Potential Effects of Blinding 174
Lexicon of Blinding 175
Masking or Blinding? 176
Placebos and Blinding 177
Does Blinding Prevent Bias? 178
What to Look for in Descriptions of Blinding 178
Blinding embodies a rich history spanning over two centuries. Most researchers worldwide understand blinding terminology, but confusion lurks beyond a general comprehension. Terms such as ‘single blind’, ‘double blind’, and ‘triple blind’ mean different things to different people. Moreover, many medical researchers confuse blinding with allocation concealment. Such confusion indicates misunderstandings of both. The term ‘blinding’ refers to keeping trial participants, investigators (usually healthcare providers), or assessors (those collecting outcome data) unaware of the assigned intervention, so they will not be influenced by that knowledge. Blinding usually reduces differential assessment of outcomes (information bias) but can also improve compliance and retention of trial participants while reducing biased supplemental care or treatment (sometimes called ‘co-intervention’). Many investigators and readers naively consider a randomised trial as high quality simply because it is double blind, as if double blinding is the sine qua non of a randomised controlled trial. Although double blinding (blinding investigators, participants, and outcome assessors) indicates a strong design, trials that are not double blinded should not automatically be deemed inferior. Rather than solely relying on terminology such as ‘double blinding’, researchers should explicitly state who was blinded, and how. We recommend placing greater credence in results when investigators at least blind outcome assessments, except with objective outcomes, such as death, which leave little room for bias. If investigators properly report their blinding efforts, readers can judge them. Unfortunately, many articles do not contain proper reporting. If an article claims blinding without any accompanying clarification, readers should remain sceptical about its effect on bias reduction.
The rich history of blinding in clinical trials spans a couple of centuries. Most researchers worldwide appreciate its meaning. Unfortunately, beyond that general appreciation lurks confusion. Terms such as ‘single blind’, ‘double blind’, and ‘triple blind’ mean different things to different people. Moreover, many medical researchers confuse the term ‘blinding’ with allocation concealment. The fact that such confusion arises suggests that both terms are misunderstood. Clear theoretical and practical differences separate the two. Blinding prevents ascertainment bias and protects the sequence after allocation. By contrast, researchers use methods of allocation concealment primarily to prevent selection bias and to protect an assignment sequence before and until allocation. Furthermore, in some trials, blinding cannot be successfully implemented, whereas allocation concealment can always be successfully implemented.
Blinding represents an important, distinct aspect of randomised controlled trials. The term ‘blinding’ refers to keeping trial participants, investigators (usually healthcare providers), or assessors (those collecting outcome data) unaware of an assigned intervention, so they are not influenced by that knowledge. Blinding prevents bias at several stages of a trial, although its relevance varies according to circumstance. Although initial forays into blinding might have used a blindfold, the processes have now become much more elaborate. In this chapter we focus on the nomenclature, attributes, and benefits of blinding. In Chapter 17 we address implementation of blinding in randomised trials.
Potential Effects of Blinding
If participants are not blinded, knowledge of group assignment can affect responses to the intervention received. Participants who know that they have been assigned to a group who will receive a new treatment might harbour favourable expectations or increased apprehension. Those assigned to standard treatment, however, might feel deprived or relieved. Despite evidence to suggest that new treatments are as likely to be worse as they are to be better than standard treatments, participants probably assume that new treatments will be better than standard treatments—‘new’ means ‘improved’. In any case, knowledge of the intervention received, and perceptions of that treatment, can affect the psychological or physical responses of the participants. Knowledge of treatment allocation can also affect compliance and retention of trial participants ( Panel 16.1 ).
|Individuals Blinded||Potential Benefits|
|Participants||Less likely to have biased psychological or physical responses to intervention|
|More likely to comply with trial regimens|
|Less likely to seek additional adjunct interventions|
|Less likely to leave trial without providing outcome data, thus less likely lost to follow-up|
|Trial investigators||Less likely to transfer their inclinations or attitudes to participants|
|Less likely to differentially administer co-interventions|
|Less likely to differentially adjust dose|
|Less likely to differentially withdraw participants|
|Less likely to differentially encourage or discourage participants to continue trial|
|Assessors||Less likely to have biases affect their outcome assessments, especially with subjective outcomes of interest|
Blinding investigators—those who contribute to a broadly defined trial team including, but not limited to, trial designers, participant enrollers, randomisation implementors, healthcare providers, intervention counsellors, and routine data collectors—is also important. Investigators especially pertinent to blinding include healthcare providers (such as an attending physician or nurse) and intervention counsellors (e.g., someone who delivers a behavioural prevention message) who might interact with the participants throughout the trial. If investigators are not blinded, their attitudes for or against an intervention can be directly transferred to participants. Their inclinations could also be manifested in differential use of ancillary interventions of supplemental care or treatment (co-interventions), differential decisions to withdraw participants from a trial, or differential adjustments to the medication dose (see Panel 16.1 ). Investigators might also encourage or discourage continuation in a trial on the basis of knowledge of the intervention group assignment.
Perhaps most importantly, blinding helps to reduce differential assessment of outcomes (often called information or ascertainment bias) (see Panel 16.1 ). For example, if outcome assessors who know of the treatment allocation believe a new intervention is better than an old one, they could register more generous responses to that intervention. Indeed, in a placebo-controlled trial in patients with multiple sclerosis the unblinded, but not the blinded, neurologists’ assessments showed an apparent benefit of the intervention.
Subjective outcomes (e.g., pain scores) present great opportunities for bias. Furthermore, some outcomes can be fraught with subjectivity (e.g., salpingitis). In general, though, blinding becomes less important to reduce observer bias as the outcomes become less subjective, because objective (hard) outcomes leave little opportunity for bias. Knowledge of the intervention would not greatly affect measurement of a hard outcome, such as death.
Lexicon of Blinding
Nonblinded (open or open label) denotes trials in which everyone involved knows who has received which interventions throughout the trial. Blinding (masking) indicates that knowledge of the intervention assignments is hidden from participants, trial investigators, or assessors.
The terminology ‘single blind’ usually means that one of the three categories of individuals (normally participant rather than investigator) remains unaware of intervention assignments throughout the trial. A single-blind trial might also, confusingly, mean that the participant and investigator both know the intervention, but that the assessor remains unaware of it.
In a double-blind trial, participants, investigators, and assessors usually all remain unaware of the intervention assignments throughout the trial. In view of the fact that three groups are kept ignorant, the terminology ‘double blind’ is sometimes misleading. In medical research, however, an investigator frequently also assesses, so in this instance the terminology accurately refers to two categories.
‘Triple blind’ usually means a double-blind trial that also maintains a blind data analysis. Some investigators, however, denote trials as triple blind if investigators and assessors are distinct people and both, as well as participants, remain unaware of assignments. Investigators rarely use ‘quadruple blind’, but those who do use the term to denote blinding of participants, investigators, assessors, and data analysts. Thus ‘quintuple blind’ must mean that the allocation schedule has been lost and nobody knows anything. Contrary to Mae West’s claim that ‘too much of a good thing can be wonderful’, such is not the case with blinding.
Confused terminology of single, double, and triple blinding permeates the literature. When investigators examined physician interpretations and textbook definitions of double blinding, they found 17 unique interpretations and 9 different definitions. Another survey of authors who had used double blinding provided 15 different operational meanings of the term ‘double blind’ and ‘typically felt that their preferred definition was the most widely used’. Not only do investigators not define double-blind trials consistently, in particular, but they make matters worse by frequently failing to report their definitions clearly in their articles. Building on the original blindfolding efforts, and the once common double-blindfold terminology, we illustrate double versus single blinding ( Fig. 16.1 ) and double versus triple blinding ( Fig. 16.2 ). More seriously, when we use ‘double blind’ or its derivatives in this chapter, we mean that steps have been taken to blind participants, investigators, and assessors to group assignments. In reporting randomised controlled trials, we urge researchers to explicitly state what steps they took to keep whom blinded.
Sparse reporting on blinding, however, is common. Many authors neglect to report whether or not their trial was blinded. For example, reports of 51% of 506 trials in cystic fibrosis, 33% of 196 trials in rheumatoid arthritis, and 38% of 68 trials in dermatology did not state whether blinding was used. If authors specifically report that their trial is blinded, many fail to report the blinding method used. In a review of blinding in reports of randomised trials of pharmacological treatments and nonpharmacological treatments, 42% and 25%, respectively, of trials reporting blinding did not report the method used. In another review of 156 trials described as ‘double blind’, 26% did not provide any relevant information on who was blinded or how anyone was blinded.
When researchers have reported their study as double blind, they frequently have not provided much further clarification. For example, of 31 double blind trials in obstetrics and gynaecology, only 14 (45%) reports indicated the similarity of the treatment and control regimens (e.g., appearance, taste, administration) and only 5 (16%) provided statements to indicate that blinding was successful. In a review of 156 articles described as ‘double blind’, only 2% explicitly described the blinding status of participants, healthcare providers, and outcome assessors while 56% did not describe the blinding status of any of the key categories. The remaining 42% provided only minimal information on who was blinded and how. In a follow-up survey of the authors of trial articles described as ‘double blind’ in the literature, 19% indicated that they had not blinded either participants, investigators (healthcare providers), or outcome assessors (data collectors) (i.e., they were not double blind by our definition).
Masking or Blinding?
Some people prefer the term ‘masking’ to ‘blinding’ to describe the same procedure. Masking might be more appropriate in trials that involve participants who have impaired vision, and could be less confusing in trials in which blindness is an outcome. Blinding, however, conveys a strong bias-prevention message. Apparently, blinding terminology emerged when Benjamin Franklin and colleagues actually blindfolded participants to shield them from knowledge in their assessments of the therapeutic claims made for mesmerism. The imagery of blindfolding, a total covering of the eyes, conveys stronger bias prevention than masking, where eye holes could permit viewing ( Fig. 16.3 ). Blinding also suggests a more secure procedure to some. The International Conference on Harmonisation (ICH) guidance, for example, primarily uses blinding terminology. (The ICH is a collaboration between regulatory authorities and the pharmaceutical industry in Europe, Japan, and the United States to develop common guidelines for the design, implementation, and reporting of clinical trials.) We prefer blinding because it has a long history, maintains worldwide recognition, creates strong imagery, and permeates the ICH guidelines.