The Journal of Allergy and Clinical Immunology
Volume 115, Issue 6 , Pages 1228-1234 , June 2005

The ethics of placebo-controlled trials: The case of asthma

  • Robert F. Onder, MD, JD

      Affiliations

    • Corresponding Author InformationReprint requests: Robert F. Onder, MD, JD, Assistant Professor of Clinical Medicine, Washington University School of Medicine, 711 Old Ballas Road, Suite 100, St Louis, MO 63141.

Received 9 September 2004 ,Revised 23 January 2005 ,Accepted 31 January 2005.

References 

  1. World Medical Association. Declaration of Helsinki, 52nd WMA Assembly. Edinburgh, Scotland, October 2000. Available at: http://www.wma.net/e/policy/17-c_e.html. Accessed March 7, 2003; last accessed March 7, 2005.
  2. Freedman B, Weijer C, Glass KC. Placebo orthodoxy in clinical research II: ethical, legal and regulatory myths. J Law Med Ethics. 1996;24:252–259
  3. Rothman KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med. 1994;331:394–398
  4. Hellman S, Hellman DS. Of mice but not men: problems of the randomized clinical trial. N Engl J Med. 1991;324:1585–1589
  5. Freedman B, Weijer C, Glass KC. Placebo orthodoxy in clinical research, I: empirical and methodological myths. J Law Med Ethics. 1996;24:243–251
  6. Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the evaluation of new treatments, part 1: ethical and scientific issues. Ann Intern Med. 2000;133:455–463
  7. Emanuel EJ, Miller FG. The ethics of placebo-controlled trials—a middle ground. N Engl J Med. 2001;345:915–919
  8. Miller FG, Shorr AF. Unnecessary use of placebo controls: the case of asthma clinical trials. Arch Intern Med. 2002;162:1673–1677
  9. Miller FG, Shorr AF. Ethical assessment of industry-sponsored clinical trials: a case analysis. Chest. 2002;121:1337–1342
  10. Carter ER. Fluticasone vs. placebo in toddlers with asthma: good science or questionable ethics?. Chest. 2002;122:122–123
  11. Council for International Organizations of Medical Sciences . international ethical guidelines for biomedical research involving human subjects. Geneva, Switzerland: CIOMS; 1993;
  12. Cockcroft DW, Jokic R, Marciniuk DD, Fitzpatrick MF. The current dilemma with spirometric inclusion criteria for asthma drug trials. Ann Allergy Asthma Immunol. 1997;79:226–228
  13. Ducharme FM. Inhaled glucocorticoids versus leukotriene receptor antagonist as single agent asthma treatment: systematic review of current evidence. BMJ. 2003;326:621–623
  14. Dubus JC, Anhoj J. A review of once-daily delivery of anti-asthmatic drugs in children. Pediatr Allergy Immunol. 2003;14:4–9
  15. Passamani E. Clinical trials—are they ethical?. N Engl J Med. 1991;324:1589–1592
  16. Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349:523–534
  17. Leon AC. Can placebo controls reduce the number of nonresponders in clinical trials?. Clin Ther. 2001;23:596–603
  18. Lazarus SC, Boushey HA, Fahy FV, et al. Long-acting beta-2-agonist monotherapy vs. continued therapy with inhaled corticosteroids in patients with persistent asthma,”. JAMA. 2001;285:2583–2593
  19. Botkin JR, Clayton E, Nelson R, Wilfond B, Munger MA. Salmeterol and inhaled corticosteroids in patients with persistent asthma. JAMA. 2001;286:3075
  20. Lazarus SC. Salmeterol and inhaled corticosteroids in patients with persistent asthma. JAMA. 2001;286:3077–3078
  21. National Heart, Lung and Blood Institute . NHLBI Expert Panel report II: guidelines for the diagnosis and management of asthma. Bethesda (MD): NHLBI/NIH; 1997;
  22. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med. 1987;317:141–145
  23. Weijer C. When argument fails. Am J Bioethics. 2002;2:10–11
  24. Miller FG, Brody H. What makes placebo-controlled trials unethical?. Am J Bioethics. 2002;2:3–9
  25. Emanuel EJ, Miller FG. The ethics of placebo-controlled trials. N Engl J Med. 2002;346:382–383
  26. [Reference withdrawn]
  27. Nuremberg Code. 1947. In:  Reich W editors. Encyclopedia of bioethics. New York: Simon and Schuster; 1995;p. 2763–2764
  28. National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research . The Belmont report: ethical principles and guidelines for the protection of human subjects of research. 1979. In:  Reich W editors. Encyclopedia of bioethics. New York: Macmillan Publishing Co; 1998;p. 2767–2773
  29. FDA Center for Drug Evaluation and Research (CDER) Pediatrics Working Group Consensus Statement. 2000. Available at: http://www.fda.gov/cder/pediatric/ethics-statement-2000.htm.
  30. Kellerman D, Schaberg A, Shah T, et al. Are placebo-controlled trials safe? an update [abstract]. Presented to the European Respiratory Society, September 1995, Barcelona. Ann Allergy Asthma Immunol 1997;79:173-5.
  31. Gallant SP. The evaluable subject. Ann Allergy Asthma Immunol. 1997;79:173–175
  32. Vastag B. Helsinki discord? a controversial declaration. JAMA. 2000;284:2983–2985
  33. Weijer C. Placebo trials and tribulations. Can Med Assoc J. 2002;166:603–604
  34. World Medical Association. Note of clarification on paragraph 29. 2002. Available at: http:www.wma.net/e/press.html. Accessed March 7, 2003; last accessed March 7, 2005.
  35. Department of Health and Human Services . DHHS regulations for the protection of human subjects. 45 CFR 46, June 18, 1991. In:  Reich W editors. Encyclopedia of bioethics. New York: Macmillan Publishing Co; 1998;p. 2773–2789at §46.111
  36. International Conference on Harmonization Steering Committee. ICH topic E9, statistical principles for clinical trials. Recommended for adoption February 5, 1998. Available at: http://www.ifpma.org/pdfifpma. Accessed March 25, 2003.
  37. International Conference on Harmonization Steering Committee. Choice of control group and related issues in clinical trials. 2.1.7.1, p. 18, recommended for adoption July 20, 2000. Available at: http://www.ifpma.org/pdfifpma. Accessed March 25, 2003.

 Disclosure of potential conflict of interest: Dr Onder is the owner and principal investigator of Midwest Clinical Research, LLC. He receives grants and research support from Glaxo, Pfizer, Schering-Plough, Aventis, Merck, and Sepracor.

PII: S0091-6749(05)00319-2

doi: 10.1016/j.jaci.2005.01.059

The Journal of Allergy and Clinical Immunology
Volume 115, Issue 6 , Pages 1228-1234 , June 2005

Article Tools