OBJECTIVES: Evidentiary standards for RWE vary across regulators and HTA bodies although differences are not well-characterized. Through six examples, we examined whether RWE submitted for regulatory decision-making was accepted across different regulators and HTAs.

METHODS: We examined feedback from regulators (FDA, HC, MHRA, EMA) and HTA bodies (NICE, G-BA, HAS, AEMPS, CADTH, SMC, TLV) on drug approvals containing RWE as supportive or substantial evidence in MAAs from 2021-present. Publicly available documents were extracted including FDA reports, EMA assessments, and HTA reports (identified via IQVIA’s Market Access Insights®, formerly known as HTA Accelerator). Two independent reviewers extracted and categorized the RWE as substantial, supportive, not adequate, or not discussed.

RESULTS: Six medicines were identified: idecabtagene vicleucel (ide-cel), omburtamab, sotorasib, alpelisib, palovarotene, and tacrolimus. Regulators were concordant on use of RWE for omburtamab (RWE not adequate) and divergent for four medicines: ide-cel (FDA: not adequate; MHRA and EMA: RWE as substantial; HC: not discussed), palovarotene (FDA and HC: RWE as substantial; EMA: not adequate), alpelisib (FDA: RWE as substantial; EMA: not adequate, application withdrawn) and sotorasib (FDA, EMA, MHRA: RWE as supportive, HC: not discussed). RWE for tacrolimus was substantial for FDA.

HTA evaluation of RWE for ide-cel was concordant for G-Ba and HAS (RWE not adequate) and CADTH, AEMPS, and TLV (RWE as supportive); two HTAs did not conduct appraisals. RWE for sotorasib was not discussed by HTAs. RWE for palovarotene was supportive for CADTH; appraisals were not conducted by other HTAs. Commonly cited concerns raised by regulators and HTA bodies included biases from incomplete data, comparability of study arms, and residual confounding.

CONCLUSIONS: RWE supporting effectiveness in MAAs was accepted more frequently by FDA than EMA, while HTA review highlighted differing standards of RWE acceptability. Consideration should be given to these differences when generating RWE for regulatory decision-making and appraisals.