In the second half of 2014, the Steering Committee of the International Council for Harmonisation endorsed the formation of an expert working group to develop an addendum to the International Council for Harmonisation E9 guideline (Statistical Principles for Clinical Trials). The addendum was to focus on two clinical trial topics: estimands and sensitivity analysis. A draft of the addendum, referred to as E9/R1, was developed by the expert working group and made available for public comments across the International Council for Harmonisation regions in the second half of 2017. A structured framework for clinical trial design and analysis proposed in the draft addendum are briefly described, including four key inputs for developing objective-driven estimands and strategies for tackling one of the inputs (‘intercurrent events’). The proposed framework aligns each clinical trial objective with the corresponding statistical target of estimation (estimand), trial design and data to be collected, main method of estimation/inference, and sensitivity analysis to pressure test key analytic assumption(s) in the main analysis. A case study from the diabetes therapeutic area illustrates how the framework can be implemented in practice. International Council for Harmonisation E9/R1 is expected to enable better planning, conduct, analysis, and interpretation of randomised clinical trials. This will facilitate improvements in new drug applications and strengthen understanding of decision making by regulatory authorities and advisory committees.
