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David Healy - Are Concerns about the Ethics of Placebos a Stalking Horse for Other Issues? - The American Journal of Bioethics 2:2 The American Journal of Bioethics 2.2 (2002) 17-19

Open Peer Commentaries

Are Concerns about the Ethics of Placebos a Stalking Horse for Other Issues?

David Healy, University of Wales College of Medicine

[Tables]

Where conditions are severe, as in amyotrophic lateral sclerosis, or mild, as in allergic rhinitis, the issue of placebo controls in clinical trials provokes few disputes. The problem appears to lie in the midground, and there are few areas of therapeutics in which the debate about placebo controls has been fought as keenly as in the case of antidepressants. Some have argued that depressed patients may lack the capacity to consent to clinical trials (Elliott 1997). Others have argued that clinical trials may be unethical because of the very serious, if relatively rare, risk of suicide from untreated depression (Weijer 2000).

Table 1, consisting of trial data from submissions to the U.S. Food and Drug Administration for agents licensed as antidepressants during the 1990s, have been adapted from Khan, Warner, and Brown (2000). The data have been modified in the light of reports obtained under freedom of information provisions (Brecher 1991; Lee 1990; 1991), which indicate that more than 50% of the suicidal acts categorized as occurring while a patient was on placebo during trials of sertraline and paroxetine in fact occurred during the placebo washout period. The washout period is the five to seven days between discontinuation of [End Page 17] a previous treatment and the start of active or placebo treatment. As a rider, it can be noted that 46% of these trials were failed trials, in that neither the new agent nor an older comparator differentiated from placebo in terms of therapeutic benefit (Laughren 2001).

These data can be analyzed by absolute numbers or patient exposure years. If analyzed by absolute numbers there is a statistically significant increase in the number of all suicidal acts on paroxetine compared to placebo and a statistically significant increase in suicides and suicidal acts on all investigational agents as a group compared to all acts on placebo as a group. If washout data are amalgamated with placebo data, the denominator must be adjusted accordingly, and this yields a statistically significantly greater risk on sertraline compared to "placebo." Similarly, there would be a significant excess of suicidal acts on mirtazapine and nefazodone compared to placebo if "washout" suicidal acts were included in the data.

Any number of relative risks can be computed from these figures; very few (unless patient exposure years are used and washouts are combined with placebo) are less than 1.0 for individual antidepressants and none are less than 1.0 for the overall group of new agents. If the data are analyzed by including washouts with placebo and then adjusting the denominator appropriately, the relative risk of suicidal acts on sertraline over placebo is 3.0, with greater relative risk figures for other agents. These trial figures of a low relative risk from placebo or nontreatment and a significantly greater risk from treatment are completely consistent with data from the real world of therapeutics (Simon and VonKorff 1998; Boardman and Healy 2001).

In coming at the question of the ethics of placebo controlled trials, Miller and Brody (2002) make a number of methodological points, all of which I would agree with. Their conclusion is that critics of placebo-controlled trials give a misleading impression that placebo controls involve giving science a priority over ethics; their contention is that the key ethical issue is to ensure that any trials are scientifically valid.

The antidepressant trials cited shed an interesting light on Miller and Brody's conclusion. In point of fact, the trials listed above are business exercises, which result in raw data that is proprietary. These and the vast majority of other trials of psychotropic drugs are primarily designed for marketing purposes; few if any have been constructed to answer scientific questions. In the face of data like these, there must be both an ethical and scientific question about the validity in continuing with currently standard antidepressant protocols--but not because of their placebo components.

David Healy, M.D., FRC Psych., is Director of the North Wales Department of Psychological Medicine and a Consultant Psychiatrist. He is the author of over 100 peer reviewed articles and 13 books, including the reference history of antidepressants, The Antidepressant Era (Harvard University Press, 1999).

References

Boardman A. P., and D. Healy. 2001. Modeling suicide risk in primary care primary affective disorders. European Psychiatry 16: 400­05.

Brecher, M. 1991. FDA review and evaluation of clinical data original NDA 20­021, Paroxetine Safety Review, 19 June 1991.

Elliott C. 1997. Caring about risks: Are severely depressed patients competent to consent to research? Archives of General Psychiatry 54:113­16.

Khan, A., H. A. Warner, and W. A. Brown. 2000. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials. Archives of General Psychiatry 57:311­17.

Laughren, T. P. 2001. The scientific and ethical basis for placebo-controlled trials in depression and schizophrenia: An FDA perspective. European Psychiatry 16:418­23.

Lee, H. 1990. Statistical review on sertraline for FDA, 14 August 1990.

------. 1991. Statistical review on sertraline for FDA, 31 January 1991.

Simon, G. E., and M. VonKorff. 1998. Suicide mortality among patients treated for depression in an insured population. American Journal of Epidemiology 147:155­60.

Weijer, C. 2000. The ethical analysis of risk. Journal of Law, Medicine, and Ethics 28:344­61.



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