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

 
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) • PERSPECTIVE
Table 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) • PERSPECTIVE
and 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) • 933
mented, 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) • PERSPECTIVE
tary 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) • 935
that their practical conclusions are       benchmarks, yet disagreeing about how                      ventions to reduce perinatal transmission of
   independent of reliable facts and                                                                     the human immunodeficiency virus in devel-
                                              to balance them in a particular case,                      oping countries. N Engl J Med 1997; 337:
   plausible assumptions about par-
                                              highlights the intricacies of ethical judg-                853–5.
   ticular societies. The arguments
                                              ments entailing multiple considerations               7.   Angell M. The ethics of clinical research in the
   begin from where we are, and ap-
                                                                                                         Third World. N Engl J Med 1997; 337:847–9.
   peal to those with whom we now             [61]. Disagreement on the balancing of
                                                                                                    8.   Varmus H, Satcher D. Ethical complexities of
   live. This is why moral relativism         the various benchmarks does not nec-                       conducting research in developing countries.
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   practical as it is in theoretical                                                                9.   Levine RJ. The “best proven therapeutic
                                              the other unethical. Rather, it may reflect
   ethics. [61, page 14–15]                                                                              method” standard in clinical trials in tech-
                                              different but legitimate ways of resolving                 nologically developing countries. IRB 1998;
                                              competing ethical claims. In fact, this                    20:5–9.
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OBJECTIONS CONSIDERED                         ments and elucidate the different under-
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   The first objection to consider is that    ensure that research is conducted ethi-              12.   Bloom BR. The highest attainable standard:
this framework is overwhelming, erecting      cally, a thoughtful process of balancing                   ethical issues in AIDS vaccines. Science 1998;
barriers to research in developing coun-                                                                 279:186–8.
                                              ethical considerations can be as impor-
                                                                                                   13.   World Medical Association. The Declaration of
tries. However, it does not add ethical re-   tant as any particular judgment.                           Helsinki. Available at: http://www.wma.net/e/
quirements; rather, it provides an explicit                                                              policy17-c_e.html. Accessed 31 January 2003.
and systematic delineation of steps already                                                        14.   Council for International Organizations of
being taken by conscientious researchers      Acknowledgments                                            Medical Sciences (CIOMS). International eth-
                                                                                                         ical guidelines for biomedical research involv-
in developing countries.                                                                                 ing human subjects [guidelines 8 and 15]. Ge-
                                                 We thank Harold Varmus, for urging us
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                                              to terminate an earlier misguided attempt
principles and benchmarks are obvious and                                                          15.   Cleaton-Jones PE. An ethical dilemma: avail-
                                              to define ethical principles for multina-                  ability of anti-retroviral therapy after clinical
do not add to existing guidance. Indeed,
                                              tional research and for asking us to think                 trials with HIV infected patients are ended.
the principles are distilled and made co-                                                                BMJ 1997; 314:887–8.
                                              harder; Anthony Fauci, for encouraging us
herent from widely accepted guidance, in-                                                          16.   Wilmshurst P. Scientific imperialism: if they
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laration of Helsinki [13], the Belmont                                                                   research. BMJ 1997; 314:840–1.
                                              ject; Dan Brock, Frank Miller, and Torrey
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[58]. The benchmarks provide more-spe-                                                                   WK. Research in developing countries: taking
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                                              in Seattle (February 2002) and partici-
common reference for all those planning,                                                                 maternal-fetal HIV transmission prevention
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                                              Bioethics Initiative in Cape Town (Feb-                    560–2.
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