MEETING REGULATORY TARGETS, MISSING REIMBURSEMENT: EVIDENCE OF A SYSTEMATIC ENDPOINT MISMATCH IN PULMONARY ARTERIAL HYPERTENSION
Author(s)
Fatima Wafqui, MSc, MD1, Panagiotis Therianos, BSc, MSc1, Panos Kanavos, BSc, MSc, PhD2.
1Medical Technology Research Group at the LSE, London, United Kingdom, 2London School of Economics and Political Science, London, United Kingdom.
1Medical Technology Research Group at the LSE, London, United Kingdom, 2London School of Economics and Political Science, London, United Kingdom.
OBJECTIVES: Regulatory approval of therapies for pulmonary arterial hypertension (PAH) relies on established clinical trial endpoints. With joint clinical assessment (JCA) establishing harmonised evidence requirements across EU member states, the fitness of existing regulatory endpoints for reimbursement decision-making has never been more consequential. This study investigates the systematic mismatch between evidence generated for regulatory approval and the comparative evidence HTA bodies require for reliable reimbursement decisions in pulmonary arterial hypertension (PAH).
METHODS: A targeted narrative review with snowballing was conducted across 16 HTA assessments of 8 PAH drugs-pair indications by NICE, HAS, G-BA, and CADTH (2010-2025), supplemented by a review of the corresponding pivotal clinical trial publications. Assessments were analysed to identify endpoints that were deemed insufficient, inconsistently defined, or incomparable across drug-indication pairs for reimbursement decision-making purposes.
RESULTS: Across 16 assessments, three primary endpoints were systematically flagged as insufficient for comparative decision-making. First, 6-minute walk distance (6MWD) was reported as absolute metre change without baseline severity stratification across all included RCTs. Second, consistent with published registry data, therapy-induced PVR reduction was not consistently followed by RV function improvement, making PVR reduction an insufficient predictor of functional outcomes compared to PVR normalisation. Third, time-to-clinical-worsening (TTCW) composite endpoints lacked a standardised definition across the 5 pivotal PAH trials in which they were used across the studied period, with components varying sufficiently across drug-indication pairs to render cross-drug comparison methodologically challenging.
CONCLUSIONS: Primary regulatory endpoints in PAH meet their intended purpose but systematically fail at the comparative stage of reimbursement decision-making. As JCA establishes shared evidence standards across Europe, prospective collaboration between regulatory agencies, HTA bodies, and the clinical community is needed to design rare/orphan disease trials that generate reimbursement decision-grade evidence along regulatory requirements.
METHODS: A targeted narrative review with snowballing was conducted across 16 HTA assessments of 8 PAH drugs-pair indications by NICE, HAS, G-BA, and CADTH (2010-2025), supplemented by a review of the corresponding pivotal clinical trial publications. Assessments were analysed to identify endpoints that were deemed insufficient, inconsistently defined, or incomparable across drug-indication pairs for reimbursement decision-making purposes.
RESULTS: Across 16 assessments, three primary endpoints were systematically flagged as insufficient for comparative decision-making. First, 6-minute walk distance (6MWD) was reported as absolute metre change without baseline severity stratification across all included RCTs. Second, consistent with published registry data, therapy-induced PVR reduction was not consistently followed by RV function improvement, making PVR reduction an insufficient predictor of functional outcomes compared to PVR normalisation. Third, time-to-clinical-worsening (TTCW) composite endpoints lacked a standardised definition across the 5 pivotal PAH trials in which they were used across the studied period, with components varying sufficiently across drug-indication pairs to render cross-drug comparison methodologically challenging.
CONCLUSIONS: Primary regulatory endpoints in PAH meet their intended purpose but systematically fail at the comparative stage of reimbursement decision-making. As JCA establishes shared evidence standards across Europe, prospective collaboration between regulatory agencies, HTA bodies, and the clinical community is needed to design rare/orphan disease trials that generate reimbursement decision-grade evidence along regulatory requirements.
Conference/Value in Health Info
2026-11, ISPOR Europe 2026, Vienna, Austria
Value in Health, Volume 29, Issue 12S
Code
HTA195
Topic
Health Policy & Regulatory, Health Technology Assessment, Methodological & Statistical Research
Topic Subcategory
Value Frameworks & Dossier Format
Disease
Rare & Orphan Diseases