The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has adopted the ICH M15 Guideline, ‘General Principles for Model-Informed Drug Development’, reaching Step 4 of the ICH harmonisation process. The Guideline, intended to facilitate a multidisciplinary understanding of model-informed drug development (MIDD) and associated evidence generation, will now move into the implementation phase (Step 5).
Before the development of M15, the absence of overarching international standards meant that the application and regulatory assessment of MIDD varied across regions and, in some cases, within individual regulatory authorities. Although existing ICH guidelines address specific elements relevant to MIDD, there has been no single guideline setting out general principles. This has contributed to uncertainty regarding regulatory acceptability and to variability in the quality and consistency of MIDD-related content in regulatory submissions, particularly for novel methods not covered by topic-specific guidance.
The M15 Guideline establishes general principles and good practices for the use of evidence derived from MIDD, with the aim of harmonising regulatory expectations globally. It addresses planning, model development, data sources, model evaluation, documentation standards, and the application of models to support drug development and regulatory decision-making.
Under M15, MIDD is defined as the strategic use of computational modelling and simulation (M&S) methods that integrate nonclinical and clinical data, prior information, and knowledge (for example, drug and disease characteristics) to generate evidence. The Guideline emphasises early planning of MIDD strategies within drug development programmes, as well as early and effective communication with regulatory authorities to facilitate acceptance of MIDD evidence.
The scope of M15 includes a wide range of M&S approaches, including population pharmacokinetics, physiologically-based pharmacokinetics and biopharmaceutics, dose-exposure–response analysis, model-based meta-analysis, quantitative systems pharmacology and toxicology, disease progression models, agent-based models, and artificial intelligence/machine learning methods, used alone or in combination.
Implementation of ICH M15 is expected to support more consistent regulatory assessment of MIDD across regions and improve the quality and predictability of MIDD-related submissions.
