  Randomized controlled trials (RCTs) are the gold standard for assessing drug
safety and efficacy. However, RCTs have some drawbacks which have led to the
use of single-arm studies to make certain internal drug development and
regulatory decisions, particularly in oncology. Hybrid controlled trials with
real-world data (RWD), in which the control arm is composed of both trial and
real-world patients, have the potential to help address some of the
shortcomings of both RCTs and single-arm studies in particular situations, such
as when a disease has low prevalence or when the standard of care to be used in
the control arm is ineffective or highly toxic and an experimental therapy
shows early promise. This paper discusses why it may be beneficial to consider
hybrid controlled trials with RWD, what such a design entails, when it may be
appropriate, and how to conduct the analyses. We propose a novel two-step
borrowing method for the construction of hybrid control arms. We use
simulations to demonstrate the operating characteristics of dynamic and static
borrowing methods, and highlight the trade-offs and analytic decisions that
study teams will need to address when designing a hybrid study.
