Nope– It’s Still Not Ethical


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Last year, Jonathan and I published a critique of unequal allocation ratios in late-phase trials. In these trials, patient-subjects are randomly allocated among the treatment arms in unequal proportions, such as 2:1 or 3:1, rather than the traditional equal (1:1) proportion. Strangely, despite introducing an additional burden (i.e., requiring larger sample sizes) the practice of unequal allocation is often defended as being “more ethical”. In that piece, published in Neurology, we showed that these purported ethical advantages did not stand up to careful scrutiny.

In a new article at Clinical Trials, Jonathan and I extend this line of argument to trials that use outcome-adaptive allocation. In an outcome-adaptive trial, the allocation ratio is dynamically adjusted over the course of the study, becoming increasingly weighted toward the better-performing arm. In contrast to the fixed but unequal ratios described above, outcome-adaptive ratios can sometimes reduce the necessary sample size to answer the study question. However, this reduction in cost and patient burden is not guaranteed. In fact, it only occurs when the difference between the observed effect sizes is large. And since there is no way to know in advance what this difference is going to be, these potential gains in efficiency due to outcome-adaptive designs are something of a gamble.

Nevertheless, just as we saw with fixed unequal ratios, proponents of outcome-adaptive trials claim that this allocation scheme is “more ethical”. Setting aside the sample size issue, they argue that outcome-adaptive trials better accommodate clinical equipoise by collapsing the distinction between research and care. As it is sometimes put rhetorically: Would you rather be the last subject treated in a trial or the first subject treated in practice? The outcome-adaptive trial dissolves any ethical tension in this question. The treatment will be the same either way.

Of course, any long-time readers of this blog will recognize a misunderstanding of clinical equipoise embodied in that question. The salient issue is not a comparison between the last subject enrolled in a study and the first patient treated in the context of clinical care. Rather, it is about ensuring that no subject is systematically disadvantaged by participating in a trial (and that all participants receive competent medical care). In which case, the relevant rhetorical question needs to be re-phrased as follows: Would you rather be the first patient enrolled in a study or the last? In a traditional 1:1 RCT design, clinical equipoise dissolves the ethical tension in that question. But for an outcome-adaptive design, you should hope to be the last–and that is a serious problem.


    title = {Nope– It’s Still Not Ethical},
    journal = {STREAM research},
    author = {Spencer Phillips Hey},
    address = {Montreal, Canada},
    date = 2015,
    month = feb,
    day = 10,
    url = {}


Spencer Phillips Hey. "Nope– It’s Still Not Ethical" Web blog post. STREAM research. 10 Feb 2015. Web. 09 May 2021. <>


Spencer Phillips Hey. (2015, Feb 10). Nope– It’s Still Not Ethical [Web log post]. Retrieved from

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