Considerations discussed in this section should also be considered by researchers at the planning and design stage of an APE trial as they influence planning and some may need to be stipulated in the protocol.

PANDA users may wish to read related issues under general considerations. 

Specifically, by design, the change in eligibility criteria during the trial signals that the treatment is doing something positive in selected subpopulations, although it does not mean the treatment is effective. This may affect equipoise among those tasked with the day-to-day running of the trial, introducing operational bias. For example, adaptation decisions made can disproportionately influence changes in clinical management of trial participants between treatment arms after an interim analysis. This is specifically problematic in open-label trials but less of an issue when all those tasked with the day-to-day conduct of the trial are blinded to treatment allocation.

The question is whether adaptations to a trial may affect the behaviour of patients (or their therapists) to enrol at different periods of the trial depending on the information they know or have inferred about the trial or communicated to them ¹. For example, could patients with less severe disease be approached or choose to take part later in the trial when they may infer the treatment is beneficial in their subpopulation? We cannot say, and there is little in the way of evidence to either support or deny this assertion. Nevertheless, the extent of potential operational biases should be considered carefully by research teams planning an APE design and the level of information that can be disclosed while the trial is ongoing (e.g., to participants, investigators, and the research community).

1. Ventz et al. The effects of releasing early results from ongoing clinical trials. Nat Commun. 2021;12(1):801.