E2B, Safety databases & Eudravigilance

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Beatrice Parsons
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1 E2B, Safety databases & Eudravigilance Delphine BERTRAM, PharmD Hospices Civils de Lyon France HOT TOPICS IN PV Hod Hasharon 7 May 2014

2 Dr Irene Fermont- ISOP ISRAEL Dganit Even Sapir -MSD

3 Spontaneous adverse drug reaction (ADR or ICSR= Individual Case safety Report) reporting is fundamental in surveillance of medicines. ADRs should be captured in a structured manner with the highest possible quality standards to support accurate detection and analysis of drug safety signals. -> Electronic submission allows harmonized ADR reporting -> One electronic format : xml 3 Electronic submissions of ADR is a cost-effective, efficient and quicker alternative to paper-based reporting

XML (extensible Markup Language) is the adopted standard for the exchange of Safety and Acknowledgement Messages XML is the most common tool for data

4 XML (extensible Markup Language) is the adopted standard for the exchange of Safety and Acknowledgement Messages XML is the most common tool for data transmissions between all sorts of applications. XML was designed to transport and store data. HTML was designed to display data. WORD FORMAT XML FORMAT Save as xml format 4

Because of national and international agreements, rules, and regulations, individual case safety reports of adverse drug reactions and adverse events need to be transmitted from identified reporting

5 Because of national and international agreements, rules, and regulations, individual case safety reports of adverse drug reactions and adverse events need to be transmitted from identified reporting sources to regulatory authorities and pharmaceutical companies; between regulatory authorities; between pharmaceutical companies and regulatory authorities; within authorities or pharmaceutical companies; from clinical investigators, via the sponsor, to ethics committees; from authorities to the World Health Organization (WHO) 5

6 The transmission of individual case safety reports currently relies on paper-based formats (e.g., yellow cards, CIOMS forms, MedWatch, ) or electronic media (e.g. within pharmaceutical companies, or with WHO), usually by on-line access, tape or file transfer. It is essential to have a common understanding and methodology to allow the data to be made immediately available for qualitative signal detection and safety evaluation, as reports are no longer subject to the regulator s internal review or manual intervention. 6 The E2B standard (developed by ICH) ensures that this information is easily transferred and therefore facilitates uniformity and high quality with regard to the content and format of ADRs/ICSRs.

7 7 ICH: International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use

ICH is a joint initiative involving both regulators and industry as equal partners in the scientific and technical discussions of the testing procedures which are required to ensure and assess the

8 ICH is a joint initiative involving both regulators and industry as equal partners in the scientific and technical discussions of the testing procedures which are required to ensure and assess the safety, quality and efficacy of medicines. 3 regions: European Union, Japan and the USA. 6 parties: (regulatory bodies and research-based industries) and 3 Observers and IFPMA. 3 observers: WHO, EFTA, and Canada (Health Canada). 8 IFPMA: International Federation of Pharmaceutical Manufacturers & Associations EFTA: European Free Trade Association

9 The ICH Topics are divided into four major categories and ICH Topic Codes are assigned according to these categories. Q S E M "Quality" Topics, relating to chemical and pharmaceutical Quality Assurance (Stability Testing, Impurity Testing, etc.) "Safety" Topics, relating to in vitro and in vivo preclinical studies (Carcinogenicity Testing, Genotoxicity Testing, etc.) "Efficacy" Topics, relating to clinical studies in human subject (Dose Response Studies, Good Clinical Practices, etc.) "Multidisciplinary" Topics, i.e., crosscutting Topics which do not fit uniquely into one of the above categories (MedDRA, ESTRI, M3, CTD, M5) 9 E2B Guideline + M2 : Electronic Transmission of Individual Case Safety Reports Message Specification

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11 11 NB: E2B is under revision ISO ICSR standard replacing progressively the current version : E2B (R2) by ICH E2B (R3) package (new ISO ICSR standard, the implementation guide (IG) accompanied by several technical appendices).

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15 The data elements are divided into sections : A: Administrative and Identification Information A.1 - Identification of the case safety report A.2 - Primary source(s) of information A.3 - Information on sender and receiver of case safety report B: Information on the Case: B.1 - Patient characteristics B.2 - Reaction(s)/event(s) B.3 - Results of tests and procedures relevant to the investigation of the patient B.4 - Drug(s) information 15 B.5 - Narrative case summary and further information

16 16 A safety database must included all theses fields to be E2B compliant

17 E2B fields E2B in practice : PV database Contains all E2B fields with validation rules To be able to export structured E2B xml ICSR directly imported in another database 17

18 E2B fields 18

19 19 Each E2B field is structured i.e number and type of characters (AN, ISO code etc ) or not for reporting are defined

20 20 Some E2B fields can be constrained by a drop-down list with defined values: i.e qualification of the reporter

21 21 Some E2B fields can have limits i.e Patient weight if not null, should not be > 650 kg. Patient height if not null, should not be > 250 cm

22 22 The adverse reaction must be coded with MedDRA dictionary (LLT term)

23 23 The MedDRA dictionary can be integrated in the database

24 Med = Medical D = Dictionary for R = Regulatory A = Activities 24

25 October 1994 - ICH adopted MEDDRA Version 1.

25 25 October ICH adopted MEDDRA Version 1.0 as basis for international terminology. An ICH M1 Expert Working Group was formed to further develop the terminology.

26 Diseases Diagnoses Signs Symptoms Therapeutic indications Investigation names & qualitative results Medical & surgical procedures Medical, social, family history About terms divided by System Organ Classes Update in March and September of each year

27 27 There are five levels to the MedDRA hierarchy, arranged from very specific to very general. The most specific is called Lowest Level Terms (LLTs)

28 28 Searching tool for finding the ad hoc LLT for coding the adverse reaction.

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30 Once the ISCR/ADR is completed and meets expedited reporting a xml file can be generated by the database xml file of the ISCR 30

31 31 Example of business rules for Safety Message processing and Message Acknowledgment applicable to all stakeholders exchanging ICSRs electronically within the EEA.

32 Examples of E2B validation done by a PV database 32

33 Example in Europe : how to report ISCR/ADR that meets expedited reporting is sent electronically to the European Pharmacovigilance database : Eudravigilance 33

medicinal products for human use Regulation (EC) No 726/2004 with respect to centrally authorised medicinal products and in Directive

34 Directive 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use Regulation (EC) No 726/2004 with respect to centrally authorised medicinal products and in Directive 2001/83/EC with respect to nationally authorised medicinal products (including those authorised through the mutual recognition and decentralised systems). 34

Mandatory save in exceptional circumstances Based on the EudraVigilance system Established and maintained by the EMA Single database for European regulatory authorities EVCT module for SUSARs in

35 Mandatory save in exceptional circumstances Based on the EudraVigilance system Established and maintained by the EMA Single database for European regulatory authorities EVCT module for SUSARs in clinical trials Allows for reporting ADRs to EMA and national authorities From industry to regulators, and between regulators Exchange of reports in ICH E2B/M2 format via central EMA gateway, or enter case reports directly using EVWEB or EV POST 35

36 Sponsor responsabilities Prerequisite Trained and qualified person SOP to ensure the quality of Data collection/ Case documentation SAE evaluation and validation SAE reporting Archiving A validated database that meets E2B requirements 36 SOP: standard operating procedure

Ethics committees Eudravigilance (EMA) ELECTRONIC REPORTING within 7 days in

37 Sponsor responsibilities To report any suspected unexpected serious adverse reaction (SUSAR) taht occurres in a clinical trial to Competent authorities Ethics committees Eudravigilance (EMA) ELECTRONIC REPORTING within 7 days in case of fatal or life-threatening events 15 days for the other seriousness criteria 37

38 Case meets criteria of SUSAR PV Database generates xml file of the case Secured connexion to Eudravigilance to send xml file 3 possibilities: By GATEWAY By EVPOST By EVWEB (xml is imported and can be re-worked) 38

EudraVigilance is the European data-processing network and management system, established at the European Medicines Agency (EMA) to support the electronic exchange, management, and

39 EudraVigilance is the European data-processing network and management system, established at the European Medicines Agency (EMA) to support the electronic exchange, management, and scientific evaluation of Individual Case Safety Reports (ICSRs) related to all medicinal products authorized in the European Economic Area (EEA). 39 Ecrin Summer School - Vienna 2008

40 Registration with EudraVigilance is mandatory for : Marketing Authorisation Holders (MAHs), National Competent Authorities (NCAs) and Sponsors to report electronically: Suspected Unexpected Serious Adverse Reactions (SUSARs) Individual Case safety Reports One Qualified Person Responsible for Pharmacovigilance / Responsible Person for EudraVigilance has to be appointed by MAH/NCA/Sponsor -> one day training with a knowledge evaluation (exam must be passed 40 to register)

41 Example of registrants Example of EV profile (can be updated anytime) 41

42 The Transmission Mode of ICSR reporting has to be selected, Gateway and EVPOST require test phase with Eudravigilance EVWEB EVPOST GATEWAY - 42

43 The test phase with Eudravigilance:10 realistic cases need to be sent Test phase can be also mandatory to send SUSAR to Concerned NCAs via Eudravigilance 43 EUDRAVIGILANCE TELEMATICS IMPLEMENTATION GROUP - Ref: EMEA/115735/2004

44 44 ICSR reporting by EVPOST : Xml attached and sent (E2B validation has to be done before)

45 45 Secure direct access to Eudravigilance Database

46 4 minimum criteria for initial expedited reporting of SUSARs 46 Eudravigilance Database

47 xml file of the case has been imported via Web Trader One reporter 47

48 48 One patient

49 coded by MedDRA Dictionary (LLT) One reaction (at least) 49

50 50 One investigational medicinal product (at least)

51 One investigational medicinal product (at least) coded by the Eudravigilance Medicinal Product Dictionary (EVMPD) 51

52 52 A summary of the case

53 53 Electronic reporting of SUSAR to Competent Authorities

54 54 E2B Validation has to be done before sending

55 Electronic reporting of SUSAR to Competent Authorities Electronic reporting of SUSAR to EVCTM Eudravigilance Clinical Trial Module 55

56 ACK message : Report ack must be 01 56

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58 Mandatory save in exceptional circumstances Based on the EudraVigilance system Established and maintained by the EMA Single database for European regulatory authorities EVPM module for ISCRs from all other sources Allows for reporting ADRs to EMA and national authorities From industry to regulators, and between regulators Exchange of reports in ICH E2B/M2 format via central EMA gateway, or enter case reports directly using EVWEB or EV POST 58

59 59 The Suspected Unexpected Serious Adverse Reaction is sent electronically to European Safety database

60 Centralisation of ISCRs to Eudravigilance -> transmission to concerned NCAs Re-routing of ICSRs to the Member State where the adverse reaction occurred WITHIN 15 DAYS

61 Main issue: lack of harmonization in medicinal product information and medicinal product terminology E2B (R2) structure E2B (R3) structure 61 Conversion rules between E2B(R2) and E2B(R3)

62 Main issue for revision : lack of harmonization in medicinal product information and medicinal product terminology IDMP standards The E2B revision has taken into account the regional healthcare standards: Health Level 7 for the US and ISO for EU New standard developed and ISCR is now supported by IDMP standards (unambiguous identification of products across ICH regions will lead to better drug safety) To come epsur and ermp 62

63 63 IDMP

64 64 Mapping rules between E2B versions

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68 Electronic reporting standardised and structured safety data (signal detection) Electronic reporting required a E2B compliant pharmacovigilance database Only valid ICSRs should be reported (reporter/patient/drug/reaction)

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Pharmacovigilance information for pharmaceutical companies

Pharmacovigilance information for pharmaceutical companies Electronic transmission of individual case safety reports (ICSRs) with ANSM (French National Agency for the safety of Medicines and Health Products)