The European Medicines Agency (EMA) has released a concept paper proposing the development of a guideline for the assessment and reporting of mechanistic models used in Model-Informed Drug Development (MIDD). This guideline aims to provide regulatory clarity on the use of mechanistic models such as Physiologically Based Pharmacokinetic (PBPK), Physiologically Based Biopharmaceutics (PBBM), and Quantitative Systems Pharmacology (QSP) models.
Mechanistic models are computer or mathematical models that integrate biological, chemical, and physiological processes to predict drug behavior and treatment outcomes.
PBPK Models – Simulate drug concentration in the body by considering absorption, distribution, metabolism, and excretion (ADME).
PBBM Models – A subset of PBPK, focusing on the interaction between drug quality attributes and clinical outcomes.
QSP Models – Integrate molecular and cellular disease mechanisms with drug action to predict treatment effects on a system level.
These models support regulatory decisions on dose selection, study design, benefit-risk assessment, and formulation comparability.
Key Topics Covered in the Guideline
Assessment Framework for MIDD Evidence
Uncertainty Quantification & Model Validation
Regulatory Data Quality & Model Assumptions
Best Practices for Reporting Simulation Results
EMA emphasizes virtual population modeling (digital twins) to enhance predictive accuracy in clinical trial simulations.
Despite the growing use of mechanistic models in drug development, there is no standardized regulatory framework for their validation, reporting, and acceptance.
Key challenges include:
Lack of clear validation criteria – Uncertainty in assessing model reliability.
Complexity of models – Many models have highly interconnected parameters, making them difficult to interpret.
Regulatory underuse – Due to unclear acceptance criteria, these models are not fully leveraged in regulatory submissions.
The Committee for Medicinal Products for Human Use (CHMP) and Scientific Advice Working Party (SAWP) will oversee guideline development. A public workshop on mechanistic modeling is planned for 2025 to gather industry feedback. The final guideline is expected to improve the regulatory acceptance of mechanistic models in EMA submissions.
📅 Public Consultation: 14 February 2025 – 31 May 2025
📌 Expected Guideline Completion: 2026
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