VI.Add I.1. Introduction

Duplicate case reports of suspected adverse reactions can pose significant problems for analysing signals arising from pharmacovigilance databases, both artificially inflating and masking signals of disproportionate reporting (see GVP Module IX Addendum I). The applicable reporting rules cannot avoid duplicate reporting. Databases should therefore be routinely screened to detect and eliminate duplicate cases and the European Medicines Agency (the ‘Agency’), competent authorities in Member States and marketing authorisation holders shall all collaborate in the detection and elimination of duplicates in the EudraVigilance database [Articles 107(5) & 107a(3) of Directive 2001/83]. The guidance in this document proposes methods for detecting, confirming and managing duplicate cases suitable for organisations receiving pharmacovigilance data in various different formats and describes methods for stakeholders to collaborate with the Agency in the detection and management of duplicate cases. This guidance is part of the good pharmacovigilance practices (GVP) and an Addendum to GVP Module VI – Management and reporting of adverse reactions to medicinal products.

Guidance is also provided for situations where individual cases might be reported by different senders e.g. where a marketing authorisation holder is aware that a healthcare professional or a patient has reported an adverse reaction to one of the medicinal products, for which they hold a marketing authorisation, to the competent authority of a Member State. GVP Module VI states that when one party is made aware that the primary source(s) may also have reported the suspected adverse reaction to another concerned party, the report should still be considered as a valid individual case safety report (ICSR). All the relevant information necessary for the detection of the duplicate case should be included in the ICSR.

A duplicate refers to the same individual case reported by a primary source to describe suspected adverse reaction(s) related to the administration of one or more medicinal products to an individual patient at a particular point of time. This individual case may be reported by different senders, through different routes, whereby the case information may be handled differently by the processor of the case, which makes it difficult to identify the reported cases as duplicates. Case handling refers e.g. to coding practices, obtaining follow-up information and processing of personal data in line with EU Data Protection legislation1,2 .

Detection and handling of duplicates by competent authorities and marketing authorisation holders form an important element of good case management and the collaboration of marketing authorisation holders and competent authorities in Member States with the Agency in the detection of duplicates in EudraVigilance (EV) is mandated by Directive 2001/83/EC3,4 . The presence of duplicates in any pharmacovigilance database can create misleading signals and therefore impact on the safety monitoring and potential regulatory actions. How duplicates can impact on the identification of potential new safety issues can be illustrated by an example of duplication in the US FDA Adverse Events Reporting System (AERS) database. In an evaluation of quinine-induced thrombocytopenia, researchers identified 20% of 141 reports as duplicates.5 Norèn et al.6 highlighted that since commonly used data-mining procedures may highlight associations with as few as three reports, one or two duplicates may severely affect their utility.

The simplified reporting rules will come into effect on 22 November 2017, and this is expected to significantly reduce the number of duplicate cases, although they can never be completely excluded.

As an initial step in 2006 to investigate which procedures exist for handling potential duplicates, the EudraVigilance Expert Working Group (EV EWG) collected some information on the various aspects of duplicate detection and management through a questionnaire to Member States, marketing authorisation holders as well as clinical trial sponsors. Based on the feedback received, the EV EWG prepared the Guideline on Duplicate Detection and Management of Individual Cases and Individual Case Safety Reports (ICSRs), which was published in 2011 and has provided competent authorities in Member States, marketing authorisation holders, sponsors and any other organisations involved in case handling and processing (e.g. third party service providers) with clear directions on the management of duplicates. The aforementioned guideline is now replaced by this GVP Module VI Addendum I, which updates the original guideline to take account of the simplified reporting rules and the changes to the responsibilities of competent authorities in Member States, marketing authorisation holders and sponsors.

The objective of this new guidance is to promote accurate detection and handling of duplicate cases, with the ultimate aim of achieving a duplicate-free database. Organisations need to implement duplicate management strategies that are most suitable for their individual situation, while taking into account that the electronic exchange of ICSRs in ICH-E2B(R2) and E2B(R3) formats7 may require specific actions to be taken upon detection of duplicates.

There are various ways in which individual case information and the related ICSRs can be recorded. In most circumstances, the method will depend on the complexity of the organisation’s database and the amount of data received. Therefore, it should be acknowledged that this document is not able to address every situation and that alternative approaches might exist. However, the key principles and processes as outlined in this guidance should be adhered to.