RECOGNITION OF TARGET TRIAL EMULATION AND THE ESTIMAND FRAMEWORK IN REGULATORY AND HTA GUIDANCE: A EUROPEAN AND NORTH AMERICAN LANDSCAPE REVIEW
Author(s)
Tatsiana Vaitsiakhovich, PhD1, Alessandro Ghiretti, PhD2, Antonio Remiro Azócar, PhD3, barbara rosettani, MSc4, Giusi Moffa, PhD5, Ilse C.L. Van dromme, PhD6, khadija RERHOU Rantell, PhD7, Matthew Knowles, MSc8, Lotte Husemoen, PhD9, Emmanuelle Boutmy, PhD10.
1Sanofi, Berlin, Germany, 2Data and Statistical Sciences Centre for RWE and EG, Daiichi Sankyo, Roma, Italy, 3Novo Nordisk, Madrid, Spain, 4F. Hoffmann - La Roche AG, Basel, Switzerland, 5Bristol Myers Squibb, Boudry, Switzerland, 6Johnson & Johnson, Beerse, Belgium, 7Medicines and Healthcare Products Regulatory Agency, London, United Kingdom, 8Astellas Pharma Europe Ltd, Addlestone, United Kingdom, 9Novo Nordisk, Bagsværd, Denmark, 10Merck KGaA, Darmstadt, Germany.
1Sanofi, Berlin, Germany, 2Data and Statistical Sciences Centre for RWE and EG, Daiichi Sankyo, Roma, Italy, 3Novo Nordisk, Madrid, Spain, 4F. Hoffmann - La Roche AG, Basel, Switzerland, 5Bristol Myers Squibb, Boudry, Switzerland, 6Johnson & Johnson, Beerse, Belgium, 7Medicines and Healthcare Products Regulatory Agency, London, United Kingdom, 8Astellas Pharma Europe Ltd, Addlestone, United Kingdom, 9Novo Nordisk, Bagsværd, Denmark, 10Merck KGaA, Darmstadt, Germany.
OBJECTIVES: Robust methodological frameworks are essential for generating real-world evidence (RWE) to support regulatory and health technology assessment (HTA) bodies’ decision-making. Two key approaches have emerged: target trial emulation (TTE), introduced in 2016, and the estimand framework, formalized with ICH E9(R1) in 2019, both grounded in causal inference. TTE is a design and analytic framework to estimate causal effects from RW data by emulating a hypothetical trial. The estimand framework provides a structured approach to define treatment effects of interest and handle intercurrent events in randomized controlled trials (RCTs), with increasing adaptation in RWE. This review assessed how these frameworks are recognized in regulatory and HTA RWE-related guidance across Europe and North America.
METHODS: A structured review of regulatory and HTA guidance documents, published from 2019 onward, was conducted in the original language of the agency documents. Predefined search terms included “target trial,” “emulation,” “estimand,” and “ICH E9(R1)”. Relevant passages were extracted verbatim, translated, and assessed for explicit framework mentions and operational guidance. Dual independent review with consensus was applied.
RESULTS: This review identified heterogeneous recognition of TTE and estimand frameworks across regulatory and HTA RWE-related guidance in Europe and North America, with variable uptake across jurisdictions. Explicit reference to at least one framework was predominantly observed in regulatory and European Joint Clinical Assessment guidance. The estimand framework achieved broader recognition; however, its application beyond RCTs remained inconsistent. TTE mentions were infrequent, primarily addressing causal inference in RWE research. Several documents showed implicit alignment with TTE principles.
CONCLUSIONS: Findings highlight the need for clearer, more harmonized guidance to support consistent and transparent evaluation of RWE. Despite increasing use of estimand and TTE frameworks in practice, their limited integration into regulatory and HTA guidance reveals a gap between methodology and policy. Addressing this gap will enhance the consistency, relevance, and acceptability of RWE in decision-making.
METHODS: A structured review of regulatory and HTA guidance documents, published from 2019 onward, was conducted in the original language of the agency documents. Predefined search terms included “target trial,” “emulation,” “estimand,” and “ICH E9(R1)”. Relevant passages were extracted verbatim, translated, and assessed for explicit framework mentions and operational guidance. Dual independent review with consensus was applied.
RESULTS: This review identified heterogeneous recognition of TTE and estimand frameworks across regulatory and HTA RWE-related guidance in Europe and North America, with variable uptake across jurisdictions. Explicit reference to at least one framework was predominantly observed in regulatory and European Joint Clinical Assessment guidance. The estimand framework achieved broader recognition; however, its application beyond RCTs remained inconsistent. TTE mentions were infrequent, primarily addressing causal inference in RWE research. Several documents showed implicit alignment with TTE principles.
CONCLUSIONS: Findings highlight the need for clearer, more harmonized guidance to support consistent and transparent evaluation of RWE. Despite increasing use of estimand and TTE frameworks in practice, their limited integration into regulatory and HTA guidance reveals a gap between methodology and policy. Addressing this gap will enhance the consistency, relevance, and acceptability of RWE in decision-making.
Conference/Value in Health Info
2026-11, ISPOR Europe 2026, Vienna, Austria
Value in Health, Volume 29, Issue 12S
Code
MSR233
Topic
Health Policy & Regulatory, Methodological & Statistical Research, Organizational Practices
Topic Subcategory
Confounding, Selection Bias Correction, Causal Inference
Disease
No Additional Disease & Conditions/Specialized Treatment Areas