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

Patrick Silva, Nora Janjan, Kenneth Ramos, George Udeani, Lixian Zhong, Marcia G. Ory, Matthew L Smith

Research output: Contribution to journalReview articlepeer-review

Abstract

Randomized controlled trials are considered the ‘gold standard’ to reduce bias by randomizing 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, cannibalizing the treatment arm population, and extending study duration. The COVID-19 pandemic has magnified aspects of constraints in 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. Conversely, in the case of contemporary control arms, a clinical trial outcome can be compared to a contemporary standard of care in cases where the standard of care is evolving at a fast pace, such as the use of checkpoint inhibitors in cancer care. Innovative statistical methods are an essential aspect of an ECA strategy and regulatory paths for these innovative approaches have been navigated, qualified, and in some cases published.

Original languageEnglish (US)
Article number1198088
Pages (from-to)1198088
JournalFrontiers in Medicine
Volume10
DOIs
StatePublished - 2023

Keywords

  • external control arm
  • oncology
  • pharmacogenomics
  • pragmatic study
  • real world data
  • regulatory science

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint

Dive into the research topics of 'External control arms: COVID-19 reveals the merits of using real world evidence in real-time for clinical and public health investigations'. Together they form a unique fingerprint.

Cite this