Mapping the Moral Terrain of Clinical Research

By Joffe, Steven; Miller, Franklin G. | The Hastings Center Report, March-April 2008 | Go to article overview

Mapping the Moral Terrain of Clinical Research


Joffe, Steven, Miller, Franklin G., The Hastings Center Report


Medical research is widely thought to have a fundamentally therapeutic orientation, in spite of the fact that clinical research is thought to be ethically distinct from medical care. We need an entirely new conception of clinical research ethics--one that looks to science instead of the doctor-patient relationship.

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Gastrointestinal stromal tumor is a rare cancer that, when inoperable or metastatic, was historically always fatal. Several years ago, imatinib, the first drug in a new class of anticancer agents, was shown to be highly effective for patients with this kind of cancer (known by the acronym GIST). (1) Unfortunately, many patients become resistant to imatinib, and until recently, no effective therapies were available for them. To address this problem, a multicenter randomized controlled trial compared sunitinib (a novel drug in the same class as imatinib) against placebo for people with imatinib-refractory GIST. The trial demonstrated that, compared with placebo, sunitinib markedly reduced the risks of both tumor progression and death. (2)

Because patients eligible for the trial have a very poor prognosis, the use of placebo controls was quite controversial. (3) According to an official at the University of Michigan Cancer Center, which had refused to join the trial, "When patients have an advanced cancer and the cancer is growing, there isn't any way the placebo can be helpful.... To argue that a placebo trial is in society's interests has nothing to do with helping these patients." The legal scholar and bioethicist George Annas endorsed this position, asserting, "You have to give people in that situation something that might help them.... I don't see any justification for withholding that drug." (4)

What's at stake in these differing views are fundamental questions about how clinical trials should be designed and conducted and the very nature of investigators' moral obligations to research participants. Such questions have become ever more pressing. Consider two more examples.

A recent open-label randomized controlled trial compared surgical to nonsurgical management of lumbar disk herniation. The trial showed differences in symptoms and outcomes that favored surgical management, but these differences were statistically insignificant. In discussing the limitations of their trial, the authors acknowledged that "practical and ethical constraints" had prevented them from using sham surgery as a placebo control. "Therefore, any improvements seen with surgery may include some degree of 'placebo effect.'" (5) An accompanying editorial challenged the decision not to use a sham surgical control: "Because of limitations in design and study operation, the proper role and benefits of these competing interventions are still unclear. Given the large number of patients potentially exposed to the risks of these strategies, a sham surgical trial may be the only effective and ethical next step." (6)

Placebos are not the only topic that raises questions about the nature of investigators' moral obligations to subjects. A few years ago, a multicenter randomized trial compared the drug letrozole to placebo for postmenopausal women who had completed five years of standard therapy for localized breast cancer. Consistent with rules specified in the study protocol and with the recommendation of the data and safety monitoring committee, the trial was stopped early because women in the letrozole arm were experiencing markedly few recurrences of cancer. (7) An accompanying editorial acknowledged the obligation to adhere to the protocol requirements, but nevertheless bemoaned the loss of information that resulted from stopping the trial. (8) The National Breast Cancer Coalition, a respected patient advocacy group, also criticized the decision: "We don't know the long term side effects, which could outweigh the benefit of fewer recurrences. More importantly, recurrence is an interim outcome measure, and is not the correct end point for this trial. …

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