Example

“Control intervention: restrictive transfusion strategy

 

Patients in the restrictive transfusion strategy group receive an RBC [red blood cell] transfusion only if their Hb [haemoglobin] is ≤70 g/L. We have chosen this threshold because it is the most studied restrictive RBC transfusion threshold [references] and reflects the current standard of care in non-bleeding critically ill patients without neurological or coronary artery diseases.[reference] It also is a frequently used and accepted threshold for clinicians who care for brain-injured patients.[reference]" [139]. 

​

“The control group will receive placebo. There is no current data on the efficacy of ivermectin against the virus in vivo; therefore the use of placebo in the control group is ethically justified. Participants of the study will have non-complicated COVID-19 and will not have risk factors to develop severe disease; thus they would not be receiving any alternative treatment for the disease [155].

 

Explanation

 

The choice of comparator has important implications for trial ethics, recruitment, results, and interpretation. In trials comparing an intervention to an active comparator, placebo or usual care, a clear description of the rationale for the comparator will facilitate understanding of its appropriateness [156, 157]. For example, a trial in which the comparator group receives an inappropriately low dose of an active drug will overestimate the relative efficacy of the study intervention in clinical practice; conversely, an inappropriately high dose in the comparator group will lead to an underestimate of the relative harms of the study intervention [157, 158]. 

The choice of comparator should not deprive trial participants of an effective treatment if one is available. In a study of hypothetical decision-making in physicians, around half indicated that they would enrol a patient in a randomised trial of biologics for rheumatoid arthritis despite considering the comparator inappropriate in the context of usual care [159]. 

 

Reviews of two samples of 108 and 292 trial protocols from 2016 found that 76% and 83% explained the choice of comparator, respectively [9, 10]. 

 

What constitutes “usual care” differs substantially across clinical settings. The explanation for choosing a usual care comparator should be complemented by a description of the content of “usual care” (Item 15a).

 

The appropriateness of using placebo-only comparator groups has been the subject of extensive debate and merits careful consideration of the existence of other effective treatments, the potential risks to trial participants, and the need for assay sensitivity (i.e., ability to distinguish an effective intervention from less effective or ineffective interventions).[160] In addition, surveys have demonstrated that a potential barrier to trial participation is the possibility of being allocated a placebo-only or active comparator intervention that is perceived to be less desirable than the study intervention [140]. 

​

If a placebo comparator group is planned, its type and components should be reported [161]. Surgical placebo interventions require additional ethical and methodological considerations, as detailed by the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines [162].

 

Summary of key elements to address

• Why the particular comparator group was chosen

• Whether the comparator represents standard of care