ICH M15 Guideline: What the Finalized Guideline Means for Model-Informed Drug Development

The ICH M15 guideline defines MIDD as the use of computational modeling and simulation methods and approaches, but not limited to population pharmacokinetics (PopPK), exposure-response (ER) analyses, physiologically based pharmacokinetics (PBPK), model-based meta-analysis (MBMA), and quantitative systems pharmacology (QSP), to integrate nonclinical data, clinical data, prior information, and knowledge into evidence relevant to drug development and regulatory decision-making.

Rather than prescribing specific methodologies, the guideline emphasizes early planning, structured thinking, clear communication, and proactive alignment with regulatory authorities to ensure regulatory clarity. It introduces key assessment elements such as:

• Question of interest
• Context of use
• Model influence
• Consequence of wrong decision
• Model risk
• Model impact

This framework formalizes expectations for model credibility in proportion to the role the modeling will have and the type of decision being supported, together with the totality of evidence informing that decision. Modeling is no longer evaluated in isolation; it is assessed based on its impact on regulatory and development decisions within the broader evidentiary context.

ICH M15 brings consistency to how modeling evidence is interpreted across global regulatory agencies. By harmonizing terminology and expectations, it reduces regional variability and enables sponsors to design modeling strategies that can be defended consistently across FDA, EMA, PMDA, and other authorities.

Eva Gil Berglund, Sr. Director, Clinical Pharmacology and Regulatory Strategy, notes:

MIDD already influences high-impact decisions:

• PBPK modeling replaces certain clinical DDI studies.
• QSP has informed FIH and dose-escalation strategies in oncology.
• Exposure-response analyses support dose optimization and labeling claims.
• Modeling informs dose selection and strengthens pediatric extrapolation strategies.

The guideline does not introduce new science; it formalizes expectations around credibility, transparency, and structured integration of modeling into development plans.

A central message of the ICH M15 guideline is that MIDD must be embedded early, not appended at submission.

Sponsors are encouraged to define, from the outset:

• The overall questions to be addressed
• The context of use, including the role and scope of the model(s) and additional information informing the answer
• The anticipated model influence, i.e., the weight of the model outcomes considering the contribution of additional data or evidence
• The consequences of a wrong decision, including the severity and likelihood of potential negative effects
• The model risk, i.e., the contribution of model outcomes to a possible wrong decision
• The model impact, i.e., how the MIDD strategy varies from regulatory expectations

Early integration enables:

• Stronger cross-functional alignment
• More efficient regulatory dialogue and drug development
• Generation of decision-ready evidence
• Reduced risk of late-stage rework

The guideline also reinforces the importance of Model Analysis Plans (MAPs), rigorous evaluation and validation, and transparent reporting, all critical to strengthening regulatory confidence.

The ICH M15 guideline represents more than a guidance document. It reflects a broader regulatory expectation that MIDD will be applied systematically, transparently, and strategically.

Organizations that adopt structured planning, multidisciplinary alignment, and robust model credibility practices will be better positioned to:

• Accelerate approvals
• Reduce regulatory risk
• Strengthen global submissions
• Improve development efficiency

For a deeper dive into the key questions sponsors are asking, explore our FAQs on ICH M15 and Model-Informed Drug Development.