Explanation

During a clinical trial, situations may emerge that necessitate changes in, or the discontinuation of, the allocated intervention/comparator for a participant. These events can be caused by a variety of factors including harms, improved health status, lack of efficacy, and withdrawal of participant consent.(234) The protocol should predefine standardised criteria for guiding intervention modifications and discontinuations. This information could be particularly important to evaluate the risk of bias due to deviations from the intended intervention/comparator,(235) an important domain of the risk of bias tool developed by the Cochrane Collaboration. Assessing this domain requires a clear understanding of deviations that occur as planned in the protocol and deviations that arise due to the experimental context.

Reviews of two samples of 108 and 292 trial protocols from 2016 found that 76% and 82% respectively reported criteria for modification of interventions.(9, 10) Regardless of any decision to modify or discontinue their assigned intervention/comparator, study participants should be retained in the trial whenever possible to enable follow-up data collection and prevent missing data (Item 25b).(236)

Summary of key elements to address

● Criteria to guide modifications to trial intervention/comparator (e.g., drug dose change in response to harms, participant request, or improving/worsening disease)

● Criteria to guide discontinuation of trial intervention/comparator