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Randomized control trials (RCTs) with placebo are the gold standard for determining efficacy of novel pharmaceutical treatments. Since their inception, over 75 years ago, researchers have amassed a large body of underutilized data on outcomes in the placebo control arms of these trials. Although rare disease indications have used these historical placebo data as synthetic controls to reduce burden on patients and accelerate drug discovery, broad use of historical controls is in its infancy. Large-scale historical placebo data could be leveraged to benefit both drug developers and patients if warehoused and made more available to guide trial design and analysis. Here, we examine challenges in utilizing historical controls related to heterogeneity in trial design, outcome ascertainment, patient characteristics, and unmeasured pharmacogenomic effects. We then discuss the advantages and disadvantages of current approaches and propose a path forward to broader use of historical controls in RCTs., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

Background: Clinical trial articles often lack detailed descriptions of the methods used to randomize participants, conceal allocation, and blind subjects and investigators to group assignment. We describe our systematic approach to implement and measure blinding success in a double-blind phase 2 randomized controlled trial testing the efficacy of acupuncture for the treatment of vulvodynia., Methods: Randomization stratified by vulvodynia subtype is managed by Research Electronic Data Capture software's randomization module adapted to achieve complete masking of group allocation. Subject and acupuncturist blinding assessments are conducted multiple times to identify possible correlates of unblinding., Results: At present, 48 subjects have been randomized and completed the protocol resulting in 87 subject and 206 acupuncturist blinding assessments., Discussion: Our approach to blinding and blinding assessment has the potential to improve our understanding of unblinding over time in the presence of possible clinical improvement.

Background: Beneficial effects of placebos are high in double-blind hot flush trials. Studies in various conditions suggest that honestly prescribed placebos may elicit symptom improvement., Objective: To determine whether open label placebo (OLP) treatment is efficacious in alleviating hot flushes among peri- and postmenopausal women., Methods/design: In this assessor-blinded, randomized-controlled trial, n = 100 women experiencing five or more daily hot flushes of at least moderate severity and bothersomeness are assigned 1:1 to a 4-week OLP treatment or no treatment. To explore the duration and maintenance of placebo effects, the OLP group is randomized a second time to either discontinue or continue the OLP treatment for another 4 weeks. All participants receive a briefing about placebo effects and study visits at baseline, post-treatment (4 weeks), and follow-up (8 weeks, OLP group only). Qualitative interviews about subjective experiences with the OLP treatment are conducted. Primary outcomes are differences between the OLP and the no-treatment group in the hot flush composite score (frequency × severity), and bothersomeness of hot flushes as assessed with the Hot Flush Rating Scale at post-treatment. Secondary outcomes include hot flush frequency, health-related quality of life, global improvement, and the number of responders at post-treatment. Data are analyzed by fitting (generalized) linear mixed models. An exploratory analysis of maintenance and duration is performed including follow-up data., Discussion: This trial will contribute to the evaluation of OLP treatments in clinical practice and further our understanding about the magnitude of placebo effects in hot flush treatments., Trial Registration: Clinicaltrials.gov, NCT03838523 . Retrospectively registered on February 12th, 2019. The first patient was enrolled on October 10th, 2018.

Participants in placebo-controlled clinical trials give informed consent to be randomized to verum or placebo. However, researchers rarely tell participants which treatment they actually received. We interviewed 4 participants in a trial of acupuncture for irritable bowel syndrome before, during, and after they received a course of placebo treatments over 6 weeks. During the final interview, we informed participants that they had received a course of placebo treatments. We used an idiographic phenomenological approach based on the Sheffield School to describe each participant's experiences of being blinded to and then debriefed to placebo allocation. The participants' experiences of blinding and debriefing were embodied, related to their goals in undertaking the study, and social (e.g., embedded in trusting and valued relationships with acupuncturists). We suggest ways in which debriefing to placebo allocation can be managed sensitively to facilitate positive outcomes for participants.

Placebos are an essential tool in randomised clinical trials, where they are used to control for bias and contextual healing effects. Placebos and their effects are also studied from multiple diverse perspectives, but the perspectives of placebo recipients are seldom considered. Research shows that people form cognitive and affective representations of active treatments such as medicines, and that they use these representations to guide their behaviour; it seems reasonable to suggest that people might also think about and develop representations of placebos. We adopted a qualitative approach to examine in detail how participants in one RCT, conducted in the USA, conceptualised placebos. 12 people were interviewed 3 times each, at the start, middle, and end of a trial of placebo effects and acupuncture for Irritable Bowel Syndrome (IBS). The interview data were analysed inductively and we identified four ways in which the participants conceptualised placebos: placebos are necessary for research; placebo effects are fake; placebo acupuncture is not real acupuncture; placebos have real effects mediated by psychological mechanisms. Participants' conceptualisations of placebos were dynamic and situated in a broader psychological and socio-cultural context. Seeing placebo effects as legitimate seemed to be facilitated by having more holistic models of healing, viewing IBS as psychological, and seeing treatment as multifactorial. However, some participants maintained a negative view of placebo effects (e.g. as illusions) that was apparently inconsistent with their other beliefs (e.g. in mind-body healing mechanisms). This may indicate a dominance of negative discourses around placebos at a socio-cultural level. Negative views of placebos are inconsistent with evidence that placebo treatments can have positive effects on symptoms. RCT participants should be informed about potential benefits of placebo treatments to avoid misunderstandings and unease. Future work should improve methods of providing participants with full accurate information about placebos and their effects., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Investigations of the effect of placebo are often challenging to conduct and interpret. The history of placebo shows that assessment of its clinical significance has a real potential to be biased. We analyze and discuss typical types of bias in studies on placebo., Study Design and Setting: A methodological analysis and discussion., Results: The inherent nonblinded comparison between placebo and no-treatment is the best research design we have in estimating effects of placebo, both in a clinical and in an experimental setting, but the difference between placebo and no-treatment remains an approximate and fairly crude reflection of the true effect of placebo interventions. A main problem is response bias in trials with outcomes that are based on patients' reports. Other biases involve differential co-intervention and patient dropouts, publication bias, and outcome reporting bias. Furthermore, extrapolation of results to a clinical settings are challenging because of a lack of clear identification of the causal factors in many clinical trials, and the nonclinical setting and short duration of most laboratory experiments., Conclusions: Creative experimental efforts are needed to assess rigorously the clinical significance of placebo interventions and investigate the component elements that may contribute to the therapeutic benefit., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The randomized controlled trial (RCT) is the gold standard for assessing the efficacy of medical treatments. Over the past 50 years, RCT methodology has proven to be quite successful in identifying effective treatments and weeding out ineffective ones, thus transforming medicine from an intuitive art into an empirical science. However, the enormous success of the RCT has inadvertently contributed to a common inferential error that is insufficiently appreciated by some clinicians and researchers. Although RCTs can effectively distinguish between placebo and active treatment effects at the level of the group, contrary to intuition, this same disentanglement is much more difficult to achieve at the level of the individual. For individual patients it is surprisingly difficult to determine who is a treatment responder and who is not. Using data from a recent RCT, we illustrate the problem and detail its negative effects for research and clinical practice. Finally, we suggest strategies for minimizing these negative effects., (Copyright 2010 Elsevier Inc. All rights reserved.)

In the West, hundreds of randomized controlled trials (RCTs) have been performed testing acupuncture. They include two types: those that compare acupuncture to other therapies, usual care or no treatment (pragmatic trials), and those that have placebo controls (efficacy trials). Acupuncture has generally performed well against other therapies or no treatment, but until recently, the evidence from placebo controlled trials has been considered equivocal or contradictory. A recent series of large RCTs, mostly performed in Germany and also in the US have included both pragmatic and placebo comparisons. The evidence poises a conundrum for the profession of acupuncture. This essay first describes the two types of RCTs used to examine acupuncture and examine the results of two recent large RCTs for chronic low back pain as representative examples of recent large studies. The essay then presents the most common Euro-American acupuncture professions' interpretation of these results. Western responses have included: (1) methodological weaknesses; (2) inappropriateness of placebo controls; (3) questions as to whether acupuncture placebo controls are "inert"; (4) rejection of evidence-based medicine epistemology; (5) discrepancy between acupuncture performed in RCTs with real world acupuncture; (6) enhanced placebo effects of acupuncture; and (7) needs to re-evaluate acupuncture theory. The authors do not necessarily agree with all of these responses; they are presented in an attempt to foster critical discussion. The paper also looks at recent neuroimaging experiments on acupuncture that may point to some worthwhile new avenues of investigation. Finally, the Euro-American health care policy consequences of these recent RCTs are discussed.

Compared with other specialties, the field of physical and rehabilitation medicine has not received the deserved recognition from clinicians and researchers in the scientific community. One of the reasons is the lack of sound evidence to support the traditional physical and rehabilitation medicine treatments. The best way to change this disadvantage is through a well conducted clinical research, such as standard placebo- or sham-controlled randomized clinical trials. Therefore, having placebo groups in clinical trials is essential to improve the level of evidence-based practice in physical and rehabilitation medicine that ultimately translates to better clinical care. To address the challenges for the use of placebo in physical and rehabilitation medicine and randomized clinical trials and to create useful recommendations, we convened a working group during the inaugural International Symposium in Placebo (February 2009, in Sao Paulo, Brazil) in which the following topics were discussed: (1) current status of randomized clinical trials in physical and rehabilitation medicine, (2) challenges for the use of placebo in physical and rehabilitation medicine, (3) bioethics, (4) use of placebo in acupuncture trials and for the treatment of low-back pain, (5) mechanisms of placebo, and (6) insights from other specialties. The current article represents the consensus report from the working group.

Background: Little is known about whether federally funded complementary and alternative medicine (CAM) research is translating into clinical practice. We sought to describe the awareness of CAM clinical trials, the ability to interpret research results, the acceptance of research evidence, and the predictors of trial awareness among US clinicians., Methods: We conducted a cross-sectional mailed survey of 2400 practicing US acupuncturists, naturopaths, internists, and rheumatologists., Results: A total of 1561 clinicians (65%) responded. Of the respondents, 59% were aware of at least 1 major CAM clinical trial; only 23% were aware of both trials. A minority of acupuncturists (20%), naturopaths (25%), internists (17%), and rheumatologists (33%) were "very confident" in interpreting research results (P < .001). Fewer acupuncturists (17%) and naturopaths (24%) than internists (58%) and rheumatologists (74%) rated the results of randomized controlled trials as "very useful" (P < .001). Twice as many internists (53%) and rheumatologists (64%) rated patient preferences as "least important" compared with acupuncturists (27%) and naturopaths (31%) (P < .001). In multivariate analyses, for clinicians aware of at least 1 trial, male sex (odds ratio [OR], 1.30 [95% confidence interval {CI}, 1.05-1.62]), prior research experience (OR, 1.45 [95% CI, 1.13-1.86]), institutional or academic practice setting (ORs, 1.98 [95% CI, 1.01-3.91], and 1.23 [95% CI, 0.73-2.09], respectively), and rating randomized trials as "very useful" (OR, 1.46 [95% CI, 1.12-1.91]) (P < .001) for clinical decision making were positively associated with CAM trial awareness. Acupuncturists, naturopaths, and internists (ORs, 0.15 [95% CI, 0.10-0.23], 0.15 [95% CI, 0.09-0.24], and 0.18 [95% CI, 0.12-0.28], respectively) were all similarly less aware of CAM trial results compared with rheumatologists., Conclusion: For clinical research in CAM to achieve its social value, concerted efforts must be undertaken to train clinicians and improve the dissemination of research results.

Although a growing body of clinical research has begun to evaluate the efficacy and safety of t'ai chi as a therapeutic tool for a variety of health conditions, little attention has been devoted to evaluating "how" t'ai chi is scientifically studied, and the advantages or limitations of different methodological approaches. In a companion to this paper (Part I), we argued that t'ai chi is a complex, multicomponent intervention, which poses unique challenges regarding the distinction of specific versus nonspecific effects and limitations regarding the use of reductionistic research frameworks. In this second, companion paper, we discuss additional obstacles inherent in precisely defining the t'ai chi intervention in an experimental paradigm. These challenges include t'ai chi's pluralism, the concept of t'ai chi dosage, and long- versus short-term evaluations of t'ai chi's efficacy and safety. To address these challenges, and with a goal to provide complete and unbiased evidence, we propose a pluralistic methodological approach to clinical research that includes controlled randomized trials of fixed protocols, community-based pragmatic trials, cross-sectional studies of long-term practitioners, and studies that integrate qualitative methods.

A successful clinical trial is dependent on recruitment. Between December 2003 and February 2006, our team successfully enrolled 289 participants in a large, single-center, randomized placebo-controlled trial (RCT) studying the impact of the patient-doctor relationship and acupuncture on irritable bowel syndrome (IBS) patients. This paper reports on the effectiveness of standard recruitment methods such as physician referral, newspaper advertisements, fliers, audio and video media (radio and television commercials) as well as relatively new methods not previously extensively reported on such as internet ads, ads in mass-transit vehicles and movie theater previews. We also report the fraction of cost each method consumed and fraction of recruitment each method generated. Our cost per call from potential participants varied from $3-$103 and cost per enrollment participant varied from $12-$584. Using a novel metric, the efficacy index, we found that physician referrals and flyers were the most effective recruitment method in our trial. Despite some methods being more efficient than others, all methods contributed to the successful recruitment. The iterative use of the efficacy index during a recruitment campaign may be helpful to calibrate and focus on the most effective recruitment methods.

Little is known about placebo effects with scientific precision. Poor methodology has confounded our understanding of the magnitude and even the existence of the placebo effect. Investigating placebo effects presents special research challenges including: the design of appropriate controls for studying placebo effects including separating such effects from natural history and regression to the mean, the need for large sample sizes to capture expected small effects, and the need to understand such potential effects from a patient's perspective. This article summarizes the methodology of an ongoing NIH-funded randomized controlled trial aimed at investigating whether the placebo effect in irritable bowel syndrome (IBS) exists and whether the magnitude of such an effect can be manipulated to vary in a manner analogous to "dose dependence." The trial also uses an innovative combination of quantitative and qualitative methods.

Objective: To explore participants' experience in placebo-controlled randomized clinical trials (RCTs) specifically in relationship to their expectations., Background: Aspects of being in RCTs, such as informed consent, perception of benefit and understanding of randomization, have been examined. In contrast, little is known concerning the formation of patient expectations before and during trials., Methods: Qualitative methods using in-depth interviews with a semi-structured interview guide of nine patients from four different RCTs. Data analysis was conducted using a codebook format arranging participant responses under broad analytical headings. The interviewer used a semi-structured interview guide to direct the conversation from one broad topic to the next within the context of the ongoing conversation. A checklist of topics encouraged participants to describe their experiences in RCTs. Narratives concerning expectation, blinding and placebo were compared to identify common themes., Results: Patient anticipatory processes were influenced and modified both before and during the trial from multiple inputs. Such factors as past experiences in RCTs, past experiences of ineffective treatment, stress of being off regular medications, fear of being a 'placebo responder', input of non-study doctors or other health professionals, the experience of other participants, measurements of health parameters made during the trial and the presence or absence of side-effects all affected patient expectation., Conclusion: Expectations in RCTs are not fixed and instead may be viewed as continuously shaped by multiple inputs that include experience and information received both before and during the trial. Variability in placebo response observed in previous studies may be related to the fluid nature of expectations. Trying to control and equalize expectations in RCTs may be more difficult than previously assumed.

Objectives: To assess whether and how investigators of placebo controlled randomised trials inform participants of their treatment allocation at trial closure and to assess barriers to feedback., Design: Postal survey with a semistructured questionnaire., Participants: All investigators who published a placebo controlled randomised trial in 2000 in five leading medical journals, and a random sample of 120 trials listed in the national research register database., Main Outcome Measures: Number of investigators who informed participants of their treatment allocation at trial closure, methods for delivering the information, and barriers to unmasking treatment., Results: 45% of investigators informed either all or most participants of their treatment allocation, and 55% did not inform any participant or only informed those who asked. The main reasons for not informing participants were that the investigators never considered this option (40%) or to avoid biasing results at study follow up (24%)., Conclusion: Further research is required to examine sensitive ways to communicate treatment information to trial participants.

The double-blind randomized controlled trial (RCT) is accepted by medicine as objective scientific methodology that, when ideally performed, produces knowledge untainted by bias. The validity of the RCT rests not just on theoretical arguments, but also on the discrepancy between the RCT and less rigorous evidence (the difference is sometimes considered an objective measure of bias). A brief overview of historical and recent developments in "the discrepancy argument" is presented. The article then examines the possibility that some of this "deviation from truth" may be the result of artifacts introduced by the masked RCT itself. Can an "unbiased" method produce bias? Among the experiments examined are those that augment the methodological stringency of a normal RCT in order to render the experiment less susceptible to subversion by the mind. This methodology, a hypothetical "platinum" standard, can be used to judge the "gold" standard. The concealment in a placebo-controlled RCT seems capable of generating a "masking bias." Other potential biases, such as "investigator self-selection," "preference," and "consent" are also briefly discussed. Such potential distortions indicate that the double-blind RCT may not be objective in the realist sense, but rather is objective in a "softer" disciplinary sense. Some "facts" may not exist independent of the apparatus of their production.