Predicting the Treatment Regimen Estimand in Phase 3 Studies from the Estimated Efficacy Estimand Based on Phase 2...

The ICH E9 (R1) addendum establishes frameworks for efficacy estimands (using a hypothetical strategy to handle intercurrent events) and treatment regimen estimands (using a treatment policy strategy to handle intercurrent events) in clinical trials. While Phase 3 studies often adopt treatment regimen estimands for regulatory purposes, direct use of the results from Phase 2 treatment regimen estimands for Phase 3 planning may produce suboptimal results due to differences in population, study duration, treatment regimen itself, and treatment delivery methods that affect adherence rates.

We developed a modeling framework that decomposes treatment regimen estimands into adherent (efficacy estimand) and non-adherent patient responses. Using historical Phase 3 study data from chronic weight management and type 2 diabetes populations, we first establish empirical linear relationships between efficacy and non-adherent responses through regression modeling without intercept. Then we estimate Phase 3 efficacy responses from Phase 2 data, project discontinuation rates for Phase 3 study, and apply the empirical relationship to predict treatment regimen responses.

Linear relationships were identified for change in absolute weight loss and glycated hemoglobin (HbA1c) endpoints using data from multiple Phase 3 studies. Model validation showed close agreement between predicted and observed treatment regimen responses in the training data. Application to the SURPASS-2 Phase 3 study demonstrated reasonable predictive accuracy, with estimates generally within expected ranges of observed results.

This approach provides a systematic method for translating Phase 2 efficacy estimand results into Phase 3 treatment regimen estimand predictions. It leverages empirical relationships between efficacy responses and non-adherent responses, and may complement direct Phase 2 data extrapolation, particularly for endpoints where treatment effects persist after discontinuation. Current applications focus on change in body weight (kg) and change in HbA1c (%).