Consideration of a Credibility Assessment Framework in Model-Informed Drug Development: Potential Application to Physiologically-Based Pharmacokinetic Modeling and Simulation

Abstract

The use of computational models in drug development has grown during the past decade. These model-informed drug development (MIDD) approaches can inform a variety of drug development and regulatory decisions. When used for regulatory decision making, it is important to establish that the model is credible for its intended use. Currently, there is no consensus on how to establish and assess model credibility, including the selection of appropriate verification and validation activities. In this article, we apply a risk-informed credibility assessment framework to physiologically-based pharmacokinetic modeling and simulation and hypothesize this evidentiary framework may also be useful for evaluating other MIDD approaches. We seek to stimulate a scientific discussion around this framework as a potential starting point for uniform assessment of model credibility across MIDD. Ultimately, an overarching framework may help to standardize regulatory evaluation across therapeutic products (i.e., drugs and medical devices).

Figure 1

Overview of the ASME V&V 40 risk‐informed credibility assessment framework. Modified from ASME V&V 40‐2018, by permission of the ASME.13 All rights reserved. ASME, American Society of Mechanical Engineers; COU, context of use; V&V, verification and validation.

Figure 2

Model risk matrix for the hypothetical physiologically‐based pharmacokinetic model. Model risk moves from low (levels 1–2) then medium (level 3) to high (levels 4–5) as model influence or decision consequence increases. The ratings for model influence and decision consequence are determined independently.