Identifying sources of potential harm to patients is a top priority for our company. The detection and communication of signals of such harms are at the heart of pharmacovigilance. Safety Signal Identification Signal work aims to identify and describe potential harm to patients caused by the medicines they use. The evidence comes mainly in the form of spontaneous reports from medical professionals around the world, pharmaceutical companies and patients. Signal work is the primary activity of our company. What is a signal? Since its publication, the WHO signal definition has become influential and widely accepted. However, as pharmacovigilance evolves, concepts and definitions continue to evolve. Our global BaseControl database of reported potential drug side effects is regularly reviewed for possible safety signals that requiring further investigation and action to prevent harm to patients. According to the WHO definition, a safety signal refers to information on a new or known side effect that may be caused by a medicine and is typically generated from more than a single report of a suspected side effect. It’s important to note that a signal does not indicate a direct cause-and-effect relationship between a side effect and a medicine, but is essentially only a hypothesis that, together with data and arguments, justifies the need for further assessment. The information in a signal can be new or additional and can be about both the adverse and beneficial effects of an intervention. It can also inform about an already-known association between a medicine and an adverse drug effect, for example: on the range of severity of the effect or its outcome, suggesting a mechanism, indicating an at-risk group, suggesting a dose range which might be riskier, a pharmaceutical group-effect, or a lack of effect caused by a medicine. Since the information reported in a signal is not conclusive it may change substantially over time as more data accumulates. Once a signal has been detected, the relationship between a medicine and the occurrence of a side effect is further evaluated in what is called an assessment of the cause-and-effect relationship. Should a credible association between a side effect and a medicine be determined, we will communicate the evaluation as a signal to the WHO members*. Subsequently, it can be published in information sources (portal). Regulators in individual countries may investigate further and decide if any action is required, such as changing the information for patients, providing a public alert or warning, or withdrawing a drug from the market. Signal detection Thanks to the unique BaseControl database and signal detection in parallel with the development of methods, we are well placed to detect new and important signals. How do we detect signals?? Signal detection aims to identify and describe possible harm to patients as it relates to their use of medicines. Signal detection is the primary activity of the Monitoring Center. We regularly screen the database, WHO’s global database of reported side effects of medicinal products, to look for previously unrecognised or incompletely documented suspected side effects. With millions of adverse event reports in the database, signal detection relies on a combination of computerised data mining methodology and clinical evaluation of reports for the prioritisation of medicine–adverse effect combinations. In parallel, qualitative screening of scientific literature provides additional insight to perform more targeted searches and determine if additional investigation into potential safety signals is needed. Regular monitoring of international regulators’ activities and close collaboration with our external expert group is also used to detect arising safety concerns and helps to avoid repetition of signal work between organisations. Selected medicine-adverse effect combinations are individually assessed by our signal team to identify medicine-adverse effect combinations needing further in-depth assessment. The initial assessment consists of checking whether the adverse effect is already adequately covered in the product information, excluding other more likely causes, and deciding on whether the combination should be further assessed. Clinical evaluation Signals of interest are further evaluated to determine the need for additional data collection, risk mitigation or minimization, or regulatory action. Clinical evaluation An in-depth evaluation of case reports and batches is used to determine whether there is a cause-and-effect relationship between a suspected adverse reaction identified and the medicine. Combinations of drug and side effects, which require in-depth evaluation, are reviewed by the signal team in consultation with external clinical experts in order to assess the severity and public health impact of the suspected side effect and prioritize combinations for in-depth evaluation. Typically, more than one case report is required to identify a safety signal, resulting in the need to evaluate a series of cases describing the same adverse event. The Bradford Hill criteria for causation, developed by Sir Austin Bradford Hill in 1965, are used for evaluati ng cause-and-effect relationship in multiple case reports. It is used to determine whether the strength of the case indicates that the signal should be formulated and transmitted. The system is intended as a practical tool for evaluating case reports, with due account taken for clinical and pharmacological aspects of the clinical history and the quality of monitoring documentation of the disease. Communicating signals Our company regularly communicates its signals to national pharmacovigilance centers around the world or publicly through information sources. Communicating signals Monitoring Centre communicates signals of suspected drug safety problems to national pharmacovigilance centres and subsequently to the wider world via the WHO Pharmaceuticals Newsletter or in scientific journals. Signals communicated to us represent suspected causes of harm, with varying levels of likelihood; they usually need further evaluation or action. Signals are primarily intended to alert and inform national regulatory authorities which are responsible for deciding if further action is required. Such action may include communicating the information to health professionals and the responsible market authorisation holders, changing the information for patients, providing a public alert or warning, or withdrawing a drug from the market. Signals are distributed from us via databases to national centres and regulatory authorities in countries that are members of the WHO. Individual signals are sent to the appropriate pharmaceutical company when they can be identified as explicitly responsible for the medicine concerned.