Furberg, Curt

Julian, Desmond

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Desmond Julian

Curt Furberg

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Desmond DesmondJulian

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Are there fundamental deficiencies in the megatrial methodology?

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Available online http://cvm.controlled-trials.com/content/2/1/001
Does size matter? Is big beautiful? The triumph of the
megatrial suggests that this is so, but Bruce Charlton, in a
provocative paper entitled ‘Fundamental deficiencies in
the megatrial methodology’, challenges this current con-
ventional wisdom [1]. He sides strongly with clinicians by
pointing out that one purpose of clinical trials is to provide
meaningful and useful information that could be easily
translated into clinical practice.
One of his major objections to the megatrial is the
assumption that patients recruited into them are homo-
geneous. This idea has always been difficult for down-to-
earth clinicians to accept, because they know that in
myocardial infarction, for example, there is a huge differ-
ence in prognosis between the elderly hypotensive
patients and young normotensive ones. Thus, when Peel
of Glasgow created his prognostic index in 1962, patients
could be categorised into groups whose mortality at 28
days ranged from 3% to 88% [2]. One of the sad truths
about even the largest megatrials is that they are too small
- that is, they are not big enough to tell us much about
subgroups. Another sad truth of large simple trials is that
simplicity is typically accomplished by not collecting
clinical data that would allow analysis of important sub-
groups. Indeed, we keep being told that subgroup analysis
is hazardous. While this is undoubtedly true, it has led to
the unfortunate mindset that because subgroup analysis is
dangerous, subgroups do not exist. This is incredible to
clinicians and is one the reasons why practitioners do not
implement the ‘results’ of trials.
However, there are megatrials that have rightly changed
practice dramatically. Perhaps the most obvious example
is the International Study of Infarct Survival (ISIS)-2 which
demonstrated not only that streptokinase and aspirin were
each capable of having a major impact on the fatality of
myocardial infarction, but that they were additive in their
effects. It is questionable whether we would have
obtained this information without a trial of great size.
Our hope is that Bruce Charlton, through his paper, will
stimulate constructive discussion and critical self-
evaluation that will improve communication between
clinical trialists and practicing clinicians.
One can conclude that we should be very careful in our
interpretation of the results of megatrials. In applying the
findings of trials in practice, clinicians should continue to
take into account their own experience and that of others
and the biological plausibility of the findings, and they
should use common sense.
References
1. Charlton BG: Fundamental deficiencies in the megatrial
methodology. Curr Control Trials Cardiovasc Med 2001, 2:2–7.
2. Peel AAF, Semple T, Wand I, Lancaster WM, Dall JLC: A coro-
nary prognostic index for grading the severity of myocardial
infarction. Br Heart J 1962, 24:745–756.
Editorial
Are there fundamental deficiencies in the megatrial
methodology?
Desmond Julian* and Curt Furberg†
*Netherall Gardens, London, UK
†Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
Curr Control Trials Cardiovasc Med 2001, 2:1
© 2001 BioMed Central Ltd
(Print ISSN 1468-6708; Online 1468-6694)
To comment on Bruce Charlton’s article, “Fundamental
deficiencies in the megatrial methodology” (pages 2–7),
or any other article, please write to the Editorial Office. 


Julian Desmond

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BG: Fundamental deficiencies in the megatrial methodology. Curr Control Trials Cardiovasc Med

JLC: A coronary prognostic index for grading the severity of myocardial infarction. Br Heart J 1962, 24:745–756. Editorial Are there fundamental deficiencies in the megatrial methodology? Desmond Julian* and Curt Furberg† *Netherall Gardens,

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Are there fundamental deficiencies in the megatrial methodology?

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