploitation: in- atically specify practical measures to de-
importantly, we propose specific and prac- dividuals or communities in developing termine the extent to which the research
countries assume the risks of research, but satisfies the principles (table 1) [30, 31].
tical benchmarks to guide researchers and
most of the benefits may accrue to people This framework of principles and
in developed countries [27]. Although pov- benchmarks is complex, because ethical
Received 1 July 2003; accepted 2 September 2003;
electronically published 17 February 2004. erty, limited health-care services, illiteracy, evaluation of clinical research is complex.
The views expressed are those of the authors, reflecting their cultural and linguistic differences, and lim- A single ethical principle is rarely abso-
own personal research, and do not necessarily reflect the views
or policies of the National Institutes of Health, the Public Health ited understanding of the nature of scien- lute; most situations implicate multiple
Service, or the Department of Health and Human Services of tific research neither cause nor are necessary principles [32–34]. Consequently, the var-
the US Government.
Reprints or correspondence: Dr. Ezekiel J. Emanuel, Dept. of
for exploitation, they increase the possibility ious principles and benchmarks will com-
Clinical Bioethics, National Institutes of Health, Bldg. 10, Rm. of such exploitation [16–20, 26–28]. Fur- pete and must be balanced against each
1C118, Bethesda, MD 20892-1156 (eemanuel@nih.gov).
thermore, the regulatory infrastructures other—a process that inevitably requires
The Journal of Infectious Diseases 2004;189:930–7
This article is in the public domain, and no copyright is claimed.
and independent oversight processes that judgment [30, 32–34].
0022-1899/2004/18905-0022 might minimize the risk of exploitation Importantly, this framework functions
930 • JID 2004:189 (1 March) • PERSPECTIVETable 1. Ethical principles and benchmarks for multinational clinical research.
Principles Benchmarks
Collaborative partnership Develop partnerships with researchers, makers of health policies, and the community.
Involve partners in sharing responsibilities for determining the importance of health problem,
assessing the value of research, planning, conducting, and overseeing research, and
integrating research into the health-care system.
Respect the community’s values, culture, traditions, and social practices.
Develop the capacity for researchers, makers of health policies, and the community to
become full and equal partners in the research enterprise.
Ensure that recruited participants and communities receive benefits from the conduct and
results of research.
Share fairly financial and other rewards of the research.
Social value Specify the beneficiaries of the research—who.
Assess the importance of the health problems being investigated and the prospective value of
the research for each of the beneficiaries—what.
Enhance the value of the research for each of the beneficiaries through dissemination of
knowledge, product development, long-term research collaboration, and/or health system
improvements.
Prevent supplanting the extant health system infrastructure and services.
Scientific validity Ensure that the scientific design of the research realizes social value for the primary
beneficiaries of the research.
Ensure that the scientific design realizes the scientific objectives while guaranteeing research
participants the health-care interventions to which they are entitled.
Ensure that the research study is feasible within the social, political, and cultural context or
with sustainable improvements in the local health-care and physical infrastructure.
Fair selection of study population Select the study population to ensure scientific validity of the research.
Select the study population to minimize the risks of the research and enhance other principles,
especially collaborative partnership and social value.
Identify and protect vulnerable populations.
Favorable risk-benefit ratio Assess the potential risks and benefits of the research to the study population in the context
of its health risks.
Assess the risk-benefit ratio by comparing the net risks of the research project with the
potential benefits derived from collaborative partnership, social value, and respect for study
populations.
Independent review Ensure public accountability through reviews mandated by laws and regulations.
Ensure public accountability through transparency and reviews by other international and
nongovernmental bodies, as appropriate.
Ensure independence and competence of the reviews.
Informed consent Involve the community in establishing recruitment procedures and incentives.
Disclose information in culturally and linguistically appropriate formats.
Implement supplementary community and familial consent procedures where culturally
appropriate.
Obtain consent in culturally and linguistically appropriate formats.
Ensure the freedom to refuse or withdraw.
Respect for recruited participants Develop and implement procedures to protect the confidentiality of recruited and enrolled
and study communities participants.
Ensure that participants know they can withdraw without penalty.
Provide enrolled participants with information that arises in the course of the research study.
Monitor and develop interventions for medical conditions, including research-related injuries,
for enrolled participants at least as good as existing local norms.
Inform participants and the study community of the results of the research.within general ethical values, such as hon- mean uncritical acceptance of practices that mation they generate informs additional
esty, that are relevant to scientific integrity might be oppressive or coercive. research that cumulatively could change
and avoidance of fraud [30, 31]. In ad- Fourth, a true collaborative partnership health care. Priorities may change while a
dition, these principles and benchmarks aspires to minimize disparities between re- study is being conducted, and the cooper-
must be specified before there can be any searchers and sponsors from developed ation of diverse groups is often needed to
enforcement mechanism. We cannot de- countries and the host community, at least make changes on the basis of research re-
termine how to enforce until we deter- disparities related to the research project. sults. Consequently, determinations of so-
mine what to enforce. This could occur through development of cial value are always uncertain and prob-
health-care research resources and invest- abilistic, entailing judgments about the
ment in the health-care sector, such as as- usefulness of a sequence of research [37].
COLLABORATIVE sistance with training of researchers and Even in wealthy countries with well-es-
PARTNERSHIP health-care workers, development and im- tablished research and health-care infra-
plementation of standard operating pro- structures, research results are imperfectly
A collaborative partnership between re- cedures for both clinical research and incorporated into clinical practice. These
searchers and sponsors in developed coun- ethics review, and the establishment of a problems are more complex in developing
tries and researchers, policy makers, and system for independent ethical review of countries, where health-care infrastruc-
communities in developing countries helps research proposals. tures and funding are less well supported
to minimize the possibility of exploitation Fifth, the community in which the re- and developed. Consequently, the social
by ensuring that a developing country de- search is being conducted should receive value of research for the host community
termines for itself whether the research is fair benefits from the conduct and/or must be explicitly specified and enhanced.
acceptable and responsive to the commu- results of the research [28]. Such bene- Four benchmarks ensure social value.
nity’s health problems [28]. Moreover, with- fits might include employment and train- First, it should be determined who will
out the engagement of researchers and host ing for community members to augment benefit from the research. It is important
communities in the developing country, a health-care services for the entire com- to delineate the prospective beneficiaries
study is unlikely to have any lasting im- munity [28]. Sixth, collaborative partner- of the research study, specifying whether
pact, and, without the investment of ship requires a fair distribution of the tan-
they include the local community from
makers of health policies, the research gible and intangible rewards of research
which research participants will be en-
results are unlikely to influence policy mak- among the partners. Very little can gen-
rolled, the host country, or people outside
ing and the allocation of scarce health-care erate more resentment, mistrust, and a
resources. A collaborative partnership also the host country.
sense of exploitation than unfair distri-
demonstrates awareness of and respect for Second, the potential value of the re-
bution of the benefits of collaboration.
cultural differences [35]. search for each of the prospective bene-
This may require agreements on sharing
What constitutes a collaborative part- ficiaries should be outlined. Each potential
intellectual property rights, royalties, and
nership? Six benchmarks seem to be es- beneficiary may rank the health problem’s
other sources of financial profit, as well as
sential (table 1). First, it requires part- importance differently. For example, be-
appropriate authorship and other credit
ners—representation of parties in the cause malaria is a substantially greater
for contributions to the research.
developing country. Second, it requires health problem for certain developing
collaboration—sharing responsibility for countries than for developed countries,
assessing the importance of the health SOCIAL VALUE improvements in interventions for cere-
problem and the value of the research to bral malaria may be of substantial value
the community, for planning and con- It is widely recognized that ethical clinical to people in developing countries, whereas
ducting the study, disseminating the re- research must have social value, through research on prophylactic medications for
sults, and ensuring that they are used for generation of knowledge that can lead to malaria will be more valuable for tourists
health improvements. improvements in health; without social from developed countries, and a malaria
Third, a collaborative partnership re- value, research exposes participants to vaccine may be of substantial value to
quires mutual respect. This entails recog- risks for no good reason and wastes re- everyone.
nition of and respect for the host com- sources [25, 36]. However, the process of Third, it is important to develop mech-
munity’s distinctive values, culture, and translating research results into health anisms to enhance the social value of
social practices, which should be incorpo- improvements is complex, incremental, research. Through collaborative partner-
rated into the design and implementation and haphazard [37]. Typically, early stud- ships, strategies should be devised to dis-
of the study. Importantly, respect does not ies are valuable only because the infor- seminate results in appropriate languages
932 • JID 2004:189 (1 March) • PERSPECTIVEand formats to key stakeholders, including value and that the data are generalizable to own interests were targeted for high-risk
the local community, health policy mak- the host community [38]. research, whereas promising research was
ers, health-care providers, and interna- Second, the study design must realize preferentially offered to more-privileged in-
tional health-care organizations. This may the research objectives while neither de- dividuals [25]. A challenge for research in
require not only presentations at scientific nying health-care services that participants developing countries is fair selection of
conferences and publications in journals are otherwise entitled to nor requiring target villages, tribes, or city neighbor-
but also novel forms of dissemination, services that are not feasible to deliver in hoods from which individual partici-
such as presentations at community gath- the context of the country’s health-care pants will be recruited. First, at a mini-
erings [35]. Social value can also be en- system [10–12, 37, 39]. Determining en- mum, the study population should be
hanced when research is integrated into a titlement to medical services in studies selected to ensure valid science [25]. Sci-
long-term collaborative strategy, so that is challenging, because entitlements differ entific reasons for choosing a particular
the research project forms part of a more among countries [40, 41]. Even in wealthy community might be high prevalence, in-
comprehensive research and health-care de- countries, participants are not entitled to cidence, or transmission rates of an in-
livery strategy to address significant health every available or effective medical service, fection, special drug-resistance patterns,
problems. because justice necessitates establishing or particular combinations of diseases.
Fourth, the conduct of the research priorities [41, 42]. For instance, it is widely Scientific considerations alone will usu-
should not undermine the community’s accepted that cardiac research should not ally under-determine which community
existing health-care services. Beyond this be required to include a coronary care or individuals are selected. Second, min-
minimal requirement, supplementing the unit, because participants would not be imizing risk is essential. For instance, in
existing system through the provision of entitled to this service under a just distri- selecting a target population for an HIV
additional resources, equipment, medi- bution of resources [9, 10, 12, 43]. Con- vaccine study, a community that does not
cations, or training appropriate to the re- versely, in a study evaluating interven- discriminate against HIV-infected persons
search can enhance value. tions to reduce mortality from cerebral and that can provide treatment for op-
malaria conducted in rural settings where portunistic infections is preferable. Third,
travel to hospitals is impracticable, pro- the community should be one in which a
SCIENTIFIC VALIDITY vision of bed nets may be part of a valid
collaborative partnership can be devel-
design, even if participants may not oth-
oped and in which social value can be
Science and ethics do not conflict; valid erwise have them [44]. If the study’s ob-
realized. Consequently, it is preferable to
science is an ethical requirement [25, 37]. jective is deemed to be socially valuable,
Unless research generates reliable and val- select communities that have established
especially to the enrolled participants’
id data that can be interpreted and used by or that are capable of establishing a sys-
community, demands for providing more-
the specified beneficiaries of the research, tem for identifying legitimate represen-
comprehensive interventions beyond
it will have no social value, and participants tatives and that will share responsibility
those to which participants are entitled or
will be exposed to risks for no benefits [25, for planning and conducting the study
beyond those that are feasible and sus-
37]. In addition to the standard require- and ensuring that results are implemented
tainable may be unethical if they under-
ments for valid research, such as adequate through health system improvements or
mine the scientific objectives or make the
sample size and unbiased measurement additional research.
results irrelevant to the community.
of outcome, multinational research should Fourth, factors such as familial coercion,
Third, the study must be designed to be
fulfill 3 benchmarks. social marginalization, political powerless-
feasible, given the social, political, and cul-
First, a research study must be designed ness, and economic deprivation must be
tural environment in which it is being con-
so that the results will be useful in the con- considered, to determine the vulnerabil-
ducted [12]. Ensuring feasibility might re-
text of the health problem in the developing ity of communities or groups within the
quire sustainable improvements to the
country [29]. Interventions should be se- community [45]. For instance, if health
health-care infrastructure, such as training
lected to ensure that the design is useful in of personnel, construction of additional fa- policy makers suggest a particular tribe,
identifying effective or appropriate inter- cilities, or provision of an affordable drug. the researchers should determine that the
ventions; implementing socially, culturally, group has been selected for good reasons,
and economically appropriate changes in such as a high incidence of disease, not
the health-care system; or providing a re- FAIR SUBJECT SELECTION because of social subjugation. If a scientif-
liable foundation for conducting subse- ically appropriate population is identified
quent research. Interventions are selected Historically, populations that were poor, as vulnerable, specific safeguards to pro-
to ensure that the design will realize social uneducated, or powerless to defend their tect the population should be imple-
PERSPECTIVE • JID 2004:189 (1 March) • 933mented, such as ensuring confidentiality INDEPENDENT REVIEW INFORMED CONSENT
and the freedom of potential research
participants to decline joining the study. To minimize concerns with regard to Individual informed consent has been
researchers’ conflicts of interest and to en- recognized as a principle of ethical clinical
sure public accountability, independent research for more than a century [52, 53].
FAVORABLE RISK-BENEFIT ethical review of all clinical research pro- Differences in language, social traditions,
RATIO tocols is necessary [25]. In addition to in- and practices make the process of in-
stitutional review board or research ethics formed consent in developing countries
All clinical research should offer partic- committee review, other regulatory ap- complex and suggest 5 benchmarks for
ipants a favorable risk-benefit ratio, or, if provals may be necessary for some types evaluating informed consent. First, the lo-
potential risks outweigh benefits to par- of research. cal community should help to establish
ticipants, the social value must justify these In multinational research, there is a spe- recruitment procedures and incentives
risks [25, 46]. Only benefits that accrue to cial need for transparency [28]. Transpar- for participants that are consistent with
participants from the interventions nec- ency enhances accountability by assuring cultural, political, and social practices. In
essary to achieve the research objectives or the public that the research is not exploit- some communities, compensation for par-
those deriving from the knowledge to be ative. Whether supplementary reviews by ticipation in research may be expected,
gained by the research should be used to local community councils, nongovern- whereas, in others, it may be considered
justify risks to participants [25, 47]. mental organizations involved with the offensive. The appropriate form and level
Two benchmarks unique to developing community, international health organi- of compensation depends on the local eco-
countries apply. First, the risk-benefit ratio zations, or ministries of health are appro- nomic and social context. Although con-
for individuals must be favorable in the priate depends on the nature of the col- cerns about inducement are frequently
laborative partnership. If such reviews are raised, high potential social value and a fa-
context in which they live. The underlying
in disagreement, it is important to clarify vorable risk-benefit ratio dispel these con-
risks of a particular disease can vary be-
the nature of the disagreement. In many cerns [54, 55]. Indeed, focusing on undue
cause of differences in incidence, drug re-
cases, disagreement reflects different ways inducement could reduce compensation
sistance, genetic susceptibility, or social or
of balancing various principles and bench- and some of the benefits for subjects and
environmental factors. When participants
marks or the appropriateness of differ- host communities. Paradoxically, balancing
confront a higher risk of disease, greater
ent ways of fulfilling them—that is, not fair compensation and undue inducement
potential benefits may justify greater risks
whether the ethical requirements are met, may result in less compensation for mem-
in research design [48]. Similarly, the risk-
but how they are met [49]. Conflicts may bers of impoverished communities.
benefit ratio for a particular study may be
also arise because of different guidelines Second, disclosure of information should
favorable in communities where the so-
or regulatory requirements, which them- be sensitive to the local context. It should
cial value of the research is high but may
selves may not have good ethical justi- be done using the local language, cul-
be unfavorable where potential value is
fication or may be insensitive to partic- turally appropriate idioms, and analogies
lower [25, 51].
ular cultural or social circumstances in that the prospective participants can un-
Second, the risk-benefit ratio for the developing countries [14, 50]. Only rarely derstand. This obviously entails a need
community should also be favorable. To are there fundamental disagreements about for collaborative partnership.
make this assessment, the risks and po- whether ethical principles and benchmarks Third, “spheres of consent,” ranging
tential benefits for the community, such are met. Unfortunately, there is no widely from village elders to leaders of the ex-
as increased antibiotic resistance or col- accepted procedure for adjudicating such tended family or heads of households, may
lection of sensitive information, must be conflicts. In practice, the requirements spec- be required before researchers can invite
specified. Benefits might include the in- ified by the review board in the sponsor’s individual participation [35]. With few ex-
formation obtained from the study, ser- country are often determinative, which con- ceptions, such as emergency research, it is
vices provided to participants, or improve- travenes the principle of collaborative part- unacceptable to supplant individual con-
ments in the health of the community. nership [51]. sent of adults by family or community
Furthermore, to be consistent with collab- Finally, review must be independent and consent [35, 56]. The family or commu-
orative partnership, the community should competent [25]. Review bodies may have nity only gives permission to invite indi-
determine whether the risks are acceptable conflicts because of relationships with the viduals to participate.
in light of the benefits to be derived from researchers or pressures from those pro- Fourth, researchers should use consent
the conduct and results of the research [28, moting the research. Supplementary train- procedures that are acceptable within the
35]. This decision should be confirmed by ing in ethics for review bodies may be local community, while ensuring that an
people familiar with other studies. necessary. independent observer could verify volun-
934 • JID 2004:189 (1 March) • PERSPECTIVEtary participation by the individuals. For taken to provide care under these circum- subjects to continue receiving treatment,
instance, US regulations requiring a writ- stances, and what compensation there will nor does it obligate investigators to pro-
ten signature are culturally insensitive in be for research-related injuries. vide continued treatment; to do so would
many cases [53, 57]. Appropriate alterna- One problematic area with regard to re- be to confuse research with clinical care.
tive procedures for documenting informed search in developing countries is the re- Finally, researchers should develop ex-
consent might include tape recordings or sponsibility of researchers for participants’ plicit strategies to inform participants and
written documentation of verbal consent. health problems that are unrelated to the host communities of the results of the re-
Fifth, special attention must be given to condition being studied. In developed coun- search [35]. Having participated in the re-
ensure that individuals are aware of their tries, researchers commonly refer partici- search and assumed risks, the participants
right to and actually are free to refuse to pants to the existing health-care system, and host community have a right to know
participate or withdraw from research [58]. notwithstanding deficiencies in insurance what was found and its implications for
To obviate familial or community coercion coverage and provision of care. In devel- public health and health-care policies.
or retribution, steps such as prorating com- oping countries, geography and scarce re-
pensation and other benefits related to the sources may make treatment for diseases
research should be taken. APPLYING THE PRINCIPLES
unrelated to the research unavailable.
AND BENCHMARKS
Currently, there are no clearly defined
parameters to guide researchers in these Together, these principles and bench-
RESPECT FOR RECRUITED situations. Clinical research is not clinical marks constitute a systematic framework
PARTICIPANTS AND STUDY care [59]. Researchers are not obligated that specifies core practical considerations
COMMUNITIES to remedy the deficits of a country’s necessary to ethically justify research in de-
health-care system or to ensure that all veloping countries. It can probably be ap-
The ethical conduct of clinical research
participants’ medical ailments are given plied to all research, regardless of setting or
does not end when informed consent is
appropriate care. Conversely, researchers sponsorship. This is a first attempt to spec-
obtained [25]. Researchers have ongoing
cannot ignore concomitant health prob- ify a comprehensive list of benchmarks. Ap-
obligations to participants, former par-
lems of their participants. At a minimum, plication to actual research studies may sug-
ticipants, and the host community. First,
researchers should ensure access to local gest refinement or the need for additional
an essential obligation is to develop and
health services or alternatives of equal benchmarks [30, 41].
implement procedures to maintain the
confidentiality of information collected. quality and meet national care guidelines Importantly, differences in health, eco-
Such procedures might include interview- when specified, such as for childhood im- nomic, social, and cultural aspects of a
ing participants outside, where they can- munizations. In some cases, researchers research setting will affect application of
not be overheard, or permitting partici- may provide interventions for unrelated the framework—specifically, how much
pants to not receive HIV test results. In health conditions that are superior to “weight or priority [is] given to different
addition, it is important to alert partici- those locally available, especially if they benchmarks” [30, page 740]. Depending
pants that, despite researchers’ best ef- are relatively easy and economical to pro- on a study’s objectives and context, par-
forts, there is no guarantee of absolute vide under local conditions. It is impor- ticular benchmarks will be given greater
confidentiality. tant that plans for provision of care of weight than others. Such balancing is in-
Second, respect for participants in- unrelated health conditions be developed evitable whenever there are multiple eth-
cludes informing them of their right to as part of the collaborative partnership ical considerations [32–34]. This does not
withdraw [58]. Third, participants and between researchers, the host commu- mean that the principles and benchmarks
the community should be informed when nity, and makers of health policies. are relativistic; rather, it means that the ad-
new information, such as a newly discov- What medical services should be pro- aptation and balancing of universal prin-
ered risk, arises during the course of re- vided to research participants after com- ciples are relative to risk, resources, social
search. Fourth, exacerbations of the dis- pletion of the study? Some have argued practices, and similar circumstances.
ease being studied, adverse events from that interventions proven to be beneficial Moral arguments take place in
research interventions, and health prob- to participants during a study should be context, and they therefore depend
lems that arise unrelated to the disease made available to them at the completion at least implicitly on matters of
being studied may require care. Research- of the study [13, 60]. Continued access to fact, estimates of risk, suppositions
experimental medications is one way in about feasibility, and beliefs about
ers should specify a strategy for monitor-
human nature and social pro-
ing the progress of the disease, adverse which subjects may benefit from research cesses.… Even those who rely on
events from the intervention, any unto- participation [28]. However, participation what they regard as universal
ward changes in health, what steps will be in research does not necessarily entitle moral principles do not presume
PERSPECTIVE • JID 2004:189 (1 March) • 935that their practical conclusions are benchmarks, yet disagreeing about how ventions to reduce perinatal transmission of
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