Benefits to research subjects in international trials: Do they reduce exploitation or increase undue inducement?

Developing World Bioethics

Volumn 8, Issue 3, 2008, Pages 178-191

  Ballantyne, Angela ^a  

^a FLINDERS UNIVERSITY   (Australia)

Author keywords

Benefit sharing; Clinical trials; Consent; Developing world; Justice; Research ethics

Indexed keywords

ARTICLE; CLINICAL TRIAL; CONFLICT OF INTEREST; DEVELOPING COUNTRY; ETHICS; FINANCIAL MANAGEMENT; HUMAN; INCOME; INTERNATIONAL COOPERATION; PATIENT SELECTION; PROFESSIONAL STANDARD; RESEARCH ETHICS; SOCIAL JUSTICE; VULNERABLE POPULATION;

CLINICAL TRIALS AS TOPIC; CONFLICT OF INTEREST; DEVELOPING COUNTRIES; ETHICS COMMITTEES, RESEARCH; ETHICS, RESEARCH; HUMANS; INCOME; INTERNATIONALITY; PATIENT SELECTION; RESEARCH SUPPORT AS TOPIC; SOCIAL JUSTICE; VULNERABLE POPULATIONS;

EID: 57349125037     PISSN: 14718731     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.1471-8847.2006.00175.x     Document Type: Article

References (113)

1. The Council for International Organizations of Medical Sciences (CIOMS) defines externally-sponsored research as: 'research undertaken in a host country but sponsored, financed, and sometimes wholly or partly carried out by an external international or national organization or pharmaceutical company with the collaboration or agreement of the appropriate authorities, institutions and personnel of the host country.' Council for International Organisations of Medical Science (CIOMS). 1993. International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: CIOMS: Guideline 3.
2. The 2001 collection of papers selected by Udo Schüklenk provides a good overview of the controversy surrounding the AZT trials, including the question of whether the trial participants were exploited. See U. Schüklenk, ed. 2001. AIDS: Society. Ethics and Law. Dartmouth: Ashgate (in particular pp. 403-431);
3. G.J. Annas & M.A. Grodin. Human Rights and Maternal-Fetal HIV Transmission Prevention Trials in Africa. Am J Public Health 1998; 88: 560-563: 561;
4. R. Bayer. The Debate over Maternal-Fetal HIV Transmission Prevention Trials in Africa, Asia and the Caribbean: Racists Exploitation or Exploitation of Racism. Am J Public Health 1998; 88: 567-570;
5. R.A. Crouch & J.D. Arras. AZT Trials and Tribulations. Hastings Cent Rep 1998; 28(6): 26-34:
6. E.J. Emanuel. A World of Research Subjects. Hastings Cent Rep 28(6): 25-26;
7. H. Varmus & D. Satcher. Ethical Complexities of Conducting Research in Developing Countries. N Engl J Med 1988; 337: 1003-1005.
8. R. Macklin. 2004. Double Standards in Medical Research in Developing Countries. Cambridge: Cambridge University Press; S.R. Benatar. Towards Progress in Resolving Dilemmas in International Research Ethics. J Law Med Ethics 2004: 32: 574-583;
9. B.A. Brody. Ethical Issues in Clinical Trials in Developing Countries. Slat Med 2002; 21: 2853-2858;
10. D. Buchanan. Principles of Early Stopping of Randomized Trials for Efficacy: A Critique of Equipoise and an Alternative Nonexploitation Ethical Framework. Kennedy Inst Ethics J 2005; 15: 161-178;
11. N.S. Jecker. Exploiting Subjects in Placebo-controlled Trials. Am J Bioeth 2002; 2(2): 19-20;
12. D. Resnik. The Ethics of HIV Research in Developing Nations. Bioethics 1998; 12: 286-306;
13. D. Resnik. Exploitation and the Ethics of Clinical Trials. Am J Bioeth 2002; 2(2): 28-30.
14. D. Resnik. Exploitation in Biomedical Research. Theor Med 2003; 24: 233-259;
15. The Participants of the 2001 Conference on Ethical Aspects of Research in Developing Countries (hereafter Participants). Moral Standards for Research in Developing Countries: From 'Reasonable Availability' to 'Fair Benefits'. Hastings Cent Rep 2004; 34(3): 17-28.
16. D.G. Arnold. Exploitation and the Sweatshop Quandary. Bus Ethics Q 2003; 13: 243-256;
17. Buchanan, ibid; Jecker, ibid; C. Meyer. Wrongful Beneficence: Exploitation and Third World Sweatshops. J Soc Philos 2004; 35: 319-333;
18. Resnik, ibid, 2003.
19. Council of International Organizations of Medical Sciences, op. cit. note 1, Guideline 7: Inducement to Participate; Nuffield Council on Bioethics. 2002. The Ethics of Research Related to Healthcare in Developing Countries. London: Nuffield Council on Bioethics: 79: paragraph 6.29;
20. National Bioethics Advisory Commission (NBAC). 2001. Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries. Bethesda, MD: NBAC: 60; Joint United Nations Programme on HIV/AIDS (UNAIDS). 2000. Ethical Considerations in HIV Preventive Vaccine Research. Geneva: UNAIDS: 42. Available at http://www.unaids.org/html/pub/ publications/irc-pub01/jc072-ethicalcons-en-pdf.pdf [Accessed 20 August 2006].
21. R. Dresser. Payment to Research Participants: The Importance of Context. Am J Bioeth 2001; 1(2): 47.
22. R. Macklin. The Paradoxical Case of Payment as Benefit to Research Subjects. IRB 1989; 11(6): 1-3: 1.
23. Analytic accounts of exploitation fall into two broad categories; these are not strict, mutually exclusive categories, rather, they represent a difference in focus and emphasis. The first category is 'fair-outcomes' accounts, which define exploitation primarily in terms of fairness; in particular they define exploitation in terms of an unfair distribution of benefits and burdens. These accounts are often characterised by concepts such as taking unfair advantage, or inadequate compensating benefits for the exploitee and/or a disproportionate gain for the exploiter. The second category is often referred to as Kantian accounts of exploitation. In addition to the concept of fairness, Kantian accounts also tend to give weight to elements of 'consent', 'use' and 'dignity'; they are characterised by concepts such as wrongful use. taking advantage and treating as a (mere) means. I favour a fair outcomes approach because the Kantian accounts define exploitation in terms of other independent moral wrongdoings and, thus, do not provide an account of what is distinctively wrong with exploitation. Further, in focusing on the unfair outcomes of transactions, the fair-outcome accounts provide clearer 'tests' of when exploitation has occurred in the real world. By contrast, Kantian concepts such as 'wrongful use' and 'using as a mere means' can be too vague to be applicable in practice. For examples of fair-outcome accounts, see: Arnold, op. cit. note 3;
24. Buchanan, op. cit. note 2;
25. Jecker, op. cit. note 2;
26. Meyer, op. cit. note 3;
27. Resnik, op. cit. note 2, 2003. For examples of Kantian accounts, see Allen Wood's account of exploitation in, A. Wood. Exploitation. Soc Philos Policy 1995; 12: 135-58;
28. D.G Arnold & N.E. Bowie. Sweatshops and Respect for Persons. Bus Ethics Q 2003; 13: 221-242;
29. A. Buchanan. 1985. Ethics, Efficiency, and the Market. Totowa, NJ: Rowman and Allanheld: 87.
30. A. Wertheimer. 1996. Exploitation. Princeton, NJ: Princeton University Press.
31. A. Ballantyne. HIV International Clinical Research: Exploitation and Risk. Bioethics 2005; 19: 476-491.
32. See, for example. Macklin, op. cit. note 2;
33. Participants, op. cit. note 2;
34. K. Shapiro & S.R. Benatar. HIV Prevention Research and Global Inequality: Steps Towards Improved Standards of Care. J Med Ethics 2005; 31: 39-47;
35. Annas & Grodin, op. cit. note 2.
36. nd ed. New Haven, CT: Yale University Press: 42-57. Summarised in this way by C. Weijer. The Ethical Analysis of Risk. J Law Med Ethics 2000; 28: 344-361.
37. N. King. Defining and Describing Benefit Appropriately in Clinical Trials. J Law Med Ethics 2000; 28: 332-347: 333.
38. P. Lurie & S.M. Wolfe. Unethical Trials of Interventions to Reduce Perinatal Transmission of the Human Immunodeficiency Virus in Developing Countries. N Engl J Med 1997; 337: 853-856.
39. Shapiro & Benatar, op. cit. note 9.
40. Macklin, op. cit. note 2. pp. 120-121.
41. Ballantyne, op. cit. note 9. Here, I argued that a standardised infrastructure charge of 10-15% (for public funding agencies) and 20-30% (for pharmaceutical companies), on top of the existing costs of the trial, should be invested in local health infrastructure that would benefit the research population and the host community. I argued that this model had the following advantages: it represents a substantial benefit that significantly increases the benefit realised by trial participants and should have a sizable impact on participants' welfare; it increases the benefit to the worst-off; the benefit is guaranteed rather than potential; the model is both financially and practically feasible; and difference in the level of the infrastructure charge reflects different sponsor's expected gain.
42. For example, the following authors argue that the provision of direct benefit to trial populations in the form of capacity building can prevent or reduce exploitation. Shapiro & Benatar, op. cit. note 9;
43. Annas & Grodin, op. cit. note 2;
44. Macklin, op. cit. note 2;
45. P. Lurie et al. Ethical, Behavioral, and Social Aspects of HIV Vaccine Trials in Developing Countries. JAMA 1994:271: 295-301: 297;
46. Nuffield Council on Bioethics, op. cit. note 4: 52: paragraph 4.20.
47. See also, Council of International Organizations of Medical Sciences, op. cit. note 1, Guideline 20 (Strengthening capacity for ethical and scientific review and biomedical research) and the text of the 2002 revised CIOMS guidelines, which make it clear that capacity building is viewed as an effective method for reducing exploitation. Council of International Organizations of Medical Sciences (CIOMS). 2002. International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: CIOMS in collaboration with the World Health Organisation (WHO). Available at: http://www.cioms.ch/frame-guidelines-nov-2002.htm [Accessed 28 July 2006].
48. Nuffield Council on Bioethics, op. cit. note 4, p. 52: paragraph 4.20.
49. M.E. Watanabe. HIV/AIDS Trials in Developing Countries Must Clear High Hurdles. Scientist 2003; 17(2): 22.
50. Shapiro & Benatar, in an article about global equity and research, for example, make a recommendation that "a minimum of 1% of the costs of a research project be allocated towards improving the SOC [standard of care] in association with the project.' Shapiro & Benatar, op. cit. note 9. I agree with Shapiro & Benatar that standardised guidelines regarding the level of required investment should be in place, but I argue for a significantly higher threshold.
51. See The Global Alliance for TB Drug Development. 2001. Economics of TB Drug Development. New York, NY: The Global Alliance for TB Drug Development: 57-58. Available at: http://66.216.124.114/pdf/ Economics%20Report%20Full%20(final).pdf [Accessed 20 Aug 2004]; and M.P. Flaherty et al. The Body Hunters: Overwhelming the Watchdogs. Washington Post 18 December: A01.
52. Research and Markets Ltd. 2003. The Global Pharmaceutical Market Experienced Sales of $466bn in 2003 up from $317bn in 2000. Press Release, 3 June. Dublin: Research and Markets Ltd. Available at: http://www.prweb.eom/releases/2004/6/prwebl 30626.htm [Accessed 20 Aug 2006].
53. For example, Prilosec, a drug for heartburn, brought in USS6 bn a year for AstraZenenca. M. Angell. 2005. The Truth About the Drug Companies. New York, NY: Random House: 15.
54. These figures are based on the fact the NIH in the United States (US) currently allows US researchers conducting trials in developing countries to apply for an extra 8% of the trial funds to be paid to the host country as a facilities and administrative cost. National Institutes of Health (NIH). 2002. Global Health Research Initiative Program for New Foreign Investigators (ROD. Bethesda. MD: National Institutes of Health. Available at http://grants2.nih.gov/grants/guide/rfa-files/RFA-TW-02-002.html [Accessed 20 Aug 2006], Eight per cent is low compared to the comparative costs of running trials in institutions in the developed world. Academic institutions in the US can receive up to 60% of research awards as overhead costs; Shapiro & Benatar, op. cit. note 10.
55. S. Rai. 2005. Drug Companies Cut Costs with Foreign Clinical Trials. New York Times 24 February: C4;
56. Angell, op. cit. note 23, p. 22. Angell confirms that clinical research is the most expensive component of research and development.
57. Rai, ibid.
58. The Global Alliance for TB Drug Development, op. cit. note 21, pp. 56-57.
59. D. Orentlicher. Universality and its Limits: When Research Ethics Can Reflect Local Circumstances. J Law Med Ethics 2002; 30: 403-410. See David Orentlicher's paper about the exploitation in AZT trials conducted in developing countries during the 1990s. Orentlicher comes. to some interesting conclusions regarding the appropriate ways of redis-tributing gains in order to reduce exploitation. He argues, that one can accept universal principles of research ethics whilst acknowledging that those principles may, when applied in different circumstances, allow for different forms of benefit for different trial populations.
60. See note 4.
61. See the review in M. Wilkinson & A. Moore. Inducement in Research. Bioethics 1997; 11: 373-389. The review includes analysis of guidelines for ethics committees in Australia, New Zealand, the United States and Britain.
62. Nuffield Council on Bioethics, op. cit. note 4, p. 78: paragraph 6.26.
63. For example, Wilkinson & Moore argue in favour of allowing cash, payments to competent people to act as research subjects. Wilkinson & Moore, op. cit. note 28, p. 375.
64. See also J. Savulescu. The Fiction of 'Undue Inducement': Why Researchers Should be Allowed to Pay Participants any Amount of Money for any Reasonable Research. Project. Am J Bioeth 2001; 1(2): 1-3.
65. C. Grady. Money for Research. Participation: Does it Jeopardize Informed Consent? Am J Bioeth 2001; 1(2): 40-44.
66. Wilkinson & Moore, op. cit. note 30, p. 380.
67. See also P. McNeill. Paying People to Participate in Research: Why Not? Bioethics 1997; 11: 390-396.
68. Wilkinson & Moore, op. cit. note 30. p. 380.
69. Council for International Organisations of Medical Science, op. cit. note 1. Guideline 7: Inducement to participate.
70. National Bioethics Advisory Commission, op. cit. note 4, p. 60.
71. Financial rewards can, in some cases, be used to 'purchase' medical care and treatment, thus resulting in an overlap between the incentives generated by financial reward and the incentives generated through access to medical care. However, in many cases financial reward cannot be directly exchanged for the desired medical care. Safe and effective treatment for the medical condition in question may not exist, may be prohibitively expensive, may not be approved for sale in the patient's country, and/or there may be inadequate medical monitoring to support the safe use of the treatment. When and how financial rewards can be exchanged for medical treatment differs from case to case and so I leave the issue aside for now. It is, however, important to be aware that in cases where financial rewards for trial participation can be easily transformed into medical care, financial rewards will generate similar incentives to those generated by the direct assess to medical care during the trial.
72. S.D. Halpern et al. Hypertensive Patients' Willingness to Participate in Placebo-controlled Trials: Implications for Recruitment Efficiency. Am Heart J 2003; 1.46: 944-945.
73. Z.A. Nurgat et al. Patient Motivations Surrounding Participation in Phase I and Phase II Clinical Trials of Cancer Chemotherapy. Br J Cancer 2005; 92: 1001-1005.
74. M.E. Mattson et al. Participation in a Clinical Trial: The Patients' Point of View. Control Clin Trials 1985; 6: 156-167.
75. A. survey of the public perception of clinical trial participation in Japan, found that survey respondents demonstrated a greater willingness to volunteer for research if there were direct benefits to themselves or their families. A. Asai et al. Focus Group Interviews Examining Attitudes toward Medical Research among the Japanese: A Qualitative Study. Bioethics 2004; 18: 448-470.
76. E.G. Bevan et al. Patients' Attitudes to Participation in Clinical Trials. Br J Clin Pharmacol 1993; 35: 204-207.
77. J. Aby et al. Motivation for Participation in Clinical Trials of Drugs for the Treatment of Asthma, Seasonal Allergic Rhinitis, and Perennial Nonallergic Rhinitis. Ann Allergy Asthma Immunol 1996; 76: 348-354.
78. S.D. Halpern. Towards Evidence Based Bioethics. BMJ 2005; 331: 901-903: 901.
79. S.D. Halpern et al. Empirical Assessment of whether Moderate Payments are Undue or Unjust Inducements for Participation in Clinical Trials. Arch Intern Med 2004; 164: 801-803.
80. J.P. Bentley & P.G. Thacker. The Influence of Risk and Monetary Payment on the Research Participation Decision Making Process. J Med Ethics 2004; 30: 293-298.
81. Ibid: 295.
82. Ibid: 296.
83. Ibid.
84. Ibid: 297.
85. For example, the research by Z.A. Nurgat et al., op. cit. note 40.
86. World Health Organisation (WHO) and Joint United Nations Programme on HIV/AIDS (UNAIDS) 2004. Consultation on Ethics and Equitable Access to Treatment and Care for HIV/AIDS. Geneva: WHO/UNAIDS: 4.
87. Quoted in The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT). 2000. A Model for HIV-AIDS Clinical Research in a Developing Country. Geneva: Joint United Nations Programme on HIV/AIDS (UNAIDS): 42.
88. Ibid: 41.
89. S. LaFraniere et al. The Dilemma: Submit or Suffer. Washington Post 19 December: A01.
90. Ibid.
91. Ibid: A01.
92. See the UNAIDS vaccine research guidance document for a list of criteria that can lead to increased vulnerability of potential research participants. Joint United Nations Programme on. HIV/AIDS 2000, op. cit. note 4, pp. 15-16.
93. T. Lemmens & C. Elliot. Guinea Pigs on the Payroll: The Ethics of Paying Research Subjects. Account Res 1999; 7: 3-20;
94. D. Resnik. Research Participation and Financial Inducements. Am J Bioeth 2001; 1(2): 54-56: 55.
95. Lemmens & Elliot, ibid: 55.
96. Ibid.
97. J. Stephens. As Drug Testing Spreads, Profits and Lives Hang in Balance. Washington Post 17 December: AOl;
98. K. Ahmad. Drug Company Sued over Research Trial in Nigeria. Lancet 2001; 358: 815;
99. D. Malakoff. Nigerian Families Sue Pfizer, Testing the Reach of U.S. Law. Science 2001; 293: 1742.
100. Resnik, op. cit. note 59, p. 55.
101. Ibid.
102. See notes 44-46.
103. The exception would again be cases where financial rewards can be exchanged for access to medical care and treatment. See note 38.
104. Research ethics committees in. different countries operate according to different terms of reference and have varying degrees of flexibility. Some committees may operate according to strict written guidelines with little room for interpretation. It may be difficult for such committees to take on the role of determining the fair infrastructure charge on a case-by-case basis. That said, the role of research ethics committees has continued to evolve and it seems reasonable that their terms of reference could be adjusted to incorporate this new role if it were seen to be a crucial means of protecting vulnerable populations from exploitation.
105. Macklin, op. cit. note 6, p. 3.
106. Ibid. See the National Bioethics Advisory Commission report which mirrors this concern, and, therefore, recommends that ethics review committees should exclude any potential post-trial interventions from the category of benefits they consider when making an assessment of the expected risk-benefits balance in research protocols under consideration. National Bioethics Advisory Commission, op. cit. note 4.
107. The Participants, op. cit. note 2.
108. Also see the discussion of the role of institutional review committees in assessing therapeutic and nontherapeutic risks and benefits in research, in C. Weijer. The Ethical Analysis of Risk in Intensive Care Unit Research. Crit Care 2004; 8: 85-86.
109. Savulescu, op. cit. note 32.
110. Indeed, Zink argues along these lines. He contends that to deny research subjects the opportunity for payment would not only exploit them but would potentially create a system of real coercion for participants. He asks, 'To what lengths would drug manufacturers go to recruit subjects who could not be offered financial compensation?' See S. Zink. Maybe We Should Pay Them More. Am. J Bioeth 2001; 1(2): 88.
111. Savulescu, op. cit. note 32, p. 3.
112. McGee raises the concern that clinical benefits may constitute an undue inducement in G. McGee. Paid in Full? Am J Bioeth 2001; 1(2): 1. Christine Grady concludes that there is nothing unique about money's ability to distort judgments about the risks and benefits of research, the chance for treatment or medical care can be equally distorting given certain background conditions.
113. See Grady, op. cit. note 33.