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

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 (I² = 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.A failure to blind assessors of outcomes in randomized clinical trials may result in bias. Observer bias, sometimes called “detection bias” or “ascertainment bias,” occurs when outcome assessments are systematically influenced by the assessors’ conscious or unconscious predispositions — for example, because of hope or expectations, often favouring the experimental intervention.¹Blinded outcome assessors are used in many trials to avoid such bias. However, the use of non-blinded assessors remains common,^2–4 especially in nonpharmacological trials; for example, non-blinded outcome assessment was used in 90% of trials involving orthopedic traumatology³ and 74% of trials involving strength training for muscles.⁴Unfortunately, the empirical evidence on observer bias in randomized clinical trials has been incomplete. Meta-epidemiological studies have compared double-blind trials with similar trials that were not double-blind.^5,6 However, such studies address blinding crudely because “double-blind” is an ambiguous term.^3,7 Furthermore, the risk of confounding is considerable in indirect between-trial analyses, as “double-blind” trials may have better overall methods and larger sample sizes than trials that are not reported as “double-blind.”A more reliable approach involves analyses of trials that use both blinded and nonblinded outcome assessors, because such a within-trial design provides a direct comparison between blinded and nonblinded assessments of the same outcome in the same patients. Our previous analysis of such trials with binary outcomes found substantial observer bias.⁸Although subjective measurement scales such as illness severity scores are popular, they may be susceptible to observer bias. They are frequently used as outcomes in clinical scenarios with no naturally distinct categories, and adjacent subcategories on a scale typically involve minor and vaguely defined differences.We decided to systematically review trials with both blinded and nonblinded assessment of outcomes using the same measurement scales. Our primary objective was to evaluate the impact of nonblinded outcome assessment on estimated treatment effects in randomized clinical trials. Our secondary objective was to examine reasons for variation in observer bias.