Explanatory models are needed to integrate RCT and observational data with the patient's unique biology.

In this review, we make the case for evidence-based medicine (EBM) to include models of disease underscored by evidence in order to integrate evidence, as it is currently defined, with the patient's unique biology. This would allow clinicians to use a pathophysiologic rationale, but underscoring the pathophysiological model with evidence would create an objective evidence base for extrapolating randomized controlled trial evidence. EBM encourages practitioners not to be passive receivers of information, but to question the information. By the same token, practitioners should not be passive executors of the process by which information is generated, appraised and applied, but should question the process. We use the historical examples of the evolution of EBM to show that its subordination of a pathophysiological perspective was unintentional, and of essential hypertension to illustrate the importance of disease models and the fact that evidence supporting them comes from many sources. We follow this with an illustration of the benefits a pathophysiological perspective can bring and a suggested model of how inclusion of pathophysiological models in the EBM approach would work. From a practical perspective, information cannot be integrated with the patient's unique biology without knowledge of that biology; this is why EBM is currently so silent on how to carry out its fourth stage. It is also clear that, regardless of whether a philosophical or practical definition of evidence is used, pathophysiology is evidence and should be regarded as such.