Supplementary file 1_A hierarchical and configurational analysis of Health Technology Assessment outcomes for cell and gene therapies.docx

BackgroundCell and gene therapies (CGTs) challenge traditional Health Technology Assessment (HTA), creating a fragmented global access landscape. This study identifies the determinants of CGT reimbursement outcomes by quantifying the influence of key variables and identifying the configurations leading to a positive recommendation.
MethodsA dual-methodology approach was employed. We constructed a comprehensive dataset of all HTA decisions for CGTs across seven major jurisdictions between January 2017 and July 2025. Hierarchical Linear Modeling (HLM) was used to identify independent predictors of HTA outcomes, and Fuzzy-Set Qualitative Comparative Analysis (fsQCA) was used to identify sufficient pathways to success. Novel composite indicators were developed to measure system-level adaptability and the influence of patient advocacy groups (PAGs).
ResultsThe HLM analysis, accounting for data clustering (Intraclass Correlation Coefficients (ICCs): 42% country-level, 24% agency-level variance), confirmed that strong clinical efficacy (Coef. = 0.40), high unmet need, and disease rarity were significant positive predictors. High therapy cost was a powerful negative predictor (Coef. = −0.29 per $1M USD). Crucially, high System Adaptability (Coef. = 0.35) and strong PAG Influence (Coef. = 0.28) emerged as major positive determinants. The fsQCA revealed three distinct pathways to a positive recommendation with high consistency: a “Transformative Value” path (consistency: 0.93), a “Strategic Mitigation” path (consistency: 0.90), and an “Economic Dominance” path (consistency: 0.94). The overall QCA solution explained a majority of positive outcomes (solution coverage: 0.68).
ConclusionHTA success for CGTs is not determined by isolated attributes but by the strategic alignment of therapy-level evidence, agency-level processes, and country-level context. The influence of organized patient advocacy and the structural flexibility of HTA systems are critical, previously under-quantified components of this alignment.