Asbjørn Hróbjartsson

Is the Placebo powerless? An analysis of clinical trials comparing placebo with no treatment

Background Placebo treatments have been reported to help patients with many diseases, but the quality of the evidence supporting this finding has not been rigorously evaluated. Methods We conducted a systematic review of clinical trials in which patients were randomly assigned to either placebo or no treatment. A placebo could be pharmacologic (e.g., a tablet), physical (e.g., a manipulation), or psychological (e.g., a conversation). Results We identified 130 trials that met our inclusion criteria. After the exclusion of 16 trials without relevant data on outcomes, there were 32 with binary outcomes (involving 3795 patients, with a median of 51 patients per trial) and 82 with continuous outcomes (involving 4730 patients, with a median of 27 patients per trial). As compared with no treatment, placebo had no significant effect on binary outcomes, regardless of whether these outcomes were subjective or objective. For the trials with continuous outcomes, placebo had a beneficial effect, but the effect decreas...

SPIRIT 2013 Statement: defining standard protocol items for clinical trials.

The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol.The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.

Comparison of descriptions of allocation concealment in trial protocols and the published reports: cohort study

Abstract Objectives To compare how allocation concealment is described in publications of randomised clinical trials and corresponding protocols, and to estimate how often trial publications with unclear allocation concealment have adequate concealment according to the protocol. Design Cohort study of 102 sets of trial protocols and corresponding publications. Setting Protocols of randomised trials approved by the scientific and ethical committees for Copenhagen and Frederiksberg, 1994 and 1995. Main outcome measures Frequency of adequate, unclear, and inadequate allocation concealment and sequence generation in trial publications compared with protocols, and the proportion of protocols where methods were reported to be adequate but descriptions were unclear in the trial publications. Results 96 of the 102 trials had unclear allocation concealment according to the trial publication. According to the protocols, 15 of these 96 trials had adequate allocation concealment (16%, 95% confidence interval 9% to 24%), 80 had unclear concealment (83%, 74% to 90%), and one had inadequate concealment. When retrospectively defined loose criteria for concealment were applied, 83 of the 102 trial publications had unclear concealment. According to their protocol, 33 of these 83 trials had adequate allocation concealment (40%, 29% to 51%), 49 had unclear concealment (59%, 48% to 70%), and one had inadequate concealment. Conclusions Most randomised clinical trials have unclear allocation concealment on the basis of the trial publication alone. Most of these trials also have unclear allocation concealment according to their protocol.

What are the main methodological problems in the estimation of placebo effects

Researchers disagree whether placebo effects are clinically important. The controversy is partly due to conceptual and methodological problems. The objective of this paper is to analyze the main methodological problems in the estimation of placebo effects. Variations in the meaning of the concept of placebo effect are described, and the main methodological problems are analyzed. The notion of placebo effect has at least two main meanings: effect of placebo intervention, and effect of patient-provider interaction. When the terms are defined pragmatically, effects of placebo can be estimated as the difference between placebo and no-treatment in randomized trials. The effect of patient-provider interaction can similarly be assessed by comparing manipulation of the patient-provider interaction with no manipulation. In both cases bias due to lack of double-blinding is a potential problem.

The Use of Placebo Interventions in Medical Practice—A National Questionnaire Survey of Danish Clinicians:

The authors sent a questionnaire to 772 randomly selected Danish clinicians and asked them about their use of placebo interventions. Sixty-five percent responded. Among the general practitioners, 86% (95% confidence interval 81-91) reported to have used placebo interventions at least once, and 48% (41-55) to have used placebo interventions more than ten times, within the last year. Hospital-based doctors and private specialists reported to have used placebo interventions less frequently (p <.001). The most important reason for the use of placebo interventions was to avoid a confrontation with the patient. Typical placebos were antibiotics for viral infections. Approximately 30% (28-36) of the clinicians believed in an effect of placebo interventions on objective outcomes, and 46% (42-50) found clinical placebo interventions generally ethically acceptable.

Bias due to lack of patient blinding in clinical trials. A systematic review of trials randomizing patients to blind and nonblind sub-studies

BACKGROUNDnBlinding patients in clinical trials is a key methodological procedure, but the expected degree of bias due to nonblinded patients on estimated treatment effects is unknown.nnnMETHODSnSystematic review of randomized clinical trials with one sub-study (i.e. experimental vs control) involving blinded patients and another, otherwise identical, sub-study involving nonblinded patients. Within each trial, we compared the difference in effect sizes (i.e. standardized mean differences) between the sub-studies. A difference <0 indicates that nonblinded patients generated a more optimistic effect estimate. We pooled the differences with random-effects inverse variance meta-analysis, and explored reasons for heterogeneity.nnnRESULTSnOur main analysis included 12 trials (3869 patients). The average difference in effect size for patient-reported outcomes was -0.56 (95% confidence interval -0.71 to -0.41), (I(2)=60%, P=0.004), i.e. nonblinded patients exaggerated the effect size by an average of 0.56 standard deviation, but with considerable variation. Two of the 12 trials also used observer-reported outcomes, showing no indication of exaggerated effects due lack of patient blinding. There was a larger effect size difference in 10 acupuncture trials [-0.63 (-0.77 to -0.49)], than in the two non-acupuncture trials [-0.17 (-0.41 to 0.07)]. Lack of patient blinding also increased attrition and use of co-interventions: ratio of control group attrition risk 1.79 (1.18 to 2.70), and ratio of control group co-intervention risk 1.55 (0.99 to 2.43).nnnCONCLUSIONSnThis study provides empirical evidence of pronounced bias due to lack of patient blinding in complementary/alternative randomized clinical trials with patient-reported outcomes.