A Conceptual Framework for Addressing Treatment Withdrawal Effects Across the Evidence Pathway

Treatment withdrawal effects represent a transient increase in clinical risk following treatment discontinuation that exceeds what would be expected from loss of treatment effect alone. They have been described across multiple therapeutic areas, yet remain insufficiently recognised across evidence generation, synthesis and translation into practice.

When unacknowledged, withdrawal effects may distort estimates of benefit and harm in randomised trials and observational studies, obscure treatment-covariate interactions, propagate bias through evidence synthesis, and undermine the applicability of guideline recommendations to routine practice.

We summarise methodological problems introduced by unrecognised withdrawal effects and propose a conceptual framework highlighting how existing methodological approaches can be applied more explicitly to identify, interpret, and account for withdrawal-related risk across the evidence pathway.