8.10.1  Rationale for concern about bias

Randomized sequence generation is a necessary but not a sufficient safeguard against bias in intervention allocation. Efforts made to generate unpredictable and unbiased sequences are likely to be ineffective if those sequences are not protected by adequate concealment of the allocation sequence from those involved in the enrolment and assignment of participants.

 

Knowledge of the next assignment – for example, from a table of random numbers openly posted on a bulletin board – can cause selective enrolment of participants on the basis of prognostic factors. Participants who would have been assigned to an intervention deemed to be ‘inappropriate’ may be rejected. Other participants may be deliberately directed to the ‘appropriate’ intervention, which can often be accomplished by delaying a participant’s entry into the trial until the next appropriate allocation appears. Deciphering of allocation schedules may occur even if concealment was attempted. For example, unsealed allocation envelopes may be opened, while translucent envelopes may be held against a bright light to reveal the contents (Schulz 1995a, Schulz 1995b, Jüni 2001). Personal accounts suggest that many allocation schemes have been deciphered by investigators because the methods of concealment were inadequate (Schulz 1995a).

 

Avoidance of such selection biases depends on preventing foreknowledge of intervention assignment. Decisions on participants’ eligibility and their decision whether to give informed consent should be made in ignorance of the upcoming assignment. Adequate concealment of allocation sequence shields those who admit participants to a study from knowing the upcoming assignments.

 

Several methodological studies have looked at whether concealment of allocation sequence is associated with magnitude of effect estimates in controlled clinical trials while avoiding confounding by disease or intervention. A pooled analysis of seven methodological studies found that effect estimates from trials with inadequate concealment of allocation or unclear reporting of the technique used for concealment of allocation were on average 18% more ‘beneficial’ than effect estimates from trials with adequate concealment of allocation (95% confidence interval 5 to 29%) (Pildal 2007). A recent detailed analysis of three of these data sets combined (1346 trials from 146 meta-analyses) sheds some light on the heterogeneity of these studies. Intervention effect estimates were exaggerated when there was inadequate allocation concealment in trials where a subjective outcome was analysed, but there was little evidence of bias in trials with objective outcomes (Wood 2008).