FAQs: The ICH M15 Guideline and What It Means for Model-Informed Drug Development

M15 formalizes expectations around model credibility, terminology, and communication. Teams are now expected to articulate the context of use, evaluate uncertainty systematically, and demonstrate that modeling approaches are appropriate for the decisions they inform. This guidance elevates MIDD from a technical activity to a structured, decision-support framework.

Credibility determines whether a model is fit for its intended regulatory or scientific use. M15 emphasizes that credibility must be evidence-based and risk-informed—not just a validation checklist. Regulators want transparency around assumptions, data quality, and uncertainty to ensure decisions are supported by sound, well-characterized analyses.

Terms like context of use, key assessment elements, model impact, and totality of evidence have specific meanings under the guideline. Using them correctly improves alignment across internal teams and ensures that regulatory reviewers interpret modeling strategies as intended. Clear, shared language prevents miscommunication and strengthens credibility.

Modeling affects clinical, regulatory, manufacturing, and safety decisions. ICH M15 reinforces that credibility cannot be assessed by modelers alone; it requires cross-functional agreement on decision needs, assumptions, and evidence standards. When teams evaluate models together, the resulting strategy is more defensible and coherent.

ICH M15 encourages sponsors to discuss modeling plans with regulators before analyses are performed. Early dialogue helps align expectations, clarify assumptions, and reduce the risk of rework. Agencies increasingly view MIDD as a collaborative process when sponsors proactively communicate reasoning, not just results.

For global programs, inconsistent expectations historically created duplication and uncertainty. M15 reduces regional variability by establishing a unified framework for credibility and communication. This means modeling plans can be designed once and defended consistently across FDA, EMA, PMDA, and other agencies.

MIDD already plays a critical role in regulatory decisions, from dose selection and exposure– response evaluation to pediatric extrapolation, PBPK-based DDI waivers, virtual bioequivalence, and reducing the need for certain clinical studies. ICH M15 strengthens the framework for applying MIDD and extends its impact beyond regulatory review, explicitly supporting its use to inform key decisions earlier in drug development, even when no direct regulatory assessment is involved.

ICH M15 represents more than a guidance document—it reflects a broader expectation from regulators that MIDD will be used systematically and transparently. Teams that understand credibility principles, terminology, and cross-functional practices will be better positioned to justify decisions and avoid downstream delays.

This guide provides the foundational concepts, frameworks, and alignment practices needed to evaluate current capabilities and identify areas where additional focus or support may be required. It helps teams understand not only what ICH M15 expects—but why those expectations matter for modern regulatory strategy.