Whilst Randomised Control Trials are likely to remain the gold standard for generating evidence to support the efficacy of new treatments, the increasing quantity, quality and availability of clinical data being captured outside of clinical trials makes the use of external controls. more attractive and worthy of consideration.  

However, understanding of the optimal usage of external controls as well as the situations where their use can be justified is still evolving.

In this paper we provided an overview of different types of external control and their applications,  a description of the different sources of bias that their use may incur along with potential mitigation and recommendations for how to justify the use of external controls. 

 In this paper we develop an approach to reflect for the additional variability and bias that will be incurred by using external controls by integrating results from considering how external controls would have behaved in a series of historical studies.