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Wednesday, July 04, 2007

Clinical trials-another aspect of their complexity

The randomized clinical trial proudly sits atop the evidence based medicine (EBM) epistemological hierarchy. The RCT's ability to minimize known and unknown confounders suits it well (when done well) to identify efficacious treatments and to identify common side effects.

However ,subtleties lurk under the surface.One seemingly simple issue turns out to be more complicated and nuanced that it seems at first analysis. that issue is "when to stop a trial"? If the treatment under study is shown to be efficacious before the trial's planned end point, is it ethical to continue the trial while depriving those who receive the placebo for the test drug's benefit? Is it ethical to stop a trial early- possibly before there has been enough experience to find out about common adverse reactions? Will "premature" conclusions prematurely limit future research into that topic? Will any harm from premature erroneous conclusions be amplified by over-reaching ,zealous guideline authors leading to economic sanctions to those physicians who shun the dogma of the day?

Two articles in the June 19, 2007 issue of the Annals of Internal Medicine explore this issue.Dr. Mueller et al have written a Perspective piece entitled "Ethical Issues in Stopping Randomized Trials Early Because of Apparent Benefit" and Steven Goodman offers an editorial that provides a counterpoint.

Like other issues that seem to be on the front burner in current medical care discussion the underlying theme is the conflict between the individual's benefits and the benefit of the group or the collective.

Mueller and co-authors in presenting the theme that early stopping of a trial may give an overestimate of the drug's benefit use the example of a RCT using bisoprolol in patients undergoing noncardiac surgery which was stopped early because of an apparent large relative risk reduction in the treatment arm.The AHA and American college of cardiology jumped on the finding and issued recommendations. Subsequently two larger trials failed to show any cardiac risk reduction.

Mueller also quotes a systematic analysis that demonstrated that early stopped trials often lead to a significant overestimation of benefit. Goodman ,however, in his rejoinder states that the analysis only looked at that trials that stopped early whereas he contends that the proper denominator should have all trials that used stopping rules and when that is considered much of the overestimation of benefit seems to evaporate.

Rather than simply not stopping trials early Goodman believes that proper use of Bayesian analysis would go a long way to mitigate the problem raised by Mueller.The Bayesian approach basically is using prior experience and context to help decide if a trial should be stopped .

There is much more to each side that I have presented so far; the issue is complex.On the one hand, we have the issue of doing what is right for those trial participants and on the other what would be right for future patients .

Goodman ( Goodman, SN, "Stopping at Nothing?Some Dilemmas of Data Monitoring in Clinical Trials", Annals Internal Medicine, 2007;146:882-887) states it this way:

This is an extraordinarily difficult question, as scientists will differ in their assessment of both how much we have learned and how much we need to learn. There is no clear ethical guidance on the matter;the utilitarian perspective will put more weight on future patients ,whereas ethical theories that place more value on obligations and individual dignity will favor the interests of patients in the trial.

Even when my caffeine titer is maximized I have difficulty sorting out conflicting arguments of the epidemiologist-statisticians. I read Goodman and he seems right , I read Mueller and his arguments are also convincing even though his are more Utilitarian based and those ideas fare less well with my libertarian biases. My simplistic conclusion is that I need to be even more skeptical ( if that is possible) when RCTs are stopped early.

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