Beyond Randomized Clinical Trials: Use of External Controls

Abstract

Randomized controlled trials are the gold standard to investigate efficacy and safety of new treatments. In certain settings, however, randomizing patients to control may be difficult for ethical or feasibility reasons. Borrowing strength using relevant individual patient data on control from external trials or real‐world data (RWD) sources may then allow us to reduce, or even eliminate, the concurrent control group. Naive direct use of external control data is not valid due to differences in patient characteristics and other confounding factors. Instead, we suggest the rigorous application of meta‐analytic and propensity score methods to use external controls in a principled way. We illustrate these methods with two case studies: (i) a single‐arm trial in a rare cancer disease, using propensity score matching to construct an external control from RWD; (ii) a randomized trial in children with multiple sclerosis, borrowing strength from past trials using a Bayesian meta‐analytic approach.

Machine learning for clinical trials in the era of COVID-19

“…In addition to identifying particularly promising drugs, the experimental and compassionate use of drugs to treat COVID-19 is yielding a large body of data, which can be exploited to produce prior information for the design of future (Bayesian) controlled trials (Schmidli et al 2020). ML methods for causal inference from observational data are especially well-suited to this task.…”

COVID‐19: A Defining Moment for Clinical Pharmacology?

“…As illustrated by the work of Garcia‐Cremades et al , 12 not only has the COVID‐19 pandemic drawn the attention of the scientific community to research in clinical pharmacology, the pandemic has presented new opportunities to advance research in all aspects of our discipline. For example, clinical pharmacologists have been leaders in clinical trial design, including use of Bayesian methods and most recently the incorporation of multiple data types, such as real‐world data in drug development and approval 14,15 . The pandemic presents a unique opportunity to advance the sciences of clinical trial design with a focus, as noted above, on trials for rapidly progressing infections and for which real‐world data should be integrated into the trial design.…”

COVID-19 and clinical pharmacology

“…В некоторых странах пандемия привлекла внимание научного сообщества к исследованиям, которые уже давно входят в сферу интересов клинической фармакологии. Например, во всем мире клинических фармакологов считают лидерами в использовании байесовских методов и анализе данных реальной клинической практики (Real world evidence, RWE) [44,45]. Действительно, последние все чаще используются при принятии решений в системе здравоохранения [46,47].…”