LAUSR

The goal of pharmacovigilance is to ensure that therapies are safe to use. The Hippocratic principle of do no harm (primum non nocere) forms the very foundation of pharmacovigilance. Pharmacovigilance systems are processes designed to identify potential adverse drug reactions (ADRs) in a timely manner, to evaluate causality and to translate this information into risk mitigation strategies. They span the complete life cycle of a therapy beginning from preclinical studies to real-world use. These processes include scrupulous risk assessments and constant surveillance by all stake holders and require significant support and funding to achieve the shared goal of safety. Despite efforts to date, ADRs continue to lead to significant burden on health services. A recently reported retrospective study utilizing VigiBase, the World Health Organization's (WHO) pharmacovigilance database, found that 23 million ADRs were recorded in the last decade, among which 1.34% were fatal. By 2010, 134 countries had joined the WHO pharmacovigilance programme. It was not until the 1960s thalidomide disaster that the formal system of modern pharmacovigilance took shape in the form of the WHO Programme for International Drug Monitoring. By the 1990s, the inception of the International Council for Harmonization, an organization created by the joint efforts of regulatory authorities (RA) and pharmaceuticals, came together with a mission to align pharmaceutical regulatory requirements globally. History is testimony to numerous drug withdrawals based on spontaneous reporting of ADRs, and >75 drugs were withdrawn by 2003, including phenformin, terfenadine, astemizole, troglitazone and cisapride. Overall, drugs are withdrawn due to organ or system toxicities such as hepatotoxicity, cardiotoxicity (mainly QT prolongation) and myelotoxicity. However, until a decade ago, there was very little progress in the technical processes of pharmacovigilance; a number of flaws exist in the process of spontaneous reporting including: under-reporting of ADRs by physicians and patient groups, issues germane to clinical trials methodology, including inadequate techniques for evaluation of safety signals, limited critical thinking, little or no audit trail, poor quality of reports, and underuse of technology and data mining applications. Additionally, specific considerations and guidelines to gather safety data in certain populations such as the elderly, children, pregnant women and socio-economically disadvantaged groups may be needed as these groups generally tend to be poorly represented in clinical trials. Fortunately, the landscape of pharmacovigilance regulation is changing, and more countries are now harmonizing their efforts towards having a centralized system of surveillance of therapy-related harms. One such example is the white paper published in a recent themed issue, providing practical considerations for paediatric pharmacovigilance, throughout the life cycle of medicinal products. Clinical trials are designed to frame the benefit vs. risk of harm for a therapy in a well-defined setting, typically for a relatively brief period of time and in well-defined, small sample of the population with robust monitoring. Thus, there is a compelling need for postmarketing (Phase 4) surveillance studies to assess the efficacy and safety of newly marketed compounds in the real world. Phase 4 studies can evaluate the effectiveness of therapies in the original indications, but importantly, they offer opportunities for identifying long-term and/or rare serious or non-serious ADRs. In addition, 2020 saw emergency use authorization and rapid approvals of new therapies and vaccines for the global pandemic of COVID-19, caused by the novel coronavirus SARS-CoV-2, based on new therapeutic platforms such as mRNA, which brought global pharmacovigilance activities into focus. Rapid detection of signals and transparency on safety monitoring in the real-world setting saw growth collaboration among key stakeholders while the communication resulting from these activities acted as a medium for educating the authorities in order to address the disparities between various countries, and healthcare professionals (HCPs) especially where the pharmacovigilance systems were weaker and failed to fulfil the International Council for Harmonization guidelines. The unprecedented and rapid growth of next-generation therapeutics such as RNA-based therapies may need further increased, longer and novel methods of surveillance, which in turn may lead to emergence of novel risk management plans. The therapeutic revolution in biological, genetic and cellular therapies will present many challenges but also many opportunities. Outside the context of clinical trials, HCPs, such as physicians, nurses and pharmacists, and patients can typically engage in spontaneous reporting of suspected ADRs using local pharmacovigilance monitoring systems such as the Yellow Card system in the UK (https://yellowcard.mhra.gov.uk/information). In the UK, > 1/3 of the reports come directly from patients, and the value of patient engagement is undeniable as, ultimately, the patient remains at the centre of the exercise of pharmacovigilance. Overall, several reports are unchanged, and this probably means that the reports from HCP are now reduced. This may partly be the result of robust labelling regulation from RA. HCPs are probably motivated to report novel potential ADRs, ADRs related to newly marketed drugs or severe ADRs. There are significant advantages and disadvantages to spontaneous reporting alone as a primary source of ADR reporting and contribution towards a signal in real-world setting. The Internet and social media as DOI: 10.1111/bcp.15584