Addressing Clinical Uncertainties in ATMP Reimbursement: A Review of European Methodological Guidelines and Practices
Author(s)
Lotte Delemarre, MD1, Isabelle Huys, PharmD, PhD1, Walter Van Dyck, MA, MSc, PhD2, Steven Simoens, BA, MA, MSc, PhD1.
1KU Leuven, Leuven, Belgium, 2Vlerick Healthcare Management Centre, Gent, Belgium.
1KU Leuven, Leuven, Belgium, 2Vlerick Healthcare Management Centre, Gent, Belgium.
OBJECTIVES: Advanced Therapy Medicinal Products (ATMPs) tend to have significant clinical uncertainties at the time of reimbursement evaluation. This study focused on two key challenges: the lack of appropriate comparators hindering randomized controlled trials (RCTs) and the absence of long-term clinical endpoints. The aim was to provide an overview of current methodological guidelines for addressing these challenges and conduct a comparative analysis of pharmaco-economic guidelines on how they are addressed for ATMPs across Europe.
METHODS: A structured literature review was conducted. A predefined search strategy was applied across PubMed and Embase, combining keywords related to ‘Health Technology Assessment’, ‘ATMPs’, ‘Indirect Treatment Comparison’, ‘Surrogate Endpoint’. This was supplemented by a search for grey literature. For the comparative analysis of European pharmaco-economic guidelines we used the ISPOR database and referenced national guidelines.
RESULTS: Among the 27 ATMPs approved by the European Medicines Agency, 20 were supported by single-arm trials, and 19 relied on surrogate endpoints. Without a common comparator, single-arm trials cannot form an anchored network for indirect comparisons, such as network meta-analysis (NMA). Population-adjusted indirect comparisons (PAICs) offer an alternative, but they are susceptible to bias from unmeasured confounding and rely on strong assumptions. While pharmaco-economic guidelines impose strict requirements on PAICs, they offer little guidance when no comparator exists. This scarcity of direct comparative data also hinders the validation of surrogate endpoints, which guidelines typically expect to be confirmed through RCTs and meta-analysis. Even when validated, the transferability of a surrogate endpoint is specific to the technology, targeted disease, and patient population. The novelty of ATMPs and their indications further complicates demonstrating such transferability, as existing surrogate validations may not apply to these new contexts.
CONCLUSIONS: ATMPs pose specific clinical challenges at the time of reimbursement evaluation, necessitating new frameworks and guidance addressing these in pharmaco-economic guidelines.
METHODS: A structured literature review was conducted. A predefined search strategy was applied across PubMed and Embase, combining keywords related to ‘Health Technology Assessment’, ‘ATMPs’, ‘Indirect Treatment Comparison’, ‘Surrogate Endpoint’. This was supplemented by a search for grey literature. For the comparative analysis of European pharmaco-economic guidelines we used the ISPOR database and referenced national guidelines.
RESULTS: Among the 27 ATMPs approved by the European Medicines Agency, 20 were supported by single-arm trials, and 19 relied on surrogate endpoints. Without a common comparator, single-arm trials cannot form an anchored network for indirect comparisons, such as network meta-analysis (NMA). Population-adjusted indirect comparisons (PAICs) offer an alternative, but they are susceptible to bias from unmeasured confounding and rely on strong assumptions. While pharmaco-economic guidelines impose strict requirements on PAICs, they offer little guidance when no comparator exists. This scarcity of direct comparative data also hinders the validation of surrogate endpoints, which guidelines typically expect to be confirmed through RCTs and meta-analysis. Even when validated, the transferability of a surrogate endpoint is specific to the technology, targeted disease, and patient population. The novelty of ATMPs and their indications further complicates demonstrating such transferability, as existing surrogate validations may not apply to these new contexts.
CONCLUSIONS: ATMPs pose specific clinical challenges at the time of reimbursement evaluation, necessitating new frameworks and guidance addressing these in pharmaco-economic guidelines.
Conference/Value in Health Info
2025-11, ISPOR Europe 2025, Glasgow, Scotland
Value in Health, Volume 28, Issue S2
Code
CO6
Topic
Clinical Outcomes, Health Technology Assessment, Methodological & Statistical Research
Topic Subcategory
Clinical Outcomes Assessment
Disease
Genetic, Regenerative & Curative Therapies