Methodological Divergence in Oncology HTA: Implications for International Harmonization and the Handling of Uncertainty

OBJECTIVES: While health technology assessment (HTA) guides public funding decisions under uncertainty, existing research often examines individual methodological issues or high-level decision variation rather than how methodological choices interact throughout the appraisal process. Using immune checkpoint inhibitors (ICIs) in non‑small cell lung cancer (NSCLC) as a case study, this study examines how varying methodological choices shape cost‑effectiveness conclusions and reimbursement outcomes between National Institute for Health and Care Excellence (NICE) and Canada's Drug Agency (CDA-AMC). METHODS: Thirty‑five published technology appraisals from NICE and CDA‑AMC through February 2026 were reviewed using a prespecified, systematic approach. Extracted data included pivotal trial characteristics, comparator selection, cost‑effectiveness conclusions, and key modeling assumptions, including modeling methods, time horizon, utility values, survival extrapolation, treatment duration, effect waning, and cure. RESULTS: Overall concordance in cost‑effectiveness conclusions was 56.3%, with NICE issuing positive conclusions more frequently than CDA‑AMC (83.3% versus 41.2%). Divergence arose from differences in appraisal processes and methodological inputs, particularly comparator selection, reimbursement populations, and long-term modeling assumptions. Approaches to treatment‑effect waning evolved from abrupt loss‑of‑effect assumptions to gradual decline models, though persistence assumptions varied across appraisals in line with data maturity. NICE more frequently explored alternative modeling approaches, whereas CDA‑AMC applied greater scrutiny to indirect evidence and long‑term projections. CONCLUSIONS: HTA decisions for ICIs by NICE and CDA‑AMC diverged across multiple uncertainty domains, reflecting interacting methodological choices throughout the appraisal process rather than isolated technical factors alone, highlighting the importance of greater alignment in approaches to uncertainty management for future HTA harmonization efforts.