Methodological considerations for analyzing enriched enrolment randomized withdrawal trials

The Enriched Enrolment Randomized Withdrawal (EERW) design has been widely employed under various names across multiple disease areas. The methodology underlying these trials remains subject to ongoing discussion. A review of the literature identified key criticisms associated with the EERW design, notably the Open-Label Effect (OLE) resulting from the initial Open-Label (OL) phase and the Selection Effect (SLE) arising from selecting responders at the conclusion of the OL period. The aim of this study was to quantify these effects using historical data and to propose a straightforward approach to mitigate their impact.

Based on proposals to estimate SLE and OLE effects, we conducted a retrospective analysis on a sample of 42 EERWs studies in various disorders and pathologies.

The OLE effect was confirmed with a highly significant additional increase of the main final endpoint (Standardized effect β_std = 0.567, p < 0.001). Likewise, the SLE was observed with a smaller but significant effect (β_std = 0.263, p = 0.028). Adding OLE and SLE effects in the covariance model assessing the significance of the studied treatment effect provided a highly significant increase of the determination coefficient ΔR² = 0.380 (p < 0.001) reducing the residual variability of the model. The treatment effect was not significantly affected by these effects (p > 0.150).

While EERW designs are widely utilized, the impact of the Open-Label (OL) phase on statistical outcomes remains under-addressed. This study quantifies two distinct and specific OLE and SLE effects increasing the residual variability and reducing the precision of the studied treatment estimate. By incorporating these effects as adjustments within the primary inferential model, researchers can mitigate extraneous noise and improve the precision and robustness of EERW trial results.