Assessing the performance of QSP models: biology as the driver for validation

Validation of a quantitative model is a critical step in establishing confidence in the model's suitability for whatever analysis it was designed. While processes for validation are well-established in the statistical sciences, the field of quantitative systems pharmacology (QSP) has taken a more piecemeal approach to defining and demonstrating validation. Although classical statistical methods can be used in a QSP context, proper validation of a mechanistic systems model requires a more nuanced approach to what precisely is being validated, and what role said validation plays in the larger context of the analysis. In this review, we summarize current thoughts of QSP validation in the scientific community, contrast the aims of statistical validation from several contexts (including inference, pharmacometrics analysis, and machine learning) with the challenges faced in QSP analysis, and use examples from published QSP models to define different stages or levels of validation, any of which may be sufficient depending on the context at hand.