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Placebo orthodoxy and the double standard of care in multinational clinical research

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Abstract

It has been almost 20 years since the field of bioethics was galvanized by a controversial series of multinational AZT trials employing placebo controls on pregnant HIV-positive women in the developing world even though a standard of care existed in the sponsor countries. The trove of ethical investigations that followed was thoughtful and challenging, yet an important and problematic methodological assumption was left unexplored. In this article, I revisit the famous “double standard of care” case study in order to offer novel consideration of the placebo orthodoxy that underlies much of the ethical debate. This majority view found in medical research is that placebo-controlled trials are methodologically superior to comparative trials that use active controls. I challenge this orthodoxy and argue that lives were unnecessarily lost in these trials as a result. Furthermore, current HIV research on vaccines and microbicides is now poised to repeat the error of subscribing to the placebo orthodoxy.

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Notes

  1. PCTs, by contrast, are typically superiority trials, which determine the difference between two interventions.

  2. Spencer P. Hey and Charles Weijer [54] similarly called for totality of evidence in properly inferring both claims of efficacy and efficiency in clinical trials. They proposed that “what is needed … is a series of trials, whose various designs are perturbed to optimally contribute toward demonstrating a robust pattern of evidence” [54, p. 3]. This convergence of conclusions is not surprising, as the “totality of evidence argument” follows from Anderson’s observation [53] that Temple and Ellenberg’s [39] concern that ACETs rely on external information is just an instance of Duhemian under-determination.

  3. While this patchwork of inferential information made a sufficiently strong case against the need for PCTs, it was not strong enough to preclude the need for further experimentation all together. Before implementing large-scale health interventions that impact the lives of many and utilize considerable resources, one needs more secure data than reasonable sounding inferences. Direct experimentation is generally more trustworthy. The inferential data, however, was compelling enough to help determine what kind of direct experimentation should be undertaken.

  4. One might object that the NIH and CDC could have been genuinely motivated by cost considerations rather than placebo orthodoxy in their promotion of PCTs, given that my arguments regarding the limits of statistical significance testing only make the case that PCTs should not be cheaper that ACETs if the former are conducted well. Instead, PCTs are cheaper when their evidentiary limits are accepted or ignored. It is not known what knowledge the NIH and CDC had regarding those design limits at the time of this controversy, and how that knowledge had impacted institutional practice. I thank an anonymous reviewer for bringing this point to my attention.

References

  1. Lurie, Peter, Sidney M. Wolfe, Wilbert Jordan, George J. Annas, Michael Grodin, and George Silver. 1997. Letter to the Department of HHS concerning their funding of unethical trials which administer placebos to HIV-infected pregnant women through NIH and the Centers for Disease Control. HRG Publication #1415. April 22, 1997. http://www.citizen.org/publications/publicationredirect.cfm?ID=6612. Accessed Sept. 25, 2014.

  2. O’Connor, Edward M., Rhoda S. Sperling, Richard Gelber, et al. 1994. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with Zidovudine treatment. New England Journal of Medicine 221(18): 1173–1180.

    Google Scholar 

  3. Varmus, Harold, and David Satcher. 1997. Ethical complexities of conducting research in developing countries. New England Journal of Medicine 337(14): 1003–1005.

    Article  Google Scholar 

  4. Pratt, Bridget, and Bebe Loff. 2013. Linking international research to global health equity: The limited role of bioethics. Bioethics 27(4): 208–214.

    Article  Google Scholar 

  5. World Medical Association. 1996. Declaration of Helsinki. 48th WMA General Assembly, Somerset West, South Africa.

  6. World Health Organization. 1994. Recommendations from the Meeting on mother-to-infant transmission of HIV by use of antiretrovirals. Geneva: WHO, 1994. http://www.columbia.edu/cu/musher/AIDS_case/geneva_conference.htm. Accessed Nov. 12, 2013.

  7. Wolfe, Sidney M., and Peter Lurie. 1997. Letter to President Clinton urging him to stop sponsoring unethical biomedical research on mother-to-infant HIV transmission in developing countries. HRG Publication #1419. June 11, 1997. http://www.citizen.org/Page.aspx?pid=4070. Accessed Oct. 7, 2013.

  8. Lurie, Peter, and Sydney M. Wolfe. 1997. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. New England Journal of Medicine 337(12): 853–856.

    Article  Google Scholar 

  9. French, Howard W. 1997. AIDS research in Africa: Juggling risks and hopes. New York Times, October 9.

  10. Cohen, Jon. 1997. Ethics of AZT studies in poorer countries attacked. Science 276: 1022.

    Article  Google Scholar 

  11. Bagenda, Danstan, Philippa Musoke-Mudido, Susan Okie, and Marcia Angell. 1997. A look at ethics and AIDS—we’re trying to help our sickest people, not exploit them: In the researcher’s code of conduct, contradictions abound. Washington Post, September 28: C3.

  12. Stolberg, Sheryl Gay. 1998. Placebo use halted in studies of AIDS: Placebo use is suspended in overseas AIDS trials. New York Times, February 19: A1, A16.

  13. Angell, Marcia. 1997. The ethics of clinical research in the third world. New England Journal of Medicine 227(12): 847–849.

    Article  Google Scholar 

  14. Macklin, Ruth. 2001. After Helsinki: Unresolved issues in international research. Kennedy Institute of Ethics Journal 11(1): 17–36.

    Article  Google Scholar 

  15. Lie, Reidar K., Ezekiel Emanuel, Christine Grady, and David Wendler. 2004. The standard of care debate: the Declaration of Helsinki versus the international consensus opinion. Journal of Medical Ethics 30(2): 190–193.

    Article  Google Scholar 

  16. Glantz, Leonard H., George J. Annas, Michael A. Grodin, and Wendy K. Mariner. 1998. Research in developing countries: Taking “benefit” seriously. Hastings Center Report 28(6): 38–42.

    Article  Google Scholar 

  17. Crouch, Robert A., and John D. Arras. 1998. AZT trials and tribulations. Hastings Center Report 28(6): 26–34.

    Article  Google Scholar 

  18. Arras, John D. 2004. Fair benefits in international medical research. Hasting Center Report 34(3): 3.

    Google Scholar 

  19. Participants in the 2001 Conference on Ethical Aspects of Research in Developing Countries. 2004. Moral standards for research in developing countries: From “reasonable availability” to “fair benefits.” Hastings Center Report 34(3): 17-26.

  20. Harris, John. 2008. Global norms, informed consent, and hypocrisy in bioethics. In Global bioethics: Issues of conscience for the twenty-first century, ed. Ronald M. Green, Aine Donovan, and Steven A. Jauss, 297–322. New York: Oxford University Press.

    Google Scholar 

  21. Baylis, Francois. 2008. Global norms in bioethics: Problems and prospects. In Global bioethics: Issues of conscience for the twenty-first century, ed. Ronald M. Green, Aine Donovan, and Steven A. Jauss, 323–339. New York: Oxford University Press.

    Google Scholar 

  22. Schuklenk, Udo. 1998. Unethical HIV perinatal trials establish bad precedent. Bioethics 12(4): 312–319.

    Article  Google Scholar 

  23. Macklin, Ruth. 2003. Bioethics, vulnerability and protection. Bioethics 17: 473–486.

    Article  Google Scholar 

  24. Benatar, Solomon R., and Peter A. Singer. 2000. A new look at international research ethics. British Medical Journal 321: 324–326.

    Article  Google Scholar 

  25. London, Alex J. 2005. Justice and the human development approach to international research. Hastings Center Report 35(1): 24–37.

    Article  Google Scholar 

  26. Levine, Carole. 1998. Placebos and HIV: Lessons learned. Hastings Center Report 28(6): 43–48.

    Article  Google Scholar 

  27. Spławiński, Jacek, and Jerzy Kuźniar. 2004. Clinical trials: Active control vs placebo—what is ethical? Science and Engineering Ethics 10(1): 73–79.

    Article  Google Scholar 

  28. Levine, Robert J. 2000. Some recent developments in the international guidelines on the ethics of research involving human subjects. Annals of the New York Academy of Science 918: 170–178.

    Article  Google Scholar 

  29. Miller, Franklin G., and Howard Brody. 2003. A critique of clinical equipoise: Therapeutic misconception in the ethics of clinical trials. Hastings Center Report 33(1): 19–28.

    Article  Google Scholar 

  30. Macklin, Ruth. 2004. Double standards in medical research in developing countries. New York: Cambridge University Press.

    Book  Google Scholar 

  31. Annas, George, and Michael Grodin. 1998. Human rights and maternal-fetal HIV transmission prevention trials in Africa. American Journal of Public Health 88(4): 560–563.

    Article  Google Scholar 

  32. Council for International Organizations of Medical Sciences (CIOMS). 2002. International ethical guidelines for biomedical research involving human subjects. Geneva: CIOMS.

    Google Scholar 

  33. World Medical Association. 2008. Declaration of Helsinki. 59th WMA General Assembly, Seoul, Korea.

  34. Shaffer, Nathan, Rutt Chuachoowong, Philip A. Mock, et al. 1999. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: A randomised controlled trial. Lancet 353: 773–780.

    Article  Google Scholar 

  35. Rothman, Kenneth J., and Karin B. Michels. 1994. The continued unethical use of placebo controls. New England Journal of Medicine 331: 394–398.

    Article  Google Scholar 

  36. Rothman, Kenneth J. 1996. Placebo mania. British Medical Journal 313: 3–4.

    Article  Google Scholar 

  37. Freedman, Benjamin, Charles Weijer, and Kathleen Cranley Glass. 1996. Placebo orthodoxy in clinical research I: Empirical and methodological myths. Journal of Law, Medicine and Ethics 24: 243–251.

    Article  Google Scholar 

  38. Temple, Robert. 1982. Government viewpoint of clinical trials. Drug Information Journal 16: 10–17.

    Google Scholar 

  39. Temple, Robert, and Susan S. Ellenberg. 2000. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: Ethical and scientific issues. Annals of Internal Medicine 133(6): 455–463.

    Article  Google Scholar 

  40. Moerman, Daniel E. 1983. General medical effectiveness and human biology: Placebo effects in the treatment of ulcer disease. Medical Anthropology Quarterly 14(4): 3–13–16.

    Article  Google Scholar 

  41. Moerman, Daniel E. 2000. Cultural variation in the placebo effect. Ulcers, anxiety, and blood pressure. Medical Anthropology Quarterly 14(1): 51–72.

    Article  Google Scholar 

  42. Freedman, Benjamin. 1990. Placebo-controlled trials and the logic of clinical purpose. IRB 12(6): 1–6.

    Article  Google Scholar 

  43. Center for Disease Control and Prevention. 1997. CDC studies of AZT to prevent mother-to-child HIV transmission in developing countries. AIDSinfo. http://aidsinfo.nih.gov/news/363/cdc-studies-of-azt-to-prevent-mother-to-child-hiv-transmission-in-developing-countries. Accessed Nov. 29, 2013.

  44. Weijer, Charles. 1999. Placebo-controlled trials in schizophrenia: Are they ethical? Are they necessary? Schizophrenia Research 35: 211–218.

    Article  Google Scholar 

  45. Hróbjartsson, A., E. Forfang, M.T. Haahr, B. Als-Nielsen, and S. Brorson. 2007. Blinded trials taken to the test: An analysis of randomized clinical trials that report tests for the success of blinding. International Journal of Epidemiology 36(3): 654–663.

    Article  Google Scholar 

  46. Shapiro, Stan, Dean Fergusson, and Glass Kathleen Cranley. 2010. Substituting placebo for established, effective therapy: Why not? Canadian Medical Association Journal 182(16): 1749–1753.

    Article  Google Scholar 

  47. Howick, Jeremy. 2009. Examining the alleged methodological superiority of placebo over ‘active’ controls. American Journal of Bioethics-Neuroscience 9(9): 34–48.

    Article  Google Scholar 

  48. Salsburg, David S. 1985. The religion of statistics as practiced in med journals. The American Statistician 39(3): 220–223.

    Google Scholar 

  49. Gardner, Martin J., and Douglas G. Altman. 1986. Confidence intervals rather than P values: Estimation rather than hypothesis testing. British Medical Journal 292: 746–750.

    Article  Google Scholar 

  50. Rothman, Kenneth J. 1986. Significance questing. Annals of Internal Medicine 105(3): 445–447.

    Article  Google Scholar 

  51. Savitz, David A. 1993. Is statistical significance testing useful in interpreting data? Reproductive Toxicology 7(2): 95–100.

    Article  Google Scholar 

  52. Pandis, Nikolaos. 2013. Confidence intervals rather than p values. American Journal of Orthodontics and Dentofacial Orthopedics 143(2): 293–294.

    Article  Google Scholar 

  53. Anderson, James A. 2006. The ethics and science of placebo-controlled trials: Assay sensitivity and the Duhem-Quine thesis. Journal of Medicine and Philosophy 31(1): 65–81.

    Article  Google Scholar 

  54. Hey, Spencer Phillips, and Charles Weijer. 2013. Assay sensitivity and the epistemic contexts of clinical trials. Perspectives in Biology and Medicine 56(1): 1–17.

    Article  Google Scholar 

  55. Hill, Austin Bradford. 1963. Medical ethics and controlled trials. British Medical Journal 1: 1043–1049.

    Article  Google Scholar 

  56. Wolfe, Sydney M., and Peter Lurie. 1997. Letter concerning unethical placebo-controlled studies on HIV-positive pregnant women in developing countries. HRG Publication #1430. October 23. http://www.citizen.org/Page.aspx?pid=2411. Accessed Jan. 2, 2015.

  57. Public Citizen. 1998. Dozens of Thai infants needlessly infected with HIV in unethical U.S. government-funded study. [Press release]. HRG Publication #1433. http://www.citizen.org/pressroom/pressroomredirect.cfm?ID=238. Accessed Jan. 2, 2015.

  58. Guay, Laura A., Philippa Musoke, Thomas Fleming, et al. 1999. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 354: 795–802.

    Article  Google Scholar 

  59. Dabis, Francois, Philippe Msellati, Nicolas Meda, et al. 1999. 6-month efficacy, tolerance, and acceptability of a short regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Côte d’Ivoire and Burkina Faso: A double-blind placebo-controlled multicentre trial. Lancet 353: 786–792.

    Article  Google Scholar 

  60. Wiktor, Stefan Z., Ehounou Ekpini, John M. Karon, et al. 1999. Short-course oral zidovudine for prevention of mother-to-child transmission of HIV-1 in Abidjan, Côte d’Ivoire: A randomised trial. Lancet 353: 781–785.

    Article  Google Scholar 

  61. Lallemant, Marc, Gonzague Jourdain, Sophie Le Coeur, et al. 2000. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. New England Journal of Medicine 343: 982–991.

    Article  Google Scholar 

  62. Macklin, Ruth. 2010. Intertwining biomedical research and public health in HIV microbicide research. Public Health Ethics 3(3): 199–209.

    Article  Google Scholar 

  63. Kourany, Janet. 2010. Philosophy of science after feminism. Oxford: Oxford University Press.

    Book  Google Scholar 

  64. Tuana, Nancy. 2010. Leading with ethics, aiming for policy: New opportunities for philosophy of science. Synthese 177(3): 471–492.

    Article  Google Scholar 

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  1. Department of Philosophy, University of Guelph, Guelph, ON, N1G 2W1, Canada

    Maya J. Goldenberg

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Goldenberg, M.J. Placebo orthodoxy and the double standard of care in multinational clinical research. Theor Med Bioeth 36, 7–23 (2015). https://doi.org/10.1007/s11017-015-9317-9

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