Observer bias in randomized clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded assessors

Abstract

Background: Clinical trials are commonly done without blinded outcome assessors despite the risk of bias. We wanted to evaluate the effect of nonblinded outcome assessment on estimated effects in randomized clinical trials with outcomes that involved subjective measurement scales.

Methods: We conducted a systematic review of randomized clinical trials with both blinded and nonblinded assessment of the same measurement scale outcome. We searched PubMed, EMBASE, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, HighWire Press and Google Scholar for relevant studies. Two investigators agreed on the inclusion of trials and the outcome scale. For each trial, we calculated the difference in effect size (i.e., standardized mean difference between nonblinded and blinded assessments). A difference in effect size of less than 0 suggested that nonblinded assessors generated more optimistic estimates of effect. We pooled the differences in effect size using inverse variance random-effects meta-analysis and used metaregression to identify potential reasons for variation.

Results: We included 24 trials in our review. The main meta-analysis included 16 trials (involving 2854 patients) with subjective outcomes. The estimated treatment effect was more beneficial when based on nonblinded assessors (pooled difference in effect size -0.23 [95% confidence interval (CI) -0.40 to -0.06]). In relative terms, nonblinded assessors exaggerated the pooled effect size by 68% (95% CI 14% to 230%). Heterogeneity was moderate (I(2) = 46%, p = 0.02) and unexplained by metaregression.

Interpretation: We provide empirical evidence for observer bias in randomized clinical trials with subjective measurement scale outcomes. A failure to blind assessors of outcomes in such trials results in a high risk of substantial bias.

Figure 1:

Flow diagram for identification of eligible trials. *A standard database (e.g., Medline) indexes publications that are searchable by title, keywords and abstract, but does not contain the full text of the publication; a full-text database (e.g., Google Scholar) indexes the searchable full-text of publications. †Other reasons for exclusion incude different interventions for patients assessed by blinded and non-blinded assessors, retrospective analysis of a risk factor, the same patients as involved in another included trial, lack of clarity as to whether nonblinded clinicians formally assessed outcomes or the use of blinded versus nonblinded assessment in only 1 arm of the trial.

Figure 2:

Estimated treatment effect as determined by blinded or nonblinded assessors of outcome. CI = confidence interval, SMD = standard mean difference, US FDA = US Food and Drug Administration.

Figure 3:

The effect of nonblinded assessors on estimated treatment effects in randomized clinical trials with subjective measurement scale outcomes. Weights were calculated using random effects analysis. CI = confidence interval, SMD = standard mean difference, US FDA = US Food and Drug Administration.