Vaccine safety signals from the Uppsala Monitoring Centre database

As requested by GACVS in June 2015, the Secretariat presented 3 recent vaccine safety signals documented by the Uppsala Monitoring Centre (UMC) in April and July 2015. These signals were associated with HPV vaccines and gastrointestinal motility disorders, rabies vaccines and erythema multiforme, and bullous pemphigoid in infancy after vaccination. Based on this experience, the GACVS discussed a process for the review of vaccine safety signals transmitted by UMC and criteria for further action by the Committee.

The UMC has developed a worldwide database of spontaneous individual case safety reports (ICSR) concerning health products, named VigiBase, under the WHO Programme for International Drug Monitoring. Within VigiBase, UMC applies a Bayesian algorithm on the subset of vaccine ICSRs in order to identify disproportions in reporting of pairs of vaccines and health outcomes coded with medical terms using WHO-ART and MedDRA as an alternative as the initial step in its process for signal detection. The process includes the use of vigiMatch, a tool to identify duplicate records, and vigiRank, a tool that incorporates disproportionate reporting as one component, but additionally considers several aspects related to the quality and the content of ICSRs. Cases of signals detected by a screening algorithm are reviewed clinically by a group of experts in pharmacovigilance before their communication to the WHO Programme for the International Drug Monitoring.

Currently, the majority of ICSRs involving vaccines are contributed by the USA and individual European countries. The processes for routine signal detection applied by the US Food and Drug Administration (FDA) in the Vaccine Adverse Events Reporting System (VAERS) data and by the European Medicines Agency (EMA) in Eudravigilance were presented. These processes not only use data from spontaneous reports, but also pre-licensure safety information, the medical literature and other sources to detect signals which are considered hypotheses to be verified and further evaluated.

In a presentation on statistical methods for signal detection, the usefulness of the UMC database and of the UMC processes for the detection of vaccine safety signals was emphasized. The limitations of the use of disproportionality analyses on their own to detect signals from large databases were highlighted, and it was suggested that statistical methods will rarely provide strong evidence of causality but are justified for signal detection that may require additional evaluation. It was noted that adverse events following immunization represent about 8.5% of all reports present in VigiBase.

The GACVS concluded that signals documented by the UMC provide useful information in monitoring the safety of vaccines from worldwide sources. It was proposed that a strengthened process of collaboration with UMC would allow use of the expertise on vaccine safety available within the GACVS and partner agencies for the review of this information before it is communicated to the network of pharmacovigilance centres and to vaccine manufacturers. This review should take into account the limitations of signal detection methods along with the reviews performed routinely by the FDA and EMA, given their extensive experience and access to more complete information with the ICSRs they receive and that may not all be shared with UMC. The GACVS Secretariat will liaise with UMC to identify mechanisms for such collaboration.

Full report of GACVS meeting of 2-3 December 2015, published in the WHO Weekly Epidemiological Record of 22 January 2016