Intended for healthcare professionals


Trials: the next 50 years

BMJ 1998; 317 doi: (Published 31 October 1998) Cite this as: BMJ 1998;317:1170

Large scale trials exacerbate risk of spurious conclusion if bias is not eliminated

EDITOR - Peto and Baigent state that randomised trials can avoid
bias.1 The problem with advocating large scale trials is that the chance
of a spurious conclusion is increased if bias is not eliminated. In
particular, small differences in mortality, as found for example in the
ISIS-2 trial,2 could be due to bias.

Larger differences in morbidity can be created by bias due to
unblinding, particularly if psychological factors are important. For
example, much of the efficacy of psychotropic medication in clinical
trials could be a modification of the placebo effect produced through
unblinding.3 Of course, psychological factors are not likely to have much
impact on mortality and there is "no need in the search for precision to
throw common sense out of the window".4 But, low-quality trials, compared
with high-quality trials, are associated with an increased estimate of
benefit.5 Even high quality reporting of trials does not mean that bias
has been totally eliminated. Admittedly, it is difficult to see how bias
could have influenced the results of the ISIS-2 trial, as allocation seems
to have been adequately concealed and an "intention-to-treat" analysis
deals with exclusions after randomisation.

A thoroughgoing scepticism, however, should be suspicious that small
differences in survival may have merely been created by large trials
exacerbating bias. Large treatment effects demonstrable without randomised
trials are believable as long as they are not placebo effects. The next 50
years of randomised evidence needs to acknowledge the failure to eliminate
bias in the literature despite the introduction of properly randomised
trials 50 years ago.

1. Peto R, Baigent C. Trials: the next 50 years. BMJ 1998;317:1170-

2. ISIS-2 (Second International Study of Infarct Survival)
Collaborative Group. Randomised trial of intravenous streptokinase, oral
aspirin, both, or neither among 17,187 cases of suspected acute myocardial
infarction. Lancet 1988;ii:349-60.

3. Fisher S, Greenberg RP. (eds) From Placebo to panacea. Putting
psychiatric drugs to the test. Chichester: John Wiley, 1997

4. Hill AB. Medical ethics and controlled trials. BMJ 1963;i:1043

5. Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does
quality of reports of randomised trials affect estimates of intervention
efficacy reported in meta-analyses? Lancet 1998;352:609-13

Competing interests: No competing interests

05 November 1998
D B Double
Consultant Psychiatrist
Norfolk Mental Health Care NHS Trust, Norwich