Academic journal article The Hastings Center Report

Therapeutic Misconception in the Ethics of Clinical Trials. (A Critique of Clinical Equipoise)

Academic journal article The Hastings Center Report

Therapeutic Misconception in the Ethics of Clinical Trials. (A Critique of Clinical Equipoise)

Article excerpt

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.

But if clinical equipoise is a basic requirement for ethical research, how could all these review boards be blind to the unethical nature of this trial? And how could two such radically divergent viewpoints exist, without research ethics being widely regarded as in a state of crisis?

Therapeutic Misconceptions

The prevailing ethical perspective on clinical trials holds that physician-investigators can discharge their "therapeutic obligation" to patients in the context of randomized clinical trials (RCTs) as long as treatments being tested scientifically satisfy clinical equipoise. We contend that this ethical perspective is fundamentally flawed. An ethical framework that provides normative guidance about a practice should accurately characterize the practice. The prevailing ethical perspective fails this test: All sound ethical thinking about clinical research, and the regulatory framework for review of protocols for clinical investigation, depends on a basic distinction between research and therapy. But the claims in the prevailing ethical perspective on clinical trials conflate research and therapy. These claims are that the ethics of the physician-patient relationship must govern RCTs, that physicians who conduct these trials have a "therapeutic obligation" to patients enrolled in them, and that RCTs must be compatible with some form of equipoise.

Certainly, investigators and ethicists recognize that clinical trials are scientific experiments, which differ from standard medical care. They also recognize that they are subject to regulatory requirements which do not apply to routine medical practice. However, the prevailing ethical framework views clinical trials through a therapeutic lens. The mainstream ethical approach to clinical trials attempts to have it both ways: to view the clinical trial as a scientific experiment, aimed at producing knowledge that can help improve the care of future patients, and as treatment conducted by physicians who retain fidelity to the principles of therapeutic beneficence and therapeutic non-maleficence that govern the ethics of clinical medicine. …

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