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JAMA Apr 2002Intense debate persists about the need for placebo-controlled groups in clinical trials of medications for major depressive disorder (MDD). There is continuing interest... (Meta-Analysis)
Meta-Analysis Review
CONTEXT
Intense debate persists about the need for placebo-controlled groups in clinical trials of medications for major depressive disorder (MDD). There is continuing interest in the development of new medications, but because effective antidepressants are already available, ethical concerns have been raised about the need for placebo groups in new trials.
OBJECTIVE
To determine whether the characteristics of placebo control groups in antidepressant trials have changed over time.
DATA SOURCES AND STUDY SELECTION
We searched MEDLINE and PsychLit for all controlled trials published in English between January 1981 and December 2000 in which adult outpatients with MDD were randomly assigned to receive medication or placebo. Seventy-five trials met our criteria for inclusion.
DATA EXTRACTION
Data were extracted from the articles by 2 of the authors and discrepancies were resolved via discussion and additional review by a third author.
DATA SYNTHESIS
The mean (SD) proportion of patients in the placebo group who responded was 29.7% (8.3%) (range, 12.5%-51.8%). Most studies examined more than a single active medication, and, in the active medication group with the greatest response, the mean (SD) proportion of patients responding was 50.1% (9.0%) (range, 31.6%-70.4%). Both the proportion of patients responding to placebo and the proportion responding to medication were significantly positively correlated with the year of publication (for placebo: n = 75; r = 0.45; 95% confidence interval [CI], 0.25-0.61; P<.001; for medication: n = 75; r = 0.26; 95% CI, 0.03-0.46; P =.02). The association between year of publication and response rate was more statistically robust for placebo than medication.
CONCLUSIONS
The response to placebo in published trials of antidepressant medication for MDD is highly variable and often substantial and has increased significantly in recent years, as has the response to medication. These observations support the view that the inclusion of a placebo group has major scientific importance in trials of new antidepressant medications and indicate that efforts should continue to minimize the risks of such studies so that they may be conducted in an ethically acceptable manner.
Topics: Adult; Aged; Antidepressive Agents; Control Groups; Depressive Disorder, Major; Female; Humans; Male; Middle Aged; Placebo Effect; Randomized Controlled Trials as Topic; Statistics as Topic
PubMed: 11939870
DOI: 10.1001/jama.287.14.1840 -
Cephalalgia : An International Journal... Sep 2003Probably because of its relative rarity as primary headache, there are few well-controlled clinical trials on cluster headache (CH) patients. Due to the severity of the... (Review)
Review
Probably because of its relative rarity as primary headache, there are few well-controlled clinical trials on cluster headache (CH) patients. Due to the severity of the pain, the placebo response in CH has been considered to be small. During the eighties the first double-blind, placebo-controlled trials were reported, and placebo responses demonstrated. Here we review the placebo response in CH trials in order to assess its magnitude and consider how future studies can be optimized. Six trials were identified with a double-blind, placebo-controlled, cross-over design testing treatments of acute CH. For those with a primary endpoint set to no or mild headache the placebo responses varied from 7 to 42%. In five of seven prophylactic trials, using a double-blind, placebo-controlled, parallel-group design, the placebo was merely used to set a baseline for comparison. The placebo responses were reported in only two trials. Here the response varies from 14 to 43%, the lowest value was reported using the strict endpoint; cessation of headache attacks. We conclude that a placebo response exists in trials of drugs on CH patients. Furthermore, this placebo response is of the same magnitude as that seen in migraine studies. We recommend the use of IHS guidelines when designing new trials. The possibility of a genuine biological mechanism responsible for the placebo response is discussed.
Topics: Cluster Headache; Humans; Placebo Effect; Placebos; Randomized Controlled Trials as Topic
PubMed: 12950375
DOI: 10.1046/j.1468-2982.2003.00531.x -
Biological Psychiatry Apr 2000The reliable evaluation of treatments intended for the management of psychiatric illness would not be possible without the use of placebo. Other types of control groups...
The reliable evaluation of treatments intended for the management of psychiatric illness would not be possible without the use of placebo. Other types of control groups can provide useful information, but none are capable of adducing a finding as compelling and unambiguously interpretable as a statistically significant drug-placebo difference. Its epistemological advantage notwithstanding, the ethicality of employing a placebo control group has been increasingly challenged in recent years. Many who object to the use of placebo on ethical grounds assume, incorrectly, that there are fungible alternatives to the use of placebo in the assessment of psychotropic drugs. This essay attempts to explain, within an historical context, not only why placebo is irreplaceable, but why it is often so difficult to communicate its advantages to those unfamiliar with the epistemological aims and methods of controlled clinical trials.
Topics: Antipsychotic Agents; Clinical Trials as Topic; History, 19th Century; History, 20th Century; Mental Disorders; Placebos
PubMed: 10773176
DOI: 10.1016/s0006-3223(99)00321-2 -
Biological Psychiatry Apr 2000Because a statistical tie between standard treatment and an innovation is uninterpretable, most trials intended to demonstrate efficacy of innovations in...
Because a statistical tie between standard treatment and an innovation is uninterpretable, most trials intended to demonstrate efficacy of innovations in psychopharmacology employ a placebo control group, despite the existence of standard medications for many disorders. In this review I consider the statistical issues that inform the ethics of the decision to use a placebo condition and make the following points: 1) the investigator is relying on the assumption that the effects of delayed standard treatment are neither long-lasting nor harmful; 2) the usual practice of truncating follow-up when a patient ceases to adhere to a study treatment makes it difficult to empirically test that assumption; 3) placebo control trials often suffer from methodological weaknesses (including nonrandom truncation) that reduce their inferential power; 4) these subtleties place a substantial burden on the informed consent process; 5) alternative designs are available but not well explored, due to the dominant role of "regulatory" trial methodology; and 6) researchers should consider other goals besides helping to introduce another treatment that improves on placebos but not the standard treatment.
Topics: Antipsychotic Agents; Clinical Trials as Topic; Humans; Mental Disorders; Placebos
PubMed: 10773178
DOI: 10.1016/s0006-3223(00)00838-6 -
The Journal of Infectious Diseases Aug 2023Adaptive platform trials were implemented during the coronavirus disease 2019 (COVID-19) pandemic to rapidly evaluate therapeutics, including the placebo-controlled... (Randomized Controlled Trial)
Randomized Controlled Trial
Adaptive platform trials were implemented during the coronavirus disease 2019 (COVID-19) pandemic to rapidly evaluate therapeutics, including the placebo-controlled phase 2/3 ACTIV-2 trial, which studied 7 investigational agents with diverse routes of administration. For each agent, safety and efficacy outcomes were compared to a pooled placebo control group, which included participants who received a placebo for that agent or for other agents in concurrent evaluation. A 2-step randomization framework was implemented to facilitate this. Over the study duration, the pooled placebo design achieved a reduction in sample size of 6% versus a trial involving distinct placebo control groups for evaluating each agent. However, a 26% reduction was achieved during the period when multiple agents were in parallel phase 2 evaluation. We discuss some of the complexities implementing the pooled placebo design versus a design involving nonoverlapping control groups, with the aim of informing the design of future platform trials. Clinical Trials Registration. NCT04518410.
Topics: Humans; COVID-19; Control Groups; Pandemics
PubMed: 37650234
DOI: 10.1093/infdis/jiad209 -
European Journal of Physical and... Jun 2019Control groups are used in clinical trials to increase confidence that any improvements in patient outcomes are due the therapy under investigation and not to other... (Review)
Review
BACKGROUND
Control groups are used in clinical trials to increase confidence that any improvements in patient outcomes are due the therapy under investigation and not to other factors. The reported effect size of any intervention is estimated from differences in outcomes achieved by intervention participants in comparison to control participants. Clinical heterogeneity in control groups across different studies can make the pooling of data from these studies in one meta-analysis questionable or reduce certainty in their results.
AIM
The aim of this study was to evaluate: 1) the variability in the types of control groups used in studies that have been pooled in meta-analyses in Cochrane reviews on neurorehabilitation interventions; and 2) how authors of Cochrane reviews on neurorehabilitation interventions have taken information about control groups into consideration when making decisions to undertake meta-analyses and interpreting their results.
METHODS
We searched the Cochrane library for reviews on neurorehabilitation interventions published between 2012 and 2016 that included at least one meta-analysis involving a control group. We extracted data from included reviews on the review characteristics, the characteristics of the included meta-analyses, and any information on how the review authors managed control groups in the conduct and interpretation of meta-analyses.
RESULTS
The 43 included reviews pooled data from 358 clinical trials, with an average of 5±5 clinical trials (range: 2-45) contributing to each meta-analysis. The majority of clinical trials involved a control group containing active treatments (61.7%; 221 of 358), often "treatment as usual" controls without any additional placebo or sham intervention. Over half (58.1%; 25 of 43) of the included meta-analyses involved pooling of data from studies with a mix of different types of control groups, with an additional 25.6% pooling data from studies where control participants had received a range of different active treatments. The influence of different control groups on the summary results from meta-analyses was not analyzed in 21 (48.8%) of the included reviews.
CONCLUSIONS
Further work is needed to develop: standardized ways to categorize control conditions in rehabilitation trials; more guidance on reporting criteria for control groups in rehabilitation trials; and agreed methods for managing different control types in one meta-analysis.
Topics: Control Groups; Humans; Meta-Analysis as Topic; Neurological Rehabilitation; Randomized Controlled Trials as Topic; Research Design; Systematic Reviews as Topic
PubMed: 30961346
DOI: 10.23736/S1973-9087.19.05795-2 -
European Journal of Clinical... Oct 2023The purpose of this article is to examine the efficacy of oxytocin in treating core symptoms of autism spectrum disorder (ASD) with children. (Meta-Analysis)
Meta-Analysis
PURPOSE
The purpose of this article is to examine the efficacy of oxytocin in treating core symptoms of autism spectrum disorder (ASD) with children.
METHODS
A systematic literature search was conducted to identify randomized controlled trials (RCTs) of oxytocin for the treatment of core symptoms in children with ASD. The search included studies published between January 1, 1999 and March 15, 2023, that were randomized, single or double-blinded, and included a placebo control group. Standard screening rules were applied to select relevant studies, resulting in the inclusion of five RCTs involving 486 children with ASD.
RESULTS
Ultimately, a total of five RCTs, involving 486 children with ASD, were included in the review using standard screening rules.One of the included studies demonstrated a statistically significant improvement in Social Responsiveness Scale (SRS) and Repetitive Behavior Scale-Revised (RBS) scores when children with ASD were treated with oxytocin (24 IU/2 days for 6 weeks). The improvement in core symptoms persisted at the 6-month follow-up. The meta-analysis findings suggested that oxytocin might have a moderate effect in improving the core symptom of narrow interests and repetitive stereotyped behaviors in children with ASD.
CONCLUSION
While the therapeutic value of oxytocin in treating core symptoms of ASD in children is not fully established, the results of this meta-analysis indicate a potential moderate effect. However, further studies with larger sample sizes and more robust RCTs are needed to directly demonstrate the efficacy of oxytocin. Future research should also focus on effect size and outcome evaluation accuracy while minimizing bias in RCT experiments.
Topics: Humans; Child; Oxytocin; Autism Spectrum Disorder; Outcome Assessment, Health Care; Control Groups
PubMed: 37540265
DOI: 10.1007/s00228-023-03545-w -
Hong Kong Medical Journal = Xianggang... Jun 2003Controversy exists regarding the ethics of using placebo control groups in clinical trials when effective treatments exist. The debate was fuelled by the announcement of... (Review)
Review
Controversy exists regarding the ethics of using placebo control groups in clinical trials when effective treatments exist. The debate was fuelled by the announcement of the fifth revision of the Declaration of Helsinki in 2000. This study reviews the history and scientific background surrounding the controversy and investigates the prevailing attitudes of Hong Kong researchers regarding this issue. The controversy has centred on several issues. The first involves the methodological superiority of placebo-controlled trials in discerning treatment effects. Secondly, it is unclear whether the treatment effects encompass absolute treatment effects (including placebo effects) or are confined to treatment-specific effects (excluding placebo effects). Thirdly, there are concerns that subjects in the placebo group could be exposed to a high risk for developing serious adverse events. Fourthly, it is unclear whether the standard of best available treatment should be local or international. Preliminary research findings suggest that the opinions of Hong Kong researchers are divided on the use of placebo control groups in clinical trials when effective treatment exists. Further research on the topic is therefore warranted, and training and consensus meeting may be necessary to minimise the confusion related to this issue.
Topics: Clinical Trials as Topic; Ethics, Medical; Helsinki Declaration; Humans; Placebos
PubMed: 12777655
DOI: No ID Found -
Mayo Clinic Proceedings Sep 2005
Topics: Control Groups; Controlled Clinical Trials as Topic; Humans; Pain; Pain Management; Placebo Effect; Placebos
PubMed: 16178490
DOI: 10.4065/80.9.1119 -
Journal of Manipulative and... Jun 2011The purpose of this study is to describe the effects in the placebo and "no treatment" arms in trials with headache patients. (Comparative Study)
Comparative Study
OBJECTIVE
The purpose of this study is to describe the effects in the placebo and "no treatment" arms in trials with headache patients.
METHOD
This is a secondary analysis of randomized controlled trials from 8 systematic reviews and selected trials with a "no treatment" or placebo control group. The different types of "no treatment" and placebo interventions were assessed and classified into 6 subgroups. The analyses were carried out according to type of outcome variable.
RESULTS
In total, 119 studies were included (7119 participants). The mean recovery rate in all control groups was 35.7%. Significantly more participants recovered in control groups of pharmacological studies than in nonpharmacological studies: 38.5% vs 15.0%, respectively. Adults were more likely to recover in nonpharmacological studies and children in pharmacological studies.
CONCLUSIONS
The mean recovery rate in the control groups was 36%. The recovery rate varied substantially between type of intervention and patients.
Topics: Adult; Bias; Child; Control Groups; Cross-Over Studies; Headache; Humans; Migraine Disorders; Placebo Effect; Randomized Controlled Trials as Topic; Recovery of Function; Risk; Tension-Type Headache; Waiting Lists
PubMed: 21640253
DOI: 10.1016/j.jmpt.2011.04.007