Possible explanations and implications of the study for clinicians and researchers
In medicine, whether in clinical or research settings, there are high levels of ethical requirements that are expected to be met. Respecting trial participants’ autonomy by providing them adequate amount of information is one of those requisites for ethical practice in medical research, and often, the PIL is presented to the participants as a tool to meet the requirements. The main purpose of the PIL, in this sense, would be to help participants voluntarily make a well-informed decision on the introduced matter. When the control intervention of the trial involves a placebo, there has to be even more cautious approach and full disclosure of such information [
1,
24,
25]. On the other hand, there are concerns on too much information may disadvantage the participants, as in increasing a nocebo effect [
26,
27], or resulting in a lengthy document that rather compromises participants’ understanding [
28]. Some argue that PILs are not in a reader friendly language [
29], nor come with decision making aids [
30]. Therefore, for a PIL to fully serve its purpose, it seems necessary to inform the participants in a way that is not only being clear about what is going to happen, but also being considerate of how it actually helps them to make an informed decision.
There has been a concerning voice that placebo-controlled trials of acupuncture are reluctant to fully disclose the existence of placebo acupuncture control [
3,
4]. However, findings of the current study show change of practice ever since, showing number of studies that accurately inform the use of placebo control, being more than a half: out of 70 placebo groups from 65 PILs, 40 were classified into FD category, and 12 of those 40 were from the older studies that were included in the previous review. These findings confirm that acupuncture trials are also trying to conform to the ethical requirements [
31,
32]. However, at the same time, given that there is still a room for improvement in providing complete and accurate information about placebos even in trials assessing conventional medicine [
9], and device-based interventions are facing challenges in maintaining blinding with a full disclosure of placebos [
33], information disclosure in PIL may be taken as an issue in clinical research across the board.
In East Asian countries, even after western medicine’s addition to the system, traditional medicine is still routinely used [
34,
35]. As a result, acupuncture is easily accessible and embedded in cultural background. Therefore, participants as well as the researchers of acupuncture trials are assumed to be more familiar with acupuncture compared to those in non-Asia region [
36]. This brings concern to Asian researchers that the study participants will easily distinguish real from placebo acupuncture. The rationale behind such fear is not simple, as studies examining the influence of the participant’s previous experience on detecting placebo acupuncture presented conflicting results [
37,
38]. The notion that blinding may be hampered if trial participants are fully informed on details of placebo acupuncture, is partly explained in our BI analysis. While 21% of the participants in the placebo acupuncture group from DD/MI category made incorrect guesses beyond chance, i.e. they believed they received real acupuncture, 16% of those in the placebo acupuncture group from FD category made such guesses. It could be interpreted that though not statistically significant, the participants on the placebo acupuncture arm who were not very well informed about placebo acupuncture tended to guess that they received real acupuncture more than participants in FD category did. It reflects participants’ wishful thinking, which may lead to an augmented placebo effect [
10]. This finding is in line with the result from the Cochrane review of all placebo interventions where a higher placebo effect was reported in trials without correct information of placebo than those with correct information [
39]. An altered placebo labeling study also has shown that placebo effect goes higher as the label on placebo changes from placebo, uncertain to valid medicine [
40]. Given our BI analysis and the results from other relevant studies, the hypothesis can be generated that full disclosure of placebo in PILs may undermine successful blinding of participants and this should be systematically evaluated in the future studies.
A meta-epidemiological study has reported that well maintained blinding resulted in a smaller effect of intervention compared to non-blinded trials [
41]. In the present study, however, pooled effect size of trials in DD category, which showed better blinding results than FD category, was greater than that of FD category. There could be two possible explanations. First, we may suspect that informing the presence of placebo acupuncture in detail lowered the participants’ expectation and as a result, possibly undermined the effect of real acupuncture in studies in FD category, whereas the participants’ expectation was maintained or enhanced in DD category and the trials favored acupuncture to a larger extent. This is supported by a pooled analysis from four, large population based German RCTs which demonstrated higher expectation was associated with a better outcome regardless of given treatment [
42]. Considering that our study was not designed to directly measure participants’ expectation of treatment, however, we cannot estimate to what extent expectation contributed to greater effect size from the studies in DD category than those in FD category. Another explanation is that the treatment effect in DD category is rather overestimated due to investigator’s bias. Not only the patients but also trialists have expectations, wittingly or unwittingly [
43]. Considering the fact that more studies in DD/MI category originated from Asia, which is an acupuncture friendly region where researchers are eager to prove its efficacy, than FD category, it may be trialists’ expectation on top of the participants’ expectation that resulted in such higher estimation. Besides, when we evaluated whether outcome assessor was blinded to the intervention in the included studies, the proportion of studies with appropriate blinding for outcome assessor was slightly lower in DD category (20 out of 25, 80%) compared to FD category (33 out of 40, 82.5%). This too supports investigator bias may have possibly played a part in overestimation of treatment effect in the studies of DD category. Nonetheless, the fact that only small number of studies were included here and that this is merely observational in nature allows for an interpretation in a narrow context. To elucidate complicated relationships between PILs, blinding, and outcomes of a trial, further studies designed to compare the links between those are warranted for more discussion.
Strengths and weaknesses of the study
One of the strengths of this study is that we are addressing a fundamental question over so-called routine clinical research procedures. We tried to provide a more comprehensive understanding of any association of placebo disclosure in PILs with methodological issues in clinical research, i.e. blinding, and the effect size. Previous studies have usually focused on ethics [
44], readability [
45], or comprehensiveness [
46], but few studies explored association of pre-trial information on placebo with blinding and trial outcomes, which definitely requires further investigations from a different point of view. Another strength would be that it encompasses qualitative and quantitative research designs. Collected PILs were subject to systematic qualitative content analysis method [
12]. Then, numerical analyses such as calculating BI and effect size were conducted in conjunction with the results from content analysis. Such integrated method can help science achieve better understanding of its discoveries [
47].
Some limitations also should be noted. Firstly, not all included documents were written in English and simple analysis such as word count, page count, or readability calculation was not feasible. Although, all documents were carefully translated into proper English by experts then analyzed in the main analysis in a standardized way, we cannot rule out the possibility that some subtle nuance of original language was not delivered in translation. Secondly, the number of studies included in blinding and outcome analysis was too small compared to that of all included studies for content analysis, which might have made it difficult to detect statistically significant differences, if any, thus to draw any firm conclusion. Even so, the number of studies included in the main content analysis was larger than 16 of a previous study [
3] and was similar to the suggested ‘medium’ sample size for integrated qualitative-quantitative research [
47]. More importantly, this study accomplished to collect the documents from many different countries of different environment and culture while the previous study had documents mostly from only few countries such as Germany, UK and USA. This diversity of documents in the present study made it possible to explore rich source of data. Last but not the least, the actual perception of the information on PIL by study participants may differ from degree of information disclosure judged in our study. Participants’ understanding and memory of the contents of PILs vary [
33] and their behavior may be influenced by other multiple factors such as prior knowledge, health literacy, preference and expectation.
Unanswered questions and future research
Our findings raise questions on routinely accepted informed consent procedures: ethical standard requires every detailed information including placebo should be given to study participants. Placebo information in other than acupuncture trials, however, has been reported far from fully informing [
9] and what information is provided to the patient about side effects is known to modulate treatment responses often to enhance nocebo effect [
8,
48]. Moreover, as we have few empirical findings on how patients are told about placebo may affect blinding and study outcomes, future studies are needed to examine this unanswered question.
Other than methodological qualities such as allocation concealment or blinding that are known to affect the direction or magnitude of treatment effect [
41,
49], we found information on placebo in PIL may be another potential factor for influencing the study outcome by possibly modulating patient expectation in the informed consent process. Therefore, further in-depth studies utilizing both qualitative and quantitative methods are warranted to better understand complicatedly intertwined factors in PILs, blinding, and outcomes of placebo-controlled trials.