Placebo groups are often included in randomized control trials evaluating drug therapy, yet we know little about the placebo effect. The purpose of our study was to evaluate how the presence of a placebo group in a randomized control trial (RCT) influences the patients' ratings of the efficacy of an active drug therapy and their reporting of its adverse effects. We identified studies published between 1966 and 1994 using MEDLINE. Randomized control trials evaluating acetylsalicylic acid, diclofenac, or indomethacin for the treatment of osteo or rheumatoid arthritis were included in our sample. Two investigators independently extracted data. Fifty-eight treatment arms met our inclusion criteria and were available for analysis. Twenty-five treatment arms evaluated a nonsteroidal antiinflammatory drug (NSAID) in placebo control trials and 33 in comparative trials. Using a logistic regression model to adjust for the differences between the evaluated drugs and between the types of arthritis, we found that patients receiving an NSAID in a placebo control trial were more likely to withdraw due to inefficacy (OR=1.3; 95% CI, 1.0 to 1.6; P=0.04). Using a similar model, withdrawals due to adverse effects were found to be more common when the NSAID was given in trials that did not include a placebo group (OR=1.5; 95% CI, 1.1 to 1.9; P=0.002) as were reports of cutaneous (OR=4.2; 95% CI, 1.7 to 9.9), gastrointestinal (OR=1.6; 95% CI, 1.3 to 2.0), and other types (OR=5.3; 95% CI, 3.8 to 7.4) of adverse effects. Although reports of central nervous system adverse effects were more frequent in the comparative trials, this difference was not significant. Including a placebo group in a RCT changes how patients rate the efficacy and adverse effects of their therapy. Our results highlight the need to consider the placebo effect in the design and analyses of clinical trials.
"In addition to registration status, we included industry sponsorship and sample size in our multivariate analysis because of their statistical significance in the univariate analysis. We also included stringency of blinding, outcome measure type, and comparator treatment type as these trial characteristics had been associated with direction of results in similar studies [9,11,13,46]. Journal impact factor was dropped from multivariate analysis because interaction testing found that its correlation with favorable results was accounted for by sample size. There was no interaction between stringency of blinding and surrogate outcome measure, or among any other variables. "
[Show abstract][Hide abstract] ABSTRACT: Registration of clinical trials has been introduced largely to reduce bias toward statistically significant results in the trial literature. Doubts remain about whether advance registration alone is an adequate measure to reduce selective publication, selective outcome reporting, and biased design. One of the first areas of medicine in which registration was widely adopted was oncology, although the bulk of registered oncology trials remain unpublished. The net influence of registration on the literature remains untested. This study compares the prevalence of favorable results and conclusions among published reports of registered and unregistered randomized controlled trials of new oncology drugs.
We conducted a cross-sectional study of published original research articles reporting clinical trials evaluating the efficacy of drugs newly approved for antimalignancy indications by the United States Food and Drug Administration (FDA) from 2000 through 2005. Drugs receiving first-time approval for indications in oncology were identified using the FDA web site and Thomson Centerwatch. Relevant trial reports were identified using PubMed and the Cochrane Library. Evidence of advance trial registration was obtained by a search of clinicaltrials.gov, WHO, ISRCTN, NCI-PDQ trial databases and corporate trial registries, as well as articles themselves. Data on blinding, results for primary outcomes, and author conclusions were extracted independently by two coders. Univariate and multivariate logistic regression identified associations between favorable results and conclusions and independent variables including advance registration, study design characteristics, and industry sponsorship.
Of 137 original research reports from 115 distinct randomized trials assessing 25 newly approved drugs for treating cancer, the 54 publications describing data from trials registered prior to publication were as likely to report statistically significant efficacy results and reach conclusions favoring the test drug (for results, OR = 1.77; 95% CI = 0.87 to 3.61) as reports of trials not registered in advance. In multivariate analysis, reports of prior registered trials were again as likely to favor the test drug (OR = 1.29; 95% CI = 0.54 to 3.08); large sample sizes and surrogate outcome measures were statistically significant predictors of favorable efficacy results at p < 0.05. Subgroup analysis of the main reports from each trial (n = 115) similarly indicated that registered trials were as likely to report results favoring the test drug as trials not registered in advance (OR = 1.11; 95% CI = 0.44 to 2.80), and also that large trials and trials with nonstringent blinding were significantly more likely to report results favoring the test drug.
Trial registration alone, without a requirement for full reporting of research results, does not appear to reduce a bias toward results and conclusions favoring new drugs in the clinical trials literature. Our findings support the inclusion of full results reporting in trial registers, as well as protocols to allow assessment of whether results have been completely reported.
"A non-steroidal anti-inflammatory drug (NSAID) produced significantly greater dropout rates related to ineffectiveness compared with the same drug being tested in an active drug comparison. On the other hand, patient dropouts were greater for adverse events in the trials in which the NSAID was compared with another drug than in placebo-controlled trials (Rochon et al., 1999). Thus, given the same active NSAID, subjects had different experiences based solely on whether the other arm of the trial was a placebo arm or an active drug arm, despite the fact the patient was not in that other arm but simply knew about it. "
[Show abstract][Hide abstract] ABSTRACT: Placebo effects are beneficial health outcomes not related to the relatively direct biological effects of an intervention and can be elicited by an agent that, by itself, is inert. Understanding these placebo effects will help to improve clinical trial design, especially for interventions such as surgery, CNS-active drugs and behavioural interventions which are often non-blinded. A literature review was performed to retrieve articles discussing placebo implications of clinical trials, the neurobiology of placebo effects and the implications of placebo effect for several disorders of neurological relevance. Recent research in placebo analgesia and other conditions has demonstrated that several neurotransmitter systems, such as opiate and dopamine, are involved with the placebo effect. Brain regions including anterior cingulate cortex, dorsolateral prefrontal cortex and basal ganglia have been activated following administration of placebo. A patient's expectancy of improvement may influence outcomes as much as some active interventions and this effect may be greater for novel interventions and for procedures. Maximizing this expectancy effect is important for clinicians to optimize the health of their patient. There have been many relatively acute placebo studies that are now being extended into clinically relevant models of placebo effect.
"This is mainly reflected by responders reporting self-interests such as expecting to get healthier, as the main reason to participate in the trial . Besides, the placebo effect also has an important role in rheumatology trials ; this was reflected in our survey by the finding that most participants stated feeling better since they were enrolled in the trial. It is also conceivable that feeling better made them think they were allocated to the study drug. "
[Show abstract][Hide abstract] ABSTRACT: To address participants' knowledge of informed consent and to explore whether knowledge level is related to clinical trial satisfaction.
One hundred and fourteen patients enrolled in three ongoing randomized controlled trials of osteoarthritis and rheumatoid arthritis were asked to complete a mailed form. The survey was related to aspects of the informed consent process: quality of information given during the informed consent process, participants' self perception of knowledge, objective evaluation of participants' knowledge and participants' overall trial satisfaction. These four aspects were categorized as high, intermediate or low. Correlation between participants' knowledge and satisfaction was measured using the Spearman's Rho test and variables associated with knowledge by standard univariable analyses. A p value< or =0.05 was considered significant.
One hundred and five participants answered the questionnaire. The quality of information given during the informed consent process was rated as being high by 81% participants, intermediate by 15.2% and low by 3.8%. Fifty-one percent of the participants believed they had a good level of knowledge, but, objective evaluation qualified as high in only 14.3% of them. Overall trial satisfaction was high in 95% of the participants. No significant correlation was found between knowledge and satisfaction (r=0.16; p=0.086). Age was negatively associated with a higher level of knowledge (48 vs. 58 years old, p=0.008).
We found a lack of correlation between satisfaction and knowledge in clinical trials participants. During a randomized controlled trial the investigator should consider encouraging activities to improve not only participants' satisfaction, but also their level of knowledge.
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