EMA Concept Paper on Model Informed Drug Development

In order to keep pace with methodological developments in the field of Model-Informed Drug Development (MIDD), the European Medicines Agency (EMA) has published a new draft guideline on the assessment and reporting of mechanistic models to include models not currently covered by regulatory guidance documents. The consultation (deadline for comments) is 31 May 2025.

Background

Mechanistic models, i.e. mathematical or computer models that integrate biopharmaceutical, physical-mechanical, (patho)physiological and pharmacological processes as well as population characteristics, are frequently and increasingly used in all phases of drug research and development.

In regulatory submissions mechanistic models have been proposed as a source of evidence to support assessment of comparability between formulations and between manufacturing processes, preclinical proof of concept (PoC), dose selection, study design optimisation, population enrichment strategies, extrapolation, benefit risk assessment and labelling.

The only EMA guidance document on mechanistic models is currently the "Guideline on the reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation", adopted by the CHMP in 2018 (EMA/CHMP/458101/2016). However, the ICH recently published a draft ICH M15 Guideline on General Principles for Model-Informed Drug Development (MIDD).

Discussion on the problem statement

The following topics will be addressed in the new guideline:

• The different types and objectives of mechanistic models
• Application of the MIDD evidence assessment framework on mechanistic models
• Uncertainty quantification
• Model structure and identifiability
• Regulatory requirement for data quality and relevance
• Model development and evaluation
• Virtual population generation and simulation scenarios
• Best practices for reporting of results of mechanistic modelling and simulation

More information is available in EMA's Concept paper on the development of a Guideline on assessment and reporting of mechanistic models used in the context of model informed drug development.