Box 1.

Glossary of terms

Term	Definition
Adverse eventa	Any untoward (i.e., noxious and unintended) medical occurrence that develops in an individual exposed to a medicinal product. Possible conditions of exposure include appropriate medical use, medication errors, off-label use, overdose, misuse, abuse, and occupational exposure. The medical occurrence does not necessarily have a causal relationship with the exposure
Adverse drug reaction (ADR)a	Any adverse event characterized by an at least reasonable possibility that the medicinal product has caused the event
Causality assessmenta	The process of evaluating and assigning a causal judgment to an observed association between a medicinal product and an adverse event, at the level of either individual ICSRs or case series. Causality assessment can rely on expert judgment/global introspection, structured guidelines and algorithms, or probabilistic approaches [19]
Drug	A drug is usually defined as any chemical substance that causes a change in an organism’s physiology or psychology when consumed. To be consistent with pharmacovigilance terminology (e.g., drug-related problem, adverse drug reaction, drug-event combination) we adopted the use of the term drug, but these guidelines are valid for disproportionality analyses on any medicinal product used in the prevention, diagnosis or cure of diseases (e.g., vaccine, medical device, gene therapy, cell therapy, supplements)
Drug-event combination	The specific combination of medicinal product(s) and event(s) of interest
Individual case safety reports (ICSRs)b	Format and content for the reporting of one or several adverse events that occurred in a single individual at a specific point of time. It accommodates clinical phenotypes involving multiple events that may manifest sequentially over time
Pharmacovigilancea	The science and activities relating to the detection, assessment, understanding, and prevention of ADRs or any other drug-related problem
Case-by-case analysis	Analysis of each ICSR recording the drug-event combination to collect further information that is useful for the causality assessment
Safety signala	Information that arises from one or multiple sources (including observations and experiments) that suggest a new potentially causal association or a new aspect of a known association between medicinal product(s) and adverse event(s). The information is judged to be sufficient to justify verificatory actions
ICSR database	A surveillance database that relies on ICSRs submitted by multiple stakeholders (healthcare providers, consumers, and pharmaceutical companies) because of spontaneous initiative or mandatory reasons)
Signal of disproportionate reporting (SDR)a	A statistical association between medicinal product(s) and event(s) identified by any disproportionality analysis within an ICSR database

CIOMS Council for International Organizations of Medical Sciences, EMA European Medicines Agency

^aDefinitions adapted from the CIOMS cumulative glossary, with a focus on pharmacovigilance (version 2.1)

^bDefinition adapted from the EMA definition of ICSR