OBJECTIVES: Drug regulatory and reimbursement approvals based on single-arm trials (SATs) are increasingly observed. While some regulatory and health technology assessment agencies provide guidance and cautionary statements on external comparator (EC) data in submissions, these agencies do not provide a gold-standard methodology on SAT appraisals. We sought to characterize National Institute for Health and Care Excellence (NICE) 2022 appraisals of SATs, their application of EC data towards indirect treatment comparisons (ITC) and associated critique.

METHODS: From the appraisals we identified: disease area; source of EC; ITC methods used; critique from the Evidence Assessment Group (EAG) and the NICE Committees’ final appraisal decision.

RESULTS: Thirteen of 73 submissions (18%; recommendations: positive [11]; negative [2]) were based on SATs (oncology [11]; chronic kidney disease [1]; acute hyperkalaemia [1]). Sources of EC were from real-world evidence (RWE), including registries (3), database studies (4) and chart reviews (2). EC creation included different propensity score (weighting) approaches (3), subset or pooling of RWE (3) and covariate adjustment (1). ITC methods included propensity weighting (4), matching-adjusted indirect comparison (6), simulated treatment comparison (1), multivariate Cox regression (1), network meta-analysis (1), piecewise modelling (1), reverse Bucher (1) and naïve ITC (2). Critique focussed on the robustness of forming the EC, although negative feedback concerning adjustment methods (or lack of) was not always associated with the final decision.

CONCLUSIONS: In 2022, there was an increase of SATs in NICE submissions and EC creation varied (likely depending on available evidence). While submission characteristics such as EC population and ITC methods aligning with NICE Technical Support Documents appeared better received over naïve approaches, there is a lack of centralized guidance towards selecting the most robust methods for submissions with SATs. A roadmap on how to handle EC challenges given the available evidence would be valuable to inform submission strategy.