A recently published article
-
Treatment at random: the ultimate science or the betrayal of Hippocrates? Retsas S. J
Clin Oncol 2004: 22(24); 5005-8; discussion 5009-11.
[Medline] [Full text]
[PDF]
attacks the randomized trial and declares it to be
a deficient research tool both on deontologic and methodologic grounds.
A response, published in the same issue,
-
A commentary on treatment at random: the ultimate science or the betrayal of hippocrates?
Wieand S, Murphy K. J Clin Oncol 2004: 22(24); 5009-11.
[Medline] [Full text]
[PDF]
is also worth reading.
Dr. Retsas tackles the difficult question of equipoise by asking
If I am genuinely uncertain about the value of a new or established treatment,
does this also apply to my colleague down the road? My colleague, perhaps with greater
experience or different perceptions than my own, may have a greater degree of certainty
about the value or otherwise of the treatment in question. Should then this colleague be
obliged to subject his or her patients to randomization to clarify my own uncertainties?
There are two differing definitions of levels of equipoise. The first states that
equipoise is genuine uncertainty by the individual physician as to which therapy is better.
The second states that equipoise is genuine uncertainty in the community of practicing
physicians. In my opinion, both forms of equipoise need to be factored into the equation.
Physicians who apply individual equipoise only place themselves in the position that they
know what is best for their patients, regardless of what their colleagues might think. Such
physicians need some open minded inquiry as to why others have a different viewpoint. On the
other hand, physicians should not abandon their knowledge and expertise and follow the
beliefs of others blindly.
But Dr. Retsas appears to be confusing two different questions: is it ethical to conduct a
randomized trial versus is it ethical to compel others to conduct a randomized trial? This is
actually a serious issue, because some have advocated that unproven treatments should be made
available only in the context of randomized trials.
Dr. Retsas also argues that randomized trials are unnecessary because well-designed
observational studies are just as good. He cites two studies
-
Randomized, Controlled Trials, Observational Studies, and the Hierarchy of Research
Designs. Concato J, Shah N, Horwitz RI. The New England Journal of Medicine 2000:
342(25); 1887-1892.
[Medline]
-
A comparison of observational studies and randomized, controlled trials. Benson K,
Hartz AJ. New England Journal of Medicine 2000: 342(25); 1878-86.
[Medline]
to support his case but does acknowledge that others disagree. He then poses the question
Is the information provided by a randomized trial of 1,000 patients more reliable
than that from 10 observational studies, each enlisting 100 patients?
and then claims (without any apparent justification) that
If the 10 observational studies report response rates between 5% and 20% with
acceptable toxicity, the true activity of the new drug or treatment lies somewhere in
between.
If each of the studies replicates the same source of bias, then it is very possible that
the true activity of the drug could be much less than 5% or much more than 20%. If, on the
other hand, the observational studies are designed in such a way that sources of bias are
deliberately and purposively varied, then perhaps you can do better. A good description of
how to deliberately and purposively vary sources of bias appears in
-
Replicating Effects and Biases. Rosenbaum PR. The American Statistician 2001: 55(3);
223-227.
He also questions the law of large numbers, in effect, by asking
However, how many unknown factors can randomization of a cohort of 500 patients
accommodate'one, 20, or an infinite number?
It turns out that a sample size of 40 or greater will provide reasonable protection
against covariate imbalance, as was shown by
-
Methodological Contributions to Clinical Research: Random Sampling, Randomization, and
Equivalence of Contrasted Groups in Psychotherapy Outcome Research. Hsu LM. Journal of
Consulting and Clinical Psychology 1989: 57(1); 131-137.
[Medline]
Although I disagree with the general conclusions of Dr. Retsas, he does raise some very
interesting issues.
07/08/2008.
