Comparison between paediatric and adult suspected adverse drug reactions reported to the European medicines agency: implications for pharmacovigilance.

BACKGROUND: Databases systematically collecting reports of suspected adverse drug reactions (ADRs) are a cornerstone of pharmacovigilance in that they provide on-going large-scale surveillance in the 'real-world' setting. Several studies have provided data on ADRs in children reported to national databases. EudraVigilance (EV) is the European Medicines Agency's (EMA) web-based system for reporting and evaluating suspected ADRs. Due to requirements on pharmaceutical companies to report ADRs that originate both inside and outside Europe, the data in EudraVigilance are global in nature. As such, it is potentially a rich source of information for paediatric pharmacovigilance. AIM: The present study sought to provide a descriptive overview comparing ADRs involving children and adolescents aged less than 18 years with those involving adults reported to EudraVigilance across national boundaries. The results will serve as a baseline to explore whether lessons can be learned for paediatric pharmacovigilance. METHODS: All ADR reports received in EudraVigilance up to 13 June 2013 were analysed for overall numbers, age, gender, and geographic origin. Accurate age was determined when reported in valid format or calculated from the interval between date of birth and the reaction start date. The nature of the ADRs and the most frequently reported drug substances and drug event combinations were evaluated using Medical Dictionary for Regulatory Activities (MedDRA) 'preferred terms' (PTs) and 'system organ classes' (SOCs). The distribution over time of reported paediatric ADRs was also analysed. RESULTS: As of 13 June 2013, EudraVigilance contained 3,291,593 spontaneous reports, for 75.9 % of which accurate age was determined; 11.2 % of these were paediatric reports. Paediatric ADRs were more common than those in adults under the MedDRA SOCs 'general and administration site', 'nervous system', 'skin and subcutaneous' and 'infections and infestations'. For children, the three most frequently reported MedDRA PTs, i.e. pyrexia, vomiting and convulsion (13, 6 and 4 % of reports, respectively), accounted for a greater proportion of reports than the corresponding top three in adults, i.e. nausea, dyspnoea and pyrexia (4, 4 and 3 % of reports, respectively). The 20 most reported active substances (12 of which are vaccines) together accounted for 52 % of paediatric reports as compared with 28 % of adult reports. CONCLUSIONS: The present study applied a first-time approach to one of the largest databases worldwide of reported ADRs. It confirmed that reports of reactions in children were different to those in adults, not only in terms of reactions and drugs involved but also more concentrated around limited sets of reaction types and drugs. The possible causal association between a medicine or vaccine and the suspected ADR was not formally assessed in this study since the study analysed the characteristics of reported ADRs that were suspected and therefore not proven. However, the findings may help to identify pharmacovigilance activities that should be strengthened to reduce the burden of ADRs in children.

CIOMS and ICH initiatives in pharmacovigilance and risk management: overview and implications.

In this article we review the current initiatives by the Council for International Organizations of Medical Sciences (CIOMS) and the International Conference on Harmonisation (ICH) on pharmacovigilance planning that are due for general release during 2004. These initiatives could form the basis for applying concepts of risk management to medicines throughout their life cycle, from preclinical and clinical development to marketed use. The CIOMS VI Working Group (with 28 senior scientists worldwide from drug regulatory authorities and pharmaceutical companies) is currently developing scientific guidance that relates to clinical trials for medicines during development. It recommends a developmental pharmacovigilance concept - a 'living' concept that would start early in drug development supporting the science and ethics of research leading up to licensing (marketing authorisation) and continuing to post-authorisation (postmarketing) pharmacovigilance. This approach is seen as complementary to current ICH initiatives called 'Pharmacovigilance Planning'. ICH will introduce two concepts in pharmacovigilance management of medicinal products: the 'Pharmacovigilance Specification' and the 'Pharmacovigilance Plan'. The 'Pharmacovigilance Specification' will summarise important knowns and unknowns about the medicine. It will include safety risks identified at the licensing stage, potential risks and any key missing information. These elements will be essential to the formulation of pharmacovigilance plans. Dialogue and common understanding between regulators and the pharmaceutical industry will be a key factor for developing pharmacovigilance plans during the life cycle of medicines. Appropriate interaction with health professionals and patients should also be planned for the future as regulatory systems become more transparent. Where no significant issues are apparent at the licensing (marketing authorisation) stage, routine pharmacovigilance practices will be followed during the marketing phase. Where issues do exist or the data are limited, further study, including epidemiological approaches can be planned. All types of medicines (new drugs, biological agents, orphan drugs) may be involved in these concepts, as would major extensions to existing medicines. Currently ongoing CIOMS and ICH initiatives are in line with emerging risk-management strategies in the US, the European Union and Japan aimed at early and proactive pharmacovigilance.