Major disruptions like the coronavirus disease (COVID-19) pandemic or the Ukrainian war can lead to significant challenges in the conduct and analysis of clinical trials. This chapter explores how the estimand framework, outlined by the ICH E9(R1) guideline, provides a structured approach to address and mitigate these challenges, ensuring scientific rigor and reliability of trial data amidst unprecedented circumstances. The framework’s structured approach facilitates the design and analysis of clinical trials, ensuring that results remain interpretable and relevant. We discuss various risk assessment and mitigation strategies, alongside a detailed exploration of different hypothetical scenarios for estimating treatment effects in disrupted trials. We also cover specific estimand considerations in view of major clinical trial disruptions in disease areas like strokeDiseasesstroke, oncology, and central nervous system trials, highlighting unique considerations for each. As global public health emergencies, geopolitical conflicts, or other major reasons for trial disruptions continue in the future, structured approaches like the estimand framework can serve as crucial tools for ensuring the continuity and data integrity of clinical trials.