Strategies for Successful Application of QSP Platform Models for Clinical Development and Regulatory Engagement

Abstract

Quantitative Systems Pharmacology (QSP) modeling is increasingly recognized as a vital tool in Model-Informed Drug Development (MIDD), offering mechanistic insights and predictive capabilities to inform clinical and regulatory decisions. Its use in regulatory submissions, particularly in Phase 2 and 3 trials, has grown substantially, reflecting its value in translating mechanistic understanding into actionable therapeutic strategies. However, extending QSP’s role toward higher-impact, higher-risk scenarios requires rigorous model credibility assessment and proactive regulatory engagement. This review distills insights from a 2024 American Conference of Pharmacometrics (ACoP) session, highlighting real-world regulatory use cases including pediatric label extension, dose optimization in cell therapy, treatment duration for COVID-19 antivirals, and dosing strategies for T cell redirecting bispecific antibodies. These cases illustrate practical strategies for model quality assessment, risk mitigation, and regulatory communication. They demonstrate the importance of aligning model design and application with the decision context, establishing confidence through robust model quality and risk assessment, and communicating findings in ways that facilitate constructive dialogue with regulatory authorities. While QSP models today primarily complement traditional decision-making, their mechanistic depth offers unique value, particularly in settings where direct clinical evidence is limited or hard to obtain. When initiated early and integrated thoughtfully, QSP can accelerate development timelines and strengthen confidence in extrapolative decisions. To fully realize this potential, the field must strengthen model credibility, deepen regulatory collaboration, and encourage open publication. A harmonized framework for model quality assessment, supported by clearer guidance and broader dissemination, will be key to expanding QSP’s impact across therapeutic areas and regulatory contexts.