OBJECTIVE: Recently, the integration of external controls to construct an externally controlled trial has gained attraction as a way to strengthen the level of evidence of single-arm trials. We aimed to systematically evaluate the reporting of key methodological features of indirect comparisons that use real-world controls to supplement single-arm drug trials. STUDY DESIGN AND SETTING: We conducted a systematic review to critically appraise the methodological features of these designs and identify key omissions. We compared studies based on methods that address selection bias by targeting covariate balance (e.g., matching, weighting, g-computation or doubly robust estimators) ("balancing-based methods") with those which do not explicitly target imbalances, using outcome-regression or unadjusted analyses for group adjustment ("other methods"). RESULTS: Our search identified 55 single-arm drug trials published from 1987 to 2024. Of these, 29 were described as using balancing-based methods and 26 used other methods. Over half of the trials were in oncology, with hematologic-oncology being the most represented pathology. Only 29% of studies provided a rationale for using an indirect comparison of the single-arm trial to real-world data. Real-world control patients were recruited over longer and earlier time periods than patients in the single-arm trial, compromising positivity assumption. Balancing-based methods were more recent compared to other methods (median of publication time, 2023 vs 2019), with the indirect comparison often following a previous publication of the trial (66% vs 8%). In the balancing-based group, sample sizes in both the experimental (median 77 vs 31) and control (median 97 vs 40) groups were higher, as well as the number of participating centers (with monocentric studies in 30% vs 57%). Assessment of post-adjustment balance was reported more frequently in the balancing-based group, though often only based on p-values (34% vs 62%), improved for those using weighting compared to matching approaches. CONCLUSION: To ensure the validity of unanchored indirect comparisons with RWD controls, future studies should adopt and transparently report on robust methodological frameworks based on the principles of causal inference.
Diouf et al. (Fri,) studied this question.