Background: Evidence suggesting adverse drug reactions often emerges unsystematically and unpredictably in form of anecdotal reports, case series and survey data. Safety trials and observational studies also provide crucial information regarding the (un-)safety of drugs. Hence, integrating multiple types of pharmacovigilance evidence is key to minimising the risks of harm. Methods: In previous work, we began the development of a Bayesian framework for aggregating multiple types of evidence to assess the probability of a putative causal link between drugs and side effects. This framework arose out of a philosophical analysis of the Bradford Hill Guidelines. In this article, we expand the Bayesian framework and add “evidential modulators,” which bear on the assessment of the reliability of incoming study results. The overall framework for evidence synthesis, “E-Synthesis”, is then applied to a case study. Results: Theoretically and computationally, E-Synthesis exploits coherence of partly or fully independent evidence converging towards the hypothesis of interest (or of conflicting evidence with respect to it), in order to update its posterior probability. With respect to other frameworks for evidence synthesis, our Bayesian model has the unique feature of grounding its inferential machinery on a consolidated theory of hypothesis confirmation (Bayesian epistemology), and in allowing any data from heterogeneous sources (cell-data, clinical trials, epidemiological studies), and methods (e.g., frequentist hypothesis testing, Bayesian adaptive trials, etc.) to be quantitatively integrated into the same inferential framework. Conclusions: E-Synthesis is highly flexible concerning the allowed input, while at the same time relying on a consistent computational system, that is philosophically and statistically grounded. Furthermore, by introducing evidential modulators, and thereby breaking up the different dimensions of evidence (strength, relevance, reliability), E-Synthesis allows them to be explicitly tracked in updating causal hypotheses.

The intuitive Variety of Evidence Thesis states that, ceteris paribus, more varied evidence for a hypothesis confirms it more strongly than less varied evidence. Recent Bayesian analyses have raised serious doubts in its validity. Claveau suggests the existence of a novel type of counter-example to this thesis: a gradual increase in source independence can lead to a decrease in hypothesis confirmation. I show that Claveau’s measure of gradual source independence suffers from two unsuspected types of inconsistencies. I hence put forward a more natural measure of gradual source independence which is not plagued by inconsistencies. Claveau’s counter-examples to the variety of evidence thesis disappear with the measure I suggest. I hence argue that my measure is preferable and that this thesis does at least not seem to be troubled by Claveau’s arguments.

Rationale, aims and objectives: The diversity of types of evidence (eg, case reports, animal studies and observational studies) makes the assessment of a drug's safety profile into a formidable challenge. While frequentist uncertain inference struggles in aggregating these signals, the more flexible Bayesian approaches seem better suited for this quest. Artificial Intelligence (AI) offers great promise to these approaches for information retrieval, decision support, and learning probabilities from data.Methods: E‐Synthesis is a Bayesian framework for drug safety assessments built on philosophical principles and considerations. It aims to aggregate all the available information, in order to provide a Bayesian probability of a drug causing an adverse reaction. AI systems are being developed for evidence aggregation in medicine, which increasingly are automated.Results: We find that AI can help E‐Synthesis with information retrieval, usability (graphical decision‐making aids), learning Bayes factors from historical data, assessing quality of information and determining conditional probabilities for the so‐called ‘indicators’ of causation for E‐Synthesis. Vice versa, E‐Synthesis offers a solid methodological basis for (semi‐)automated evidence aggregation with AI systems.Conclusions: Properly applied, AI can help the transition of philosophical principles and considerations concerning evidence aggregation for drug safety to a tool that can be used in practice.

Real World Evidence (RWE) and its uses are playing a growing role in medical research and inference. Prominently, the 21st Century Cures Act—approved in 2016 by the US Congress—permits the introduction of RWE for the purpose of risk-benefit assessments of medical interventions. However, appraising the quality of RWE and determining its inferential strength are, more often than not, thorny problems, because evidence production methodologies may suffer from multiple imperfections. The problem arises to aggregate multiple appraised imperfections and perform inference with RWE. In this article, we thus develop an evidence appraisal aggregation algorithm called EA³. Our algorithm employs the softmax function—a generalisation of the logistic function to multiple dimensions—which is popular in several fields: statistics, mathematical physics and artificial intelligence. We prove that EA³ has a number of desirable properties for appraising RWE and we show how the aggregated evidence appraisals computed by EA³ can support causal inferences based on RWE within a Bayesian decision making framework. We also discuss features and limitations of our approach and how to overcome some shortcomings. We conclude with a look ahead at the use of RWE.