  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.
