Randomization and Clinical Equipoise

Randomized controlled trials (RCTs) permit the comparison of standard care with one or more new interventions. RCTs are the gold standard of clinical research. Controls and some form of randomization have been used for about 100 years,11 although the first modern randomized, placebo-controlled trial was conducted only in 1948 to evaluate streptomycin for pulmonary tuberculosis.12 There are many concerns about the ethics of randomization, including the need for researchers to suspend their suspicions about what treatment is superior and to follow a protocol rather than provide individualized care.13 In addition, randomization is probably the aspect of informed consent most commonly misunderstood by research participants.

Controlling for factors that are unknown but might influence outcomes is the scientific justification for randomization. Clinical equipoise is the dominant ethical justification for randomization.14-16 Originally, the concept of theoretical equipoise was articulated as a justification for RCTs.17 Theoretical equipoise held that it was ethical to conduct a randomized research study when there was exactly balanced evidence for the various interventions being tested. Theoretical equipoise has many problems. Rarely is the evidence exactly balanced. It is "overwhelmingly fragile. . . balanced on a knife's edge [because] it is disturbed by a slight accretion of evidence" for one intervention or the other.14 Furthermore, it relies on the personal views of individual physicians; it requires each physician who enrolls a patient to be in a state of uncertainty about which intervention is better—a situation that rarely occurs.

In 1987, as an alternative, Freedman proposed clinical equipoise.14 It is based on the recognition that the purpose of a clinical trail is social, to change standards of medical practice within the community. Consequently, clinical equipoise exists when there is uncertainty or disagreement among the expert medical community about which intervention is better. An RCT is conducted to resolve this uncertainty within the medical community. Clinical equipoise is the ethical manifestation of the statistical dictum that an RCT must begin with an honest null hypothesis.14 More importantly, "clinical equipoise is consistent with a decided treatment preference on the part of the investigators. [Physicians] must simply recognize that their less-favored treatment is preferred by colleagues whom they consider to be responsible and competent."14 Thus, it is the absence of consensus among the medical experts about the best intervention that ethically justifies the research study.

One virtue of clinical equipoise is that it rejects special ethical significance for any individual physician's hunch or intuitions about what is best. It relies on data, not on emotions. This approach can help convince patients that a trial is just as good an option as any alternative. Indeed, when there is clinical equipoise, then, at the start of the trial, whatever arm the patient is randomized to, should be as good as any other arm; all arms could be said to be in the patients' best interest. The recent experience with the trial of bone marrow transplantation for breast cancer should emphasize to the oncology community the dangers—ethical, scientific, as well as for individual patients—of relying on feelings rather than data from RCTs to choose what treatment to receive.

One important empirical question is whether clinical research does adhere to clinical equipoise. If it did, we should find that in many trials there is no difference between the new intervention and standard care, and that the numbers of trials demonstrating that the intervention arm is superior to standard care should be comparable with the number of trials demonstrating the superiority of standard care. The few meta-analyses that exist suggest that intervention arms are shown to be superior more frequently than standard care arms (Table 9.2).18,19 Indeed, at least some data suggest that there is an equal balance between studies that show superiority of the intervention arm and those showing superiority of standard therapy when research is sponsored by government agencies. However, when sponsored by commercial organizations, the innovative interventions were significantly more likely to be proven superior. These data suggest that at least when commercially sponsored, there may be too high a threshold for testing a new intervention in an RCT; that is, researchers initiate a new RCT when there is more than sufficient evidence favoring the new intervention's effectiveness. This choice may be explained by the fact that launching an RCT is costly both in terms of effort and resources. Because of the costs, the research community may hesitate to initiate RCTs except when there is substantial evidence supporting the new intervention.20

Although clinical equipoise seems to solve many ethical problems with randomized control trials, some residual problems remain. For instance, why is a P value of 0.05 the level at which the community of medical experts is convinced that one intervention is better than another? Similarly, when the trial is nearing full accrual, clinical equipoise may not hold as data may suggest one arm is better than another. In such circumstances, there may be questions about the ethics of enrolling additional participants, even if the P value is not 0.05.

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