Enhanced Paediatric Pharmacovigilance at the European Medicines Agency: A Novel Query Applied to Adverse Drug Reaction Reports.

BACKGROUND: Databases of suspected adverse drug reactions (ADRs) are a cornerstone of pharmacovigilance. With increasing numbers of reports, additional statistical approaches are needed to better use the data. AIM: The present study was aimed at elucidating the European Medicines Agency's (EMA) use of a novel 'paediatric' query to analyse the data in its ADR database 'EudraVigilance'. METHODS: The proportional reporting ratio (PRR) is a measure of disproportionality for which the underlying principle is that a drug-event pair of interest is reported more often than expected relative to an independence model. The EMA's paediatric query, based on PRRs, was applied to the data in EudraVigilance to investigate the extent to which the known association between enalapril and renal toxicity was reflected in reported ADRs comparing children with adults and with adjustment for the effect of multiplicity. RESULTS: The comparison of PRRs for children (14.91, 95% confidence interval [CI] 13.05-17.04) versus adults (2.66, 95% CI 2.52-2.82) confirmed a higher risk of renal ADRs with enalapril when used in children compared with all other medicines and compared with adults. CONCLUSIONS: The EMA's paediatric query can be used to highlight an imbalance for a drug-event pair among ADRs for a medicine when used in children and as compared with adults. Applying the query in practice can help the EMA to decide on whether stand-alone paediatric medicine development is warranted, and which, if any, further studies are necessary. Ongoing evaluation of the query is contributing to the development of new methods and guidance.

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.

Increasing scientific standards, independence and transparency in post-authorisation studies: the role of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance.

PURPOSE: The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), an initiative coordinated by the European Medicines Agency, aims to build capacity for and increase trust in post-authorisation studies to further support medicine decision making. METHODS: ENCePP seeks to promote and support high standards throughout the post-authorisation research process based on robust methodologies, transparency and scientific independence. RESULTS: ENCePP provides a point of access to researchers for industry, academia and regulatory authorities seeking collaboration for the conduct of post-authorisation studies. As of 30 November 2011, the network consisted of 98 research centres, 13 networks and 18 data sources, mostly academic and publicly funded institutions but also data source providers and contract research organisations with expertise in the conduct of post-authorisation studies. All are listed in the free, public and fully searchable electronic Database of Research Resources. A guide and a checklist on methodological standards have been published; the concept of an 'ENCePP study', including a Code of Conduct, introduced; and an electronic register of studies have been launched. CONCLUSION: It is envisaged that application of the ENCePP study concept will result in an increase in trust in post-authorisation studies of medicines. The register of studies will allow for ready access to study protocols and results, thereby enhancing transparency and facilitating review. Through the network, standards, transparency and clarity of relationships, ENCePP is expected to add to the European Union capacity to conduct robust post-authorisation studies, thereby benefiting public health. Copyright © 2012 John Wiley & Sons, Ltd.

European Medicines Agency review of post-authorisation studies with implications for the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance.

PURPOSE: A review of post-authorisation studies requested in 2007 by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) was undertaken to determine compliance and the need for research capacity in the European Union (EU), with implications for the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). METHODS: Information from the EMA's electronic records management systems was analysed. RESULTS: As of 31 January 2010, of the 60 relevant studies identified, 52 had been progressed to being able to start data collection (including six merged into a single study). Of the remaining eight studies, the agreement of the CHMP that a proposed study was no longer required is documented for six, with a final decision having not been reached for another study and an acknowledgement by the CHMP that a further study would not be progressed. Of the 47 studies that could therefore have commenced data collection or extraction, 38 were ongoing, four were complete and five had not yet started. Most studies were conducted within the EU. CONCLUSION: Compliance with the request of the CHMP to conduct studies is very good. The review identified the need for careful consideration of the necessity of studies and of timely dialogue on protocols in advance of a CHMP opinion. The need for expertise and capacity within the EU for the conduct of post-authorisation studies is confirmed. ENCePP as a transparency and excellence network and as an initiative to build research capacity will enhance post-authorisation medicines research.

Breastfeeding and overweight: longitudinal analysis in an Australian birth cohort.

OBJECTIVE: To examine adiposity in relation to breastfeeding using longitudinal analysis in an Australian birth cohort. STUDY DESIGN: Repeated surveys from 16 weeks gestation to 8 years in a cohort (N = 2087) recruited through antenatal clinics. Overweight was defined by National Center for Health Statistics 95th percentiles for weight-for-length at 1 year and body mass index (BMI) at 3, 6, and 8 years. Overweight was examined using Generalized Estimating Equations with results summarized as OR. BMI Z scores were analyzed in mixed models. RESULTS: At 1 year, infants breastfed >12 months were the leanest group (mean Z score -0.16, 95% CL -0.28, -0.04; not breastfed 0.16, 95% CL 0.02, 0.29; breastfed < or = 4 months 0.31, 95% CL 0.22, 0.40; 5-8 months 0.17, 95% CL 0.06, 0.27; 9-12 months 0.11, 95% CL 0.01, 0.22). From 1 to 8 years, children breastfed < or = 4 months had the greatest risk of overweight (OR 1.29, 95% CL 0.89, 1.97) and the highest prevalence of maternal obesity, smoking, and lower education. CONCLUSIONS: Infants breastfed >12 months were leaner at 1 year but not at 8 years. Breastfeeding < or = 4 months was associated with greatest risk of overweight and adverse maternal lifestyle. Familial factors may modify associations between breastfeeding and adiposity beyond infancy.

Indicators of fetal growth do not independently predict blood pressure in 8-year-old Australians: a prospective cohort study.

Inverse associations between size at birth and blood pressure (BP) in later life are commonly statistically significant only after adjustment for current size, consistent with change in size as the determinant. Few studies have been prospective or have included a range of potential confounders. Using regression models, including maternal and demographic variables, we examined associations between size at birth and BP in Australian children followed from week 16 of gestation to the age of 8 years. BP measurements were available from 1417 children born after 37 weeks gestation without congenital abnormalities. In models adjusted only for sex, the birthweight (BW), birth length, ponderal index, head circumference, chest circumference, abdominal girth, mid-arm circumference, triceps skinfold, placental weight, or BW/placental weight ratio did not significantly predict SBP in 8-year-olds. With adjustment for current size, associations were inverse but not statistically significant (regression coefficients: BW, -1.11; 95% confidence limits [CL], -2.22, 0.01; birth length, -0.25; 95% CL, -0.52, 0.24) and remained nonsignificant after adjustment for confounders. Current weight, height, or body mass index significantly predicted SBP and DBP (P<0.001) with differences of 8/4 mm Hg between upper and lower quartiles; effects were similar in infants with lower and higher BW. These findings are consistent with postnatal change in size as the major determinant of BP in 8-year-olds and are important in the context of the worldwide "epidemic" of obesity in childhood as a likely precursor of increasing rates of hypertension in adults.