AUTHOR=Silva Patrick , Janjan Nora , Ramos Kenneth S. , Udeani George , Zhong Lixian , Ory Marcia G. , Smith Matthew Lee 

TITLE=External control arms: COVID-19 reveals the merits of using real world evidence in real-time for clinical and public health investigations

JOURNAL=Frontiers in Medicine

VOLUME=Volume 10 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1198088

DOI=10.3389/fmed.2023.1198088

ISSN=2296-858X

ABSTRACT=Randomized controlled trials are considered the ‘gold standard’ to reduce bias by randomized patients to an experimental intervention, versus placebo or standard of care cohort.  There are inherent challenges to enrolling a standard of care or cohorts: costs, site engagement logistics, socioeconomic variability, patient willingness, ethics of placebo interventions, and extending study duration.  The COVID-19 pandemic has constrained aspects of trial recruitment and logistics, spurring innovative approaches to reducing trial sizes, accelerating trial accrual while preserving statistical rigor.  Using data from medical records and databases allows for construction of external control arms that reduce the costs of an external control arm (ECA) randomized to standard of care.   Simultaneously examining covariates of the clinical outcomes in ECAs that are being measured in the interventional arm can be particularly useful in phase 2 trials to better understand social and genetic determinants of clinical outcomes that might inform pivotal trial design.  The FDA and EMA have promulgated a number of publicly available guidance documents and qualification reports that inform the use of this regulatory science tool to streamline clinical development, of phase 4 surveillance, and policy aspects of clinical outcomes research.    Availability and quality of real-world data (RWD) are a prevalent impediment to the use of ECAs given such data is not collected with the rigor and deliberateness that characterizes prospective interventional control arm data.