Current issues of ACP Journal Club are published in Annals of Internal Medicine


Editorial

“Double blind, you are the weakest link—good-bye!”

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ACP J Club. 2002 Jan-Feb;136:A11. doi:10.7326/ACPJC-2002-136-1-A11



Double blind is the term researchers frequently use, and readers frequently accept, as a key marker of validity of a randomized controlled trial (RCT). Clinical trial experts and clinicians, when asked, all claim to “know” what double blind means. Unfortunately, however, it means diverse things to those questioned (1). The term lacks consistency in its use and interpretation, a critical flaw for any technical term if it is to be understood. In this editorial, we advocate abandoning the current blinding lexicon (i.e., single, double, and triple blinding) and recommend transparent reporting of the blinding status of each group involved in the execution, monitoring, and reporting of clinical trials.

Blinding (or masking) in RCTs is the process of withholding information about treatment allocation from those who could potentially be influenced by this information. Blinding has long been considered an important safeguard against bias. Benjamin Franklin, in 1784, was probably the first to use blinding in scientific experimentation (2). Louis XVI commissioned Franklin to evaluate mesmerism, the most popular unconventional “healing fluid” of the eighteenth century (2). By applying a blindfold to participants, Franklin removed their knowledge of when mesmerism was and was not being applied. Blinding eliminated the intervention’s effects and established mesmerism as a sham (2). From this work, the scientific community recognized the power of blinding to enhance objectivity, and it quickly became, and remains, a commonly used strategy in scientific research.

The groups who can potentially introduce bias into an RCT through knowledge of the treatment allocation are shown in the Table.


Table. Groups that can potentially be blinded in RCTs

Participants Individuals who are randomly assigned to the interventions being evaluated
Health care providers The physicians, nurses, physiotherapists, or other personnel who care for the participants during the study period or those who administer the interventions
Data collectors Individuals who collect data for the study outcomes; data collection could include administering a questionnaire, taking a physical measurement, or eliciting symptoms
Judicial assessors of outcomes The individuals who ultimately decide whether a participant has had the outcome, or outcomes, of interest
Data analysts The individuals who conduct the data analysis
Data safety and monitoring committee The committee that reviews the data to advise on the continuing safety of the trial and persistent uncertainty of the efficacy of the intervention being evaluated
Manuscript writers The individuals who write the versions of the manuscript before the breaking of the randomization code: In a fully blinded stuffy, one version is written with the assumption that group A received the experimental intervention, and the other is written with the assumption that group B received the experimental intervention.

Individuals in the 7 groups in the Table are likely to have or to develop opinions about the efficacy of the intervention being investigated. Because of these opinions, unblinded individuals can systematically bias trial findings through conscious or unconscious mechanisms. When unblinded, participants may introduce bias through use of other effective interventions, differential reporting of symptoms (3), psychological or biological effects of receiving a placebo (although recent studies show conflicting evidence) (4, 5), or dropping out. Unblinded health care providers can distort trial results if they differentially prescribe effective cointerventions, influence compliance with follow-up, or influence patient reports (3). Unblinded data collectors can introduce bias through differential encouragement during performance testing, differential timing or frequency of outcome measurements, and variable recording of outcomes (6, 7). Unblinded judicial assessors may introduce bias in their assessments of outcomes, this being most likely during assessment of subjective outcomes (3). Unblinded data analysts have the potential to introduce systematic bias through decisions on patient withdrawals, post hoc selection of outcomes or analytic approaches, selection of time points that show the maximum or minimum effects, and many other decisions (8). Unblinded members of the data safety and monitoring committee may introduce bias at the time of interim analyses through their recommendations to stop or continue a study (8). Blinding of authors, while seldom done (8, 9), may reduce the biases in the presentation and interpretation of results.

Case reports document individual examples of the biases described above (7, 8, 10, 11). However, no high-quality methodologic studies have been done to evaluate whether blinding of individual groups systematically affects the estimate of effect in RCTs. Investigators have published 2 high-quality methodologic studies (i.e., studies that assessed RCTs from meta-analyses, thereby controlling for the confounders of disease state and intervention), but they assessed the influence of investigators’ statements that the trials were double blinded on the estimate of effect (12, 13). Although 1 study showed lower estimates of effect in RCTs reported as double blinded (12), the other study did not find any association between the reporting of double blinding and the estimate of effect (13). Who was actually blinded in these studies probably varied and is certainly open to question. Heterogeneity in who was blinded in the studies reported as double blinded may be responsible for these discrepant findings.

Although the true magnitude of bias introduced by unblinding remains (and is likely to remain) uncertain, clinicians should consider the blinding status of each group in assessing study validity. Unfortunately, suboptimum reporting of blinding status in full-text publications and secondary journals has hindered readers (14, 15). Authors have commonly relied on conventional blinding terminology (single, double, and triple blinding) to convey blinding status (1). We have shown great variability in physician interpretations and textbook definitions of these terms (1). It is for this reason that we recommend, and the editors of ACP Journal Club and Evidence-Based Medicine have adopted, a strategy of abandoning the current blinding terminology for transparent reporting of the blinding status of the groups listed in the Table. As a result of this policy, readers will be able to make more informed decisions about the validity of the studies on which they base their practice.

P. J. Devereaux, MD
McMaster University
Hamilton, Ontario, Canada

Mohit Bhandari, MD, MSc
McMaster University
Hamilton, Ontario, Canada

Victor M. Montori, MD, MSc
Mayo Clinic
Rochester, Minnesota, USA

Braden J. Manns, MD
University of Calgary
Calgary, Alberta, Canada

William A. Ghali, MD, MPH
University of Calgary
Calgary, Alberta, Canada

Gordon H. Guyatt, MD, MSc
McMaster University
Hamilton, Ontario, Canada


References

1. Devereaux PJ, Manns BJ, Ghali WA, et al. Physician interpretations and textbook definitions of blinding terminology in randomized controlled trials. JAMA. 2001;285:2000-3.

2. Kaptchuk TJ. A history of blind assessment and placebo controls in medicine. Bull Hist Med. 1998;72:389-433.

3. Altman DG, Schulz KF, Moher D, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med. 2001;134:663-94.

4. de la Fuente-Fernandez R, Ruth TJ, Sossi V, et al. Expectation and dopamine release: mechanism of the placebo effect in Parkinson’s disease. Science. 2001;293:1164-6.

5. Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med. 2001;344:1594-602.

6. Jadad AR. Randomised Controlled Trials: A User’s Guide. London: BMJ Books; 1998.

7. Guyatt GH, Pugsley SO, Sullivan MJ, et al. Effect of encouragement on walking test performance. Thorax. 1984;39:818-22.

8. Gøtzsche PC. Blinding during data analysis and writing of manuscripts. Control Clin Trials. 1996;17:285-90.

9. Dong BJ, Hauck WW, Gambertoglio JG, et al. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA. 1997;277:1205-13.

10. Karlowski TR, Chalmers TC, Frenkel LD, et al. Ascorbic acid for the common cold. A prophylactic and therapeutic trial. JAMA. 1975;231:1038-42.

11. Noseworthy JH, Ebers GC, Vandervoort MK, et al. The impact of blinding on the results of a randomized, placebo-controlled multiple sclerosis clinical trial. Neurology. 1994;44:16-20.

12. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273:408-12.

13. Moher D, Pham B, Jones A, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet. 1998;352:609-13.

14. Devereaux PJ, Manns BJ, Ghali WA, Quan H, Guyatt GH. The CONSORT checklist as a means to enhance completeness of reporting in randomized controlled trials [Abstract]. Clin Invest Med. 2000;23(Suppl):S12.

15. Devereaux PJ, Manns BJ, Ghali WA, Quan H, Guyatt GH. Reviewing the reviewers: the quality of reporting in three secondary journals. CMAJ. 2001;164:1573-6.