A review of the ethical issues related to the use of placebo controls in conducting clinical trials_Chinese Journal of Evidence-Based Medicine

Authors：

Joseph TF Lau ¹ , PhD ¹

1. Centre for Clinical Trials and Epidemiological Research2. Department of Community and Family Medicine3. Department of Medicine and Therapeutics The Chinese University of Hong Kong;

Corresponding author：

Keywords：

Clinical trials; placebo; ethics

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Controversy exists regarding the ethics of using placebo control groups in clinical trials when effective treatments exist. The debate was fueled by the announcement of the 5th revision of the Declaration of Helsinki (2000). This study reviews the history and scientific background surrounding the controversy and investigates the prevailing attitudes of Hong Kong researchers regarding this issue. The controversy has centered on a few issues. The first involves the methodological superiority of placebo-controlled trials in discerning treatment effects. Secondly, it is unclear if the treatment effects encompass absolute treatment effects (including placebo effects) or are confined to treatment-specific effects (excluding placebo effects). Thirdly, there are worries that subjects in the placebo group could be exposed to higher risk for developing serious adverse events. Fourthly, it is debated whether the standard of best available treatment should be a local one, or an international one. Preliminary research findings suggest that the opinions of the Hong Kong researchers seemed to be divided on the use of placebo control groups in clinical trials when effective treatment exists. Further researcher on the topic is therefore warranted, training and consensus meeting may be necessary to minimize the confusion related to this issue.

Citation： Joseph TF Lau,PhD,Jing Mao,M,Sc,Jean Woo,MD. A review of the ethical issues related to the use of placebo controls in conducting clinical trials. Chinese Journal of Evidence-Based Medicine, 2003, 03(3): 210-216. doi: Copy

1.	［1］Emanuel EJ, Miller FG. The ethics of placebo-controlled trials-a middle ground[J]. N Eng J Med 2001 ;345:915-919.
2.	［2］World Medical Association. Declaration of Helsinki V: Ethical principles for medical research involving human subjects. 52ndWorld Medical Assembly, Edinburgh, Scotland, October 2000.
3.	［3］World Medical Association. Note of clarification on paragraph 29 of the WMA Declaration of Helsinki. October 2001.
4.	［4］Temple R. Government viewpoint of clinical trials[J]. Drug Information J 1982; 16:10-17.
5.	［5］Freedman B. Equipoise and the ethics of clinical research[J]. N Eng J Med 1987;317:141-145.
6.	［6］Huston P, Peterson R. Withholding proven treatment in clinical research[J]. N Eng J Med 2001;345:912-914.
7.	［7］Rothman KJ, Michels KB, Baum M. For and against: Declaration of Helsinki should be strengthened[J]. BMJ 2000;321:442-444.
8.	［8］Rothman KJ, Michels KB. The continuing unethical use of placebo controls[J]. N Eng J Med 1994;331:455-463.
9.	［9］Forster HP, Emanuel E, Grady C. The 2000 revision of the Declaration of Helsinki: a step forward or more confusion[J]? Lancet 2001 ;358:1449-1453.
10.	［10］Turner JA, Deyo RA, Lieser JD et al. The importance of placebo effects in pain treatment and research[J]. JAMA 1994;271:1609-1614.
11.	［11］Simon R. Are placebo-controlled clinical trials ethical or needed when alternative treatment exists[J]? Ann Intern Med 2000;133:474-475.
12.	［12］Reynolds T. The ethics of placebo-controlled trials[J]. Ann Intern Med 2000; 133:491-492.
13.	［13］Vastag B. Helsinki discord? A controversial Declaration[J]. JAMA 2000;284:2983-2985.
14.	［14］Temple R, Ellenberg SS. Placebo-controlled trials and activecontrolled trials in the evaluation of new treatment. Part 1: ethical and scientific issues[J]. Ann Intern Med 2000;133:455-463.
15.	［15］ICH Steering Committee. ICH harmonized tripartite guideline:Choice of control group and related issues in clinical trials. July 2000.
16.	［16］The European Agency for the Evaluation of Medicinal Products, Preauthorization evaluation of medicines for human use. EMEA/CPMP position statement on the use of placebo in clinical trials with regard to the revised Declaration of Helsinki. EMEA2001;17424/01.
17.	［17］Orentlicher D. Placebo-controlled trials of new drugs: ethical considerations[J]. Diabetes Care 2001;24:771-772.
18.	［18］Simon R. Are placebo-controlled trials ethical or needed when alternative treatment exists[J]? Ann Intern Med 2000;166:474-475.
19.	［19］Vickers A, de Craen AJM. Why use placebos in clinical trials? A narrative review of the methodological literature[J]. J Clin Epidemiology 2000;53:157-161.
20.	［20］Benson H, Friedman R. Harnessing the power of the placebo effect and renaming it "remembered wellness" [J]. Annue Rev Med 1996;47:193-199.
21.	［21］Roberts LW, Lauriello J, Geppert C, Keith SJ. Placebos and paradoxes in psychiatric research: an ethics perspective[J]. Biol Psychiatry 2001 ;49:887-893.
22.	［22］Leber P. The placebo control in clinical trials (a view from the FDA)[J]. Psychopharmacol Bull 1986;22:30-32.
23.	［23］Weihrauch TR, Gauler TC. Placebo-efficacy and adverse effects in controlled clinical trials[J]. Arzneimittelforschung 1999;49:385-393.
24.	［24］Khan A, Warner HA, Brown WA. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials[J]. 2000;57:311-317.
25.	［25］Storosum JG, van Zwieten B J, van den Brink W, Gersons BPR,Broekman AW. Suicide risk in placebo-controlled studies of major depression[J]. Am J Psychiatry 2001; 158:1271 - 1275.
26.	［26］Collins R, Peto R, MacMahon S. et al. Blood pressure, stroke, and coronary heart disease. Part 2, Short-term reductions in blood pressure: overview of randomized drug trials in their epidemiological context[J]. Lancet 1990;335:827-38.
27.	［27］Al-Khatib SM, Califf RM, Hasselblad V, Alexander JH, McCrory DC, Sugarman J. Placebo-controls in short-term clinical trials of hypertension[J]. Science 2001; 292:2013-2015.
28.	［28］Bell DSH. Ethics in diabetic clinical trials[J]. Diabetes Care 2001 ;24:606.
29.	［29］Shapiro HT, Meslin EM. Ethical issues in the design and conduct of clinical trials in developing countries[J]. N Eng J Med 2001;345:139-141.

1. ［1］Emanuel EJ, Miller FG. The ethics of placebo-controlled trials-a middle ground[J]. N Eng J Med 2001 ;345:915-919.
2. ［2］World Medical Association. Declaration of Helsinki V: Ethical principles for medical research involving human subjects. 52ndWorld Medical Assembly, Edinburgh, Scotland, October 2000.
3. ［3］World Medical Association. Note of clarification on paragraph 29 of the WMA Declaration of Helsinki. October 2001.
4. ［4］Temple R. Government viewpoint of clinical trials[J]. Drug Information J 1982; 16:10-17.
5. ［5］Freedman B. Equipoise and the ethics of clinical research[J]. N Eng J Med 1987;317:141-145.
6. ［6］Huston P, Peterson R. Withholding proven treatment in clinical research[J]. N Eng J Med 2001;345:912-914.
7. ［7］Rothman KJ, Michels KB, Baum M. For and against: Declaration of Helsinki should be strengthened[J]. BMJ 2000;321:442-444.
8. ［8］Rothman KJ, Michels KB. The continuing unethical use of placebo controls[J]. N Eng J Med 1994;331:455-463.
9. ［9］Forster HP, Emanuel E, Grady C. The 2000 revision of the Declaration of Helsinki: a step forward or more confusion[J]? Lancet 2001 ;358:1449-1453.
10. ［10］Turner JA, Deyo RA, Lieser JD et al. The importance of placebo effects in pain treatment and research[J]. JAMA 1994;271:1609-1614.
11. ［11］Simon R. Are placebo-controlled clinical trials ethical or needed when alternative treatment exists[J]? Ann Intern Med 2000;133:474-475.
12. ［12］Reynolds T. The ethics of placebo-controlled trials[J]. Ann Intern Med 2000; 133:491-492.
13. ［13］Vastag B. Helsinki discord? A controversial Declaration[J]. JAMA 2000;284:2983-2985.
14. ［14］Temple R, Ellenberg SS. Placebo-controlled trials and activecontrolled trials in the evaluation of new treatment. Part 1: ethical and scientific issues[J]. Ann Intern Med 2000;133:455-463.
15. ［15］ICH Steering Committee. ICH harmonized tripartite guideline:Choice of control group and related issues in clinical trials. July 2000.
16. ［16］The European Agency for the Evaluation of Medicinal Products, Preauthorization evaluation of medicines for human use. EMEA/CPMP position statement on the use of placebo in clinical trials with regard to the revised Declaration of Helsinki. EMEA2001;17424/01.
17. ［17］Orentlicher D. Placebo-controlled trials of new drugs: ethical considerations[J]. Diabetes Care 2001;24:771-772.
18. ［18］Simon R. Are placebo-controlled trials ethical or needed when alternative treatment exists[J]? Ann Intern Med 2000;166:474-475.
19. ［19］Vickers A, de Craen AJM. Why use placebos in clinical trials? A narrative review of the methodological literature[J]. J Clin Epidemiology 2000;53:157-161.
20. ［20］Benson H, Friedman R. Harnessing the power of the placebo effect and renaming it "remembered wellness" [J]. Annue Rev Med 1996;47:193-199.
21. ［21］Roberts LW, Lauriello J, Geppert C, Keith SJ. Placebos and paradoxes in psychiatric research: an ethics perspective[J]. Biol Psychiatry 2001 ;49:887-893.
22. ［22］Leber P. The placebo control in clinical trials (a view from the FDA)[J]. Psychopharmacol Bull 1986;22:30-32.
23. ［23］Weihrauch TR, Gauler TC. Placebo-efficacy and adverse effects in controlled clinical trials[J]. Arzneimittelforschung 1999;49:385-393.
24. ［24］Khan A, Warner HA, Brown WA. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials[J]. 2000;57:311-317.
25. ［25］Storosum JG, van Zwieten B J, van den Brink W, Gersons BPR,Broekman AW. Suicide risk in placebo-controlled studies of major depression[J]. Am J Psychiatry 2001; 158:1271 - 1275.
26. ［26］Collins R, Peto R, MacMahon S. et al. Blood pressure, stroke, and coronary heart disease. Part 2, Short-term reductions in blood pressure: overview of randomized drug trials in their epidemiological context[J]. Lancet 1990;335:827-38.
27. ［27］Al-Khatib SM, Califf RM, Hasselblad V, Alexander JH, McCrory DC, Sugarman J. Placebo-controls in short-term clinical trials of hypertension[J]. Science 2001; 292:2013-2015.
28. ［28］Bell DSH. Ethics in diabetic clinical trials[J]. Diabetes Care 2001 ;24:606.
29. ［29］Shapiro HT, Meslin EM. Ethical issues in the design and conduct of clinical trials in developing countries[J]. N Eng J Med 2001;345:139-141.

Chinese Journal of Evidence-Based Medicine

A review of the ethical issues related to the use of placebo controls in conducting clinical trials

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