Contemporary Clinical Trials

  

.  Please see the attached brief article and explain  what blinding is in a scientific investigation, and the purpose of blinding. In your response, include how bias enters into the overall process

Contemporary Clinical Trials 32 (2011) 240–243

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Contemporary Clinical Trials

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Short communication

The blind leading the blind: Use and misuse of blinding in randomized
controlled trials

Larry E. Miller⁎, Morgan E. Stewart
Research and Clinical Services, Sprim Advanced Life Sciences, 235 Pine Street, Suite 1175, San Francisco, CA 94104, United States

a r t i c l e i n f o

⁎ Corresponding author. Tel.: +1 928 607 9657; fax
E-mail addresses: larry.miller@sprim.com (L.E. Mil

morgan.stewart@sprim.com (M.E. Stewart).

1551-7144/$ – see front matter © 2010 Elsevier Inc.
doi:10.1016/j.cct.2010.11.004

a b s t r a c t

Article history:
Received 30 July 2010
Accepted 4 November 2010
Available online 9 November 2010

The use of blinding strengthens the credibility of randomized controlled trials (RCTs) by
minimizing bias. However, there is confusion surrounding the definition of blinding as well as
the terms single, double, and triple blind. It has been suggested that these terms should be
discontinued due to their broad misinterpretation. We recommend that, instead of abandoning
the use of these terms, explicit definitions of blinding should be adopted.We address herein the
concept of blinding, propose standard definitions for the consistent use of these terms, and
detail when different types of blinding should be utilized. Standardizing the definition of
blinding and utilizing proper blinding methods will improve the quality and clarity of reporting
in RCTs.

© 2010 Elsevier Inc.

All rights reserved.

Keywords:
Bias
Blinding
Double blind
Masking
Randomized controlled trial
Single blind
Triple blind

1. What is blinding?

Clinical trial outcomes may be biased by human expecta-
tions, especially when treatment allocation, assessment
methods, and outcome measures have a subjective compo-
nent [1]. At a basic level, blinding (also called “masking,”
especially in ophthalmology studies) is utilized to eliminate
or minimize these biases. For example, subjects entering a
study might be differentially allocated to unblinded treat-
ment groups such that those deemed most likely to benefit
from the active treatment are assigned to receive it, while the
remaining subjects are allocated to placebo (selection bias).
Even when subjects are randomly allocated to receive active
or placebo treatment, those who are knowingly randomized
to a treatment that is perceived as superior to a placebo may
offer overly optimistic responses that create an exaggerated
treatment effect (self-report bias). These subjects may also
differ in their tendency to drop out of a trial or in their desire
to seek additional and potentially confounding treatments

: +1 928 268 3563.
ler),

All rights reserved.

versus those allocated to placebo [2], which complicates the
interpretation of clinical trial results.

Investigators and research staff are also prone to bias. A
subjective investigator-graded outcome scale is a commonly
reported end point in clinical trials and knowledge of a
subject’s treatment assignment may consciously or uncon-
sciously influence the investigator to assign better evalua-
tions to those who are taking the active test product
(observer bias). Unblinded randomized controlled trials
(RCTs) result in larger treatment effects compared to blinded
studies [3,4] and diagnostic test performance is overesti-
mated when evaluations are made with prior knowledge of
the diagnosis [5].

2. Confusion in blinding terminology

The double-blind RCT is widely considered the gold
standard study design that most convincingly demonstrates
the effectiveness of a product or intervention [6]. However,
there is great confusion surrounding the definition of blinding
and, specifically, what conditions constitute a single-, double-,
or triple-blind trial [7]. A review of 200 double-blind RCTs
reported 8 unique combinations of two or more groups

http://dx.doi.org/10.1016/j.cct.2010.11.004

mailto:larry.miller@sprim.com

mailto:morgan.stewart@sprim.com

http://dx.doi.org/10.1016/j.cct.2010.11.004

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241L.E. Miller, M.E. Stewart / Contemporary Clinical Trials 32 (2011) 240–243

that were blinded, including subjects, investigators, outcome
assessors, data managers, biostatisticians, and (rarely) man-
uscript writers [8]. Almost 1 in 2 double-blind RCTs do not
specify which groups were actually blinded [8]. The definition
of blinding is somisunderstood that themost recent CONSORT
Statement (CONSORT 2010) recommends that the terms
“single blind,” “double blind,” and “triple blind” be abandoned
and, instead, blinded RCTs should only detail whowas blinded
after treatment allocation and how [9,10]. Given the broad
misunderstanding of the concept of blinding, all individuals
involved in clinical trial design and conduct should develop a
basic understanding of blinding terminology and methods.
We briefly address herein the concept of blinding and propose
standard definitions for the consistent use of these terms in
clinical trials.

3. Types of blinding and the proposed standard definitions

Although the definitions of single, double, and triple blind
vary widely among physicians and textbooks [7], the pro-
posed standardized definitions of these terms are offered as
follows.

3.1. Single blind

A single-blind trial is traditionally defined as one where
only subjects are blinded to treatment allocation, and almost
3 out of 4 clinical research textbooks concur with this
definition [7]. Clinical trials that utilize blinding of any single
group are sometimes labeled as single blind, but this
definition is uncommon. In order to improve clarity in the
reporting of clinical trials, we propose that the term “single
blind” should be reserved only for studies where subjects, but
not investigators or outcome assessors, are blinded. Further-
more, the blinding status of other groups (e.g., data managers
and biostatisticians) should be identified but should not
impact the designation of “single blind.”

3.2. Double blind

The standard definition of double blind is that neither the
subjects nor the investigators (including those who admin-
ister treatment) and outcome assessors are aware of the
treatment assignment, regardless of the blinding status of
other groups [7]. We concur with this definition and propose
that the term “double blind” should be specifically reserved
for trials where these groups are blinded and the blinding
status of other groups should also be described.

3.3. Triple blind

There is great disagreement among physicians and text-
books regarding the definition of triple blind and, in fact, no
single definition predominates [7]. However, the common
thread among most proposed definitions and, as such, our
proposed definition of triple blind is blinding of subjects,
investigators (including those who administer treatment),
outcome assessors, and those involved in data management
(i.e., data managers and biostatisticians). Again, the blinding
status of all groups should always be specified in accordance
with the recommendations of CONSORT 2010 [9,10].

4. Who needs to be blinded?

A rarely discussed aspect of blinding involves a priori
consideration of which groups involved in a clinical study
need to be blinded. Open label, or unblinded, clinical trials are
susceptible to self-report and observer bias, although the use
of these designs is sometimes unavoidable. For example, a
clinical trial comparing the effectiveness of a minimally
invasive procedure versus open surgery cannot easily blind
subjects or investigators to the assigned treatment. Conse-
quently, studies incorporating sham procedures and inactive
devices have become more widespread in order to minimize
the confounding effects associated with subject knowledge of
treatment assignment [11,12].

The single-blind trial, where only the subjects are blinded
to the intervention, is conducted when the investigator
requires knowledge of treatment allocation (e.g., sham
surgery). This design is effective in preventing the subject
knowledge of the treatment assignment from confounding
study outcomes. Nonetheless, this design remains prone to
bias from the investigator, especially in trials with subjective
endpoints, e.g., investigator-graded degree of clinical im-
provement, since they may harbor a vested interest in a
positive subject outcome.

As previously mentioned, the double-blind RCT represents
a distinct improvement over open-label and single-blind
trials and, when feasible, represents the strongest design for
minimizing subject- and investigator-related bias. Double-
blind RCTs are often required to attain regulatory approval for
new drugs, dietary supplements, and, in some cases, medical
devices. The potential bias reduction associated with double
blinding is noteworthy as a meta-analysis indicated that
some double-blind studies reported 15% lower treatment
effects compared to unblinded studies [3].

The rarely utilized triple-blind trial arguably offers only
minor advantages beyond that of a double-blind design.
Blinding of data managers and biostatisticians is generally
less critical than blinding of subjects and investigators,
because data management personnel usually have no contact
with subjects or site staff and because data analysis is
typically conducted only after the database has been locked.
Therefore, the risk of introducing significant bias is lower in
these groups, especially when pre-defined data management
methods and statistical analysis plans are utilized. However,
bias may result when statistical analyses are performed in the
absence of pre-specified guidelines. The implementation of
triple-blind trials also incorporates logistic challenges that
must be considered, which partly explains why they are
rarely utilized [13]. For example, a requirement for the
biostatistician to remain blinded adds a level of complexity to
the study implementation since the person who prepares the
randomization list would need to be someone other than the
study biostatistician.

5. Assessment of blinding success

There has been considerable discussion regarding the
value of evaluating blinding success after a study has been
completed by asking subjects and/or investigators to guess
which treatment each subject was administered [14]. Formal
statistical methods for evaluating blinding success have even

Fig. 1. Blinding definitional flowchart.

242 L.E. Miller, M.E. Stewart / Contemporary Clinical Trials 32 (2011) 240–243

been proposed [15]. The evaluation of blinding success is
controversial and has generated numerous publications for
and against the practice [14,16–25]. Comprehensive coverage
of this topic is, therefore, beyond the scope of this brief
communication.

6. Conclusion

Although the latest CONSORT statement encourages authors
and editors to discontinue use of the term “blinded trial” [9,10],
these terms are heavily entrenched in clinical research jargon
[26] and their use will likely continue despite this recommen-
dation. Furthermore, specifying the type of blinding used is in
agreementwith the International Conference onHarmonisation
(ICH) guidelines [27]. We therefore propose that, instead of
abandoning the use of this term, explicit definitions for these
terms should be proposed and advanced, ultimately resulting
in the widespread adoption of standardized terminology. We
have presented a standard definition of blinding and have
created aflowchart to aid in decision-making that identifies the
most common groups that are blinded in clinical studies
(Fig. 1). Standardizing the definition of blinding and utilizing
proper blindingmethodswill improve the quality and clarity of
reporting in RCTs.

References

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• The blind leading the blind: Use and misuse of blinding in randomized controlled trials

What is blinding?
Confusion in blinding terminology
Types of blinding and the proposed standard definitions
Single blind
Double blind
Triple blind
Who needs to be blinded?
Assessment of blinding success
Conclusion
References