e2b, safety databases & eudravigilance topics dbertam -e2b -7 may... · 07/05/2014 · 6 the...
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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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