Influence of lack of blinding on the estimation of medication-related harms: a retrospective cohort study of randomized controlled trials

Chang Xu; Fengying Zhang; Suhail A R Doi; Luis Furuya-Kanamori; Lifeng Lin; Haitao Chu; Xi Yang; Sheyu Li; Liliane Zorzela; Su Golder; Yoon Loke; Sunita Vohra

doi:10.1186/s12916-024-03300-7

Influence of lack of blinding on the estimation of medication-related harms: a retrospective cohort study of randomized controlled trials

BMC Med. 2024 Mar 7;22(1):83. doi: 10.1186/s12916-024-03300-7.

Authors

Chang Xu¹, Fengying Zhang², Suhail A R Doi³, Luis Furuya-Kanamori⁴, Lifeng Lin⁵, Haitao Chu^{6

7}, Xi Yang⁸, Sheyu Li⁹, Liliane Zorzela¹⁰, Su Golder¹¹, Yoon Loke¹², Sunita Vohra¹³

Affiliations

¹ Proof of Concept Center, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital, Second Military Medical University, Naval Medical University, Shanghai, China. xuchang2016@runbox.com.
² Chinese Evidence-Based Medicine Center, West China Hospital, Sichuan University, Chengdu, China.
³ Department of Population Medicine, College of Medicine, QU Health, Qatar University, Doha, Qatar.
⁴ UQ Center for Clinical Research, The University of Queensland, Herston, Australia.
⁵ Department of Epidemiology and Biostatistics, University of Arizona, Tucson, AZ, USA.
⁶ Statistical Research and Innovation, Global Biometrics and Data Management, Pfizer Inc, New York, NY, USA.
⁷ Division of Biostatistics and Health Data Science, University of Minnesota School of Public Health, Minneapolis, MN, USA.
⁸ Proof of Concept Center, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital, Second Military Medical University, Naval Medical University, Shanghai, China.
⁹ Department of Endocrinology and Metabolism, MAGIC China Centre, West China Hospital, Sichuan University, Chengdu, China.
¹⁰ Department of Pediatrics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada.
¹¹ Department of Health Sciences, University of York, York, UK.
¹² Norwich Medical School, University of East Anglia, Norwich, UK.
¹³ Departments of Pediatrics & Psychiatry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada.

Abstract

Background: Empirical evidence suggests that lack of blinding may be associated with biased estimates of treatment benefit in randomized controlled trials, but the influence on medication-related harms is not well-recognized. We aimed to investigate the association between blinding and clinical trial estimates of medication-related harms.

Methods: We searched PubMed from January 1, 2015, till January 1, 2020, for systematic reviews with meta-analyses of medication-related harms. Eligible meta-analyses must have contained trials both with and without blinding. Potential covariates that may confound effect estimates were addressed by restricting trials within the comparison or by hierarchical analysis of harmonized groups of meta-analyses (therefore harmonizing drug type, control, dosage, and registration status) across eligible meta-analyses. The weighted hierarchical linear regression was then used to estimate the differences in harm estimates (odds ratio, OR) between trials that lacked blinding and those that were blinded. The results were reported as the ratio of OR (ROR) with its 95% confidence interval (CI).

Results: We identified 629 meta-analyses of harms with 10,069 trials. We estimated a weighted average ROR of 0.68 (95% CI: 0.53 to 0.88, P < 0.01) among 82 trials in 20 meta-analyses where blinding of participants was lacking. With regard to lack of blinding of healthcare providers or outcomes assessors, the RORs were 0.68 (95% CI: 0.53 to 0.87, P < 0.01 from 81 trials in 22 meta-analyses) and 1.00 (95% CI: 0.94 to 1.07, P = 0.94 from 858 trials among 155 meta-analyses) respectively. Sensitivity analyses indicate that these findings are applicable to both objective and subjective outcomes.

Conclusions: Lack of blinding of participants and health care providers in randomized controlled trials may underestimate medication-related harms. Adequate blinding in randomized trials, when feasible, may help safeguard against potential bias in estimating the effects of harms.

Keywords: Adverse effects; Blinding; Harms; Randomized controlled trials.

MeSH terms

Health Personnel*
Humans
Linear Models
Randomized Controlled Trials as Topic
Retrospective Studies
Systematic Reviews as Topic

Abstract

MeSH terms

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