Placebo controlled trials: Restrictions, not prohibitions

Cambridge Quarterly of Healthcare Ethics

Volumn 13, Issue 4, 2004, Pages 380-393

  Iltis, Ana Smith ^a  

^a SAINT LOUIS UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIDEPRESSANT AGENT;

BENEFICENCE; CLINICAL PRACTICE; CULTURAL ANTHROPOLOGY; ETHICS; EXPECTATION; GENERAL PRACTITIONER; HEALTH CARE; HUMAN; INFORMED CONSENT; LEGAL ASPECT; MEDICAL INFORMATION; MEDICAL RESEARCH; MENTAL DISEASE; MORALITY; OXYGEN CONCENTRATION; PATIENT ATTITUDE; PHYSICIAN; PUBLIC HEALTH; REVIEW; RISK ASSESSMENT;

EID: 7044254698     PISSN: 09631801     EISSN: None     Source Type: Journal    
DOI: 10.1017/s0963180104134099     Document Type: Review

References (46)

1. See: Freedman B. Equipoise and the ethics of clinical research. New England Journal of Medicine 1987;317:141-5; Miller FD, Rosenstein DL, DeRenzo EG. Professional integrity in clinical research. JAMA 1998;280:1449-54; Rothman K, Michels K. The continuing unethical use of placebo controls. New England Journal of Medicine 1994;331:394-8; Freedman B, Glass K, Weijer C. Placebo orthodoxy in clinical research: part 1. empirical and methodological myths. Journal of Law, Medicine, and Ethics 1996a;24:243-51; Freedman B, Glass K, Weijer, C. Placebo orthodoxy in clinical research: part 2. ethical, legal, and regulatory myths. Journal of Law, Medicine, and Ethics 1996b;24:252-9; Rothman K. Declaration of Helsinki should be strengthened. BMJ 2000;321:442-5; Emanuel E, Miller F. The ethics of placebo-controlled trials: a middle ground. New England Journal of Medicine 2001;345:915-9; Miller F, Brody H. What makes placebo-controlled trials unethical? American Journal of Bioethics 2002;2(2):3-9.
2. See: Freedman B. Equipoise and the ethics of clinical research. New England Journal of Medicine 1987;317:141-5; Miller FD, Rosenstein DL, DeRenzo EG. Professional integrity in clinical research. JAMA 1998;280:1449-54; Rothman K, Michels K. The continuing unethical use of placebo controls. New England Journal of Medicine 1994;331:394-8; Freedman B, Glass K, Weijer C. Placebo orthodoxy in clinical research: part 1. empirical and methodological myths. Journal of Law, Medicine, and Ethics 1996a;24:243-51; Freedman B, Glass K, Weijer, C. Placebo orthodoxy in clinical research: part 2. ethical, legal, and regulatory myths. Journal of Law, Medicine, and Ethics 1996b;24:252-9; Rothman K. Declaration of Helsinki should be strengthened. BMJ 2000;321:442-5; Emanuel E, Miller F. The ethics of placebo-controlled trials: a middle ground. New England Journal of Medicine 2001;345:915-9; Miller F, Brody H. What makes placebo-controlled trials unethical? American Journal of Bioethics 2002;2(2):3-9.
3. See: Freedman B. Equipoise and the ethics of clinical research. New England Journal of Medicine 1987;317:141-5; Miller FD, Rosenstein DL, DeRenzo EG. Professional integrity in clinical research. JAMA 1998;280:1449-54; Rothman K, Michels K. The continuing unethical use of placebo controls. New England Journal of Medicine 1994;331:394-8; Freedman B, Glass K, Weijer C. Placebo orthodoxy in clinical research: part 1. empirical and methodological myths. Journal of Law, Medicine, and Ethics 1996a;24:243-51; Freedman B, Glass K, Weijer, C. Placebo orthodoxy in clinical research: part 2. ethical, legal, and regulatory myths. Journal of Law, Medicine, and Ethics 1996b;24:252-9; Rothman K. Declaration of Helsinki should be strengthened. BMJ 2000;321:442-5; Emanuel E, Miller F. The ethics of placebo-controlled trials: a middle ground. New England Journal of Medicine 2001;345:915-9; Miller F, Brody H. What makes placebo-controlled trials unethical? American Journal of Bioethics 2002;2(2):3-9.
4. See: Freedman B. Equipoise and the ethics of clinical research. New England Journal of Medicine 1987;317:141-5; Miller FD, Rosenstein DL, DeRenzo EG. Professional integrity in clinical research. JAMA 1998;280:1449-54; Rothman K, Michels K. The continuing unethical use of placebo controls. New England Journal of Medicine 1994;331:394-8; Freedman B, Glass K, Weijer C. Placebo orthodoxy in clinical research: part 1. empirical and methodological myths. Journal of Law, Medicine, and Ethics 1996a;24:243-51; Freedman B, Glass K, Weijer, C. Placebo orthodoxy in clinical research: part 2. ethical, legal, and regulatory myths. Journal of Law, Medicine, and Ethics 1996b;24:252-9; Rothman K. Declaration of Helsinki should be strengthened. BMJ 2000;321:442-5; Emanuel E, Miller F. The ethics of placebo-controlled trials: a middle ground. New England Journal of Medicine 2001;345:915-9; Miller F, Brody H. What makes placebo-controlled trials unethical? American Journal of Bioethics 2002;2(2):3-9.
5. See: Freedman B. Equipoise and the ethics of clinical research. New England Journal of Medicine 1987;317:141-5; Miller FD, Rosenstein DL, DeRenzo EG. Professional integrity in clinical research. JAMA 1998;280:1449-54; Rothman K, Michels K. The continuing unethical use of placebo controls. New England Journal of Medicine 1994;331:394-8; Freedman B, Glass K, Weijer C. Placebo orthodoxy in clinical research: part 1. empirical and methodological myths. Journal of Law, Medicine, and Ethics 1996a;24:243-51; Freedman B, Glass K, Weijer, C. Placebo orthodoxy in clinical research: part 2. ethical, legal, and regulatory myths. Journal of Law, Medicine, and Ethics 1996b;24:252-9; Rothman K. Declaration of Helsinki should be strengthened. BMJ 2000;321:442-5; Emanuel E, Miller F. The ethics of placebo-controlled trials: a middle ground. New England Journal of Medicine 2001;345:915-9; Miller F, Brody H. What makes placebo-controlled trials unethical? American Journal of Bioethics 2002;2(2):3-9.
6. See: Freedman B. Equipoise and the ethics of clinical research. New England Journal of Medicine 1987;317:141-5; Miller FD, Rosenstein DL, DeRenzo EG. Professional integrity in clinical research. JAMA 1998;280:1449-54; Rothman K, Michels K. The continuing unethical use of placebo controls. New England Journal of Medicine 1994;331:394-8; Freedman B, Glass K, Weijer C. Placebo orthodoxy in clinical research: part 1. empirical and methodological myths. Journal of Law, Medicine, and Ethics 1996a;24:243-51; Freedman B, Glass K, Weijer, C. Placebo orthodoxy in clinical research: part 2. ethical, legal, and regulatory myths. Journal of Law, Medicine, and Ethics 1996b;24:252-9; Rothman K. Declaration of Helsinki should be strengthened. BMJ 2000;321:442-5; Emanuel E, Miller F. The ethics of placebo-controlled trials: a middle ground. New England Journal of Medicine 2001;345:915-9; Miller F, Brody H. What makes placebo-controlled trials unethical? American Journal of Bioethics 2002;2(2):3-9.
7. See: Freedman B. Equipoise and the ethics of clinical research. New England Journal of Medicine 1987;317:141-5; Miller FD, Rosenstein DL, DeRenzo EG. Professional integrity in clinical research. JAMA 1998;280:1449-54; Rothman K, Michels K. The continuing unethical use of placebo controls. New England Journal of Medicine 1994;331:394-8; Freedman B, Glass K, Weijer C. Placebo orthodoxy in clinical research: part 1. empirical and methodological myths. Journal of Law, Medicine, and Ethics 1996a;24:243-51; Freedman B, Glass K, Weijer, C. Placebo orthodoxy in clinical research: part 2. ethical, legal, and regulatory myths. Journal of Law, Medicine, and Ethics 1996b;24:252-9; Rothman K. Declaration of Helsinki should be strengthened. BMJ 2000;321:442-5; Emanuel E, Miller F. The ethics of placebo-controlled trials: a middle ground. New England Journal of Medicine 2001;345:915-9; Miller F, Brody H. What makes placebo-controlled trials unethical? American Journal of Bioethics 2002;2(2):3-9.
8. See: Freedman B. Equipoise and the ethics of clinical research. New England Journal of Medicine 1987;317:141-5; Miller FD, Rosenstein DL, DeRenzo EG. Professional integrity in clinical research. JAMA 1998;280:1449-54; Rothman K, Michels K. The continuing unethical use of placebo controls. New England Journal of Medicine 1994;331:394-8; Freedman B, Glass K, Weijer C. Placebo orthodoxy in clinical research: part 1. empirical and methodological myths. Journal of Law, Medicine, and Ethics 1996a;24:243-51; Freedman B, Glass K, Weijer, C. Placebo orthodoxy in clinical research: part 2. ethical, legal, and regulatory myths. Journal of Law, Medicine, and Ethics 1996b;24:252-9; Rothman K. Declaration of Helsinki should be strengthened. BMJ 2000;321:442-5; Emanuel E, Miller F. The ethics of placebo-controlled trials: a middle ground. New England Journal of Medicine 2001;345:915-9; Miller F, Brody H. What makes placebo-controlled trials unethical? American Journal of Bioethics 2002;2(2):3-9.
9. See note 1, Freedman 1987; Freedman, Glass, Weijer 1996a, 1996b.
10. See note 1, Freedman 1987; Freedman, Glass, Weijer 1996a, 1996b.
11. See note 1, Freedman, Glass, Weijer 1996b:253.
12. Cohen P. The placebo is not dead: three historical vignettes. IRB: A Review of Human Subjects Research 1998;20(2-3):6-8. For further discussion of this issue, see: Cohen P. Failure to conduct a placebo-controlled trial may be unethical. American Journal of Bioethics 2002;2(2):24; Helicobacter pylori in peptic ulcer disease. NIH Consensus Statement 1994;12(1):1-23; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288(3):321-33; Moseley JB, O'Malley K, Petersen NJ, Menke TJ, Brody BA, Kuykendall DH, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. New England Journal of Medicine 2002;247(2):81-8.
13. Cohen P. The placebo is not dead: three historical vignettes. IRB: A Review of Human Subjects Research 1998;20(2-3):6-8. For further discussion of this issue, see: Cohen P. Failure to conduct a placebo-controlled trial may be unethical. American Journal of Bioethics 2002;2(2):24; Helicobacter pylori in peptic ulcer disease. NIH Consensus Statement 1994;12(1):1-23; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288(3):321-33; Moseley JB, O'Malley K, Petersen NJ, Menke TJ, Brody BA, Kuykendall DH, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. New England Journal of Medicine 2002;247(2):81-8.
14. Cohen P. The placebo is not dead: three historical vignettes. IRB: A Review of Human Subjects Research 1998;20(2-3):6-8. For further discussion of this issue, see: Cohen P. Failure to conduct a placebo-controlled trial may be unethical. American Journal of Bioethics 2002;2(2):24; Helicobacter pylori in peptic ulcer disease. NIH Consensus Statement 1994;12(1):1-23; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288(3):321-33; Moseley JB, O'Malley K, Petersen NJ, Menke TJ, Brody BA, Kuykendall DH, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. New England Journal of Medicine 2002;247(2):81-8.
15. Cohen P. The placebo is not dead: three historical vignettes. IRB: A Review of Human Subjects Research 1998;20(2-3):6-8. For further discussion of this issue, see: Cohen P. Failure to conduct a placebo-controlled trial may be unethical. American Journal of Bioethics 2002;2(2):24; Helicobacter pylori in peptic ulcer disease. NIH Consensus Statement 1994;12(1):1-23; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288(3):321-33; Moseley JB, O'Malley K, Petersen NJ, Menke TJ, Brody BA, Kuykendall DH, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. New England Journal of Medicine 2002;247(2):81-8.
16. Cohen P. The placebo is not dead: three historical vignettes. IRB: A Review of Human Subjects Research 1998;20(2-3):6-8. For further discussion of this issue, see: Cohen P. Failure to conduct a placebo-controlled trial may be unethical. American Journal of Bioethics 2002;2(2):24; Helicobacter pylori in peptic ulcer disease. NIH Consensus Statement 1994;12(1):1-23; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288(3):321-33; Moseley JB, O'Malley K, Petersen NJ, Menke TJ, Brody BA, Kuykendall DH, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. New England Journal of Medicine 2002;247(2):81-8.
17. Glass KC, Waring D. Effective trial design need not conflict with good patient care. American Journal of Bioethics 2002;2(2):25-6.
18. See note 6, Glass, Waring 2002:26.
19. See note 1, Miller, Brody 2002.
20. See: Veatch R. Indifference of subjects: an alternative to equipoise in randomized clinical trials. Social Philosophy and Policy 2002;19(2):295-323.
21. See: Veatch R. Subject indifference and the justification of placebo-controlled trials. American Journal of Bioethics 2002;2(2):12-3.
22. Lemmens T, Miller P. Avoiding a Jekyll-Hyde approach to the ethics of clinical research and practice. American Journal of Bioethics 2002;2(2):14-7.
23. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Biomedical and Behavior Research. Washington, DC: National Commission for the Protection of Human Subjects of Biomedical and Behavior Research; 1979.
24. See note 1, Freedman, Glass, Weijer 1996b:253.
25. An interesting difficulty here is assigning blame. It is not clear we can say precisely who acts wrongly or who is blameworthy for the failure to study such treatments. However, we can say it is poor medical practice never to study them yet continue to use them.
26. See note 1, Freedman, Glass, Weijer 1996a; Rothman, Michels 1994.
27. Temple R, Ellenberg, SE. Placebo-controlled trials and active-controlled trials in the evaluation of new treatments: part 1. ethical and scientific issues. Annals of Internal Medicine 2000a;133:455-63; Temple R, Ellenberg SE. Placebo-controlled trials and active-controlled trials in the evaluation of new treatments: part 2. practical issues and specific cases. Annals of Internal Medicine 2000b;133:464-70.
28. Temple R, Ellenberg, SE. Placebo-controlled trials and active-controlled trials in the evaluation of new treatments: part 1. ethical and scientific issues. Annals of Internal Medicine 2000a;133:455-63; Temple R, Ellenberg SE. Placebo-controlled trials and active-controlled trials in the evaluation of new treatments: part 2. practical issues and specific cases. Annals of Internal Medicine 2000b;133:464-70.
29. Hart C. The mysterious placebo effect. Modern Drug Discovery 1999;2(4):30-40.
30. Price DD, Fields HL. The contribution of desire and expectation to placebo analgesia: implications for new research strategies. In: Harrington A, ed. The Placebo Effect: An Interdisciplinary Exploration. Cambridge, MA: Harvard University Press; 1997:117-37; Kirsch I. Specifying nonspecifics: psychological mechanisms of placebo effects. In: Harrington A, ed. The Placebo Effect: An Interdisciplinary Exploration. Cambridge, MA: Harvard University Press; 1997:166-86.
31. Price DD, Fields HL. The contribution of desire and expectation to placebo analgesia: implications for new research strategies. In: Harrington A, ed. The Placebo Effect: An Interdisciplinary Exploration. Cambridge, MA: Harvard University Press; 1997:117-37; Kirsch I. Specifying nonspecifics: psychological mechanisms of placebo effects. In: Harrington A, ed. The Placebo Effect: An Interdisciplinary Exploration. Cambridge, MA: Harvard University Press; 1997:166-86.
32. See note 1, Emanuel, Miller 2001.
33. Leon A. Can placebo controls reduce the number of nonresponders in clinical trials? a power-analytic perspective. Clinical Therapeutics 2001;23:596-603; See note 1, Miller, Brody 2002:7.
34. Appelbaum P, Roth L, Lidz C. The therapeutic misconception: informed consent in psychiatric research. International Journal of Law and Psychiatry 1982;5:319-29; Appelbaum P, Roth L, Lidz C. False hopes and best data: consent to research and the therapeutic misconception. Hastings Center Report 1987;17(2):20-4.
35. Appelbaum P, Roth L, Lidz C. The therapeutic misconception: informed consent in psychiatric research. International Journal of Law and Psychiatry 1982;5:319-29; Appelbaum P, Roth L, Lidz C. False hopes and best data: consent to research and the therapeutic misconception. Hastings Center Report 1987;17(2):20-4.
36. Appelbaum recently has supported PCTs with some qualification, so discussion of the therapeutic misconception on his part should not be taken as an absolute criticism of PCTs. It should be understood as a warning and an indication of the need to be careful in informing potential subjects about a trial and the circumstances of medical research. See: Appelbaum P. Clarifying the ethics of clinical research: a path toward avoiding the therapeutic misconception. American Journal of Bioethics 2002;2(2):22-3.
37. See note 11, Lemmens, Miller 2002:15.
38. Horng S, Grady C. Misunderstanding in clinical research: distinguishing therapeutic misconception, therapeutic misestimation, and therapeutic optimism. IRB Ethics and Human Research 2003;25(1):11-6.
39. See note 1, Freedman 1987; see note 11, Lemmens, Miller 2002:15.
40. See note 6, Glass, Waring 2002:25.
41. See: Elliot C. Caring about risks: are severely depressed patients competent to consent to research? Archives of General Psychiatry 1997;54:113-6; Weijer C. The ethical analysis of risk. Journal of Law, Medicine, and Ethics 2000;28:344-61; Healy D. Are concerns about the ethics of placebos a stalking horse for other issues? American Journal of Bioethics 2002;2(2):17-9.
42. See: Elliot C. Caring about risks: are severely depressed patients competent to consent to research? Archives of General Psychiatry 1997;54:113-6; Weijer C. The ethical analysis of risk. Journal of Law, Medicine, and Ethics 2000;28:344-61; Healy D. Are concerns about the ethics of placebos a stalking horse for other issues? American Journal of Bioethics 2002;2(2):17-9.
43. See: Elliot C. Caring about risks: are severely depressed patients competent to consent to research? Archives of General Psychiatry 1997;54:113-6; Weijer C. The ethical analysis of risk. Journal of Law, Medicine, and Ethics 2000;28:344-61; Healy D. Are concerns about the ethics of placebos a stalking horse for other issues? American Journal of Bioethics 2002;2(2):17-9.
44. See note 22, Appelbaum 2002.
45. Itoh K, Sasaki Y, Miyata Y, Fujii H, Ohtsu T, Wakita H et al. Therapeutic response in phase I clinical trials of anticancer agents conducted in Japan. Cancer Chemotherapy and Pharmacology 1994;34:451-4.
46. Dresser R. When Science Offers Salvation: Patient Advocacy and Research Ethics. London/New York: Oxford University Press; 2001.