1 Section of Biostatistics, Department of Public Health, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet3 unknown4 Section of Biostatistics, Department of Public Health, Faculty of Health and Medical Sciences, Københavns Universitet5 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
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.
Journal review article
International Journal of Epidemiology, 2014, Vol 43, Issue 4, p. 1272-1283