An Open-Source Framework for Virtual Bioequivalence Modeling and Clinical Trial Design

This publication presents an open-source framework for virtual bioequivalence (vBE) to inform clinical trial design.

The tutorial introduces the vBE Toolbox R package, a key component within the Open Systems Pharmacology framework. This toolbox is specifically designed to streamline and standardize computational vBE workflows, with a primary function of training pharmacokinetic models. It achieves this through the integration of in vitro and in vivo data, the inference of inter-individual variability from clinical data, and the establishment of in vitro-to-in vivo extrapolations. The use of the vBE tool is illustrated through two case studies that highlight essential considerations for model development, training, and extrapolation toward vBE assessment applications.

The vBE assessment between a reference and a test product is a computational evaluation that plays a crucial role in addressing feasibility challenges. It assesses the probability of bioequivalence (BE) between the two products given a particular study design. vBE assessments can be used to replace or decrease the number of sampling times or study subjects of an in vivo BE study in cases where completing in vivo BE studies would be challenging due to data sparsity, as in the case of rare diseases and specific populations, where it may be difficult or unethical to recruit subjects. In cases of drugs with long half-lives, a virtual BE assessment may enable shorter in vivo BE studies, which helps reduce the risks of increased dropout rates and the ethical concerns associated with extended washout periods. In such cases, a vBE assessment can support regulatory decision-making throughout the life cycle of a drug product.