Background: External data using matching and other methodological techniques is increasingly used as a comparator for clinical trials, for generating evidence on efficacy and/or safety. No published article has systematically summarized trials using external controls, across indications and geographies.
Objectives: The objectives of this systematic review were to describe: 1) characteristics of published externally controlled (EC) trials; 2) data used in EC trials; 3) application of EC trials in regulatory decision-making in the US (FDA) and EU (EMA).
Methods: PubMed was searched (2000-2023) utilizing common terminology on EC trials. Predetermined inclusion and exclusion criteria were applied on unique citations, including original research and review articles. Reference lists of included articles reporting EC trials were additionally screened. Included citations had to present EC trials that investigated the efficacy and/or safety of small molecule drugs, biologic drugs, or advanced therapies. No restrictions were set on patient demography, geography, care settings, therapeutic area, or endpoints. For identified EC trials, additional information was searched from trial registrations and FDA/EMA approvals (when available). Data extracted on each EC trial included 1) investigational and control agent(s), indication, possible orphan designation, primary and other endpoints including if they were subjective/objective; 2) used data on investigational arm and the EC arm, e.g. another trial, real-world secondary data (charts, claims etc.), or real-world primary data collection, possible historical control data, availability of individual-level and/or aggregated data, geographies of data collection, and use of EC data in formal comparative analysis; 3) approval status at FDA/EMA, and approval pathway/regulatory status. The screening of citations and the data extraction from articles, trial registrations, and FDA/EMA data (using a standardized form) were performed by 2 independent researchers. The extracted data is described descriptively.
Results: The PubMed search identified 1,225 unique citations, 11% were published in 2000-2009, 43% in 2010-2019, and 46% in 2020-2023. Based on the currently ongoing screening of abstracts, 16% of the 1,225 citations (ca 200) are being included to the review of full-text articles and extraction of data on the included EC trials. Results on the extracted data items according to the methods will be reported at the conference.
Conclusions: The results of this systematic review will inform the scientific community about the characteristics of known EC trials to-date across regions and therapy areas, the data used in them, and their role for regulatory decision-making.
