OBJECTIVES: External control arm (ECA) studies use control patients external to a clinical trial to establish comparative evidence. The aim of this review is to provide an overview of guidance and evaluation by health technology assessment bodies concerning the conduct and reporting of ECA studies.

METHODS: We performed a targeted literature search of guidance for ECA studies from the German Institute for Quality and Efficiency in Health Care (IQWiG) and UK National Institute for Health and Care Excellence (NICE). Furthermore, we screened our internal database of all published German AMNOG benefit dossiers for reported ECA studies and reviewed their evaluation by the IQWiG.

RESULTS: In 2015 and 2020, the NICE and IQWiG provided detailed guidance on the conduct and reporting of ECA studies. Both institutes stated that non-randomized comparative studies should aim to emulate the target randomized trial in terms of population, intervention, comparator, outcomes, and setting and emphasized the importance of a priori study planning, confounder adjustment, and transparent reporting. In particular the IQWiG imposed high requirements on the confounder identification, recommending a systematic literature review combined with expert interviews. Since 2020, more than 25 AMNOG benefit dossiers reported results from ECA studies. Key points of criticism by the IQWiG were missing information on relevant confounders and missing overlap in patient populations, leading to inadequately controlled comparative studies.

CONCLUSIONS: ECA studies are becoming more commonly accepted in the context of pricing and reimbursement assessments when ethics, orphan diseases, or enrolment challenges limit the conduct of randomized controlled trials. Guidance by the IQWiG and NICE poses similar requirements on the conduct and reporting of such studies. Overall, implementation of those requirements needs improvement according to evaluations by the IQWiG.