Bias due to lack of patient blinding in clinical trials. A systematic review of trials randomizing patients to blind and nonblind sub-studies

Abstract

Background: Blinding patients in clinical trials is a key methodological procedure, but the expected degree of bias due to nonblinded patients on estimated treatment effects is unknown.

Methods: Systematic review of randomized clinical trials with one sub-study (i.e. experimental vs control) involving blinded patients and another, otherwise identical, sub-study involving nonblinded patients. Within each trial, we compared the difference in effect sizes (i.e. standardized mean differences) between the sub-studies. A difference <0 indicates that nonblinded patients generated a more optimistic effect estimate. We pooled the differences with random-effects inverse variance meta-analysis, and explored reasons for heterogeneity.

Results: Our main analysis included 12 trials (3869 patients). The average difference in effect size for patient-reported outcomes was -0.56 (95% confidence interval -0.71 to -0.41), (I(2)=60%, P=0.004), i.e. nonblinded patients exaggerated the effect size by an average of 0.56 standard deviation, but with considerable variation. Two of the 12 trials also used observer-reported outcomes, showing no indication of exaggerated effects due lack of patient blinding. There was a larger effect size difference in 10 acupuncture trials [-0.63 (-0.77 to -0.49)], than in the two non-acupuncture trials [-0.17 (-0.41 to 0.07)]. Lack of patient blinding also increased attrition and use of co-interventions: ratio of control group attrition risk 1.79 (1.18 to 2.70), and ratio of control group co-intervention risk 1.55 (0.99 to 2.43).

Conclusions: This study provides empirical evidence of pronounced bias due to lack of patient blinding in complementary/alternative randomized clinical trials with patient-reported outcomes.

Keywords: Bias; blinding; patient blinding; randomized clinical trials; systematic review.

Figures 1a-1c.

Diagrams of the design of eligible randomized clinical trials. (a) Four-armed trials (main trials). (b) Three-armed trials with nondisclosed placebo (main trials). (c) Three-armed trials with disclosed placebo (auxiliary trials). R, randomized; B, blinded; NB, non-blinded; E, experimental group; C: control group; C*, placebo control presented to patients as an experimental intervention; Ø, missing non-blind experimental group. In the three-armed trials with nondisclosed placebo, patients were not informed that the trial involved a placebo but instead led to believe that two experimental interventions were compared with a no-treatment control. Such trials are equivalent to four-armed trials as the patients in the experimental intervention group are blinded with regard to the nature of the ‘experimental’ interventions (one is in fact a blind control), and nonblinded with regard to whether they receive an experimental intervention or no intervention (no-treatment group). In the three-armed trials with disclosed placebo, patients were informed that the trial involved a possibility of receiving a placebo, and this implies a lack of a non-blind experimental group.

Figure 2.

Meta-analysis of randomized clinical trials with sub-studies of blinded and nonblinded patients. dSMD: the difference between SMD (standardized mean difference, or effect size) based on blinded patients and the corresponding SMD based on nonblinded patients (95% confidence interval). A dSMD <0 indicates than nonblinded patients generate more optimistic estimates of intervention effect.