E2B, Safety databases &

Eudravigilance

Delphine BERTRAM, PharmD

Hospices Civils de Lyon

France

HOT TOPICS IN PV

Hod Hasharon

7 May 2014

Dr Irene Fermont- ISOP ISRAEL

Dganit Even Sapir -MSD

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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

Electronic submissions of ADR is a cost-effective, efficient

and quicker alternative to paper-based reporting

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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

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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)

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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.

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.

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ICH: International Conference on Harmonisation of

Technical Requirements for the Registration of

Pharmaceuticals for Human Use

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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).

IFPMA: International Federation of Pharmaceutical Manufacturers & Associations

EFTA: European Free Trade Association

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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 pre-

clinical 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., cross-

cutting Topics

which do not fit

uniquely into one of

the above

categories

(MedDRA, ESTRI,

M3, CTD, M5)

The ICH Topics are divided into four major categories and ICH Topic Codes

are assigned according to these categories.

E2B Guideline + M2 : Electronic Transmission

of Individual Case Safety Reports Message

Specification

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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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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

B.5 - Narrative case summary and further information

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A safety database

must included all

theses fields to

be E2B compliant

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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

E2B fields

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E2B fields

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Each E2B field is structured i.e

number and type of characters (AN ,

ISO code etc…) or not for reporting

are defined

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Some E2B fields can be

constrained by a drop-down

list with defined values: i.e

qualification of the reporter

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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

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The adverse reaction must be

coded with MedDRA dictionary

(LLT term)

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The MedDRA dictionary can be

integrated in the database

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Med = Medical

D = Dictionary for

R = Regulatory

A = Activities

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October 1994 - ICH adopted MEDDRA Version 1.0 as basis for

international terminology. An ICH M1 Expert Working Group was formed

to further develop the terminology.

Diseases

Diagnoses

Signs

Symptoms

Therapeutic indications

Investigation names & qualitative results

Medical & surgical procedures

Medical, social, family history

About 70 000 terms divided by System Organ Classes

Update in March and September of each year

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There are five levels to the

MedDRA hierarchy, arranged from

very specific to very general. The

most specific is called “Lowest

Level Terms” (LLTs)

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Searching tool for finding the ad

hoc LLT for coding the adverse

reaction.

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Once the ISCR/ADR is completed

and meets expedited reporting a

xml file can be generated by the

database

xml file of the ISCR

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Example of business rules for Safety Message processing and

Message Acknowledgment applicable to all stakeholders

exchanging ICSRs electronically within the EEA.

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Examples of E2B validation done by a PV database

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Example in Europe : how to report ISCR/ADR that meets

expedited reporting is sent electronically to the European

Pharmacovigilance database : Eudravigilance

• 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

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• 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).

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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

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

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Sponsor responsabilities

SOP: standard operating procedure

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

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Sponsor responsibilities

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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)

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Ecrin Summer School - Vienna 2008

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).

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Marketing Authorisation Holders (MAHs), National Competent

Authorities (NCAs) and Sponsors to report electronically:

Suspected Unexpected Serious Adverse Reactions (SUSARs)

Individual Case safety Reports

Registration with EudraVigilance is mandatory for :

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

to register)

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Example of registrants

Example of EV profile (can be updated anytime)

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GATEWAY EVPOST EVWEB

-

The Transmission Mode of ICSR reporting has to be selected,

Gateway and EVPOST require test phase with Eudravigilance

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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

EUDRAVIGILANCE TELEMATICS IMPLEMENTATION GROUP - Ref: EMEA/115735/2004

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ICSR reporting by EVPOST :

Xml attached and sent (E2B validation has to be done before)

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Secure direct access to

Eudravigilance Database

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Eudravigilance

Database

4 minimum criteria

for initial expedited

reporting of SUSARs

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One reporter

xml file of the case has been imported

via Web Trader

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One patient

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One reaction

(at least)…

…coded by

MedDRA Dictionary

(LLT)

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One investigational

medicinal product

(at least)

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One investigational

medicinal product

(at least)…

…coded by the

Eudravigilance

Medicinal Product

Dictionary (EVMPD)

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A summary of

the case

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Electronic

reporting of

SUSAR to

Competent

Authorities

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E2B Validation

has to be done

before sending

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Electronic reporting

of SUSAR to EVCTM

Eudravigilance

Clinical Trial Module

Electronic

reporting of

SUSAR to

Competent

Authorities

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ACK message :

Report ack must be 01

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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

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The Suspected Unexpected Serious Adverse Reaction is

sent electronically to European Safety database

WITHIN 15

DAYS

Re-routing of

ICSRs to the

Member State

where the

adverse reaction

occurred

Centralisation of ISCRs to Eudravigilance ->

transmission to concerned NCAs

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Main issue: lack of harmonization in medicinal product

information and medicinal product terminology

E2B (R2)

structure

E2B (R3)

structure

Conversion rules between E2B(R2) and E2B(R3)

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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

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IDMP

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Mapping rules between E2B versions

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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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