The Use of External Controls in FDA Regulatory Decision Making and Bayesian Borrowing

An good article by Jahanshahi et al "The Use of External Controls in FDA Regulatory Decision Making". The authors reviewed and summarized FDA regulatory approval decisions between 2000 and 2019 for drug and biologic products and summarized the pivotal studies that leveraged external controls, with a focus on select therapeutic areas.

The paper is open-access and available at "The Use of External Controls in FDA Regulatory Decision Making". 

The leading author is from BioMarin Pharmaceutical whose biological product Brineura for treatment of the rare Batten disease was approved by FDA based on an single arm study leveraging the external control from a historical registry. 

In the latest issue of the New England Journal of Medicine, Richeldi et al published a paper "Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis". The trial was designed as a smaller (in sample size) trial with 2:1 randomization ratio by leveraging the data from the Placebo control groups in historical clinical trials. Bayesian borrowing (or Bayesian dynamic borrowing) approach was used for the analyses, as depicted below. While this is an example of successful use of external control in phase 2 study, it is unlikely that the same approach can be employed in their phase 3 pivotal studies mainly because that idiopathic pulmonary hypertension is a rare disease, but not rare enough.