Pharmacovigilance

Electronic ADR reporting in E2B standard (EudraVigilance) - Questions and Answers

Electronic ADR reporting in E2B standard - EudraVigilance

Questions and Answers

1. When will the Agency for Medicinal Products and Medical Devices (HALMED) be ready to start receiving Individual Case Safety Reports (ICSRs) electronically (ICH E2B guidelines) using the EudraVigilance system?

The information system of the Agency for Medicinal Products and Medical Devices has been fully operational since March 2010 and Marketing Authorisation Holders (MAHs) and Clinical Trial Authorisation Holders (CTAHs) (Sponsors - SPs) can start the electronic submission of adverse drug reaction (ADR) reports to the HALMED based on the ICH E2B (R2) guidelines using the EudraVigilance system.

The system is used for submitting Individual Case Safety Reports (ICSRs) for all spontaneous ADR reports from the territory of the Republic of Croatia to the Marketing Authorisation Holder irrespectively of seriousness of the report, namely ICSR containing SUSAR from the clinical trial in the Republic of Croatia submitted by the sponsor of the clinical trial. Starting from 1 July 2013 submission of ICSRs will be possible exclusively electronically, and sending ICSRs electronically will be mandatory. From the said date CIOMS forms in paper form will no longer be accepted by HALMED!

Reported ICSRs will be entered in HALMED's local national database of adverse drug reactions. Starting from 1 July 2013 HALMED will send spontaneous ADR reports from the Republic of Croatia in ICSR form to the EudraVigilance database of the European Medicines Agency (EMA) in London using EudraVigilance gateway until the complete establishment of the electronic system of direct submitting adverse reactions to EMA's EudraVigilance database, which should occur in 2015 at the earliest. SUSARs from the clinical trials in the Republic of Croatia will not be transmitted by HALMED onward to the EMA's EudraVigilance database, instead will be analysed only remain for review in the national database of ADR reports, and will serve to inform as well as for informing of the the Central Ethics Committee (CEC).

MAHs and SPs using gateway are urged to start testing the electronic exchange of ADRs with HALMED - ICSR (E2B) as soon as possible, and after such transmission is successfully tested, to switch from paper format to electronic reporting. The software application used by HALMED (EudraVigilance Member State edition, EV MSe) is practically identical to the one used by the European Medicines Agency (EMA), therefore no difficulties regarding the validation of ICSRs and/or E2B interpretations are expected if you have already successfully completed the testing program with the EMA.

Before they start their preparations for electronic exchange, MAHs using EudraVigilance WEB Trader to transmit ICSRs should first contact HALMED for exchange of the Organisation Identifiers (IDs) for sending electronic messages.

MAHs who have been submitting ICSRs electronically will be contacted by HALMED in order to test sending ICSRs from HALMED to MAH (from 1 July 2013 exchange of ICSRs will be conducted completely electronically, without submitting PDF excerpts from the national database of adverse drug reactions to MAHs, contrary to the current practice).

2. Who can submit electronic ADR reports?

Marketing Authorisation Holder (MAH) in the Republic of Croatia and Clinical Trial Authorisation Holder (CTAH) (Sponsor - SP) in the Republic of Croatia.

3. How is E2B system for electronic ADR reporting implemented in HALMED?

HALMED uses the EudraVigilance Member State edition software (EVMSe) developed in collaboration with the EMA for the European Union's EudraVigilance project. This database is used by HALMED for sending and receiving electronic ICSR reports from the MAHs and CTAHs (SPs) in the Republic of Croatia, as well as sending them towards the European Medicines Agency (EMA).

It allows the sending, receiving and processing of messages compliant with the ICH E2B guideline automatically, validating of all incoming messages including integrity and consistency checking and generating automatic acknowledgements (ACKs) based on the outcome of transaction.

The main difference between the EMA's system and HALMED's system is in the modules (of Organisation Identifiers) for acceptance of ADRs related to clinical trials and spontaneous ADR reports. Similar to the EMA's system, it is not possible to mix spontaneous ADR reports with those from the clinical trials in a single message. However, where the EMA's system uses two different Organisation Identifiers (EVHUMAN and EVCTMPROD) to determine which set of business rules will be applied (for spontaneous reports or for clinical trial reports), HALMED uses a single Organisation Identifier (ALMP) for both modules (Clinical Trial - CT) and spontaneous reports (Post Marketing - PM). Depending on the first report (ICSR) in the message, the system determines which set of business rules will be applied to the complete message:

  • If the first report in a message is an adverse reaction in a clinical trial (SUSAR), the entire message will be validated against the SUSAR business rules. If there are any PM reports in this message, they will be rejected and 02 ACKs generated for these PM reports.
  • If the first report in a message is a PM report, the entire message will be validated against the PM business rules. If there are any CT reports in the same message, they will be rejected and the system will generate 02 ACKs for these CT reports.

This is particularly important for the MAHs sending more than one ICSR in a single message.

4. How to start electronic submission of ICSRs to HALMED?

Before testing and electronic transmission of ICSRs to the HALMED, it is necessary to register with the EMA and the EudraVigilance system. Only after MAHs' official acceptance by the EMA, they can proceed with HALMED's testing programme. Once registered, the MAH or the SP will receive two Organisation Identifiers: one for the Testing Environment and the other for the Production Environment.
It should be emphasised that it is not possible to send cases from the Sender's Testing Environment to HALMED's Production Environment.

Following a successful registration with the EMA, the next step is to contact the Responsible Person for EudraVigilance at HALMED, Darko Krnić, M.D., at eudravigilance@halmed.hr with the following information:

  • Organisation Identifiers (ID) of the MAHs and SPs for the Testing and Production Environments, respectively (two different IDs):
  • MAH's or SP's name and address
  • Name and address, phone number, e-mail address of the Responsible Person for EudraVigilance in the Republic of Croatia (affiliate) or of the Responsible Person who is globally responsible for EudraVigilance on behalf of the EU MAH (of the person registered with the EMA)

An ID is necessary for adjustment of the EudraVigilance Gateway via which electronic ICSRs are received by the HALMED.

The ID of the Agency for Medicinal Products and Medical Devices (HALMED) for:

  • Testing Environment is: ALMPT
  • Production Environment is: ALMP

Following successful compliance and entry of the Sender's ID, HALMED will contact the MAH's Responsible Person for EudraVigilance, confirm that the ID was entered and approve the start of the electronic registration process by initiating (if necessary) the test transmission of electronic ICSRs to the Testing Environment.

5. How to test electronic ICSR exchange with HALMED?

When a MAH receives an approval from HALMED to start the testing of electronic transmission of ICSRs, it should send to HALMED's Testing Environment (ID: ALMPT) ICSR testfiles with realistic data, which are not necessarily real cases. Two test reports have to be sent:

  1. Spontaneous report from healthcare worker/patient in the Republic of Croatia
  2. SUSAR from the clinical trial in the Republic of Croatia

The initial test cases should be sent from the MAH's Testing Environment to HALMED's Testing Environment (ALMPT). The CIOMS I forms in pdf format should be sent by e-mail to eudravigilance@halmed.hr. Please use the table to enter the case number which will be used in the reply, after the testfiles are compared with the test CIOMS I reports in pdf format. The table can be found here.

6. How to switch to the regular electronic ADR reporting (production)?

Upon successful completion of the test phase for those using gateway, HALMED will approve electronic transmission of ICSRs to the Production Environment (ID: ALMP) by providing the MAH with an official notification of the date when it can start the regular electronic ADR reporting (via e-mail). The MAH will then notify the actual starting date to the Responsible Person for EudraVigilance at HALMED. It should be highlighted that from 1 July 2013 the electronic ADR reporting will be mandatory. Eudravigilance WEB Trader users proceed directly to the production transmission after they had exchanged the Organisation Identifiers (IDs) with HALMED and had been informed by HALMED they could start submitting reports (see Question 7).

7. How can ICSRs be electronically communicated by legal persons who are MAHs for a fewer number of medicinal products in the Republic of Croatia?

The legal persons who are the MAHs for a fewer number of medicinal products and therefore have a lesser inflow of adverse reactions which is why they have not developed their own database linked to the Agency via the Gateway, may also send their reports electronically, but not as an attachment to an e-mail, but using the safe route, via EudraVigilance WEB Trader.
In order to start using this reporting mechanism, MAHs have to complete EudraVigilance Training Course organised by the EMA and the DIA, obtain a Certificate of Completion and then register with the EMA's EudraVigilance system. After this, EudraVigilance WEB Trader will become available and the MAH can start sending electronic reports by entering the ADR data directly into the application or by loading the data from the MAH's local E2B compatible database.

Before the start of transmission, the MAH should first contact the Responsible Person for EudraVigilance at HALMED, in order to obtain additional instructions because HALMED's address in this moment is still not visible in EudraVigilance WEB Trader application so it needs to be entered manually.

Those MAHs who enter report data directly into the application do not have to go through the test phase described in the answer to Question 5; instead they can proceed directly to the production transmission described in the answer to Question 6.

The MAHs who load their reports from the local database into the application must go through the test phase described in the answer to Question 5.

8. Does the electronic system accept all ADR reports irrespectively of seriousness or expectedness?

Yes, HALMED's EudraVigilance MSe system accepts all ICSRs irrespectively of seriousness or expectedness because all spontaneously reported adverse reactions from the Republic of Croatia have to be reported to HALMED.

9. Which version of the Medical Dictionary for Regulatory Activities (MedDRA) is supported by HALMED's electronic ICSR exchange system?

Production Environment supports the latest MedDRA version and its previous version. For instance: the current version is 16.0, but 15.1 is also supported. In line with the EMA's policy and the MedDRA MSSO recommendations, the new version of MedDRA is implemented in the system within 30 days of the official release of the new edition.

10. Which data need to be entered in fields A.3.2 (A.3.2.1, A.3.2.2 and A.3.2.3.) in the ICSRs sent to the HALMED?

MAHs can use the following data to complete fields A.3.2.; completion of this field is recommended but not mandatory:

Description Values
Receiver Type Regulatory Authority
Receiver Organization ALMP (for production)
ALMPT (for test environment)
Receiver Department Pharmacovigilance
Receiver Title -
First Name Darko
Middle Name -
Last Name Krnic
Street Address Ksaverska cesta 4
City Zagreb
State or Province -
Postal Code 10000
Country HR
Telephone 01 48 84 100
Telephone Extension -
Telephone Country Code 385
Fax 01 48 84 110

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