Active placebo control groups of pharmacological interventions were rarely used but merited serious consideration

a methodological overview

Jakob Solgaard Jensen*, Andreas Ørsted Bielefeldt, Asbjørn Hróbjartsson

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Objectives Active placebos are control interventions that mimic the side effects of the experimental interventions in randomized trials and are sometimes used to reduce the risk of unblinding. We wanted to assess how often randomized clinical drug trials use active placebo control groups; to provide a catalog, and a characterization, of such trials; and to analyze methodological arguments for and against the use of active placebo. Study Design and Setting An overview consisting of three thematically linked substudies. In an observational substudy, we assessed the prevalence of active placebo groups based on a random sample of 200 PubMed indexed placebo-controlled randomized drug trials published in October 2013. In a systematic review, we identified and characterized trials with active placebo control groups irrespective of publication time. In a third substudy, we reviewed publications with substantial methodological comments on active placebo groups (searches in PubMed, The Cochrane Library, Google Scholar, and HighWirePress). Results The prevalence of trials with active placebo groups published in 2013 was 1 out of 200 (95% confidence interval: 0–2), 0.5% (0–1%). We identified and characterized 89 randomized trials (published 1961–2014) using active placebos, for example, antihistamines, anticholinergic drugs, and sedatives. Such trials typically involved a crossover design, the experimental intervention had noticeable side effects, and the outcomes were patient-reported. The use of active placebos was clustered in specific research settings and did not appear to reflect consistently the side effect profile of the experimental intervention, for example, selective serotonin reuptake inhibitors were compared with active placebos in pain trials but not in depression trials. We identified and analyzed 25 methods publications with substantial comments. The main argument for active placebo was to reduce risk of unblinding; the main argument against was the risk of unintended therapeutic effect. Conclusion Pharmacological active placebo control interventions are rarely used in randomized clinical trials, but they constitute a methodological tool which merits serious consideration. We suggest that active placebos are used more often in trials of drugs with noticeable side effects, especially in situations where the expected therapeutic effects are modest and the risk of bias due to unblinding is high.

OriginalsprogEngelsk
TidsskriftJournal of Clinical Epidemiology
Vol/bind87
Sider (fra-til)35-46
ISSN0895-4356
DOI
StatusUdgivet - 2017

Fingeraftryk

Placebos
Control Groups
Publications
Randomized Controlled Trials
Therapeutic Uses
PubMed
Pharmaceutical Preparations
Histamine Antagonists
Serotonin Uptake Inhibitors
Cholinergic Antagonists
Hypnotics and Sedatives
Cross-Over Studies
Libraries
Confidence Intervals
Depression

Citer dette

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title = "Active placebo control groups of pharmacological interventions were rarely used but merited serious consideration: a methodological overview",
abstract = "Objectives Active placebos are control interventions that mimic the side effects of the experimental interventions in randomized trials and are sometimes used to reduce the risk of unblinding. We wanted to assess how often randomized clinical drug trials use active placebo control groups; to provide a catalog, and a characterization, of such trials; and to analyze methodological arguments for and against the use of active placebo. Study Design and Setting An overview consisting of three thematically linked substudies. In an observational substudy, we assessed the prevalence of active placebo groups based on a random sample of 200 PubMed indexed placebo-controlled randomized drug trials published in October 2013. In a systematic review, we identified and characterized trials with active placebo control groups irrespective of publication time. In a third substudy, we reviewed publications with substantial methodological comments on active placebo groups (searches in PubMed, The Cochrane Library, Google Scholar, and HighWirePress). Results The prevalence of trials with active placebo groups published in 2013 was 1 out of 200 (95{\%} confidence interval: 0–2), 0.5{\%} (0–1{\%}). We identified and characterized 89 randomized trials (published 1961–2014) using active placebos, for example, antihistamines, anticholinergic drugs, and sedatives. Such trials typically involved a crossover design, the experimental intervention had noticeable side effects, and the outcomes were patient-reported. The use of active placebos was clustered in specific research settings and did not appear to reflect consistently the side effect profile of the experimental intervention, for example, selective serotonin reuptake inhibitors were compared with active placebos in pain trials but not in depression trials. We identified and analyzed 25 methods publications with substantial comments. The main argument for active placebo was to reduce risk of unblinding; the main argument against was the risk of unintended therapeutic effect. Conclusion Pharmacological active placebo control interventions are rarely used in randomized clinical trials, but they constitute a methodological tool which merits serious consideration. We suggest that active placebos are used more often in trials of drugs with noticeable side effects, especially in situations where the expected therapeutic effects are modest and the risk of bias due to unblinding is high.",
keywords = "Active placebo, Blinding, Methodological overview, Placebo, Randomised clinical trials",
author = "Jensen, {Jakob Solgaard} and Bielefeldt, {Andreas {\O}rsted} and Asbj{\o}rn Hr{\'o}bjartsson",
year = "2017",
doi = "10.1016/j.jclinepi.2017.03.001",
language = "English",
volume = "87",
pages = "35--46",
journal = "Journal of Clinical Epidemiology",
issn = "0895-4356",
publisher = "Elsevier",

}

Active placebo control groups of pharmacological interventions were rarely used but merited serious consideration : a methodological overview. / Jensen, Jakob Solgaard; Bielefeldt, Andreas Ørsted; Hróbjartsson, Asbjørn.

I: Journal of Clinical Epidemiology, Bind 87, 2017, s. 35-46.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Active placebo control groups of pharmacological interventions were rarely used but merited serious consideration

T2 - a methodological overview

AU - Jensen, Jakob Solgaard

AU - Bielefeldt, Andreas Ørsted

AU - Hróbjartsson, Asbjørn

PY - 2017

Y1 - 2017

N2 - Objectives Active placebos are control interventions that mimic the side effects of the experimental interventions in randomized trials and are sometimes used to reduce the risk of unblinding. We wanted to assess how often randomized clinical drug trials use active placebo control groups; to provide a catalog, and a characterization, of such trials; and to analyze methodological arguments for and against the use of active placebo. Study Design and Setting An overview consisting of three thematically linked substudies. In an observational substudy, we assessed the prevalence of active placebo groups based on a random sample of 200 PubMed indexed placebo-controlled randomized drug trials published in October 2013. In a systematic review, we identified and characterized trials with active placebo control groups irrespective of publication time. In a third substudy, we reviewed publications with substantial methodological comments on active placebo groups (searches in PubMed, The Cochrane Library, Google Scholar, and HighWirePress). Results The prevalence of trials with active placebo groups published in 2013 was 1 out of 200 (95% confidence interval: 0–2), 0.5% (0–1%). We identified and characterized 89 randomized trials (published 1961–2014) using active placebos, for example, antihistamines, anticholinergic drugs, and sedatives. Such trials typically involved a crossover design, the experimental intervention had noticeable side effects, and the outcomes were patient-reported. The use of active placebos was clustered in specific research settings and did not appear to reflect consistently the side effect profile of the experimental intervention, for example, selective serotonin reuptake inhibitors were compared with active placebos in pain trials but not in depression trials. We identified and analyzed 25 methods publications with substantial comments. The main argument for active placebo was to reduce risk of unblinding; the main argument against was the risk of unintended therapeutic effect. Conclusion Pharmacological active placebo control interventions are rarely used in randomized clinical trials, but they constitute a methodological tool which merits serious consideration. We suggest that active placebos are used more often in trials of drugs with noticeable side effects, especially in situations where the expected therapeutic effects are modest and the risk of bias due to unblinding is high.

AB - Objectives Active placebos are control interventions that mimic the side effects of the experimental interventions in randomized trials and are sometimes used to reduce the risk of unblinding. We wanted to assess how often randomized clinical drug trials use active placebo control groups; to provide a catalog, and a characterization, of such trials; and to analyze methodological arguments for and against the use of active placebo. Study Design and Setting An overview consisting of three thematically linked substudies. In an observational substudy, we assessed the prevalence of active placebo groups based on a random sample of 200 PubMed indexed placebo-controlled randomized drug trials published in October 2013. In a systematic review, we identified and characterized trials with active placebo control groups irrespective of publication time. In a third substudy, we reviewed publications with substantial methodological comments on active placebo groups (searches in PubMed, The Cochrane Library, Google Scholar, and HighWirePress). Results The prevalence of trials with active placebo groups published in 2013 was 1 out of 200 (95% confidence interval: 0–2), 0.5% (0–1%). We identified and characterized 89 randomized trials (published 1961–2014) using active placebos, for example, antihistamines, anticholinergic drugs, and sedatives. Such trials typically involved a crossover design, the experimental intervention had noticeable side effects, and the outcomes were patient-reported. The use of active placebos was clustered in specific research settings and did not appear to reflect consistently the side effect profile of the experimental intervention, for example, selective serotonin reuptake inhibitors were compared with active placebos in pain trials but not in depression trials. We identified and analyzed 25 methods publications with substantial comments. The main argument for active placebo was to reduce risk of unblinding; the main argument against was the risk of unintended therapeutic effect. Conclusion Pharmacological active placebo control interventions are rarely used in randomized clinical trials, but they constitute a methodological tool which merits serious consideration. We suggest that active placebos are used more often in trials of drugs with noticeable side effects, especially in situations where the expected therapeutic effects are modest and the risk of bias due to unblinding is high.

KW - Active placebo

KW - Blinding

KW - Methodological overview

KW - Placebo

KW - Randomised clinical trials

U2 - 10.1016/j.jclinepi.2017.03.001

DO - 10.1016/j.jclinepi.2017.03.001

M3 - Journal article

VL - 87

SP - 35

EP - 46

JO - Journal of Clinical Epidemiology

JF - Journal of Clinical Epidemiology

SN - 0895-4356

ER -