Review: Role of Model-Informed Drug Development Approaches in the Lifecycle of Drug Development and Regulatory Decision-Making

Abstract

Model-informed drug development (MIDD) is a powerful approach to support drug development and regulatory review. There is a rich history of MIDD applications at the U.S. Food and Drug Administration (FDA). MIDD applications span across the life cycle of the development of new drugs, generics, and biologic products. In new drug development, MIDD approaches are often applied to inform clinical trial design including dose selection/optimization, aid in the evaluation of critical regulatory review questions such as evidence of effectiveness, and development of policy. In the biopharmaceutics space, we see a trend for increasing role of computational modeling to inform formulation development and help strategize future in vivo studies or lifecycle plans in the post approval setting. As more information and knowledge becomes available pre-approval, quantitative mathematical models are becoming indispensable in supporting generic drug development and approval including complex generic drug products and are expected to help reduce overall time and cost. While the application of MIDD to inform the development of cell and gene therapy products is at an early stage, the potential for future application of MIDD include understanding and quantitative evaluation of information related to biological activity/pharmacodynamics, cell expansion/ persistence, transgene expression, immune response, safety, and efficacy. With exciting innovations on the horizon, broader adoption of MIDD is poised to revolutionize drug development for greater patient and societal benefit. KEY WORDS biopharmaceutics • generic drugs • gene therapy • model-informed drug development • new drugs * Rajanikanth Madabushi

Editorial: Model-informed drug development and evidence-based translational pharmacology

“…The scope of MIDD applications rapidly expanded in the first decade of the 21st century. Since 2013, the FDA has published numerous regulatory guidelines on MIDD, which include characterising safety, guiding trial design, guiding dose selection and assisting effectiveness evaluation ( Madabushi et al, 2022 ). The applications of MIDD are continuously evolving and, in the late 21st century, physiologically based pharmacokinetic (PBPK) modelling and simulations have become prevalent, in addition to classical pharmacometrics applications in modern drug development ( Madabushi et al, 2022 ).…”

“…Modelling techniques that are frequently employed include population pharmacokinetics (popPK) modelling, PBPK modelling and exposure-response modelling ( Marshall et al, 2016 ; Keizer et al, 2018 ; Bi et al, 2019 ; Marshall et al, 2019 ; Darwich et al, 2021 ; Lesko, 2021 ; Madabushi et al, 2022 ). Currently, several stages in the development of new drugs have also made use of emerging modelling techniques, such as QSP modelling and artificial intelligence (AI)/machine learning (ML) ( Madabushi et al, 2022 ). Drug development is complex, and a combination of different modelling approaches must often be utilised to adequately address questions that arise at various stages.…”

“…Model-informed drug development (MIDD) is unarguably the cornerstone of pharmacological research in the 21st century ( Marshall et al, 2016 ; Bi et al, 2019 ; Lesko, 2021 ; Rayner et al, 2021 ; Madabushi et al, 2022 ). It refers to the strategic creation and integration of mathematical models with throughout plan of execution (key questions, assumption, modelling approach and documentation) to facilitate the decision-making process in pharmaceutical research ( Marshall et al, 2016 ; Madabushi et al, 2022 ).…”

“…MIDD is also increasingly used to evaluate causal links between drug physiochemical properties, disease/pathogen biology and patient physiology. This has facilitated an integrated approach for effective trial designs and data-to-knowledge transformation while also helping narrow knowledge gaps and maximise the therapeutic potential of drug candidates ( Wang et al, 2008 ; Lesko, 2021 ; Madabushi et al, 2022 ).…”

“…Model-informed drug development (MIDD) is unarguably the cornerstone of pharmacological research in the 21st century ( Marshall et al, 2016 ; Bi et al, 2019 ; Lesko, 2021 ; Rayner et al, 2021 ; Madabushi et al, 2022 ). It refers to the strategic creation and integration of mathematical models with throughout plan of execution (key questions, assumption, modelling approach and documentation) to facilitate the decision-making process in pharmaceutical research ( Marshall et al, 2016 ; Madabushi et al, 2022 ). The applications of MIDD range from novel target identification, formulation design, non-clinical and clinical development and biopharmaceutical research to trial design and cost-effectiveness evaluations ( Madabushi et al, 2022 ).…”