TL13 - Estimand-Oriented Sample Size Calculation for Neuroscience Clinical Trials

The ICH E9 (R1) Addendum on Estimands and Sensitivity Analysis in Clinical Trials was finalized in Nov 2019 and has been subsequently implemented by many regulatory agencies, including the FDA. While the ICH E9 (R1) suggests aligning trial design to the estimands that reflect trial objectives, sample size calculation, as a critical component in trial design, has not been fully updated to reflect the chosen estimands and the associated intercurrent event (ICE) strategies for many neuroscience clinical trials.

Our proposed roundtable discussion focuses on estimand-oriented sample size calculation for neuroscience clinical trials with ICEs. Neuroscience clinical trials share numerous common characteristics including high cost, high failure rate, and many operational challenges such as difficulty in collecting post-ICE efficacy follow up data and difficulty in estimating the pattern and extent of data missingness resulted from ICEs. While a few methods exist to adjust for the impact of ICEs in sample size calculation, these operational challenges often call for a more simulation intensive approach which provides the study sponsor and key stakeholders a better understanding of how different ICE strategies and missing data pattern/extent will affect the sample size and study design prior to study execution, thereby enhancing the quality and feasibility of the trial. A key point for discussion may therefore be the consideration of various missing data handling approaches as well as choice of estimators and corresponding analysis methods in the parametrization of such simulation-based methodology to better facilitate estimand-oriented sample size calculation.

This roundtable discussion is intended for audiences across regulatory agencies, pharmaceutical companies, and academia who are interested in further developing estimand-oriented sample size calculation methods in neuroscience clinical trials.

estimands

sample size calculation

intercurrent events

missing data

neuroscience clinical trails

simulation 

Clinical Trial Design (e.g., Innovative/Complex Design, Estimands, Master Protocol)

ASA Biopharmaceutical Section Regulatory-Industry Statistics Workshop 2023