This study provides a detailed description and classification, with examples of reporting, of different methods of blinding participants, health care providers or other caregivers, and outcome assessors in a large series of RCTs assessing NPT. Our results highlight innovative methods of blinding and allow for a description of possible placebos for NPT in trials.
Although evidence has demonstrated that lack of blinding could bias treatment effect estimates, reports of RCTs describe blinding poorly [4
] especially RCTs assessing NPTs [18
]. Lack of blinding in trials assessing NPTs is probably associated, in part, with a lack of awareness of existing methods of blinding. To improve this situation, we developed an inventory of blinding methods and classified them according to what seemed reasonable after having read through the various methods. We hope that disseminating this classification scheme along with the detailed examples of reporting (Tables S1
) will help clinical trialists better integrate blinding into the design and conduct of their trials. As well, those critically appraising the health care literature need adequate knowledge of all possible methods of blinding to be able to determine the feasibility of blinding in a published report of an RCT [37
Use of a placebo is a standard method to blind participants and health care providers in RCTs. Although fabrication of placebo is relatively easy for pharmacological treatment, it is more difficult for surgery, rehabilitation, or psychotherapy. Our review identified several ingenious placebo methods, such as sham surgery, sham manipulation, or sham acupuncture. However, these methods raise some issues. First, the use of sham procedures in surgery is debatable, because it is not without risk, such as with general anesthesia and intraoperative procedures. Moreover, the optimal placebo should appear exactly like the “real” treatment but lack the “supposed” specific component. Debate surrounds the use of attention-control interventions in trials assessing participative intervention, because these treatments have a specific therapeutic effect linked, for instance, to the relationship between participants and health care providers. Consequently, the use of attention-control interventions could underestimate the treatment effect [38
]. Finally, use of placebo for NPT could be a barrier for the participation of patients and health care providers in such a trial. A selection bias might have been introduced in the RCT assessing arthroscopy surgery for osteoarthritis of the knee because 44% of the eligible patients declined to participate in the study. This high rate of refusal to participate probably resulted from the fact that all patients knew they had a one-in-three chance of undergoing a placebo procedure [39
Some researchers reported using a placebo control intervention that was not identical to the active treatment, for example, in comparing an experimental rehabilitation program to sham ultrasonography. These methods could be a solution when assessing NPT. Spigt et al. [40
], in assessing lifestyle advice, proposed using a syrup placebo, and assessed and validated the methodological and ethical consideration of these designs. In such trials, participants should be informed in part and blinded to the study hypothesis.
Blinding participants to study hypotheses could also be proposed when the comparator is an active control treatment of the same nature or different nature by use of a modified Zelen design [33
]. Such design is a two-stage procedure, in which patients are asked to provide consent for an observational study in the first stage. Then patients are randomized to the experimental treatment and the control arm, and in the second stage are asked to provide a second consent for treatment. In these situations, ethical considerations require that participants be told that for scientific reasons, they were not informed about the specific goal of the study and that full information will be provided at the study's conclusion [40
]. Further, such trials should be conducted carefully to avoid disclosure of the trial hypothesis and, especially, to avoid contact between participants in each arm. Using such a design, trialists should be aware that depending on the appearance of the experimental treatment and placebo, differences in expectations could influence the outcome, particularly for outcomes sensitive to psychological factors. In these situations, the psychological strength of the treatment could be assessed by measuring the credibility of the treatment (i.e., use of validated credibility scales [43
]), participants' expectations (i.e., asking participants to rate their expected effect of both intervention on a Likert scale), or by registering participants' preference at the beginning of the trial before randomization [40
Our classification scheme highlights the fact that blinding outcome assessors depends mainly on the primary outcome. We focused on the outcome because of some evidence that the risk of bias varies according to the outcome. Wood et al. [52
] showed that lack of blinding yielded exaggerated treatment effect estimates for subjective outcomes but had no effect on objective outcomes. In most situations blinding outcome assessors should therefore be possible with a centralized assessment of complementary investigation, physician-mediated data, and clinical events (). These methods are likely to be more successful than those consisting of instructing participants not to tell outcome assessors the treatment they received. In fact, a study comparing splinting and surgery in the treatment of carpal tunnel syndrome involved an attempt to blind the outcome assessor by encouraging the participants not to reveal their treatment and by masking the surgical scar. Despite these efforts, at the end of the trial assessors guessed correctly the treatment performed [53
]. However, asking assessors to guess treatment assignment during a RCT may not be adequate for assessing the success of blinding [15
]. Authors have suggested that the success of blinding should be systematically assessed in RCTs [14
]. However, this recommendation was vigorously debated [15
]. In fact, when asking participants to guess treatment assignment, those feeling better will tend to guess they are receiving the experimental treatment rather then the control treatment. Consequently, if the treatment is effective, the success of blinding may be discussed although the method of blinding was adequate. Blinding is more likely to be considered successful when a treatment is ineffective. Finally, for participant-reported outcomes, for which the participant is the outcome assessor, if no methods can overcome the difficulties in establishing and maintaining blinding of participants, no methods should be used so as to avoid ascertainment bias by a blinded outcome assessment.
The description of all these methods also highlights some issues such as the possible economic burden of blinding within these trials that might well be substantial and requires additional investigation. Further, some methods such as blinding patients to the study hypothesis could lead to partial blinding, and the success of these methods could be questionable [18
Our study might not have captured some specific methods of blinding. In fact, we assessed only RCTs published in high-impact-factor journals during 2004. However, our aim was not to be exhaustive but to provide a description of several possible methods of blinding. Furthermore, we added reports found by searching reference lists of relevant selected articles or reports known by members of our team or experts in this field. In addition, this study assessed only the reporting of trials, not the trials themselves, and some methods might not have been reported [10
]. However, we allowed for highlighting creative methods of blinding. Finally, the results are evolving, and readers are invited to inform us of other methods of blinding not captured in this survey.
In conclusion, we provide a classification of methods of blinding participants, health care providers, and outcome assessors in trials of NPT and a detailed description of methods that could overcome barriers to blinding in such trials. This classification should be helpful for trialists to determine the method of blinding according to the aim of the trial and for readers to assess the feasibility of blinding in and quality of RCTs assessing NPTs.