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.

Keywords: biopharmaceutics; gene therapy; generic drugs; model-informed drug development; new drugs.

Fig. 1

Evolution of MIDD at the FDA. A brief summary of key highlights for every decade with future aspirations are provided. Abbreviations: ICIVC – in vitro-in vivo correlation; PK/PD – pharmacokinetics/pharmacodynamics; popPK – population pharmacokinetics; D/R – dose-response; E/R – exposure-response; CTS – clinical trial simulations; EOP2A – end of phase 2A; PBPK – physiologically based pharmacokinetics; DDI – drug-drug interactions; DDT – drug development tools; MIDD – model-informed drug development; QCP – quantitative clinical pharmacology; PBBM – physiologically based biopharmaceutics models; RWD/RWE – real world data/real world evidence; RTRT – real time release test; MIE – model-integrated evidence; PDUFA - Prescription Drug User Fee Act.

Fig. 2

Relationship between clinical trials and relevant in vitro tests illustrating the concept of nested surrogacy. Abbreviations: S&E – safety and efficacy; PK – pharmacokinetics; PK/PD – pharmacokinetics/pharmacodynamics.

Fig. 3

Commonly used MIDD toolsets in generic drug development. Abbreviations: BE – bioequivalence; PK – pharmacokinetics; PBPK – physiologically based pharmacokinetics; ANDA – abbreviated new drug application.