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Known biases in Random Controlled Trials may not have been avoided in the PACE Trial
The PACE Trial Identifier claims at section 1.1 that the trial is a random controlled trial (RCT).
The RCT is the recognised way of reducing bias, but Jadad and Enkin’s classic treatise on the known biases
that may occur even in an RCT is essential reading for anyone considering the PACE Trial (Randomized
Controlled Trials. Alejandro Jadad and Murray Enkin. Oxford: Blackwell Publishing, 2007; 1 st published in
1998). Jadad currently advises the WHO as a member of its Strategic Advisory Group of Experts and Enkin
is Professor Emeritus, Clinical Epidemiology and Biostatistics, McMaster University, Toronto.
The second edition challenges over‐reliance on the RCT and includes a chapter on the ethics of RCTs.
The following quotations from the second edition may be relevant when considering the PACE Trial:
“Randomization, if done properly, can keep study groups as similar as possible….Random allocation does not, however,
protect RCTs against other types of bias (and) important research studies…have confirmed that RCTs are vulnerable to
many types of bias throughout their entire life span.
“Biases in clinical trials most often lead to an exaggeration in the magnitude or importance of the effects of the new
interventions.
“Selection bias can occur if some potentially eligible individuals are selectively excluded from the study.
“There are many ways in which randomisation can be subverted by investigators.
“Perhaps one of the least recognised forms of bias in an RCT is hidden in the choice of the question that the trial intends
to answer (which) may have profound effects on its external validity, or generalisability. This bias can take many
forms.
“Hidden agenda bias occurs when a trial is mounted, not to answer a question, but in order to demonstrate
a pre‐required answer….Closely related to this is the self‐fulfilling prophecy bias, in which the very
carrying out of the trial ensures the desired result.
“Closely related to this is the funding availability bias where studies tend to concentrate on questions that
are more readily fundable, often for a vested or commercial interest.
“Regulation bias: This is sometimes referred to as the Bureaucracy bias. It occurs when (institutional review boards)
allow or even encourage studies that may not be scientifically or socially valid…..Complicated ‘informed consent’
regulations may block the participation of many otherwise eligible subjects and hence bias the results.
“The wrong research design can produce misleading answers.
“Population choice bias: “The sample population studied can have a major effect on the generalisability of an
RCT. If the sample is overly restrictive (gender bias; age bias; special circumstances bias; recruitment bias),
the results may not be generalisable to people who do not belong to the groups.
“Severity of illness bias is an important subgroup of the sample choice bias. Patients with a mild form of
an illness may not respond in the same way as those with a more severe form.
“Comparison choice (or control group) bias: If an intervention is compared to a poorly chosen control
group, it can erroneously appear to be more effective than it really is. An obvious way to make an intervention
appear to be more effective than it really is would be to choose an ineffective comparison group.