Toward Efficient Estimation of Regional Treatment Effects in Multi-Regional Clinical Trials

Abstract

A multi-regional clinical trial (MRCT) is a single clinical trial conducted in multiple regions simultaneously under a common protocol, which may be used to support parallel submissions to multiple regulatory authorities. For a regional regulatory authority, treatment effects defined specifically for its own region are more relevant to consider than overall treatment effects based on all regions included in an MRCT. A regional treatment effect can be estimated consistently using local data from the region of interest; however, this approach is generally inefficient as it excludes data from other regions and ignores possible similarities between regions. On the other hand, simply pooling data across regions requires strong assumptions and may introduce bias when the required assumptions are not met. Here, we propose a simple and robust approach to estimating a regional treatment effect in a two-arm randomized MRCT. The proposed approach uses a working regression model to incorporate information from baseline covariates as well as data from other regions for improved efficiency. The model accounts for residual regional differences (after adjusting for measured covariates) using interaction terms that describe how the dependence of outcome on treatment and covariates may vary across regions. The adaptive lasso is used to identify null interactions and thus achieve selective borrowing of information from other regions. The resulting regional treatment effect estimator is consistent and asymptotically normal even when the working model is misspecified, and able to improve efficiency over local estimation when there are similarities between regions in the form of null interactions.