HTA and Regulatory Perspectives on Robustness of Evidence and Management of Uncertainties
Author(s)
David McConnell, PhD1, Dominik Karres, MD2, Lea Trela-Larsen, PhD1, Beate Wieseler, PhD3, Randi Krontveit, PhD4, Kirsti Hjelme, PhD4, Hilde Røshol, PhD4, Philip Kranz, PhD3, Mattias Neyt, PhD5, Sofia Dias, PhD6, Lars Beckmann, PhD3, Frank Hulstaert, MD, MSc5, Marc Van de Casteele, PhD7, Joy Leahy, PhD1, Niamh Carey, PhD1, Hans Hillege, PhD8, Michael Berntgen, PhD2, Denise Umuhire, MSc2, Peter GM Mol, PhD9, Ralf Bender, PhD3, Anke Schulz, PhD3, María José del Pino, PhD10, Cathal Walsh, PhD11, Kit Roes, PhD12, Patrice Verpillat, PhD2, Ilona Reischl, PhD13, Emmely de Vries, PhD9, Frauke Naumann-Winter, PhD14, Olga Kholmanskikh, PhD15, Filip Josephson, PhD16, Bruno Delafont, MSc17, Christian Gartner, MSc13, Finbarr Leacy, PhD18, Sylvie Benchetrit, PhD17, Roisin Adams, PhD1, Bruno Sepodes, PhD19.
1National Centre for Pharmacoeconomics, Dublin, Ireland, 2European Medicines Agency, Amsterdam, Netherlands, 3Institute for Quality and Efficiency in Healthcare (IQWiG), Cologne, Germany, 4Norwegian Medicines Agency, Oslo, Norway, 5Belgian Health Care Knowledge Centre, Brussels, Belgium, 6University of York, York, United Kingdom, 7National Institute for Health and Disability Insurance (RIZIV-INAMI), Brussels, Belgium, 8UMCG, Haren, Netherlands, 9Medicines Evaluation Board (CBG-MEB), Utrecht, Netherlands, 10Spanish Agency of Medicines and Medical Devices (AEMPS), Madrid, Spain, 11Trinity College Dublin, Dublin, Ireland, 12Radboud University Medical Center, Nijmegen, Netherlands, 13Austrian Federal Office For Safety In Health Care, Vienna, Austria, 14Federal Institute For Drugs And Medical Devices, Bonn, Germany, 15Federal Agency For Medicines And Health Products, Brussels, Belgium, 16Swedish Medical Products Agency, Uppsala, Sweden, 17National Agency For The Safety Of Medicine And Health Products, Paris, France, 18Health Products Regulatory Authority, Dublin, Ireland, 19National Authority Of Medicines And Health Products (INFARMED), Lisbon, Portugal.
1National Centre for Pharmacoeconomics, Dublin, Ireland, 2European Medicines Agency, Amsterdam, Netherlands, 3Institute for Quality and Efficiency in Healthcare (IQWiG), Cologne, Germany, 4Norwegian Medicines Agency, Oslo, Norway, 5Belgian Health Care Knowledge Centre, Brussels, Belgium, 6University of York, York, United Kingdom, 7National Institute for Health and Disability Insurance (RIZIV-INAMI), Brussels, Belgium, 8UMCG, Haren, Netherlands, 9Medicines Evaluation Board (CBG-MEB), Utrecht, Netherlands, 10Spanish Agency of Medicines and Medical Devices (AEMPS), Madrid, Spain, 11Trinity College Dublin, Dublin, Ireland, 12Radboud University Medical Center, Nijmegen, Netherlands, 13Austrian Federal Office For Safety In Health Care, Vienna, Austria, 14Federal Institute For Drugs And Medical Devices, Bonn, Germany, 15Federal Agency For Medicines And Health Products, Brussels, Belgium, 16Swedish Medical Products Agency, Uppsala, Sweden, 17National Agency For The Safety Of Medicine And Health Products, Paris, France, 18Health Products Regulatory Authority, Dublin, Ireland, 19National Authority Of Medicines And Health Products (INFARMED), Lisbon, Portugal.
OBJECTIVES: There is a joint ambition, enabled through the HTA Regulation, for a more coordinated approach between European regulators and HTA bodies (HTAb) to enhance the quality and relevance of evidence for decision-making, and ultimately improve patient access. We report on a joint workshop series organised with the objective of understanding each other’s assessment challenges and jointly exploring potential solutions at the level of evidence generation, accounting for the different scopes and subsequent evidence needs of HTAb and regulators.
METHODS: Over the course of three workshops, HTAb and regulatory participants discussed challenges in generating adequate evidence to support decision-making by looking into three case-studies of authorised medicinal products, each examining distinct methodological issues. Detailed follow-up discussions were held to summarise key conclusions on evidence generation and uncertainty management, and to identify priorities for future collaboration on methodology.
RESULTS: Key points agreed: HTAb-regulatory collaboration at the time of study design and throughout a product's lifecycle is essential to address mutual evidence needs and manage respective uncertainties. Product-specific collaboration is facilitated via the parallel HTAb-EMA Joint Scientific Consultation procedure. In general, there is a strong preference for randomised evidence to answer questions of clinical effectiveness, which can sometimes be challenging. Participants highlighted the potential for randomised trials conducted within registries and/or alongside routine care to play a greater role in evidence generation. There was agreement on using the estimand framework as a valuable, shared language for aligning study design with regulatory and HTA objectives. Improving collection, analysis and reporting of outcomes other than the ‘primary’ study outcome(s), and leveraging opportunities to complement clinical trial data with real-world data, can also mitigate uncertainties.
CONCLUSIONS: Next Steps: Further follow-up activities are ongoing, related to the estimand framework and the supportive use of real-world data. Joint HTAb-regulatory assessors’ discussion meetings are planned following the publication of the first JCAs.
METHODS: Over the course of three workshops, HTAb and regulatory participants discussed challenges in generating adequate evidence to support decision-making by looking into three case-studies of authorised medicinal products, each examining distinct methodological issues. Detailed follow-up discussions were held to summarise key conclusions on evidence generation and uncertainty management, and to identify priorities for future collaboration on methodology.
RESULTS: Key points agreed: HTAb-regulatory collaboration at the time of study design and throughout a product's lifecycle is essential to address mutual evidence needs and manage respective uncertainties. Product-specific collaboration is facilitated via the parallel HTAb-EMA Joint Scientific Consultation procedure. In general, there is a strong preference for randomised evidence to answer questions of clinical effectiveness, which can sometimes be challenging. Participants highlighted the potential for randomised trials conducted within registries and/or alongside routine care to play a greater role in evidence generation. There was agreement on using the estimand framework as a valuable, shared language for aligning study design with regulatory and HTA objectives. Improving collection, analysis and reporting of outcomes other than the ‘primary’ study outcome(s), and leveraging opportunities to complement clinical trial data with real-world data, can also mitigate uncertainties.
CONCLUSIONS: Next Steps: Further follow-up activities are ongoing, related to the estimand framework and the supportive use of real-world data. Joint HTAb-regulatory assessors’ discussion meetings are planned following the publication of the first JCAs.
Conference/Value in Health Info
2025-11, ISPOR Europe 2025, Glasgow, Scotland
Value in Health, Volume 28, Issue S2
Code
HTA183
Topic
Health Policy & Regulatory, Health Technology Assessment, Study Approaches
Topic Subcategory
Decision & Deliberative Processes
Disease
Oncology, Personalized & Precision Medicine, Rare & Orphan Diseases