Artificial intelligence (AI) and advanced modeling are reshaping how drugs and biologics are developed, reviewed, and regulated worldwide. In late 2024 and early 2025, the FDA released draft guidance on AI use in regulatory submissions, while the International Council for Harmonization (ICH) finalized its M15 guideline on model-informed drug development (MIDD). Together, these documents signal a fundamental shift toward harmonized, risk-based, multidisciplinary approaches that accelerate innovation while safeguarding public health.
The ICH M15 guideline, part of ICH’s Multidisciplinary Guidelines, offers a harmonized framework for model-informed drug development (MIDD). It provides general recommendations on planning, model evaluation, documentation of evidence, and regulatory interaction. The guideline defines key concepts such as the question of interest, context of use, model risk and impact, and recommends documentation tools like model analysis plans and reports to support transparent regulatory evaluation.
M15’s core objective is to ensure consistent interpretation and use of models (including AI/ML, quantitative simulations, and other computational methods) across regulatory submissions. It encourages early alignment between sponsors and regulators through multidisciplinary planning to boost acceptance of modeling evidence. Although not exclusively about AI, M15 includes artificial intelligence and machine learning as examples of modeling approaches that fall under MIDD when integrated with pharmacometric and simulation methods.
In January 2025, the FDA published draft guidance titled Considerations for the Use of Artificial Intelligence To Support Regulatory Decision-Making for Drug and Biological Products. This guidance offers non-binding recommendations for using AI to generate information or data that influence regulatory decisions regarding safety, effectiveness, or quality. The guidance centers on a risk-based credibility assessment framework that helps sponsors evaluate and justify the reliability of an AI model for a specific context of use. A context of use describes the role the AI model plays in answering a regulatory question, which then determines the level of validation and documentation needed. Notably, the draft guidance excludes AI used solely for internal workflows (e.g., drafting submissions) and focuses on AI that impacts public health decisions.
The ICH M15 guideline emerged from a consensus-driven process involving global regulators and industry stakeholders through the ICH Working Group and public consultation phases, starting from concept papers in 2022 and draft reviews in 2024–2025. This reflects ICH’s broader mission to harmonize technical requirements across regions so that high-quality medicines can be developed more efficiently and consistently worldwide. M15 fills a longstanding gap in ICH’s multidisciplinary portfolio by consolidating principles for model-informed decisions, improving clarity around documentation standards, and promoting transparency in regulatory interactions. Its development process involved iterative reviews and public comment periods to align diverse regional expectations.
The FDA’s AI draft guidance complements M15 by offering practical frameworks specifically for AI credibility and contextual justification, building on decades of submissions involving AI components. The agency’s experience with hundreds of AI-inclusive regulatory filings informed this guidance, indicating the growing importance of AI in drug development. Together, ICH M15 and the FDA’s AI considerations reflect a larger shift in regulatory science toward data-driven credibility, explainability, and multidisciplinary evaluation. This evolution aligns with global harmonization efforts led by ICH, as regulators adapt to more complex computational tools in submissions.
The ICH M15 and FDA’s AI draft guidance are paving the way for a more predictable, transparent, and AI-inclusive regulatory landscape. By emphasizing risk-based credibility, robust model documentation, and harmonized evaluation, these frameworks help sponsors leverage advanced modeling and AI responsibly. As AI continues to transform drug development, regulators and industry alike must embrace these guidelines to balance innovation with patient safety and regulatory rigor.
