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.
- clinical trials
- drugs and drug industry
- ethics committees
- history of health ethics
- poor and low-income countries
- research ethics
- risk assessment
- social control of human experimentation
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- clinical trials
- drugs and drug industry
- ethics committees
- history of health ethics
- poor and low-income countries
- research ethics
- risk assessment
- social control of human experimentation
There is growing ethical concern related to the ever-increasing involvement of populations of poor and low-income countries in clinical research originating 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 individuals; 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.1–12
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 application of these procedures within the lifestyles structures of low-income communities and discuss 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 assessment 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 internationalisation 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 professionals 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 countries.
The discrepancy between the increasing participation of poor and low-income countries in transnational 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 involvement of poor and low-income countries in multicentre clinical trials has been the greatest, only slightly more than 1% of pharmacological innovations 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 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 disproportionately 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 autonomous 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.8–13 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.17–29 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 pharmaceutical 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 importance in conducting the ethical assessment of clinical research. However, in clinical research—and in particular in international clinical research—risk 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 risk–benefit 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 individuals 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 communication 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 application of these criteria also depends on the quality of information 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 health–disease 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 clinical 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 responsible for monitoring data on side effects and provision of care; the quality of equipment available in the healthcare units that provide the monitoring and the rapidity of transfer to an emergency service of a participant who has been affected by a serious undesirable event.
In general, in poor and low-income countries, public health institutions have serious difficulties in providing adequate health care, something that creates obstacles with regard to the recruitment, training and support of specialised healthcare professionals. In rural areas in sub-Saharan Africa and Latin America, life conditions are even worse than in the cities. A good access to health care exists only for populations belonging to the highest social strata, and from which participation in clinical trials is rare.39
Therefore, if a pharmaceutical company that is conducting a clinical trial in a city of a low-income country does not guarantee quality clinical interventions for research participants but leaves such care to the local healthcare institution, there is a considerable risk that in situations of severe adverse events such as, for example, gastrointestinal bleeding or cardiac arrhythmia, efficient emergency intervention would not be a realistic option. So, even if the frequency of an event such as this can be calculated through the use of quantitative methods of risk assessment applicable to all countries, there remain serious uncertainties about the magnitude of its consequences for poor and low-income countries.
The situations of housing can worsen this problem when the enrolled subjects are not hospitalised but take the drug in their domiciles. In most large cities in the developing world, the rural exodus and the disordered demographic growth brought large populations to urban centres. These populations were thus ghettoised on the slopes and valleys surrounding the cities where access to such urban facilities as pure water, transport and communication is very difficult.40 Therefore, if we take the previous example of a severe side effect occurring under such conditions the transfer to an emergency service could be substantially hampered and with possibly detrimental consequences for the injured research participant. This reality is not usually considered in conventional risk considerations and calculations, and therefore remains a hidden risk not only to the subjects themselves but also to the researchers and members of ethics review committees.
Effective communication networks connecting participants and the research group
In a clinical trial, a good communication network is of prime importance for the minimisation of both the magnitude and the frequency of possible harms. Rapid telephone contact in case of a serious undesirable event facilitates transfer to another health unit and reduces the magnitude of the event. Such contact also ensures that other participants can interrupt their use of the test drug immediately, thus also reducing its frequency. When the living conditions of the greater portion of the population in poor and low-income countries are taken into account, it becomes clear that the provision of an effective communication network is difficult and sometimes even impossible. In many areas, whether on the outskirts of cities or in rural districts, access to the phone service and transport service is rare or simply non-existent. A subject using a test drug who lives under such 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 communication network may thus increase the severity of estimated risks, and reduce efficiency with regard to the application of risk-minimising procedures. From these observations it becomes evident that when recruiting research subjects from such communities, more information about housing conditions, access to communication and transport services etc, will be needed to ensure adequate protection from harm.
Sound capacity for social control of the study by the community in which it is conducted
Social control of the research is based on ethical provisions, such as the formulation of normative documents, activities of ethics review committees and the power of civil society to perform critical monitoring of research activities. The quality and effectiveness of the application of ethical provisions depend as much on political actions as on how developed social institutions are. The more unstable the democratic institutions of a society, the more difficult will be the application of these provisions.
South America and Africa, two continents with a large number of poor and low-income countries, are good examples to illustrate the relationship between democratic stability, organisation of civil society and the efficiency of systems of ethical review of clinical trials. In South America, democracy was restored to all countries during the last two decades, after the wave of military dictatorships that dominated the whole continent during the cold war period. However, most countries are characterised by a heavy dependency on foreign capital and suffer from the existence of fragile democratic institutions and poorly organised civil societies. The case of Africa is graver still both socioeconomically and politically. Besides, chronic food shortages, climatic conditions that are sometimes extremely hostile, and the spread of epidemics such as AIDS, numerous ethnic conflicts, tribal clashes and civil wars make state restructuring difficult, and contribute to these societies seeing basic human rights suspended. This reality is reflected directly in the difficulty of many of these countries to develop sustainable ethical review systems of research.
Several difficulties have been reported with regard to the application of ethical norms of research in these countries, such as inadequate training of the members of ethics review committees, lack of logistical support to carry out the work, inability to supervise ongoing research studies, lack of recognition of the legitimacy of committees by the research community, and the absence of accreditation systems to supervise the quality of the formation and functioning of the committees, and, in some instances, the complete absence of an institutionalised system of ethical review. A questionnaire about the ethical review processes in the developing world submitted by Hydder et al41 to 670 health researchers that work in several regions of the planet shows that 44% of the studies were not reviewed by ethics committees in the host countries or by institutions of the health ministries in these countries.
The extreme weakness of social monitoring of research studies has two main practical implications in relation to risk. First, studies can be carried out without either the society at large or the individuals involved being in a position to review the risk–benefit assessment. Second, in the event of an extremely grave and undesirable event, such as death or disability, dissemination of the information, both to the scientific community and to other key stakeholders of society, is made much more difficult precisely by the socioeconomic circumstances of the individuals harmed.
Discussion and conclusions
This paper aimed to demonstrate that contextual aspects related to lifestyles structures of populations in poor and low-income 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, multidisciplinary 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 institutional research committees, public or private and nationwide.
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 rationality that at present seem to dominate the so-called globalisation 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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