OBJECTIVES: External control arms (ECAs) derived from real-world data (RWD) are increasingly being used to generate comparative evidence when a randomized controlled trial (RCT) is not ethical or feasible, or to increase power when sample size is limited. ECAs can be applied to a single-arm trial as an independent control group or to augment an already existing RCT control arm. To date, most ECAs have been used in regulatory submissions in oncology and rare diseases. Broader use of ECAs could be to support early stopping decisions during drug development, health technology assessment submissions or engagement with healthcare providers when evidence against comparators not included in trials is needed. However, the use of ECAs outside the oncology/rare indications is limited. This literature review was conducted to describe the existing use of ECAs in non-oncology prevalent disease settings and to discuss the benefits of using external data in clinical development and post-marketing.

METHODS: This targeted review utilized a PubMed and web-based search to identify review papers and case studies of non-oncology and non-rare disease ECAs.

RESULTS: Outside of rare/oncology indications, published ECAs were utilized in gastrointestinal, cardiovascular and infectious disease settings. Key challenges addressed by ECAs in inflammatory bowel disease trials were the declining patient enrollment and the need for early-stage decisions regarding therapeutic efficacy. In the infectious diseases area, researchers demonstrated that the use of an ECA was sufficient in replacing an RCT control arm for COVID-19 treatment.

CONCLUSIONS: ECAs could save resources while maintaining high evidentiary standards. This review showed that ECAs have a potential for a wide array of applicability beyond oncology and rare diseases, in more prevalent disease contexts. Further research and education are needed to address their limitations and expand its use in decision-making to effectively leverage the benefit of ECAs.