Blinding

Explanation

Achieved blinding of trial participants or personnel requires adequate procedures for both induction and maintenance of blinding. Often, blinding of trial participants and intervention providers, involves matching of the compared interventions, i.e., producing two externally indistinguishable interventions, one experimental containing the causal component the trial is testing and one comparator without the component. Classically this is achieved by producing a placebo comparator that matches the experimental intervention, not only regarding the format (e.g., tablet) but also in its external characteristics (e.g., colour, taste, size, etc.).(162)

In some trials testing two active interventions (e.g., one as a tablet and the other as an injection) a double-dummy procedure is used, in which the compared interventions involve experimental tablet + placebo injection vs. placebo tablet + experimental injection. The conventional placebo used in most trials is matched on the external characteristics of the experimental intervention, but not to any discernible non-therapeutic effects of the experimental intervention. If such side effects are regarded potentially important, some drug trials use “active” placebo, i.e., a placebo to which has been added a pharmacological active substance that mimics (some) of the side effects of the experimental intervention.(371, 372)

Blinding of an external outcome assessor is almost always possible, even in situations where blinding of trial participants and intervention providers is not. This usually requires that the outcome assessor does not participate in patient care.

Maintaining blinding of participants, care providers, and outcome assessors may be challenging. Indeed, inadequate matching, i.e., distinguishable differences in the physical properties of compared interventions, appears to be the main mechanism for unblinding in drug trials.(373) Notably, inadequate matching related to discernible differences in colour and taste seem particularly problematic.(373) The risk of unblinding is higher in trials designed such that patients are exposed to both the experimental and the comparator intervention, e.g., cross-over trials and parallel-group trials with a placebo run-in period.

Another obvious example of the risk of unblinding is use of a fixed code (versus a unique code for each participant) to denote each trial group assignment (e.g., A = experimental; B = comparator). In these circumstances, the unblinding of one participant could result in the inadvertent unblinding of many trial participants. High risk of unblinding of outcome assessors occurs when they interact closely (e.g., during an interview) with unblinded patients.

Some have suggested that the success of blinding be formally tested at the end of the trial by asking key trial persons to guess the study group assignment and comparing these responses to what would be expected by chance.(374) However, it is unclear how best to interpret the results of such tests.(373, 375-377)

The reporting in trial protocols of the plans for inducing and maintaining blinding was studied in a sample of protocols from 1994.(5) Out of 55 protocols of trials planned as “double-blind”, five (9%) provided no information beyond “double-blind”, 25 (45%) reported a double-dummy procedure, and 32 (58%) reported the compared interventions as “similar”.

If trial researchers contend that the trial investigators, participants, and assessors will be blinded, then the protocol should provide information about the mechanism (e.g., capsules, tablets, film), and similarity of treatment characteristics (e.g., method of administration, appearance, smell, taste, use of special flavours to mask a distinctive taste). Furthermore, any strategies to reduce the potential for unblinding should be described in the protocol, such as pre-trial testing of blinding procedures.(378) We also encourage investigators to describe any procedures intended to reduce or evaluate the risk of compromised blinding,(373, 377) including cases of overt unblinding.(373, 377)

Summary of key elements to address

For blinded trials:

● Mechanism to establish blinding (e.g., identical placebo, double-dummy)

● Any similarities or differences in characteristics (e.g., appearance, taste) of the interventions being compared

● Any procedures intended to maintain blinding and reduce risk of accidental unblinding

● Any procedures intended to evaluate blinding procedures (e.g., pre-trial testing of blinding procedures)