AEs that require timely i.e. expedited reporting
Serious adverse events that qualify as “suspected unexpected serious adverse reactions” (SUSAR) are subject to timely (i.e. expedited) reporting to the Clinical Trial Module of the EudraVigilance database (EVCTM), the national competent authorities (CA) of the EU member states where the trial is conducted, the ethics committees (EC) and the investigators. Timing depends on whether the SUSAR is fatal/life-threatening (7 days rule) or not (15 days rule).
Details on the related rulings can be found under EU Clinical Trial Directive Article 17(1)(a), (b) and (d) and EudraLex Volume 10 CT-3 (Chapter 7 – Article 37-42). EudraLex Volume 10 CT-3 Chapter 7 also provides due specification on what is to be reported, when and how.
Note: The need for ‘timely’ reporting to CA, EC, and investigators applies also for a series of non-SUSAR safety findings acc. EudraLex Volume 10 CT-3 Art. 121 and the EU Clinical Trial Regulation Art. 48.
Such non-SUSAR relevant PV-findings subject to ‘timely reporting’ do not match the EVCTM framework and thus cannot be reported to EV. They should be reported to the CA (‘directly’), to the ECs and investigators. (see also EudraLex Volume 10 CT-3 Art. 123).
Role and assignment of the EV RP
The EudraVigilance Responsible Person (EV RP) i.e. the person who represents the sponsor interacting with Eudravigilance (EV) with regard to uploading pertinent safety reportsinto the Clinical Module of the EudraVigilance database (EVCTM). This is a central sponsor-based trial-unrelated authority. Assignment of the EV RP depends on the sponsor’s regulatory status in the EEA as specified in EMA/353007/2016 (EudraVigilance Registration – Questions and answers – Mar.2017) –In brief:
- For a sponsor, who is also a marketing authorisation holder (MAH) or a marketing authorisation applicant (MAA) in the EEA, the EU Qualified Person for Pharmacovigilance (EU QPPV) of the EEA headquarter of the sponsor’s organisation continues to be the organisation’s representative in the EV registration process. No additional registration of a responsible person for EudraVigilance (EV RP) is required.
- For a sponsor (established in the EEA), who is not a MAH or MAA, an organisation’s representative for the EudraVigilance registration process (EV RP) should be appointed. Only one responsible person for EudraVigilance should be appointed by the sponsor for all clinical trials conducted by the sponsor in the EEA; in this event, the EV RP should be appointed by the ‘sponsor named person’ as identified in Section B 1.2 of the EudraCT-application.
- For sponsors not established in the EEA, an organisation’s representative (EV RP) for the EudraVigilance registration process should be appointed. The EV RP does not need to reside in the EEA. Only one EV RP should be appointed for the sponsor for all clinical trials conducted by the sponsor in the EEA; the EV RP should be appointed by the legal representative of the sponsor as identified in Section B 2 of the EudraCT-application).
Whatever its prime assignment (see above), the role of EU QPPV / EV RP can be delegated by the sponsor to a service provider in compliance with Article 6 of the Commission Implementing Regulation (EU) No 520/2012 (“Performance of Pharmacovigilance Activities Provided for in Regulation (EC) No 726/2004 article”), GCP-Directive Section 3 Article 7 Item 1, and EudraLex Volume 10 CT-01 Article 3 §19.
In the EudraCT-application (“Module 1”), the EV RP (whether delegate or not) is named in Section G.5 under item G.5.1.15 (“SUSAR-reporting”). In order to ensure continuity, the authority of the EVRP should be extended by naming a “trusted deputy” within the EVRP’s organisation who is also registered as EV user (as per EMA/288747/2016 – Mar.2017).
The assigned EV RP needs to have completed training to operate in the EVCTM environment and needs to have been registered as user of the reporting system:
- Training: The EV RP is due to have completed certified training to operate in the EVCTM environment (eXtended EudraVigilance Medicinal Product Dictionary [XEVMPD] Data-Entry Tool [EVWEB]) – Note: Training needs to account for the major EV update scheduled for release Nov.2017 (see EMA/835422/2016 – EudraVigilance training plan – v4)
- User registration: The EV RP (and his ‘trusted deputy’) is due to have completed user registration in accordance with EMA/286818/2016, EMA/353007/2016, and EMA/288747/2016.
- Re-assignment: The EV RP assignment is sponsor-specific, but trial- and product-unrelated. Therefore, there might be interest and need to re-assign the EV RP authority once a trial (for which a specific EV RP delegate had been assigned) is completed. This re-assignment is subject to EMA/87465/2016.
Alignment of the EV RP with the CTSO
At ACPS we advocate that two distinct, but complementary functions are named for orderly Pharmacovigilance of Clinical Trials:
- the Clinical Trial Safety Officer (CTSO) who directs the trial-specific quality managements system for pharmacovigilance of the trial as an essential, albeit subordinate aspect of the overall GCP-compliant quality management of the trial. The CTSO acts as primary contact named in the CTP, receives SAE-reports from the investigator, analyses and evaluates the information, organises due follow-up and clarification by the investigator and raises initial and follow-up reports (in compliance with ICH E2A) that are ‘fit for EVCTM-reporting’ (acc. ICHE2B and EMA GVP Module VI) by the EV RP.
- the EudraVigilance Responsible Person (EV RP) i.e. the sponsor-specific trial-unrelated priviliged party for reporting of SUSAR to the EVCTM
The CTSO and EV RP operate conjointly (4-eye principle) to check and validate the ICSR for EVCTM reporting and follow-up thereof. Within this setting, the CTSO and EV RP will need to decide who is responsible to parties other than EVCTM.