Therapeutic Misconception in the Ethics of Clinical Trials. (A Critique of Clinical Equipoise) (Hypericum Depression Trial Study Group, 2002‪)‬

The Hypericum Depression Trial Study Group published in 2002 the results of a randomized trial comparing hypericum (St. John's Wort), sertraline (Zoloft), and placebo in the treatment of major depression. (1) In the study, funded by the National Institutes of Health, 340 subjects from twelve participating centers were randomized to three trial arms for an eight-week period, with careful monitoring to assure that patients who worsened significantly or who became suicidal were removed from the study and received adequate treatment. Neither hypericum nor sertraline was found to be superior to placebo on the primary outcome measures. The authors noted, "From a methodological point of view, this study can be considered an example of the importance of including inactive and active comparators in trials testing the possible antidepressant effects of medications. In fact, without a placebo, hypericum could easily have been considered as effective as sertraline." (2) What can we conclude about the ethics of this trial? One dominant viewpoint in research ethics would have prohibited the study. On this viewpoint, a randomized trial is ethical only in circumstances of "clinical equipoise"--a genuine uncertainty within the medical community as to whether (in this case) any of the three treatment arms are superior to the other two. No such uncertainty exists. Approximately twenty-five clinically available antidepressants, including sertraline, have been shown to be superior to placebo. (3) Moreover, the majority opinion within psychiatry probably holds that sertraline is definitely superior to hypericum for major depression, even if hypericum has potential for the treatment of mild to moderate depression. But another widespread viewpoint would hold that the trial was ethically sound. Depressed individuals widely use hypericum, a "natural" agent, despite the lack of proven efficacy. Accordingly, a rigorous evaluation offered scientific, clinical, and social value. According to the report of trial results, the study was approved by institutional review boards (IRBs) at twelve sites and subjects provided written informed consent.