Reporting of justifications for withholding established effective interventions in randomised placebo-controlled trials: a systematic review

Randomised-controlled-trials (RCTs) are crucial for assessing the efficacy of new treatments. Some RCTs are placebo-controlled, which is uncontroversial when there is no established effective intervention or when a placebo is added to one. However, withholding an established effective intervention from participants requires justification.

This systematic review aims to examine reporting practices around withholding established effective interventions from participants in placebo-controlled RCTs. Our objectives are (i) to determine the frequency with which established effective interventions are withheld in placebo-controlled RCTs without reported justification; (ii) to ascertain whether these relate to control arms only or both; (iii) to ascertain whether research participants are communicated this information; and (iv) explore factors associated with this practice.

Protocols of placebo-controlled RCTs, published in the journal Trials in 2022, were identified. Full-text of included protocols and available materials were accessed to estimate the proportion that withheld established effective interventions without reported justification. The withholding of effective interventions was categorised as either withholding a known effective intervention from the placebo arm or withholding a known effective concomitant treatment from both arms. We explored associations with: study conduct region, industry sponsorship, therapeutic area and complementary medicine.

A total of 134 protocols met the inclusion criteria. Only a minority (27, 20%) provided participant-facing material. Of these 134 protocols, (14, 10%) were identified as withholding effective interventions without reported justification. The majority (12, 86%) involved withholding concomitant medications in both arms, whilst (2,14%) withheld effective interventions from only the placebo arm; none reported justification in the participant-facing materials (although in only one was this material available). Most (9, 64%) of the protocols that withheld effective interventions, without reported justification, were conducted in Asia; most were testing complementary medicines (10, 71%); only (3, 21%) were industry-sponsored.

In this sample of protocols published in Trials in 2022, 10% withheld an established effective intervention without a reported justification, and this mostly related to withholding effective concomitant medications from both study arms. The majority of studies do not make their participant facing material available and so it cannot be determined what information is provided to study participants.