The use of external controls: To what extent can it currently be recommended?

TL;DR

This paper reviews the current state, applications, biases, and recommendations for using external controls in clinical research as an alternative when randomized trials are infeasible.

Contribution

It provides a comprehensive overview of external control types, discusses biases and mitigation strategies, and offers guidelines for justified use in clinical studies.

Findings

External controls can supplement but not replace randomized trials.

Biases in external controls can be mitigated with specific strategies.

Guidelines for justified use of external controls are proposed.

Abstract

With more and better clinical data being captured outside of clinical studies and greater data sharing of clinical studies, external controls may become a more attractive alternative to randomized clinical trials. Both industry and regulators recognize that in situations where a randomized study cannot be performed, external controls can provide the needed contextualization to allow a better interpretation of studies without a randomized control. It is also agreed that external controls will not fully replace randomized clinical trials as the gold standard for formal proof of efficacy in drug development and the yardstick of clinical research. However, it remains unclear in which situations conclusions about efficacy and a positive benefit/risk can reliably be based on the use of an external control. This paper will provide an overview on types of external control, their applications and the different sources of bias their use may incur, and discuss potential mitigation steps. It will also give recommendations on how the use of external controls can be justified.