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Editor's Correspondence |

Continued Need for Placebo in Many Cases, Even When There Is Effective Therapy—Reply

Franklin G. Miller, PhD; Andrew F. Shorr, MD, Shorr
Arch Intern Med. 2003;163(3):373. doi:10.1001/archinte.163.3.371-a.
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In reply

Whether placebo controls are methodologically indicated depends on the questions that clinical trials are designed to answer. We argued that placebos were not needed in 2 asthma trials comparing combination therapy with monotherapy and in a third trial comparing 2 dosing regimens of the same inhaled corticosteroid.1 Temple and Meyer suggest that a placebo might have been warranted to test assay sensitivity in the first 2 trials. However, both these adequately powered studies were designed to test the superiority of the combination therapy to monotherapy. Given that the component treatments in these 2 trials had previously been demonstrated to be effective, we see the potential increase in rigor from including a placebo control as having marginal scientific value. The key ethical question is whether this theoretical increment of rigor justifies the risks of asthma worsening for those randomized to placebo. Temple and Meyer suggest that use of placebo did not place study participants at undue risk, citing that in 1 of these 2 trials, those randomized to placebo did not fare significantly worse than those randomized to montelukast monotherapy. In the second trial, however, 49% of the patients receiving placebo, compared with 35% receiving salmeterol, were withdrawn from the study because of worsening asthma—a difference that was statistically significant.2 In any case, if the placebo control was not methodologically necessary for a valid trial, then there was no justification for the risk of symptom worsening experienced by the subjects in the placebo arm of these trials. By including a placebo control when it was not methodologically required, these 2 studies failed to satisfy the ethical and regulatory requirement of minimizing risk.3,4 In the case of the third study, Temple and Meyer argue that a placebo control was needed to demonstrate that the once-daily dose had efficacy. On reflection, we think that their point has merit.

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