Abstract
Background: The successful application of randomized, double-blind placebo-controlled studies requires maximum blinding. Organoleptic properties of the placebo should be similar to the drug, making it difficult to distinguish between the two. The uniqueness of traditional Chinese medicine (TCM) preparations makes it challenging to prepare placebo. Evaluation of the TCM placebo simulation effect can determine whether the preparation of placebo can be genuinely blind in clinical trials. There is still a lack of well-established methods to evaluate TCM placebos. Hence, this study aimed to explore the evaluation methodology of TCM placebo simulation. Methods: An independent evaluation method and three comparative evaluation methods were proposed, and three dosage forms (oral liquid, capsule, and granule) were tested. The independent evaluation, in which each person was given an experimental drug or a placebo, gave an overall assessment of organoleptic properties in a blind state. We comparatively evaluated the similarity in organoleptic properties between the experimental drug and placebo. According to different distribution methods, we divided comparative evaluation methods into three. In method 1, the evaluator was given the experimental drug and placebo and was told that there must be a placebo among them. In method 2, each evaluator was randomly assigned to the combination group or two investigational drugs group. In method 3, the evaluator was assigned to a set of three coded samples, numbered by random three-digit numbers, each different, two of which were identical, and the two samples were equally frequent. Results: In the independent evaluation, there was no difference between TCM placebo and experimental drugs in a blind state at the level of p = 0.05. Even though the comparative evaluation methods enabled identification of potential differences between the two samples, methods 2 and 3 were better than method 1 in eliminating psychological factors. Also, in method 3, the completely random method combined with the blind method eliminated the subjectivity and objectivity bias and improved the experiment’s credibility compared with the previous two methods. Conclusion: Regardless of the methods that could evaluate the placebo’s simulated effect in actual clinical trials, we suggest that independent evaluation and comparative evaluation (method 3) should be combined to reflect better whether the placebo is truly blind.
Highlights
Masking of participants and researchers has long been used in randomized clinical trials (RCTs) to eliminate the potential impacts of nondrug effects, including the natural course of the disease; the evaluator and researchers; and subjective factors in treatment, diagnosis, and clinical assessment (Jamshidian et al, 2014; Dube et al, 2007)
In the independent evaluation of three dosage forms of traditional Chinese medicine (TCM) placebos, there were no significant differences across the groups
In the actual clinical application, we suggest that the combination of independent and comparative evaluation can be closer to the real double-blind placebo-controlled studies, so as to avoid the placebo and nocebo effects to the greatest extent
Summary
Masking of participants and researchers has long been used in randomized clinical trials (RCTs) to eliminate the potential impacts of nondrug effects, including the natural course of the disease; the evaluator and researchers; and subjective factors in treatment, diagnosis, and clinical assessment (Jamshidian et al, 2014; Dube et al, 2007). Compared with western medicine placebo drugs, the unique odor, taste, and color of TCM preparations make it challenging to prepare placebo. The placebo prepared by the simple excipient method placebo does not contain pharmacodynamic components. It uses flavorants (edible additives), colorants (edible pigments), and volatiles (agents to simulate a placebo) (Lu et al, 2018). To explore whether the organoleptic properties of the placebo are exactly the same as those of experimental drugs, it is imperative to evaluate the TCM placebo’s simulation effect. Evaluation of the TCM placebo simulation effect can determine whether the preparation of placebo can be genuinely blind in clinical trials. This study aimed to explore the evaluation methodology of TCM placebo simulation
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