ICH M15 Guideline: General Principles for Model-informed Drug Development

The integration of modeling and simulation into drug development has evolved from a supportive analytical tool to a central pillar of regulatory decision-making. Recognising this shift, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use has formally adopted ICH M15: Guideline on General Principles for Model-Informed Drug Development (MIDD) at Step 5.

The guideline was:

• Endorsed under Step 2 on 6 November 2024

• Adopted by regulatory members under Step 4 on 29 January 2026

• Finally adopted by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency on 23 January 2026

• Effective from 23 July 2026

What Is MIDD?

ICH M15 defines Model-Informed Drug Development (MIDD) as the use of computational modeling and simulation (M&S) methods to integrate nonclinical data, clinical data, prior information, and knowledge about drug and disease characteristics to generate evidence that informs drug development and regulatory decisions. The objective of M15 is to establish a harmonised assessment framework for MIDD evidence. It provides structured recommendations for:

• Planning MIDD activities

• Evaluating models

• Reporting model analyses

• Submitting MIDD evidence to regulators

The guideline is intended to be used alongside topic-specific ICH guidelines such as E4, E9, E11, E17, M12, M13, and S7B. At the heart of ICH M15 is a structured framework for assessing whether model outcomes can be considered MIDD evidence.

Beyond the core elements, the guideline introduces additional considerations at both the planning and submission stages:

• Technical criteria for evaluating model performance

• Appropriateness of the proposed MIDD strategy

• Evaluation of model outcomes

• Multidisciplinary assessment of whether model outcomes qualify as MIDD evidence

M15 defines model evaluation as consisting of three core components:

Verification

Ensuring that user-generated code, equations, and calculations are correct and error-free.

Validation

Assessing whether the model adequately represents observed data, prior knowledge, and biological plausibility.

Applicability Assessment

Determining whether the model and data are fit-for-purpose for the specific question of interest.

The rigor of these activities must be commensurate with model risk. For high-risk applications, external validation and robust uncertainty analyses may be essential.

To promote transparency and reproducibility, ICH M15 recommends structured documentation:

Model Analysis Plan (MAP)

A pre-defined plan outlining objectives, data, methods, model evaluation activities, and technical criteria.

Model Analysis Report (MAR)

A comprehensive report documenting:

• Data sources

• Model development and assumptions

• Verification and validation results

• Simulation outputs

• Interpretation and limitations

Appendix 2 of the guideline provides detailed MAR content recommendations.

For complete official guidance and adoption details, kindly refer to:

• ICH M15 Guideline – General Principles for Model-Informed Drug Development (Step 5, EMA Publication)

• ICH Announcement: Harmonised ICH M15 Guideline Adopted