Estimand framework in Oncology drug development – impact and opportunities


A draft addendum of the ICH E9 guideline on Statistical Principles for Clinical Trials was released in August 2017 and introduced an estimand framework. The new framework aims at aligning trial objectives with design and statistical analyses by requiring a precise definition of the inferential quantity of interest, the estimand. The addendum is anticipated to have a major impact on drug development, as the choice of estimands will drive the trial design, sample size, data collection, trial conduct, analysis, and interpretation. An industry working group for estimands in oncology was formed in February 2018, with members from 19 companies. The focus areas of the working group are treatment switching, censoring, hematology and solid tumor case studies, and causal estimands in the time-to-event setting. In this talk we will review common estimands of interest and intercurrent events proposed in oncology regulatory guidelines and applications. Several strategies to handle intercurrent events were described in the ICH E9 addendum. These strategies generally interpret intercurrent events as informative or counterfactual outcomes rather than noninformative “missing” data. We will embed those in the time-to-event framework discussing the differences and highlighting the consequences for study design, data collection, analysis and interpretation. Since estimation methods targeting estimands using the proposed strategies often require strong assumptions, the guideline emphasizes sensitivity analyses to justify these. We will discuss sensitivity analyses for key estimands. The concepts will be illustrated using case studies and we will provide recommendations of the industry working group for practical implementation of the estimand framework.

London, UK