Current perspectives for external control arms in oncology clinical trials: Analysis of EMA approvals 2016-2021.

ABSTRACT

Leveraging external control data, especially real-world data (RWD), has drawn particular attention in recent years for facilitating oncology clinical development and regulatory decision-making. Medical regulators have published guidance on accelerating the use of RWD and external controls. However, few systematic discussions have been conducted on external controls in cancer drug submissions and regulatory feedback. This study aimed to identify European oncology drug approvals using external control data to demonstrate clinical efficacy. We included 18 eligible submissions employing 24 external controls and then discussed the use of external control, data sources, analysis methods, and regulators' feedback. The external controls have been actively submitted to the European Medical Agency (EMA) recently. We found that 17 % of the EMA-approved cancer drugs in 2016-2021 used external controls, among which 37 % of the cases leveraged RWD. However, nearly one-third of the external controls were not considered supportive evidence by EMA due to limitations regarding heterogeneous patient populations, missing outcome assessment in RWD, and inappropriate statistical analysis. This study highlighted that proper use of external controls requires a careful assessment of clinical settings, data availability, and statistical methodology. For better use of external controls in oncology clinical trials, we recommend prospective study designs to avoid selection bias, sufficient baseline data to ensure the comparability of study populations, consistent endpoint measurements to enable outcome comparison, robust statistical methodology for comparative analysis, and collaborative efforts of sponsors and regulators to establish regulatory frameworks.