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A hierarchical and configurational analysis of Health Technology Assessment outcomes for cell and gene therapies
Ziyad S Almalki1, Renad M Alshammari2, Nadia A Dahduli2
1Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj/Riyadh, Saudi Arabia.
Insights
Cell and gene therapy (CGT) reimbursement relies on aligning clinical evidence with system adaptability and patient advocacy. Successful outcomes depend on strategic value, mitigation, or economic dominance pathways, not just isolated factors.
Area of Science:
- Health Technology Assessment (HTA)
- Pharmacoeconomics
- Health Policy
Background:
- Cell and gene therapies (CGTs) present unique challenges to traditional Health Technology Assessment (HTA) processes.
- This results in a fragmented global landscape for patient access to these innovative treatments.
Purpose of the Study:
- To identify key determinants influencing reimbursement outcomes for CGTs.
- To quantify the impact of specific variables on HTA recommendations.
- To uncover distinct configurations of factors leading to positive reimbursement decisions.
Main Methods:
- Employed a dual-methodology approach combining Hierarchical Linear Modeling (HLM) and Fuzzy-Set Qualitative Comparative Analysis (fsQCA).
- Analyzed a comprehensive dataset of HTA decisions for CGTs across seven major jurisdictions (January 2017 - July 2025).
- Developed novel indicators for system-level adaptability and patient advocacy group (PAG) influence.
Main Results:
- HLM identified strong clinical efficacy, high unmet need, and disease rarity as positive predictors, while high therapy cost was a negative predictor.
- System Adaptability and PAG Influence emerged as significant positive determinants of HTA success.
- fsQCA revealed three sufficient pathways to positive reimbursement: "Transformative Value," "Strategic Mitigation," and "Economic Dominance."
Conclusions:
- HTA success for CGTs is contingent upon the strategic alignment of therapy evidence, HTA processes, and national contexts.
- The influence of patient advocacy and the structural flexibility of HTA systems are critical, under-quantified factors.
- Understanding these complex interactions is crucial for improving global access to CGTs.
Background:
Cell 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.
Methods:
A 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).
Results:
The 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).
Conclusion:
HTA 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.
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