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Developing World Bioethics ISSN 1471-8731 (print); 1471-8847 (online) doi:10.1111/j.1471-8847.2008.00229.x SPECIAL REPORT ETHICAL ISSUES IN MEDICAL RESEARCH IN THE DEVELOPING WORLD: A REPORT ON A MEETING ORGANISED BY FONDATION MÉRIEUX CHRISTOPHE PERREY, DOUGLAS WASSENAAR, SHAWN GILCHRIST AND BERNARD IVANOFF Keywords developing world, clinical trials, investigators, informed consent, pharmaceutical, practice guidelines, ethics ABSTRACT This paper reports on a multidisciplinary meeting held to discuss ethical issues in medical research in the developing world. Many studies, including clinical trials, are conducted in developing countries with a high burden of disease. Conditions under which this research is conducted vary because of differences in culture, public health, political, legal and social contexts specific to these countries. Research practices, including standards of care for participants, may vary as a result. It is therefore not surprising that ethical issues emerge. This meeting sought to identify and discuss these issues from the perspectives of the many actors in such research, including community representatives, with a view to finding ethical and pragmatic solutions to these issues. Dialogue between these actors was also promoted, with a view to identifying the need to develop such dialogue in future. Drawing from the experiences of the speakers, the colloquium attempted to outline some answers to several key questions characterising the field today. Experiences related to epidemiologic research, vaccine trials, drug trials, diagnostic tests and to some fundamental ethical issues in health research. Speakers were from different countries, disciplines and professions. The meeting provided a forum for consultation and debate between different ethics actors. Both encouraging findings and challenges emerged. INTRODUCTION More and more clinical trials are performed in developing countries where populations suffer from a high burden of disease. Various factors affect the conditions under which this research is conducted, such as differences in culture, local standards of care and public health, as well as differences in the political, legal and social environment specific to the host country. Under these circumstances, it is not surprising that ethical issues emerge. The objective of the meeting organised by the Mérieux Foundation1 in April 2006 was to share information and debate questions relevant to ethics of research in developing countries, and to foster dialogue between a range of disciplines, institutions (public and private) and 1 Fondation Mérieux was set up in 1967 by Doctor Charles Mérieux in memory of his father, Marcel Mérieux, a pupil of Louis Pasteur and founder of the Mérieux Institute in 1897. It is now an independent foundation which works to serve the interests of public health, especially by combating infectious disease in developing countries. Address for correspondence: Christophe Perrey, 131 Boulevard du Général Koenig, Neuilly sur Seine 92200, France. [email protected] © 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd., 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main Street, Malden, MA 02148, USA. 2 Christophe Perrey, Douglas Wassenaar, Shawn Gilchrist and Bernard Ivanoff geographical areas on ethical issues related to clinical trials. This article presents a summary of the different issues that were tackled. After briefly describing some differences in conducting clinical research in developed and developing countries, several challenges faced in the South were identified and solutions proposed. Speakers subsequently examined the roles of various key actors (clinicians, philosophers, social scientists, patients’ associations, etc.). Issues related to ethics committees in developing countries were then discussed (composition, role, legal status, etc.), as was the role of international organizations (governmental or other) in fostering a competent ethical review process. Finally, the role of lawyers and media professionals in upholding ethical standards was discussed. To address the different challenges that the ethics of research raises, a multidisciplinary approach is essential. To narrow the gap between current practices and the ideal, actors from different fields need to collectively review the issues and propose new approaches to better align universal principles with particular values. The world must face the challenge of ‘crossbred ethics’ and find a means to articulate the different requirements of various cultures in a harmonious way, while avoiding the dangers of uniformity and of ethical relativism.2 There is also a responsibility to support ongoing innovation in therapy and prevention and ensure the best possible protection against abuses. As one speaker stated: ‘The most profoundly unethical course is to do nothing to prevent or alleviate such suffering.’ Therefore, the ethics of research has to evolve with the growing complexity of the research enterprise. However, differences do exist, even if varied in number and degree.4 These differences, of varying importance, give rise to several difficulties, depending on the country and the type of research undertaken (epidemiology, diagnostics development, new drug or vaccine development, etc). In addition, there may be a perception by some that the countries of the South constitute ‘guinea-pig populations’ for those of the North. Several major challenges related to conducting research in developing countries were raised. ETHICS AND FIELD RESEARCH IN DEVELOPING COUNTRIES The principle of ‘equity’ should be scrupulously respected. It would be unethical to test a vaccine or drug There are similarities in conducting clinical research in developed and developing countries. In both environments, a clinical trial always takes place in a network made up of different actors. The decision to participate in a trial does not result from a perfect understanding of the delivered information or from a perfect rational evaluation of the benefit/risk balance.3 It corresponds to an overall wish to be better taken care of. d’Engagement dans des Essais Vaccinaux Contre le VIH. Psychologie Française 1997; 42: 291–300; R. Jenkins, L. Temoshok & K. Virochsiri. Incentives and Disincentives to Participate in Prophylactic HIV Vaccine Research. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 9: 36–42; P. Amiel & A. Fagot-Largeault (dir). 2000. Enquête sur les Pratiques et Conceptions de l’Information et du Recueil du Consentement dans l’Expérimentation sur l’être Humain. Paris. Convention MIRE, n°15–97. 4 Some factors may distinguish developing from developed countries: scarcity of research skills, poor quality of infrastructure (e.g. hospitals, laboratory facilities, communications networks), limited legislative constraints, paucity of experience in biomedicine, low levels of income, limited availability of resources for scientists, differing human rights environments (statutory and operational), differing perception of diseases, weaknesses of the health care system, lower regulatory stringency of the research environment (leading to temptation to operate at a lower costs with less ethical consideration in a less constrained environment), limited availability of epidemiological data, relative weaknesses of some research ethics committees and lack of enabling legislation. 2 R. Macklin, ed. 2004. Double Standards in Medical Research in Developing Countries. Cape Town: Cambridge University Press. 3 F.J. Ayd. Motivations and Rewards for Volunteering to be an Experimental Subject. Clin Pharmacol Ther 1971; 13: 771–778; A. Giami & C. Lavigne. Motivations et Représentations Chez les Volontaires Engagés dans des Essais Vaccinaux Contre le VIH (Phase 1). Psychologie Française 1996; 41: 173–188; A.Giami & C. Lavigne. Refus A lack of reliable epidemiological data for a given disease This often requires an additional study to predetermine the real incidence of the disease and the justifiability of specific proposed research studies, especially clinical trials in order to ensure that such trials are clinically relevant to the health needs of the host country. Limited involvement of researchers from the South in the conceptualization of research The type of research to be conducted will depend on the purpose: for example, to guide public health policy, to support a file for licensure of a new drug or vaccine, etc. Therefore, developing countries (host countries) need to be involved, from the start, in the conceptualization of the research to maximise the relevance of studies conducted and ensure the building of local capacity to conduct and direct health research. Achieving equitable sharing of risks and benefits © 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd. Ethical Issues in Medical Research in the Developing World in a country that would not derive a subsequent benefit. Moreover, there is an obligation during the trial to facilitate access to care, and treatment should be of a globally acceptable effective standard or at least a significant improvement over what is locally available. Post trial access to eventual products should be discussed in advance of trials and preferential agreements should be negotiated by partners to ensure access to effective products arising out of clinical research. Strengthening capacity and transferring knowledge Field research can be an opportunity to strengthen local technical capabilities. In this regard, as many of the investigations as possible should be conducted locally. Capacity building should also include the following: establishing or strengthening scientific capacity and infrastructure, training scientists in research ethics,5 ethical review committees, and health-related education of the communities from which participants are drawn. Respecting the right to privacy/confidentiality and good research practices Restricted access to data is justified by a study subject’s right to autonomy and because personal harm may ensue if the data were disclosed. Community participation and informed consent There was unanimous agreement on the absolute need to obtain individual informed consent except in specified unusual circumstances (e.g. mental disorder, incapacity, etc.). Informed consent should, however, not be reduced to the simple gathering of a signature. Instead, consent may be a complex process with multiple stages, depending on the complexity of the research and the related risks and benefits involved. Adequate informed consent should usually involve the following: (1) Obtaining the assent of local leader. As suggested in the Council of International Organanisations of Medical Sciences (CIOMS),6 local or 5 D.R. Vasgird. Prevention over Cure: The Administrative Rationale for Education in the Responsible Conduct of Research. Acad Med 2007; 82: 835–837. 6 Council for International Organizations of Medical Sciences (CIOMS). 2002. International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: CIOMS. Available at: http://www.cioms.ch/frame_guidelines_nov_2002.htm [Accessed 12 Dec 2007]. © 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd. 3 traditional leaders may need to be consulted in order to obtain courteous access to the community in question in certain developing country contexts.7 Although this is not a substitute for informed consent, this dimension may be problematic if the leader refuses, or if the leader makes stipulations that are unworkable or unethical. Community participation is an alternate operationalisation of this process;8 (2) Providing information in the language of the recipient and at a reading level appropriate to the recipient’s reading level; (3) Ensuring understanding of the information. Several recent studies have examined different ways of determining whether information is understood.9 Informed refusals may be an index of a sound consent process; (4) Ensuring that the decision is taken freely and voluntarily. To date there has been relatively little research exploring the voluntariness component of consent, probably because it is more difficult to conceptualise and study empirically than understanding.10 However, at the very least, there should be no undue inducement to participate. Coercion, which is probably very rare in research,11 should also not be present. Those approached for research should also be allowed time to discuss enrolment with their relatives before consenting to research, particularly in relation to risks and benefits; and (5) Reporting the agreement. (Signature or videotape.) The signature provides a legal record of consent but its importance may be overemphasised in developed countries. For oral cultures, it can be substituted by other 7 P.O. Tindana, N. Kass & P. Akweongo. The Informed Consent Process in a Rural African Setting: A Case Study of the KassenaNankana District of Northern Ghana. IRB 2006; 28: 1–6; R. Upshur, J.V. Lavery & P.O. Tindana. Taking Tissue Seriously Means Taking Community Seriously. BMC Med Ethics 2007; 8: 11; C. Weijer, G. Goldsand & E.J. Emanuel. Protecting Communities in Research: Current Guidelines and Limits of Extrapolation. Nat Genet 1999; 23: 275–80. 8 E. Emanuel et al. What Makes Clinical Research in Developing Countries Ethical? The Benchmarks of Ethical Research. J Infect Dis 2004; 189: 930–937; D.P. Diallo et al. Community Permission for Medical Research in Developing Countries. Clin Infect Dis 2005; 41: 255–259. 9 G. Lindegger et al. Beyond the Checklist: Assessing Understanding for HIV Vaccine Trial Participation in South Africa. AIDS 2006; 43: 560–566; A. Leach, S. Hilton & B.M. Greenwood. An Evaluation of the Informed Consent Procedure Used during a Trial of Haemophilus Influenzae Type B Conjugate Vaccine Undertaken in the Gambia, West Africa. Soc Sci Med 1999; 48: 139–48; D.W. Fitzgerald et al. Comprehension during Informed Consent in a Less-developed Country. Lancet 2002; 360: 1301–1302; J. Sugarman. Empirical Research on Informed Consent: An Annotated Bibliography. Hasting Center Rep 1999; 29(1): S1–S42. 10 N.W. Barsdorf & D.R. Wassenaar. Racial Differences in Public Perceptions of Voluntariness of Medical Research Participants in South Africa. Soc Sci Med 2005; 60: 1087–1098. 11 J.S. Hawkins & E.J. Emanuel. Clarifying Concerns about Coercion. Hastings Center Rep 2005; 35(5): 16–19. 4 Christophe Perrey, Douglas Wassenaar, Shawn Gilchrist and Bernard Ivanoff forms of validation (for example by videotape, through participants’ advocates, or independent witnesses), ideally negotiated in advance by preparatory social science fieldwork. Developed country sponsors and ethics committees may require signed consent to minimise liability or rejection by regulatory bodies. Using placebo or comparative treatment From a universal ethical perspective, the same rules for field trial design should apply everywhere to prevent exploitation of developing country populations. However, from a pragmatic and contextual ethical perspective, medical and economic inequalities may justify differences in the design and methods of trials. The ‘gold standard’ of clinical trials is the randomised, doubleblinded, placebo-controlled trial. In fact, Guideline 11 of CIOMS allows for placebo or ‘no treatment’ under certain conditions.12 Another issue is whether the ‘best attainable’ treatments should be used in the host country at the time of the trial or simply a known effective treatment. There was agreement that it was desirable to offer comparator treatments that were better than those locally available and that ‘locally available’ was an unacceptable comparator if no effective treatment was available in the local public health sector. Meeting obligations in the post-trial period Several obligations lie with the sponsor (or government of host country): (1) the storage of samples and data; (2) the dissemination of the results to participants, stakeholders (local, national and international e.g. the World Health Organization (WHO)), regulatory authorities, and scientific and public health communities; (3) the availability of new drugs or vaccines after the trial. There was consensus that this question must be settled by pretrial agreement – it may constitute a precondition. Complexities involve determining who should be responsible for funding and providing such treatment. These details should ideally be negotiated in advance of the study;13 (4) the maintenance of the site and surveillance – it is the responsibility of local stakeholders to maintain the activity of the trial site by utilising the acquired capacity and attracting other projects; and (5) there should also be ongoing respect for the confidentiality of the personal 12 Council for International Organizations of Medical Sciences, op. cit. note 6, Guideline 11. 13 T. Tucker & C.M. Slack. Not If, But How? Caring for HIV-1 Vaccine Trial Participants in South Africa. Lancet 2003; 36: 995. records, and, in the case of socially sensitive research, the identity of the community should be concealed. Following the above points, discussion turned to other partners who should ideally be included in field research, especially in the developing country context. Patient organizations With the emergence of AIDS, patient groups play an increasingly important role in the ethical scrutiny of health research. For example, in France the coalition of AIDS patient organizations work on the issues of research and treatment (TRT-514). They closely review study protocols and may sometimes ensure that patient representatives are included in review committees. Other initiatives could involve technical support for nongovernmental organizarions (NGOs) in developing countries, training (North/South and South/South), networking, advocacy for access to care, support for the creation of local patient associations, and alliances of researchers, politicians, patient organizations and trial participants. Such organisations promote education, legal and ethical analysis, and policy development related to AIDS. They produce quality of information for patients, provide advice on negotiations for participation in a research project, and organise the training of civil society actors on ethics of research. They have played a role in the denunciation of nonethical research, for example, the Tenofovir trial in sex workers.15 Social scientists The major contribution to biomedicine by researchers in the social sciences is to objectively demonstrate, through field studies, the gap between the desirable and the actual conduct of research. Various roles include the following: (1) Prior to biomedical studies: contributions to the debate on relativism and universalism of ethics,16 evaluation of 14 TRT-5 (Therapeutic Research and Treatment group). J.A. Singh & E.J. Mills The Abandoned Trials of Pre-exposure Prophylaxis for HIV: What Went Wrong? PLoS Med 2005; 2(9): e234. They analyzed the study protocol and found out that no female condoms were going to be made available to study participants. No access to care was planned if participants were screened out (being already HIV+) or became infected during the trial. The informed consent was only available in English and difficult to understand for Cameroonian women. Access to the study drug after the trial was not planned if the study results were positive. 16 R. Massé. L’Anthropologie au Défi de l’Éthique. Anthropologie et Sociétés 2000; 24(2): 5–11. 15 © 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd. Ethical Issues in Medical Research in the Developing World the role of ethics committees,17 analysis of the different decision-making processes, identification of local authority structures and consent procedures,18 documentation of local ethics and traditional values and beliefs, classification of risk categories (e.g. ethnic groups in epidemiological surveys) while avoiding labeling; (2) During biomedical studies: reviews of the conduct of clinical research, examination of specific issues such as informed consent (e.g. assessment of community participatory processes and structures, decision-making processes, understanding of information, etc), observance of confidentiality, etc; and (3) For post-biomedical studies: evaluation to improve communication of certain results to individuals (e.g. in the event of seropositivity) and communities, evaluation of such processes to improve presentation of study results to participants and lay public. Philosophers Moral philosophy informs many questions related to the ethics of research. Philosophers contribute to the formulation and justification of ‘principles’ that can guide conduct for issues arising from biomedicine, and, in particular, from research on human beings.19 The basis of good and evil is not entirely independent of sociocultural context. Philosophers can contribute to the development of local and national ethics and can advise on alignment, or not, with other ethical frameworks. In addition to contributing theory, philosophers can contribute to decision-making within ethics committees or international bodies for the establishment of guidelines. ETHICS COMMITEES IN DEVELOPING COUNTRIES Several studies of the existence and resources of ethics committees in developing countries, like those undertaken in Africa by Networking for Ethics in Biomedical Research in Africa (NEBRA), the WHO/Joint United Nations Programme on HIV and AIDS (UNAIDS) African AIDS Vaccine Programme (AAVP),22 or in South America by the Bioethics unit of the Pan American Health Organization (PAHO), reveal that there are great disparities between and within countries.23 These inconsistencies relate to the existence or absence of the committees themselves, their guiding documents, their personnel and procedures, their physical resources and status, legally and institutionally, and their workloads per meeting. The findings of these studies highlight the need for individualised or regional capacity building efforts. Several other needs of ethics committees were identified in discussion, including: • Historians Historians can provide a historical dimension that can help to elucidate the gap between ‘the seductive vice of utopia’ and ‘the stringent call of reality’.20 There is no doubt that case studies can be very informative. The responsibilities of historians could also be ‘to remind the academic community, political body and industrial partners of unfulfilled promises.’21 17 Many questions can be addressed, such as the existence of such a committee, their independence, their material and intellectual capacity, training, procedures, legal status, etc. 18 C. Molyneux et al. Community Voices on the Notion and Practice of Informed Consent for Biomedical Research. Soc Sci Med 2005; 61: 443–454. 19 L.A. Eckenweiler & F.G. Cohn, eds. 2007. The Ethics of Bioethics: Mapping the Moral Landscape. Baltimore, MA: Johns Hopkins. 20 A.M. Moulin. Extracts from the meeting’s conclusive remarks. 21 Ibid. © 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd. 5 • Training for ethics committee members. Many institutions in the North provide training workshops in developing countries. But their real long-term impact has limited value for several reasons: (1) the acquisition of the needed theoretical tools for an ethical evaluation of research requires more than a ready-touse tool kit, (2) the best theoretical knowledge cannot be applied if the basic material conditions for the functioning of ethics committees are not ensured, (3) repeated workshops may be attended by a select group of individuals who receive repeated training and who do not go on to train their colleagues. However, for many ethics actors, these workshops are their only exposure to bioethics and therefore do serve a useful purpose, particularly if tailored to specific audiences or types of trials. Definition of the mandate of ethics committees. Their primary function is the protection of study participants. Should they evaluate both ethical and scientific aspects of a study? Positions differ on this subject. For some, what is not scientific cannot be ethical, and a simultaneous two-pronged evaluation is essential.24 However, available scientific expertise is limited and the same individuals who develop the studies are often 22 See C. Milford, D.R. Wassenaar & C.M. Slack. Perceived Capacity of Selected African Research Ethics Committees to Review HIV Vaccine Trial Protocols. IRB 2006; 28(2): 1–9. 23 N. Kass et al. The Structure and Function of Research Ethics Committees In Africa: A Case Study. PLoS Med 2007; 4(1): e03. 24 E. Emanuel. Ending Concerns about Undue Inducement. J Law Med Ethics 2004; 32: 100–105. 6 Christophe Perrey, Douglas Wassenaar, Shawn Gilchrist and Bernard Ivanoff called upon to evaluate them from a scientific perspective. A minority view holds that ethics committees must be confined to ethical review, and other organizations made responsible for the scientific review. • The composition of ethics committees. Consensus emerged on the need for multidisciplinary and multisectarian representation. But there was little agreement on the ideal profile for membership. Ideally, the committee should include clinicians, lawyers, social scientists (e.g. sociologists, psychologists, anthropologists), patient groups (to limit ideological conflicts), as well as persons external to the reference institution. Philosophers, ethicists, economists, representatives of political or religious groups, and nurses should also be sought. • Funding of ethics committees. This raises issues related to the conditions of existence, and to independence from the sponsors.25 Generally, the sponsors of studies should pay an administration fee to the host institution of the ethics committees. These financial contributions primarily cover the ethics committee’s operating expenses (logistics, etc.). Moreover, true independence is not readily achievable because ethics committees are accountable to their home institutions and to their communities. Committees must, however, avoid conflicts of interest (e.g. by excluding persons with financial interests in the institution that sponsors the trial). Attention was drawn to the CIOMS26 and Nuffield Council on Bioethics27 documents in which developed country sponsors should provide funds for ethics review capacity along with scientific funding. Funding of ethics committees in Africa was reported as inadequate in many cases.28 • Reference texts. In the best of cases these are guidelines published by national or international institutions, established procedures for referring and analysing processing cases, rules describing the ethics committees functioning and reports of sessions. However, the multiplicity of available texts may create confusion in some instances. Milford et al. found that few chairs and members of research ethics committees 25 E. Bekelman, Y. Li & C.G. Gross. Scope and Impact of Financial Conflicts of Interest in Biomedical Research: A Systematic Review. JAMA 2003; 289: 454–465. 26 Council for International Organizations of Medical Sciences, op. cit. note 6. 27 Nuffield Council on Bioethics. 2002. The Ethics of Research Related to Healthcare in Developing Countries. London: Nuffield Council on Bioethics. 28 C. Milford., D.R. Wassenaar & C.M. Slack. Perceived Capacity of Selected African Research Ethics Committees to Review HIV Vaccine Trial Protocols. IRB 2006; 28(2): 1–9. were aware of applicable national laws relating to health research and research ethics.29 To address the needs of ethics committees, several institutional actors must be mobilised: • • NGOs (e.g. Foro Latinoamericana de Comités de Ética en la Investigación en Salud (FLACEIS)) may motivate development in the field of ethics when the actions of the state are insufficient, without substituting for the state. They allow for (1) the establishment of a network between countries of the same continent, (2) sharing of experiences, (3) action on both pragmatic and theoretical levels, and (4) building bridges between ethics committee members, regulatory agencies, researchers and the sponsors. Their principal challenge is that many research ethics committees (RECs) lack legitimacy. However, members with standing and alliances with key institutions (like WHO) can help to overcome this. International institutions like the European Union, WHO, United Nations Educational, Scientific and Cultural Organization (UNESCO), World Medical Association (WMA), CIOMS, or foundations associated with research structures (e.g. Fogarty/NIH) may provide advice, regulatory frameworks and organise or sponsor training to foster ethics committees. For example, some agencies (like the WHO/UNAIDS AAVP) are supporting law reform to enhance participant protections and to give RECs more legitimacy. In spite of the extensive divide between the ideal and current epidemic realities, it remains possible to bring about concrete improvements in participant protections though efforts to contribute to developing institutional and individual research ethics capacity. Some such efforts were discussed and are mentioned below. ROLE OF INTERNATIONAL INSTITTUTIONS IN FOSTERING AN ETHICAL REVIEW PROCESS Several international institutions have contributed to the development of ethical review processes: the Council on Health Research for Development (COHRED), WMA, CIOMS, the European and Developing Countries Clinical Trials Partnership (EDCTP), the Wellcome Trust, the United States National Institutes of Health (NIH) Fogarty International Center, and the Council of Europe. 29 Ibid. © 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd. Ethical Issues in Medical Research in the Developing World Several possible actions and associated issues were identified The first action is the coordination and centralization of work related to research ethics, as well as the organization of dialogue between researchers from the South and North. Since 2000, one major international forum for bioethics debate has been provided by the Global Bioethics Forum, supported by various research institutions (NIH, WHO, Wellcome Trust, Institut National de la Santé et de la Recherche Médicale (INSERM), NIH/ Fogarty, Medical Research Council (MRC) (UK & SA)). COHRED has recently been appointed as the secretariat of the Global Bioethics Forum to ensure continuity between meetings, sustain focussed debates and generate useful ethical outputs, thereby promoting increased and sustained North and South participation in discussions, and giving more consideration to ethics in ethics versus science debates. The second action is the development of guidance and standards for framing international research. The specific roles of the WMA and CIOMS, respectively, in fostering an ethical review process were presented. The WMA essentially exerts its role in the ethics of research by producing policy development and review. Many researchers declare in their publications that their work was conducted in strict compliance with the Declaration of Helsinki,30 which is also used by various ethics committees in countries of the South. The WMA also plays a role in capacity building31 and ethics education.32 CIOMS is a ‘forum to consider and prepare advice on contentious issues in health and research ethics.’33 It is an international nonprofit organisation, established in 1949 by UNESCO and WHO. It focuses on aspects of research in developing countries. Special consideration is given to sociocultural, religious, and community aspects, the national legal and administrative context, the quality of care and the particular health needs of countries. 7 Particular attention is also paid to the ethical justification of research (meeting a country’s needs, translation of research into policy and practice, etc.), procedures for evaluation of ethics (ethical and scientific review, multicentre trials, etc), choice of control groups, and additional actions (strengthening capacity building in the field of ethics, provision of health care given during and beyond the trial period). The Council of Europe also plays an important role. This intergovernmental organization (regrouping 46 countries) carries out a normative function within the European Union (EU) by defining fundamental principles, seeking a balance between scientific/medical progress and human protection, and by helping EU countries to implement those principles. The major text is the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine34 (Oviédo) with an additional protocol on biomedical research, and a recommendation on research on biological material of human origin (2005).35 This text reflects European consensus and takes into account the international dimension of research. In light of the proliferation of national and international guidelines, harmonisation appears unlikely in the short term, and some questioned the desirability of harmonisation. The third possible action is the funding of a long-term partnership between Europe and developing countries to promote clinical trials through the EDCTP for investigations in tuberculosis, HIV/AIDS and malaria.36 Clinical trials in developing countries should not be undertaken without also promoting the development of the requisite capacity to evaluate the ethical dimension (Nuffield Council of Bioethics Report). Establishing and sustaining such ethical review processes is part of EDCTP activities, which are operationalised through inviting grant 30 World Medical Association (WMA). 1964. Declaration of Helsinki. As amended by the WMA 52nd General Assembly, Edinburgh, Scotland, 2000. Ferney-Voltaire: WMA. Available at: http://www.wma.net/ e/policy/b3.htm [Accessed 3 Dec 2007]. 31 They are associated with the Networking for Ethics in Biomedical Research in Africa (NEBRA) project and to two European and Developing Countries Clinical Trials Partnership (EDCTP) proposals. 32 They produce the WMA Medical Ethics Manual, write articles and organise conferences. 33 CIOMS includes over 100 international/national biomedical science organizations/bodies. This institution produced the International Ethical Guidelines For Biomedical Research Involving Human Subjects – first published in 1982, and revised in 1993, with the latest revised version being published in 2002: See Council for International Organizations of Medical Sciences op. cit. note 6. © 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd. 34 Council of Europe. 1997. Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine. Strasbourg: Council of Europe. Available at: http://conventions.coe.int/ treaty/en/Treaties/Html/164.htm [Accessed 21 Dec 2007]. 35 Council of Europe. 2005. Additional Protocol to the Convention on Human Rights and Biomedicine, Concerning Biomedical Research. Strasbourg: Council of Europe. Available at: http://conventions.coe.int/ treaty/en/Treaties/Html/195.htm. [Accessed 21 Dec 2007]. 36 The different scopes covered by this programme are: (1) the integration of European national programmes, (2) North-South partnerships to conduct clinical trials in Africa, (3) capacity building in developing countries, and (4) South-South network. 8 Christophe Perrey, Douglas Wassenaar, Shawn Gilchrist and Bernard Ivanoff applications for general capacity building, general initiatives37 and partnerships with other structures.38 The fourth field is the strengthening of local capacities in the field of ethics. WHO has a department of Ethics, Trade Human Rights and Health Law which is engaged in ethics research and capacity strengthening in all WHO’s regions. It works with countries to strengthen the ethical review process of health research, to develop capacity building, to offer technical assessment for standard-setting and regulatory issues, and to promote networking to facilitate access to information, experience exchanges and public debates. The US NIH Fogarty International Center has taken the lead in funding several large research ethics training initiatives in developed and developing countries, aimed at building sustainable training capacity and centers of excellence for scholarship and policy development in the North and South as required. The EU has begun to offer limited funding to develop international capacity in research ethics. ROLE OF THE MEDIA IN MAINTAINING ETHICAL STANDARDS The denunciation of studies on ethical grounds can seriously damage the reputation of researchers, sponsors, or investigators. Because of the ease of worldwide dissemination of information, the media have become real actors in regulation of international research. The example of Tenofovir in Cameroon demonstrates the impact of the mainstream print media working with patient groups. Yet, the mainstream press does not function with the same logic as the scientific press. It focuses more on scoops and sensational events to the detriment of rigorous analysis. Training in bioethics of research would be very beneficial to journalists and allow for better understanding and reportage of key aspects of clinical trials. Research ethics training for scientific editors may also play an important role as they determine what gets published. Publications are central to the evaluation and validation of any research and researcher. Editors’ level of involvement can be both general and specific. Editors can exert pressure on the pharmaceutical industry, or sponsors, to adhere to a high level of ethical standard 37 By supporting (1) networking with other national ethics committees at a regional level, (2) online literature and websites on ethics and clinical access, and (3) funding participants to the 6th Global Forum in Bioethics Research. 38 World Health Organisation/Special Programme for Research and Training in Tropical Diseases Strategic Initiative for Developing Capacity in Ethical Review, Networking for Biomedical Research in Africa and others. through the ‘International Committee Of Medical Journals Editors’ (Vancouver group) that published guidance for those who want to publish. Similarly, the Committee of Publishing Editors (COPE) checks research submitted for publication for conformity to the Helsinki Declaration. The Lancet has also a ‘protocol service’ which allows researchers to submit protocols for review before studies are started. Ethical considerations can thus be identified and addressed in the early stages of the research process. Editors are responsible for what they publish. The peer review process, already in debate,39 could be further undermined in the event of failure in this field. Without replacing scientific and ethical review prior to studies, editorial boards should also consider the ethical dimensions of studies they are considering for publication. Taking into consideration the very low number of studies that are rejected for publication on ethical grounds, the above arguments may appear theoretical. In this regard, some argue a difference between intent and practice. Editors and scientists alike should strive for publications reflecting the highest possible ethical and scientific standards.40 CONCLUSION The past 25 years have seen a large increase in clinical trials in developing countries, and, encouragingly, there are increasing rates of publication, training, guidance documents and workshops on the associated ethical issues. Many sponsors now systematically integrate ethical requirements into the development of research protocols and long-term projects (e.g. the South African AIDS Vaccine Initiative (SAAVI) sponsored HIV/AIDS Vaccines Ethics Group (HAVEG) in South Africa). Ethics committees in developing countries have specific capacity needs that should be carefully assessed and met, and various initiatives have taken some important steps in this regard. With the support of countries from the North, patient groups are further developing in the South. Patient advocacy groups and other professionals, such as philosophers, historians and social scientists, are also active in contributing to the ethical conduct of clinical trials. Some developing countries have given legal status to RECs and have developed supporting guidelines and policies. Lastly, recent experiences highlight the 39 40 A. Mulligan. Is Peer Review in Crisis? Oral Oncol 2005; 41: 135–141. Vasgird, op. cit. note 5. © 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd. Ethical Issues in Medical Research in the Developing World role of the media as whistle-blower, generating political attention. However, progress still needs to be made in dealing with ethics in research and promoting deep interdisciplinarity. The meeting provided the opportunity for exchange between different actors in the ever-evolving field of research ethics. Coordinated international efforts must continue to ensure that science that serves the developing and developed worlds also promotes respect for human dignity Acknowledgements This meeting was made possible by an unrestricted educational grant from Sanofi-Pasteur. Christophe Perrey, PharmD, PhD in Social Anthropology, is a researcher associated with the Groupe de Travail en Éthique et Philosophie des Sciences (GTEPS) at the Collège de France in Paris and is also an expert in ethics for the European Commission. For this institution, he reviews submitted studies and has also participated in the Networking for Ethics on Biomedical Research in Africa (NEBRA) project © 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd. 9 aimed at evaluating the needs of the ethics committees in Africa. Douglas Wassenaar is director of the South African Research Ethics Training Initiative (SARETI) and is Director of the WHO/UNAIDS African Aids Vaccine Programme working group on Ethics, Law, and Human Rights, both based at the School of Psychology, University of KwaZulu-Natal, Pietermaritzburg, South Africa, where he is Associate Professor of Psychology. Shawn Gilchrist, MD, MSc in International Health in the Tropics, and Diploma in Tropical Medicine and Hygiene from the London School of Hygiene and Tropical Medicine is the Director of Public Affairs at Sanofi Pasteur. He is responsible for relationships with international organizations and UN agencies and represents his company in professional associations. He is currently the International Federation of Pharmaceutical Manufacturers Associtation (IFPMA) vaccine industry representative on the GAVI Working group. Dr Gilchrist has a deep interest, and longstanding experience, in international health, primarily in west and central Africa. Bernard Ivanoff, PharmD, PhD, is a scientist educated in France, including at the Institut Pasteur, Paris, with a specialization in microbiology and immunology. He has a long experience in bacterial vaccines, particularly in enteric vaccines development. Dr Ivanoff spent six years in Africa as a General Director of a medical research centre and is working as Scientific Director of Fondation Mérieux. He has retired from his work at WHO.