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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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 (%).</p>

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

  • 期刊论文

  • 发表日期：

    2026年6月18日

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  • Zhili Qiao,
  • Yu Du,
  • Jitong Lou,
  • Yongming Qu

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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 (%).