Navigating RWE Strategies in HTA Submissions for Ultra-Rare Diseases in Key European Healthcare Systems

OBJECTIVES: Ultra-rare diseases pose significant challenges while conducting conventional clinical trials, making Real-World Evidence (RWE) essential for Health Technology Assessments (HTA). RWE can bridge evidence gaps and support reimbursement decisions in key European markets. This study assesses the acceptability of RWE by agencies for ultra-rare conditions, focusing on NICE, HAS, and G-BA.

METHODS: We reviewed NICE evaluations of highly specialized technologies (HST) from 2021 to 2023 for ultra-rare conditions medications, and G-BA and HAS databases - for the same indications. Reports examination included all types of RWE (e.g., natural history, observational, chart reviews) and indirect treatment comparison (ITC) techniques. Two reviewers evaluated the submission justifications regarding the use of RWE strategies and resulting recommendations.

RESULTS: Reports from fifteen drugs targeting various ultra-rare conditions across NICE, HAS, and G-BA were reviewed. RWE studies were accepted as evidence for submissions in NICE HST (12/15), HAS (11/15), and G-BA (6/15). Most reports incorporated retrospective natural history studies (90%) as external controls. Unadjusted comparison methods predominated (NICE: 10/15, HAS: 11/15, G-BA: 11/15), while ITC techniques, including propensity score matching and inverse probability weighting, were less common (NICE: 4/15, HAS: 3/15, G-BA: 3/15). HTA agencies noted several limitations about the RWE strategies employed such as reliance on non-comparative methodologies, inadequate patient-relevant endpoints, and lack of better confounding adjustments, highlighting the need for more real-world data to supplement short-term evidence and provide long-term findings.

CONCLUSIONS: This study reveals significant differences in RWE acceptance among major European HTA agencies. NICE and HAS demonstrate flexibility in evaluating treatments for ultra-rare diseases given data constraints, while G-BA maintains stringent criteria for robust evidence. Harmonizing guidelines and enhancing RWE use are essential to improve HTA processes and outcomes for ultra-rare diseases across Europe. Further research should focus on aligning HTA practices and optimizing RWE integration into clinical and regulatory decisions.