SURROGATE ENDPOINTS, CLINICAL UNCERTAINTY, AND REAL-WORLD DECISION-MAKING: LESSONS FROM HB-HTA OF TOFERSEN IN AMYOTROPHIC LATERAL SCLEROSIS
Author(s)
Ana Soares, PharmD1, Tiago ferreira, PharmD2, Armando Alcobia, PharmD2.
1Pharmacist, ULS Almada-Seixal, Almada, Portugal, 2ULS Almada-Seixal, Almada, Portugal.
1Pharmacist, ULS Almada-Seixal, Almada, Portugal, 2ULS Almada-Seixal, Almada, Portugal.
OBJECTIVES: To evaluate the role of surrogate endpoints in decision-making within hospital-based health technology assessment (HB-HTA), and to explore how real-world decisions may diverge from structured HTA recommendations.
METHODS: A structured HB-HTA evaluation of tofersen was conducted, incorporating clinical efficacy, safety, and economic evidence. Outcomes from the phase 3 VALOR trial were analysed, including functional decline (ALSFRS-R), survival-related endpoints, and biomarker changes. Decision outcomes from the Pharmacy and Therapeutics Committee were reviewed, including both formal recommendations and real-world use.
RESULTS: Tofersen did not demonstrate statistically significant improvement in the primary clinical endpoint (ALSFRS-R) compared to placebo at 28 weeks (difference: 1.2 points; p=0.97), nor in survival-related outcomes. Significant reductions were observed in disease-related biomarkers, including SOD1 protein in cerebrospinal fluid and neurofilament light chain levels, although these lack validated correlation with clinical benefit. The treatment was associated with high costs (approximately €280.000annually) and safety concerns related to intrathecal administration. Based on these findings, the HB-HTA recommendation was non-adoption. However, at the time of evaluation, national HTA appraisal was ongoing, and access was possible through an early access program approved on a case-by-case basis. In this context, treatment was authorized for an individual patient, reflecting the interplay between regulatory mechanisms, unmet clinical need, and patient expectations.
CONCLUSIONS: This case highlights a gap between structured HB-HTA recommendations and real-world clinical decision-making.In rare diseases with high unmet need, access pathways, regulatory timelines, and patient expectations may influence decisions beyond clinical and economic evidence. HB-HTA frameworks support transparent and consistent decision-making, but flexibility remains essential to accommodate these real-world pressures.
METHODS: A structured HB-HTA evaluation of tofersen was conducted, incorporating clinical efficacy, safety, and economic evidence. Outcomes from the phase 3 VALOR trial were analysed, including functional decline (ALSFRS-R), survival-related endpoints, and biomarker changes. Decision outcomes from the Pharmacy and Therapeutics Committee were reviewed, including both formal recommendations and real-world use.
RESULTS: Tofersen did not demonstrate statistically significant improvement in the primary clinical endpoint (ALSFRS-R) compared to placebo at 28 weeks (difference: 1.2 points; p=0.97), nor in survival-related outcomes. Significant reductions were observed in disease-related biomarkers, including SOD1 protein in cerebrospinal fluid and neurofilament light chain levels, although these lack validated correlation with clinical benefit. The treatment was associated with high costs (approximately €280.000annually) and safety concerns related to intrathecal administration. Based on these findings, the HB-HTA recommendation was non-adoption. However, at the time of evaluation, national HTA appraisal was ongoing, and access was possible through an early access program approved on a case-by-case basis. In this context, treatment was authorized for an individual patient, reflecting the interplay between regulatory mechanisms, unmet clinical need, and patient expectations.
CONCLUSIONS: This case highlights a gap between structured HB-HTA recommendations and real-world clinical decision-making.In rare diseases with high unmet need, access pathways, regulatory timelines, and patient expectations may influence decisions beyond clinical and economic evidence. HB-HTA frameworks support transparent and consistent decision-making, but flexibility remains essential to accommodate these real-world pressures.
Conference/Value in Health Info
2026-11, ISPOR Europe 2026, Vienna, Austria
Value in Health, Volume 29, Issue 12S
Code
HTA255
Topic
Health Technology Assessment
Topic Subcategory
Decision & Deliberative Processes
Disease
Neurological Disorders