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1
Department of Public Health,
University of Brası́lia, Brazil
Post-Graduation Program of
Bioethics, Brası́lia, Brazil
2
UNESCO Chair of Bioethics,
Post-Graduation Program of
Bioethics, University of Brası́lia,
Brası́lia, Brazil 3Section for
Medical Ethics, Department of
General Practice and Community
Medicine, University of Oslo,
Oslo, Norway 4Centre for
International Health, University
of Bergen, Bergen, Norway
5
UNESCO Regional Programme
of Bioethics and Ethics of
Science, SHS Sector, UNESCO
Regional Office for Science,
Montevideo, Uruguay
Correspondence to
Professor Cláudio Lorenzo,
Núcleo de Estudos e Pesquisas
em Bioética, NEPeB, Campus
Universitário Darcy Ribeiro,
Faculdade de Ciências da Saúde,
Brası́lia, DF e Brasil Caixa Postal
04451, CEP 70.904-970, Brazil;
claudiolorenzo@unb.br
Received 17 June 2009
Revised 3 November 2009
Accepted 5 November 2009
Published Online First
13 January 2010
J Med Ethics 2010;36:111e115. doi:10.1136/jme.2009.031708
Hidden risks associated with clinical trials
in developing countries
Cláudio Lorenzo,1 Volnei Garrafa,2 Jan Helge Solbakk,3,4 Susana Vidal5
ABSTRACT
The academic literature in research ethics has been
marked in the past decade by a much broader focus on
the need for the protection of developing communities
subjected to international clinical trials. Because of the
proximity of the revision of the Declaration of Helsinki,
completed in October 2008, most papers have
addressed the issue of a double standard of care
following the use of placebo. However, other no less
important issues, such as interactions between the
lifestyles structures of low-income communities and the
efficiency of risk-minimising procedures also deserve
attention. The purpose of this paper is to discuss forms
of uncertainty involved in clinical trials in poor and low-
income countries that are not addressed by conventional
methods of risk assessment. Furthermore, the increase
in size of risks that are identified by conventional
assessment methods will be addressed. Besides, the
difficulty in properly applying risk-minimising procedures
will be discussed. Finally, this paper proposes the
involvement of research ethics committees in the risk
evaluation process and the establishment of national
ethics evaluation systems.
There is growing ethical concern related to the ever-
increasing involvement of populations of poor and
low-income countries in clinical research origi-
nating from affluent countries, especially industry-
sponsored clinical research. These concerns are
mainly related to the medical and social relevance
of these studies; the quality of informed consent
procedures and the freedom of choice of individ-
uals; the possibility of a double standard of care
related to the use of placebo in clinical trials and
post-trial availability of interventions that has
proved to be useful.1e12
However, other no less important issues, such as
the interactions between the lifestyles structures of
low-income communities and the efficiency of risk-
minimising procedures also deserve attention.
In the literature on clinical research ethics and in
international ethical guidelines reference is made to
four main risk-minimisation procedures to protect
individuals undergoing clinical trials:
< Appropriate selection of research subjects;
< Clinical monitoring of participants, with the
possibility of emergency interventions;
< Effective communication networks connecting
participants and the research group;
< Sound capacity for social control of the study by
the community in which it is conducted.
The purpose of this paper is to view the appli-
cation of these procedures within the lifestyles
structures of low-income communities and discuss
Research ethics
additional forms of risks involved in clinical trials in
this context, that is, forms of risk that are not
addressed by conventional methods and procedures
of risk assessment. Besides, the increase in the size
of risks that are identified by conventional assess-
ment procedures will be discussed. Finally, the
difficulty in properly applying standard procedures
of risk minimising will be addressed.
THE CONTEXT OF TRANSNATIONAL CLINICAL
TRIALS
It is important to recognise that the internation-
alisation of clinical research, which is mainly
caused by private pharmaceutical and device
companies, can bring benefits to poor and low-
income countries13 if there is a state capable of
imposing regulations that put local individual and
public interests above private and public interests in
affluent countries. Internationalisation could also
contribute to the alleviation of priority problems,
both in health care and in health-related research as
well as to the growth of research capacities of host
countries. This could partly be achieved through the
provision of equipment for healthcare and research
institutions and through the facilitation of the
transfer of know-how in research to health profes-
sionals in host countries. In general, however, there
are too few political and institutional conditions in
place in many host countries to deal effectively with
the regulation of research activities. Besides, the
conduct of transnational clinical trials has so far
contributed marginally to the improvement of the
health situation of the populations in these coun-
tries.
The discrepancy between the increasing partici-
pation of poor and low-income countries in trans-
national clinical trials and the investments in drug
trials targeting diseases that affect mainly patients
in the sponsoring countries is evident in several
recent studies. For example, Chirac and Torreele14
found that out of 1556 new drugs developed
worldwide between 1975 and 2004, only 10 drugs
were directed at diseases that were predominantly
prevalent in low-income countries. When malaria
and tuberculosis are included, this number of new
drugs rises to 21. This indicates that during the past
30 years, that is, the period in which the involve-
ment of poor and low-income countries in multi-
centre clinical trials has been the greatest, only
slightly more than 1% of pharmacological innova-
tions were directed at diseases that predominantly
affect the populations in these countries. In a recent
study Glickman et al.15 found that approximately
one-third of the trials they reviewed (157 of 509)
were conducted outside the USA, and that many
of these trials were being conducted in poor and
111
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Research ethics

low-income countries. Besides, they found that among the
ongoing phase 3 clinical trials sponsored by US-based companies,
none were trials of diseases such as tuberculosis that dispropor-
tionately affect the populations of these countries. Instead they
found a variety of trials for conditions such as allergic rhinitis and
overactive bladder! Another factor that could increase this
discrepancy is the imposition of TRIPS-Plus provisions to poor
and low-income countries, something that could significantly
reduce the capacity of these countries to provide adequate public
access to medicines and jeopardise the development of autono-
mous biomedical industry production.16
In view of this situation of international clinical research, the
bioethics debate has been marked in the past decade by a much
broader focus on the need for protection of developing
communities.8e13 Besides, in view of the proximity of the last
revision of the Declaration of Helsinki (October 2008), many
papers during recent years have addressed the controversial issue of
a double standard of care following from the use of placebo in
clinical trials.17e29 It gives reason for deep concern, however, to
observe that despite the current situation of international clinical
research, the permission to use placebo in clinical trials conducted
in poor and low-income countries was finally included in the
Declaration, thus favouring the interests of science and the phar-
maceutical market over the ethical imperatives of protecting the
safety and wellbeing of individual humans undergoing research.
RISK-MINIMISATION PROCEDURES APPLIED IN CLINICAL
TRIALS IN DEVELOPING COUNTRIES
Risk can be defined as the set of all the possibilities that an
undesirable event has of provoking harm. It consists of two
components, the magnitude of the harm and the frequency of its
occurrence.30 In the literature there is consensus that assessment
of the possible risks involved in a trial is of fundamental impor-
tance in conducting the ethical assessment of clinical research.
However, in clinical researchdand in particular in international
clinical researchdrisk is neither the only form of uncertainty at
play, nor an absolute factor; it is relative to the expected benefits
of the trial31 as well as to the risks involved in routine daily
activities or in standard therapies, as defined by the concept of
minimal risk.32 33
A review of the main international declarations and guidelines in
research ethics shows that the risk concept in use is a concept
related to expected direct benefits, establishing the famous
riskebenefit ratio. The same concept is at play in the last version of
the Declaration of Helsinki in 2008.34 However, during recent years
other forms of benefit, so-called ‘inclusion benefits’, which are not
directly related to the research intervention in question, such as free
goods or services provided as an enrolment incentive, improvement
of health facilities (hospitals or health centres), capacity building
(knowledge or tools) and the provision of medicines for other
health problems, have also been included.35 These benefits are
clearly among those that international research can bring to poor
and low-income countries, but they are addressed to society as
a whole and to local scientific development. Such benefits can
therefore not be considered as a compensation for biological
hazards to which individuals are exposed during a study, as this
would be at odds with the most fundamental ethical imperative in
research ethics, that is, the primacy of the human being over the
interests of science or society.35 36
From these considerations about benefits not directly related
to the risks involved in a clinical trial, we shall turn attention to
the notion of ‘social vulnerability’, an idea that has come to play
a more important role in discussions on risk.
Social vulnerability focuses on the lifestyle structure of indi-
viduals and communities and relates to factors such as: lack of
income, information, knowledge and technology; lack of access
to political power and other types of social representation;
a highly restricted network of social contacts; diversity of beliefs
and customs with respect to the majority and extreme age and
physical deficiencies.37 38
As stated in the introduction to this paper there are four main
risk-minimisation procedures involved in protecting individuals
undergoing clinical trials: appropriate selection of research
subjects; clinical monitoring of participants; effective commu-
nication networks and adequate capacity of social control. The
interactions of these procedures with the lifestyles structures of
populations and communities in poor and low-income countries
can generate the production of forms of risks not previously
envisaged, increase the severity of estimated risks and reduce
efficiency with regard to the application of risk-minimising
procedures.
APPROPRIATE SELECTION OF RESEARCH SUBJECTS
Suitable subject selection is dependent on the quality of the
procedure of selection and on the quality of the information
provided by the researchers as well as by the targeted subjects. It
is probably easier to assess the quality of the selection procedure
than of the information, as the selection procedure is based on
an appropriate definition of the criteria for inclusion and
exclusion of subjects in relation to the stated objectives of the
study and of a good clinical examination. However, the appli-
cation of these criteria also depends on the quality of informa-
tion provided by the subjects recruited about previous and
present health problems. In turn, the quality of this information
may be heavily influenced by educational level, cultural
conceptions of the healthedisease process as well as by the kind
of access to health services that the subjects under recruitment
have been enjoying.
A low level of schooling in the population in tandem with the
absence of a public healthcare system, both a frequent situation
in poor and low-income countries, implies the possibility that
subjects recruited are prone to be underinformed about their
own health and disease status, resulting in the omission of
information about clinical situations in the past or present that
would, if known, have excluded them from being enrolled in the
study under consideration. A history of hepatitis, for example,
which would have automatically excluded subjects from a clin-
ical trial with a drug of potentially hepatotoxic nature, could be
unknown to the subject or not possess a disease-related meaning
in their culture, generating omissions of relevant information
that would expose the subject to a risk described in the protocol,
but hidden to the research group. Consequently, clinical trials in
populations with a low level of education and low accessibility
to healthcare services may require additional scrutiny to confirm
whether inclusion in the study under consideration is warranted
or not. When there is no possibility to confirm or deny by
interviews the conditions investigated, the additional risks that
would be involved in a situation like this can only be justified if
the benefits of research are directly related to the group
recruited. In this case, the clinical monitoring needs to be even
more rigorous.
CLINICAL MONITORING OF PARTICIPANTS, WITH THE
POSSIBILITY OF EMERGENCY INTERVENTIONS
The control of the magnitude of a given harm depends on three
factors: the technical quality of the health professionals

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Research ethics

responsible for monitoring data on side effects and provision of cation of risk-minimising procedures. From these observations it
care; the quality of equipment available in the healthcare units becomes evident that when recruiting research subjects from
that provide the monitoring and the rapidity of transfer to an such communities, more information about housing conditions,
emergency service of a participant who has been affected by access to communication and transport services etc, will be
a serious undesirable event. needed to ensure adequate protection from harm.
In general, in poor and low-income countries, public health
institutions have serious difficulties in providing adequate health
SOUND CAPACITY FOR SOCIAL CONTROL OF THE STUDY BY
care, something that creates obstacles with regard to the recruit-
THE COMMUNITY IN WHICH IT IS CONDUCTED
ment, training and support of specialised healthcare professionals.
Social control of the research is based on ethical provisions, such
In rural areas in sub-Saharan Africa and Latin America, life condi-
as the formulation of normative documents, activities of ethics
tions are even worse than in the cities. A good access to health care
review committees and the power of civil society to perform
exists only for populations belonging to the highest social strata,
critical monitoring of research activities. The quality and effec-
and from which participation in clinical trials is rare.39
tiveness of the application of ethical provisions depend as much
Therefore, if a pharmaceutical company that is conducting
on political actions as on how developed social institutions are.
a clinical trial in a city of a low-income country does not guar-
The more unstable the democratic institutions of a society, the
antee quality clinical interventions for research participants but
more difficult will be the application of these provisions.
leaves such care to the local healthcare institution, there is
South America and Africa, two continents with a large
a considerable risk that in situations of severe adverse events
number of poor and low-income countries, are good examples to
such as, for example, gastrointestinal bleeding or cardiac
illustrate the relationship between democratic stability, organi-
arrhythmia, efficient emergency intervention would not be
sation of civil society and the efficiency of systems of ethical
a realistic option. So, even if the frequency of an event such as
review of clinical trials. In South America, democracy was
this can be calculated through the use of quantitative methods
restored to all countries during the last two decades, after the
of risk assessment applicable to all countries, there remain
wave of military dictatorships that dominated the whole
serious uncertainties about the magnitude of its consequences
continent during the cold war period. However, most countries
for poor and low-income countries.
are characterised by a heavy dependency on foreign capital and
The situations of housing can worsen this problem when the
suffer from the existence of fragile democratic institutions and
enrolled subjects are not hospitalised but take the drug in their
poorly organised civil societies. The case of Africa is graver still
domiciles. In most large cities in the developing world, the rural
both socioeconomically and politically. Besides, chronic food
exodus and the disordered demographic growth brought large
shortages, climatic conditions that are sometimes extremely
populations to urban centres. These populations were thus
hostile, and the spread of epidemics such as AIDS, numerous
ghettoised on the slopes and valleys surrounding the cities where
ethnic conflicts, tribal clashes and civil wars make state
access to such urban facilities as pure water, transport and
restructuring difficult, and contribute to these societies seeing
communication is very difficult.40 Therefore, if we take the
basic human rights suspended. This reality is reflected directly in
previous example of a severe side effect occurring under such
the difficulty of many of these countries to develop sustainable
conditions the transfer to an emergency service could be
ethical review systems of research.
substantially hampered and with possibly detrimental conse-
Several difficulties have been reported with regard to the
quences for the injured research participant. This reality is not
application of ethical norms of research in these countries, such
usually considered in conventional risk considerations and
as inadequate training of the members of ethics review
calculations, and therefore remains a hidden risk not only to the
committees, lack of logistical support to carry out the work,
subjects themselves but also to the researchers and members of
inability to supervise ongoing research studies, lack of recogni-
ethics review committees.
tion of the legitimacy of committees by the research commu-
nity, and the absence of accreditation systems to supervise the
quality of the formation and functioning of the committees,
EFFECTIVE COMMUNICATION NETWORKS CONNECTING
and, in some instances, the complete absence of an institution-
PARTICIPANTS AND THE RESEARCH GROUP
alised system of ethical review. A questionnaire about the ethical
In a clinical trial, a good communication network is of prime
review processes in the developing world submitted by Hydder
importance for the minimisation of both the magnitude and the
et al41 to 670 health researchers that work in several regions of the
frequency of possible harms. Rapid telephone contact in case of
planet shows that 44% of the studies were not reviewed by ethics
a serious undesirable event facilitates transfer to another health
committees in the host countries or by institutions of the health
unit and reduces the magnitude of the event. Such contact also
ministries in these countries.
ensures that other participants can interrupt their use of the test
The extreme weakness of social monitoring of research studies
drug immediately, thus also reducing its frequency. When the
has two main practical implications in relation to risk. First,
living conditions of the greater portion of the population in poor
studies can be carried out without either the society at large or the
and low-income countries are taken into account, it becomes
individuals involved being in a position to review the riskebenefit
clear that the provision of an effective communication network
assessment. Second, in the event of an extremely grave and
is difficult and sometimes even impossible. In many areas,
undesirable event, such as death or disability, dissemination of
whether on the outskirts of cities or in rural districts, access to
the information, both to the scientific community and to other
the phone service and transport service is rare or simply non-
key stakeholders of society, is made much more difficult precisely
existent. A subject using a test drug who lives under such
by the socioeconomic circumstances of the individuals harmed.
conditions is thus subject to risks much higher than those
suggested by standard clinical trial methodologies of calculation.
Obstacles related to the establishment of an efficient DISCUSSION AND CONCLUSIONS
communication network may thus increase the severity of This paper aimed to demonstrate that contextual aspects related
estimated risks, and reduce efficiency with regard to the appli- to lifestyles structures of populations in poor and low-income

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Research ethics
countries generate risks not foreseen in the standard protocol
of clinical trials and increase the frequency and magnitude of
predictable risks. To this is added that the application of
standardised mechanisms to minimise these risks are easily
hampered. It was also emphasised that there is a need for
a revision of the methods of risk evaluation for clinical trials as
well as a need for increasing the ability of risk minimisation
procedures to cope adequately with local contexts. Finally, the
need for strengthening the ethical review system in poor and
low-income countries has also been emphasised.
A well-structured ethical review system also makes
a pronounced difference with regard to the protection of
vulnerable populations.42 It may fill the gaps in international
regulations by providing local guidelines and by interpreting the
international rules in view of existing interactions between the
local context and research activities.43 If adequate ethics review
systems exist, the quality of the protection offered will be
substantially higher. However, the strategy for the development
of these systems must consider the different stages of economic
and political development of the peripheral countries.
In some countries, such as Argentina, Brazil, Chile, Mexico or
South Africa, greater efforts could be made to improve the
national systems. The creation of specific taxes on studies that
are not directly related to the health priorities of the country
may be a means of guaranteeing financial resources for these
reforms. Otherwise, the degree of poverty, the fragility of
democratic institutions and economic difficulties of other low-
income countries, especially in Africa, point towards the need
for the creation of an international mechanism for the control
and monitoring of research involving human subjects, which
would have the power to sanction corporations and research
groups that failed to respect established universal standards.
In recent years, the World Health Organization has initiated
some interesting initiatives with respect to guaranteeing ethical
standards in international research, including the development of
an international system for the registration of clinical trials44 and
the creation of ethics review committees to operate in Africa.45
Nevertheless, the evidence of mismanagement in the national
systems of ethical review and the various cases of exploitation of
vulnerable populations already documented in the literature has
confirmed the need to amplify these initiatives.46
Besides, the Universal Declaration on Bioethics and Human
Rights proposes the establishment of independent, multidisci-
plinary and pluralistic national bioethics committees (article 19)
as a main way for deliberation and advice with regard to such
issues. We believe that this proposal will become increasingly
important for member states of the United Nations to pursue,
because institutional review boards and committees often work
in isolation. For this reason, they themselves will probably not
be able to provide the kind of change needed, that is, a change
towards a stronger protection of the rights of research subjects,
including the right to protection from unwarranted risks.
Therefore, we also propose that the national bioethics
committees and institutional review boards and committees
should be strengthened through a national system of ethics
evaluation of ongoing trials. In a system like that, the national
committees of bioethics, besides acting as an advisory body of
the state in decision-making on matters related to bioethics,
could also work as a body that approves and oversees the
activities of institutional review boards and committees. In
Brazil, for example, there is the National Commission on
Research Ethics, linked to the National Health Council, which is
responsible for the accreditation and supervision of all institu-
tional research committees, public or private and nationwide.
114
This is another reason why the establishment of national
ethical review systems becomes so important to deal with
assessing context-related forms of vulnerability, including social
vulnerability, and cope with the pressures of economic ratio-
nality that at present seem to dominate the so-called global-
isation of clinical research, in particular the conduct of clinical
trials for new drugs in the third world.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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J Med Ethics 2010;36:111e115. doi:10.1136/jme.2009.031708 115

 Downloaded from http://jme.bmj.com/ on April 23, 2015 - Published by group.bmj.com

Hidden risks associated with clinical trials in

developing countries
Cláudio Lorenzo, Volnei Garrafa, Jan Helge Solbakk and Susana Vidal

J Med Ethics 2010 36: 111-115

doi: 10.1136/jme.2009.031708

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