The acceleration of the market globalisation process over the last three decades has internationalised clinical research and influenced both the way in which it is funded and the development and application of research practices. In addition, in recent years international multicentre randomised clinical trials have become the model par excellence for research on new medicines. The neoliberal model of globalisation has induced a decline in state power, both with regard to establishing national research for health priorities and to influencing the development of adequate ethical guidelines to protect human beings that participate in multinational research. In this respect, poor and low-income countries, which lack sustainable control and review systems to deal with the ethical and methodological challenges of complex studies conducted by researchers from affluent countries and funded by large multinational pharmaceutical companies, are particularly vulnerable. The aim of the present paper is to explore critically some of the actual and possible ethical pitfalls of globalisation of clinical research and propose mechanisms for turning transnational clinical research into a more cooperative and fairer enterprise.
- Benefit sharing
- clinical ethics
- double standards
- human rights
- social vulnerability
- scientific research
- ethics committees/consultation
- social aspects
- social control of human experimentation
- cultural pluralism
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- Benefit sharing
- clinical ethics
- double standards
- human rights
- social vulnerability
- scientific research
- ethics committees/consultation
- social aspects
- social control of human experimentation
- cultural pluralism
The acceleration of the market globalisation process over the last three decades, greatly facilitated by the expanding influence of neoliberalism in international economic politics, has boosted the internationalisation of clinical research and has influenced both the way in which it is funded and the development and application of research practices.
Neoliberalism is here understood as the economic theory and political philosophy advocating the transfer of economic control from the public sector to the private sector in order to increase government efficiency and improve the economic indicators of countries. Its main features are: liberalisation of inward foreign direct investment; elimination of regulations that impede the free entry of private capital in all fields of social activities; promotion of free competition between enterprises; and greater production of regulations for the protection of patents on scientific and technological inventions and discoveries.1 Introduced during the 1940s as a developmental proposal for western democracies, its expansion to poor and low-income countries with different political, economic and sociocultural systems has, according to many critics, generated an increase of social disparities in the world and paved the way for economic exploitation and cultural conflicts.2 3
To give some examples, in 1960 the richest 20% of the world's population was 30 times richer than the poorest 20%. In 1990 this rate had increased 60 times. In the same year––that is in 1990—the debt of poor and low-income countries was $US1.3 trillion, twice as high as in 1980, while in 1995 the debt had grown to $US1.9 trillion.4
Today, private funding clearly holds supremacy over public investments in clinical research5 and the neoliberal model applied to the health field has induced a decline in state power, both with regard to establishing national priorities in research and with regard to influencing the development of adequate ethical guidelines for this kind of research. In addition, over recent years international multicentre randomised clinical trials have become the model par excellence for research on new medications.
The aim of the present paper is to explore critically some of the actual and possible ethical pitfalls of globalisation of clinical research and propose mechanisms for turning transnational clinical research into a more cooperative and fair enterprise.
Clinical research and globalisation
The international pharmaceutical industry is one of the branches of economic activity with the largest concentration of capital. In 2005 the pharmaceutical market generated about $US590 billion. In the same year, eight pharmaceutical companies accounted for about 40% of all revenue worldwide.6 A captive market and a monopoly of patents have been crucial factors in causing these enormous earnings on part of the industry,7 According to Moynihan,8 there are about 80, 000 pharmaceutical industry representatives in the USA. In Germany, there are 17, 000 laboratory representatives for approximately 130, 000 physicians, thus giving a ratio of 7.64 physicians for every sales representative.9 These figures are similar to those found in Great Britain and France and gives reason for concern with regard to the freedom and independence of clinical researchers in their selection of clinical research projects to pursue.
The proportionally small number of investigations conducted by multinational companies with the aim of producing medicines to meet the particular needs of poorer countries, for example drugs to treat malaria, Chagas disease or schistosomiasis, gives further reasons for concern.10 During the last decade poor and low-income countries have been increasingly involved in multicentre clinical trials aimed at expanding the fields of testing and market. In 2005 Petryna estimated that of the 50, 000 international clinical trials conducted globally, more than 40% took place in poor and low-income countries.11 A recent review indicated that about one-third of 509 clinical trials sponsored by US-based companies in 1995–2005 were conducted outside the USA, many in poor and low-income countries. It is worth noting, though, that none of these trials have been directed towards diseases that preferentially affect the countries involved.12 Similarly, Chirac and Torreele found that only 10 of 1556 new drugs produced between 1975 and 2004 were targeting diseases specifically prevalent in poor and low-income countries.13 Since 1996 this discrepancy between prevalent health needs and research priorities have been labelled the 10/90 gap. This metaphor was introduced to depict the monstrous inequity in the world with respect to whose diseases are favoured in ongoing or planned research programmes. In concrete terms this means that at least 90% of the economical resources spent annually on medical research are targeting the health needs of the richest 10% of the world's population, something that implies that the needs of 90% of the world's population have to be met from the remaining 10% of research funding.14 Unfortunately, figures from the studies mentioned earlier give reason to believe that this gap has not diminished, although during the last 15 years the number of people from poor and low-income countries enrolled in clinical trials has increased substantially.15 Indeed, evidence from these studies suggests that during this trial period the relative availability of new drugs to populations in poor and low-income countries has not increased, while the gap between wealthy nations and poor and low-income countries with regard to who benefits from the advances of clinical research and development continues to widen.16
The internationalisation of research may, without doubt, be beneficial for poor and low-income countries if sustainable plans and programmes for benefit-sharing and development of the investigative capacity of the countries hosting such research is added to the profit requirements of the funding institutions. This may be achieved partly through bilateral agreements between the funding institutions and the host countries, bearing in mind four objectives:
that the research aims at developing therapeutic, preventive or diagnostic methods targeting health problems that are a priority for the populations of the host countries;
that the targeted populations are given the possibility to have access to the outcome of the research;
that the human rights of the participants are respected;
that it contributes to the development of research capacity of the countries involved, understood as: capacity to identify and formulate research priorities according to the main health problems of its population; financial independence with regard to investments in priority research; ability to implement independent ethical review mechanisms and systems to assess and monitor research conducted within its own territory.
Under such conditions, international clinical research could certainly become cooperative. On the other hand, instead of being cooperative in nature, such research may lead to increased exploitation of impoverished countries and communities, especially in situations where:
the aim in having participation from such countries and communities is only to avoid the more rigorous supervision mechanisms that exist in the countries from which the research originates;
economic and educational disadvantages of research subjects are used with the aim of either accelerating the recruitment process or having them undergo procedures that would not be accepted in the countries of origin; or
the benefits generated at the end of the study are not made available to the subjects and communities that took part in the research,
and the ‘surplus benefit’ of outsourcing clinical trials to these parts of the world are not adequately shared with ‘the vulnerable part’, that is the communities in which the studies are conducted.17
The relevance of this line of reasoning has increased considerably lately for two reasons: problems reported over recent years regarding clinical trials carried out in ‘peripheral’ countries that may have harmed the subjects involved in them or violated international normative standards for research18 19 20and the attempts, through the latest revisions of the Declaration of Helsinki 2008,21 to facilitate the use of placebo, dilute the requirements of care in such situations and weaken the sponsors' responsibility towards subjects once the study has been concluded. This weakening of international normative standards for research has been accompanied by a progressive growth of research in poor and low-income countries and attempts to use other normative standards for these countries. For all these reasons, it seems appropriate to add to this analysis a context-sensitive interpretation of what is conventionally called ‘social vulnerability’ and focus the attention on why poor and low-income countries deserve special attention in the field of research ethics.
The concept of social vulnerability
Despite the variety of interpretations, social vulnerability is generally conceived as a phenomenon determined by the structure of people's and communities' daily lives. There is consensus in the literature regarding the factors determining it22:
lack of income, information, knowledge and technology;
lack of access to public authorities and other types of social representation;
limited networks of social relationships;
diversity of beliefs and customs among the majority of the population;
advanced age; and
Social vulnerability gives rise to contexts of fragility, lack of protection, debility, disadvantaged states (disadvantaged populations) and even to neglect or abandonment, encompassing various forms of social exclusion or isolation of certain population groups from the advances, discoveries or benefits that may already be underway within the dynamic process of world development.23 Thus understood, states of social vulnerability fall beyond the domain of self-determination and they lead to significantly increased exposure to risks caused by situations of social exclusion. By reviewing the scholarly literature on ethical conflicts within international biomedical research in poor and low-income countries, Lorenzo24 indentified some contextual factors that generate social vulnerability in biomedical research:
poverty and low educational level among the population25–28;
low capacity for research in the country.35–37
These contextual factors are associated with cultural diversity, different political traditions and various stages of economic development, and have a direct influence on the relationships of these countries with international biomedical research. More specifically, these factors may cause lack or inadequate functioning of research ethics committees; flexibility with regard to the application of normative standards; reduced costs to sponsors with regard to legal actions in case of adverse events, since the amounts to be paid to insurance companies are different; and a lower incidence of lawsuits against the sponsors in case of serious side effects, since the social and civil rights of much of the population are not fully guaranteed in these countries.
Double ethical standards and social vulnerability
The expression ‘double standards’ in relation to clinical research came into use in the 1990s through several papers that denounced the use of different standards for research protocols and participants in the ‘first’ and in the ‘third’ world.18 19 The core of the double standard argument—also labelled ‘the minimalist position’38—is that it is ethically justifiable under certain socioeconomic conditions to use different ethical standards for biomedical research. It implies that a local standard, that is the status quo of the community, is considered the suitable normative baseline for evaluating international research. As pointed out by one of the most prominent critics of this position it:
… assumes that members of the host population do not have grounds to claim an entitlement to more or better than they currently receive. We fully endorse this critic's verdict: Beginning moral enquiry from this starting point, however, simply begs the most important question of justice.38
Thus, according to this minimalist view, the basic level to build the ethical norms to evaluate biomedical research is the contextual situation of each community. We believe that the concept of social vulnerability may be of use when testing the validity of this argument, because viewed in the light of the previous description of social vulnerability it becomes clear that this represents an attempt to build an ethics funded in unfair previous conditions. Arguments along similar lines of those seeking to justify the use of double standard of ethics in research has already been used in the past and at present to justify child labour, lack of labour rights and the establishment of industries with great pollutant potential in the peripheral countries.39
If we take into account the latest revisions of the Declaration of Helsinki, it seems appropriate to say that today's international research ethics runs the risk of making research participants and populations in poor and low-income countries victims of alterable forms of vulnerability; that is, forms of vulnerability that could have been dealt with through affirmative and context-sensitive forms of actions of a social and remedial kind.40 41 These trends in international research ethics, of justifying ‘local’ research practices rooted in unfair conditions of the guest community, emerge in a time period that has also been characterised by a steady growth of transnational research in poor and low-income countries.
On the level of international normative regulations, these trends are clearly traceable as well, as for example:
in the attempt to modify international ethical guidelines and declarations that support the use of universal standards, as is the case not only with the Declaration of Helsinki but also with the Council for International Organizations of Medical Sciences (CIOMS)' International Ethical Guidelines for Biomedical Research Involving Human Subjects. This adds to the strong critique that has been levelled against the Universal Declaration on Bioethics and Human Rights42 43;
in the attempt to implement different normative documents developed in the affluent part of the world to serve as a reference to develop guidelines in poor and low-income countries44;
and, more frequently, in the silent return to the principles of the Belmont Report and the implementation of the International Conference on Harmonisation–Good Clinical Practice (ICH-GCP) guidelines.
A Latin American reaction to the latest revisions of the Declaration of Helsinki
The forms of interaction between stakeholders of international clinical research and research subjects and communities in poor and low-income countries are not of the same kind as those in the affluent part of the world. For example the difference in the quality of government actions, research capacity and development of civil society point towards the need to emphasise international normative standards as a universal baseline, while at the same time safeguarding the development and implementation of national ethical assessment systems“47
The use of the expression developing country in the literature, which is excessively generic, makes it difficult to go more deeply into the implied questions relating to protection of vulnerable populations in different regions of the world, given that such questions deal equally with socioeconomic, cultural and political contexts that are as different as those of countries in sub-Saharan Africa or other contexts relating to Latin America, southern Asia or even eastern Europe.
The ethical conflicts stemming from great social disparities in countries at intermediate levels of industrialisation, such as Brazil and Mexico, on the other hand, present particular challenges regarding questions of risk minimisation and benefit-sharing that are very different from the situation in poor and low-income countries with a more homogenous expression of poverty among the population, as is the case in most countries in sub-Saharan Africa. It is therefore presumptuous to lump all the peripheral countries of the world at the same level for assessments and scheduling with regard to clinical research.
Latin America has been considered particularly attractive for international clinical research, principally due to the existence in the large cities of specialists trained in research48 49 and because of easy recruitment of naive subjects, as a result of the large concentration of patients in public hospitals.50 51
The latest revisions of the Declaration of Helsinki was the subject of intense discussion at a congress in bioethics organised by the Latin American and Caribbean Bioethics Network of UNESCO (Redbioética) in Cordoba, Argentina, in November 2008, and with the participation of 300 scholars in bioethics from 12 Latin American countries. During the final plenary of the congress the Declaration of Cordoba (About Ethics in Research involving Human Beings)52 was unanimously adopted. This Declaration states that:
the new version of the Declaration of Helsinki can seriously affect the safety, the well-being and the rights of persons who participate as volunteers in clinical trials;
the acceptance of different standards of medical care—due to methodological, scientific or other reasons––is ethically untenable;
the new possibilities for using placebo are considered ethically unacceptable practices and are contrary to the idea of human's dignity and human and social rights; and
the lack of hard post-study obligations in relation to study subjects and host communities offends people's integrity, amplifies the social inequity and injures the Declaration of Helsinki's own notion of justice.
For these reasons the Declaration of Cordoba advises countries, governments and institutions that dedicate their work to bioethical issues to reject the 6th version of the Declaration of Helsinki and recommends instead the Universal Declaration on Bioethics and Human Rights as an ethical and normative frame of reference.53
This reaction follows a trend in Latin American bioethics to understand the mechanisms of protection against the exploitation of humans beings by research from a universalistic perspective based on human rights. This human-rights-based approach to bioethics and research ethics has been recognised as valid by the United Nations and by its auxiliary institutions such as UNESCO and WHO. According to this view, contextual and local differences between countries may interfere with the adequacy of strategies to enforce the rights of people, but they can never be used as an excuse to reduce such rights, as advocated by the champions of double ethical standards.
Towards a fair ethics of benefit sharing in clinical research
It is absolutely essential for humanity that clinical research continues to be carried out. But it is indispensable that policy documents, guidelines and mechanisms created internationally to ethically control and promote clinical research contribute to a control that is transparent and a promotion of research that helps to reduce dramatically the 10/90 gap. For the process to be as transparent and fair as possible, and to be able to dismiss any doubt regarding undesirable external interference or influences that disregard the social vulnerabilities, the most appropriate way forward, we believe, is for poor and low-income countries to create their own autonomous regulatory systems, with transparent social control mechanisms that are operated democratically at all levels.
International standards and guidelines are indispensable for providing the direction to be followed in developing clinical research in each place around the world and they need to be funded in a universal principle of justice. However, the peculiarities of each country's regulatory systems should be established definitively in accordance with each country's particular characteristics and needs. Independence is fundamental in making decisions and it is also related to the technical and intellectual capacity that poor and low-income countries need to put in place, with the support from affluent nations and from international organisations such as UNESCO and WHO.
Article 15, paragraph 1 of the Universal Declaration of Bioethics and Human Rights states that sharing of benefits is a duty that all Member States of the United Nations have committed themselves to.53 In addition, the article states that affluent countries have a particular duty in this respect vis-à-vis developing countries:
Benefits resulting from any scientific research and its applications should be shared with society as a whole and within the international community, in particular with developing countries.
If governments in the affluent part of the world were willing to take the political consequences of such a commitment, this could have a profound implications for the way future science policies and research strategies for clinical research are formulated and implemented. The first implication would be that even when clinical research is conducted in affluent countries then these countries have committed themselves to share the benefit of this research, in particular with developing countries. Second, for a global strategy for clinical research to become true it is not sufficient to develop a global medical science policy and research strategy that takes into account the particular research needs of poor and low-income countries. What is needed in addition is the development of national research policies in the richer part of the world that include sustainable plans for how the benefits resulting from national research programmes may be shared with poor and low-income countries. Third, this raises the question of how affluent countries could assist in the co-evolution of a fair and global policy on medical forms of scientific literacy and benefit-sharing. Four tentative answers will here be suggested.
The first suggestion is that by focussing attention on ways of involving stakeholders from poor and low-income countries in the design, conduct and evaluation of their own national research programmes (academic stakeholders, members of National Bioethics Committees and policy-makers), affluent countries could contribute to such a development. Second, such a development could be facilitated by giving priority to national research programmes in the affluent part of the world that aim at forms of benefit also transferable to poor and low income countries. Third, affluent countries could assist poor and low-income countries in the establishment of economically robust, independent National Ethics Committees with the task not only of supervising the systems of ethical review of research, but also of identifying national research for health needs and of proposing national priorities in clinical research. Finally, by contributing financially to the creation of a Global Health Research Fund (GHRF) targeting clinical research needs in poor and low-income countries, affluent countries could contribute substantially to the development of a fair and sustainable ethics of benefit-sharing in clinical research.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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