🤖 AI Summary
This study addresses the lack of robust quantitative methods in clinical trial safety assessment that integrate clinical knowledge, control error rates, and rely on sufficient evidence. To this end, the authors propose SAFE, a two-tier framework that first leverages clinical prior knowledge to identify clinically meaningful signal areas (SAs), and then applies cross-area false discovery rate (FDR) control for multiplicity adjustment. SAFE is the first approach to jointly model signal areas and enforce global FDR control, thereby enhancing clinical interpretability without compromising statistical rigor. Simulation studies and real-data analyses demonstrate that SAFE effectively controls both within-area and cross-area error rates while filtering out extreme values, leading to more reliable safety conclusions.
📝 Abstract
Safety assessment plays a fundamental role in developing a new drug via clinical trials for ethical considerations. Due to complexity, manual review is typically conducted on the totality of data to draw safety conclusions. There are some existing quantitative methods to facilitate or tailor further medical review, with a controlled error rate and integration of clinical knowledge. In addition to those two key aspects, we emphasize the importance of relying on substantial evidence to draw robust conclusions on safety. Motivated by these three important properties, we propose a two-layer Synergy Area with FDR-controlled Evaluation (SAFE) structural framework to robustly assess the safety profile in clinical trials. In the first layer of SAFE, we investigate each clinically meaningful Synergy Area (SA) based on compelling evidence. In the next layer, the false discovery rate (FDR) is controlled for potential findings across all SAs. Simulation studies show that SAFE properly controls error rates within and across SAs at the nominal level. We further apply the proposed approach to two case studies based on real data from the Historical Trial Data (HTD) Sharing Initiative of the DataCelerate platform. As compared to some direct methods, SAFE demonstrates an appealing feature of screening out extreme data and reaching solid safety conclusions. It can act as either a building block in another framework, or a platform to incorporate additional components.