How placebo characteristics can influence estimates of intervention effects in trials

Howick, Jeremy; Hoffmann, Tammy

doi:10.1503/cmaj.171400

Cited by 24 publications

(19 citation statements)

References 35 publications

(37 reference statements)

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“…JH, TH, and RKW conducted preliminary research exploring the need to describe placebo and sham components adequately [2,3,19]. JH drafted and registered the protocol [20].…”

Section: Preliminary Researchmentioning

confidence: 99%

TIDieR-Placebo: A guide and checklist for reporting placebo and sham controls

et al. 2020

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Background Placebo or sham controls are the standard against which the benefits and harms of many active interventions are measured. Whilst the components and the method of their delivery have been shown to affect study outcomes, placebo and sham controls are rarely reported and often not matched to those of the active comparator. This can influence how beneficial or harmful the active intervention appears to be. Without adequate descriptions of placebo or sham controls, it is difficult to interpret results about the benefits and harms of active interventions within placebo-controlled trials. To overcome this problem, we developed a checklist and guide for reporting placebo or sham interventions. Methods and findings We developed an initial list of items for the checklist by surveying experts in placebo research (n = 14). Because of the diverse contexts in which placebo or sham treatments are used in clinical research, we consulted experts in trials of drugs, surgery, physiotherapy, acupuncture, and psychological interventions. We then used a multistage online Delphi process with 53 participants to determine which items were deemed to be essential. We next convened a group of experts and stakeholders (n = 16). Our main output was a modification of the existing Template for Intervention Description and Replication (TIDieR) checklist; this allows the key features of both active interventions and placebo or sham controls to be concisely summarised by researchers. The main differences between TIDieR-Placebo and the original TIDieR are the explicit requirement to describe the setting (i.e., features of the physical environment that go beyond geographic location), the need to report whether blinding was successful (when this was measured), and the need to present the description of placebo components alongside those of the active comparator.

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“…JH, TH, and RKW conducted preliminary research exploring the need to describe placebo and sham components adequately [2,3,19]. JH drafted and registered the protocol [20].…”

Section: Preliminary Researchmentioning

confidence: 99%

TIDieR-Placebo: A guide and checklist for reporting placebo and sham controls

et al. 2020

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“…Such comparisons rely on the assumption that the placebo/sham intervention used is appropriate . This assumption is sometimes unjustified . For example, in trials of oseltamivir, the placebo contained dehydrocholic acid and dibasic calcium phosphate dehydrate.…”

Section: Introductionmentioning

confidence: 99%

“…However, dehydrocholic acid can cause gastrointestinal symptoms, as can oseltamivir . Hence, while placebo‐controlled trials of oseltamivir often found an increased risk of gastrointestinal symptoms in the oseltamivir group compared with the placebo group, this was probably an underestimate of the true incidence of the harms …”

Section: Introductionmentioning

confidence: 99%

“…13 This assumption is sometimes unjustified. 14 For example, in trials of oseltamivir, the placebo contained dehydrocholic acid and dibasic calcium phosphate dehydrate. This was presumably to mimic the bitter taste of the active intervention (oseltamivir powder) and thus maintain blinding.…”

Section: Introductionmentioning

confidence: 99%

“…16 Hence, while placebo-controlled trials of oseltamivir often found an increased risk of gastrointestinal symptoms in the oseltamivir group compared with the placebo group, this was probably an underestimate of the true incidence of the harms. 14 Some placebo or sham interventions can also lead to exaggerated active intervention effects. For example, a 2016 review (including 1973 trials) found that up to 64% of placebo control interventions were not matched in terms of physical properties.…”

Section: Introductionmentioning

confidence: 99%

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Inadequate description of placebo and sham controls in a systematic review of recent trials

Webster

Howick

Hoffmann

et al. 2019

Eur J Clin Investigation

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Background Poorly described placebo/sham controls make it difficult to appraise active intervention benefits and harms. The 12‐item Template for Intervention Description and Replication (TIDieR) checklist was developed to improve the reporting of active interventions. The extent to which TIDieR has been used to improve description of placebo or sham control is not known. Materials and methods We systematically identified and examined all placebo/sham‐controlled randomised trials published in 2018 in the top six general medical journals. We reported how many of the TIDieR checklist items were used to describe the placebo/sham control(s). We supplemented this with a sample of 100 placebo/sham‐controlled trials from any journal and searched Google Scholar to identify placebo/sham‐controlled trials citing TIDieR. Results We identified 94 placebo/sham‐controlled trials published in the top journals in 2018. None reported using TIDieR, and none reported placebo or sham components completely. On average eight TIDieR items were addressed, with placebo/sham control name (100%) and when and how much was administered (97.9%) most commonly reported. Some items (rationale, 8.5%, whether there were modifications, 25.5%) were less often reported. In our sample of less well‐cited journals, reporting was poorer (average of six items) and followed a similar pattern. Since TIDieR’s first publication, six placebo‐controlled trials have cited it according to Google Scholar. Two of these used the checklist to describe placebo controls; neither one completely desribed the placebo intervention. Conclusions Placebo and sham controls are poorly described within randomised trials, and TIDieR is rarely used to guide these descriptions. We recommend developing guidelines to promote better descriptions of placebo/sham control components within clinical trials.

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The importance of context (placebo effects) in conservative interventions for musculoskeletal pain: A systematic review and meta‐analysis of randomized controlled trials

Saueressig,

Owen,

Pedder

et al. 2023

European Journal of Pain

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Background and ObjectiveContextual effects (e.g. patient expectations) may play a role in treatment effectiveness. This study aimed to estimate the magnitude of contextual effects for conservative, non‐pharmacological interventions for musculoskeletal pain conditions. A systematic review and meta‐analysis of randomized controlled trials (RCTs) that compared placebo conservative non‐pharmacological interventions to no treatment for musculoskeletal pain. The outcomes assessed included pain intensity, physical functioning, health‐related quality of life, global rating of change, depression, anxiety and sleep at immediate, short‐, medium‐ and/or long‐term follow‐up.Databases and Data TreatmentMEDLINE, EMBASE, CINAHL, Web of Science Core Collection, CENTRAL and SPORTDiscus were searched from inception to September 2021. Trial registry searches, backward and forward citation tracking and searches for prior systematic reviews were completed. The Cochrane risk of bias 2 tool was implemented.ResultsThe study included 64 RCTs (N = 4314) out of 8898 records. For pain intensity, a mean difference of (MD: −5.32, 95% confidence interval (CI): −7.20, −3.44, N = 57 studies with 74 outcomes, GRADE: very low) was estimated for placebo interventions. A small effect in favour of the placebo interventions for physical function was estimated (SMD: −0.22, 95% CI: −0.35, −0.09; N = 37 with 48 outcomes, GRADE: very low). Similar results were found for a broad range of patient‐reported outcomes. Meta‐regression analyses did not explain heterogeneity among analyses.ConclusionThe study found that the contextual effect of non‐pharmacological conservative interventions for musculoskeletal conditions is likely to be small. However, given the known effect sizes of recommended evidence‐based treatments for musculoskeletal conditions, it may still contribute an important component.SignificanceContextual effects of non‐pharmacological conservative interventions for musculoskeletal conditions are likely to be small for a broad range of patient‐reported outcomes (pain intensity, physical function, quality of life, global rating of change and depression). Contextual effects are unlikely, in isolation, to offer much clinical care. But these factors do have relevance in an overall treatment context as they provide almost 30% of the minimally clinically important difference.

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How placebo characteristics can influence estimates of intervention effects in trials

Cited by 24 publications

References 35 publications

TIDieR-Placebo: A guide and checklist for reporting placebo and sham controls

TIDieR-Placebo: A guide and checklist for reporting placebo and sham controls

Inadequate description of placebo and sham controls in a systematic review of recent trials

The importance of context (placebo effects) in conservative interventions for musculoskeletal pain: A systematic review and meta‐analysis of randomized controlled trials

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