From a pyramid to an amphitheatre (triangle to circle): embracing the totality of evidence for the postmarketing evaluation of the safety of therapeutic interventions.

objectivesTo propose a novel approach to evidence-based medicine (EBM) for medication safety. To critically evaluate the appropriateness of the traditional pyramid hierarchy of evidence for pharmacovigilance. KEY ARGUMENTS: For over three decades, the traditional pyramid hierarchy of evidence has guided the practice of EBM, primarily in evaluating the efficacy of medications. While the traditional pyramid has a place in evaluating evidence for efficacy outcomes, this model is usually inappropriate for the evaluation of safety outcomes of therapeutic interventions in the postmarketing setting. In the context of pharmacovigilance, a rigid hierarchy fails to accommodate the complexity and diversity of data required for evaluation of medication safety.This article critically evaluates the appropriateness of this traditional hierarchy of evidence for decision-making in pharmacovigilance and argues for using a non-hierarchical approach to how evidence is appraised in this context. It explores the expanding role of real-world data (RWD) and real-world evidence, which increasingly contribute to therapeutic decision-making in the postmarketing setting, noting that clinical trials and real-world studies are complementary rather than competitive. To address the limitations of the traditional EBM model in the context of pharmacovigilance, we propose an 'amphitheatre (circular) approach' which embraces the totality of evidence available for the safety of an intervention with no rigid hierarchy and emphasises the integration of diverse data sources to answer research questions and provide healthcare.

conclusionsThe amphitheatre of evidence offers a more flexible, inclusive and pragmatic alternative to the traditional pyramid hierarchy for assessing safety outcomes in pharmacovigilance. By embracing the totality of evidence, this model uses a more holistic approach to support clinical decision-making and protection of public health. While this review is focused on pharmacotherapeutic interventions in the postmarketing setting, the proposed novel approach may be generalised to a broader evaluation of therapeutic and diagnostic interventions.