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Pharmacovigilance and electronic reporting Background and procedures. Wendy Huisman EU QP Teva Pharmaceuticals Europe. Content. What is pharmacovigilance Why do we need pharmacovigilance Principles of electronic reporting EMEA database structure of reporting - PowerPoint PPT Presentation
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© Teva Pharmaceuticals Europe 02 October 2007
Pharmacovigilance and electronic reporting
Background and procedures
Wendy HuismanEU QP Teva Pharmaceuticals Europe
© Teva Pharmaceuticals Europe 02 October 2007
ContentContent
• What is pharmacovigilance• Why do we need pharmacovigilance• Principles of electronic reporting
– EMEA database – structure of reporting– Structure of the report (xml files)– Different data in database (expedited, PSUR,
backlog)– Compliance– Quality of cases
© Teva Pharmaceuticals Europe 02 October 2007
Pharmacovigilance - Rescue dogPharmacovigilance - Rescue dog
© Teva Pharmaceuticals Europe 02 October 2007
© Teva Pharmaceuticals Europe 02 October 2007
© Teva Pharmaceuticals Europe 02 October 2007
© Teva Pharmaceuticals Europe 02 October 2007
© Teva Pharmaceuticals Europe 02 October 2007
© Teva Pharmaceuticals Europe 02 October 2007
© Teva Pharmaceuticals Europe 02 October 2007
PharmacovigilancePharmacovigilance
• Making sure we do not unnecessarily harm patients with the companies medicinal products.
• It is– the complete system on collecting, assessing and
submitting adverse events to authorities in all phases of the drugs life cycle including early development.
– taking all measures to be able to identify changes in the safety profile of the drug
• Changes frequency• New risks
© Teva Pharmaceuticals Europe 02 October 2007
Adverse event
Any untoward medical occurrence in a patient or clinical investigation participant who was administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment.
Also misuse, abuse, use in pregnancy, lack of efficacy
Serious adverse eventAn SAE is an AE that results in any of the following:•Fatality•Life-threatening symptoms•Requires or prolongs hospitalization•Disability or incapacity•A congenital anomaly or birth defect•A Medically serious condition
DefinitionsDefinitions
© Teva Pharmaceuticals Europe 02 October 2007
Adverse event – Adverse reactionAdverse event – Adverse reaction
Adverse events judged by reporting HCP or Sponsor (or both) as having a reasonable suspected causal relationship to the medicinal product qualify as adverse drug reaction.
© Teva Pharmaceuticals Europe 02 October 2007
Sources of adverse eventsSources of adverse events
• Receptionist• Sales department• Sales reps• QA• Medical information• Legal• Solicited programs• Websites
© Teva Pharmaceuticals Europe 02 October 2007
How do we get themHow do we get them
• Phone calls
• Regular mail
• Fax
• Websites; general questions
• Visits sales reps
© Teva Pharmaceuticals Europe 02 October 2007
TerminologyTerminology
• SPC: Summary of Product Characteristics; the leaflet for the health care professional indicating the adverse reactions of the drug. The patient information leaflet (PIL) is a lay summary of the SPC. Available for all products.SPC and PIL might be country dependant
• CCDS: Company Core Data Sheet; corporate SPC including all indications and dosages which might not be all valid for all countries.
• CCSI: Company Core Safety Information; Contains only the items 4.3 – 4.9 of the CCDS.
© Teva Pharmaceuticals Europe 02 October 2007
TerminologyTerminology
• PSUR: Periodic Safety Update Report; This report evaluates the cases in database and literature. This will be compared with the CCDS or SPC to see whether the safety information needs to be adapted. Cycle initially short than every 3 years.
• IB (IDB): Investigators Brochure; This brochure is in use in clinical trials with products which are not marketed (no SPC available). It is summary of all information available.
© Teva Pharmaceuticals Europe 02 October 2007
TerminologyTerminology
• Expected– Event is described SPC, the CCDS or the IB, so the event
is not “new”
• Listed– Used in PSURs. PSURs are usually written with reference
to the SPC/CCDS which was in use at the first day of the PSUR evaluation. In the meantime however, new SPCs could have come in place. That’s why the term “listed” is used as compared to expected.
© Teva Pharmaceuticals Europe 02 October 2007
TerminologyTerminology
• Spontaneous reports
– Events which are reported to us spontaneous by whatever source. Spontaneous reports are as per definition possibly related
• Study reports
– Reported because of the specific requirements in study protocols. SAEs send out immediately and AEs in the final evaluation
• Solicited
– Patient support programs, organised data collection systems, named patient programs, disease management programs, registries, phase IV studies
© Teva Pharmaceuticals Europe 02 October 2007
Why do we need Pharmacovigilance? Why do we need Pharmacovigilance?
Drug Effect Species
Contraceptives Bleeding of retina Monkeys, mice
Contraceptives Eye Cancer Monkeys, mice
DDT and phenobarbital
Liver tumours Mice
Penicillin Rapid death after single dose
Guinea pig
Aspirin Fetal abnormalities rats
Animal Adverse Reactions Not Seen in Humans
© Teva Pharmaceuticals Europe 02 October 2007
Why do we need Pharmacovigilance?Why do we need Pharmacovigilance?
Drug Effect Species where effect NOT seen
Thalidomide Fetotoxicity Most rat strains
Practolol Eye lesions All species
Halothane Liver failure All species
Contraceptives Thrombosis All Species
Azauracil CNS effects All species
Clioquinol Optic neuritis All species
Phenacetine Nephrotoxicity All species
Chloramphenicol Aplastic anemia All species
Human adverse reactions Not Seen in Animals
© Teva Pharmaceuticals Europe 02 October 2007
Why do we need PharmacovigilanceWhy do we need Pharmacovigilance
• Chloroform reports of cardiac arrest in 1880• First thalidome victoms in 1961• Cisapride withdrawn of the market in 2000• Vioxx cardiovascular problems in 2004• …• ..• .
• Also generics are not “safe”
© Teva Pharmaceuticals Europe 02 October 2007
Why pharmacovigilance?Why pharmacovigilance?
• Responsibility to the patient• Increase product knowledge
– Indications– Dosages– Adverse events– Quality defects
• Improving communication on the products– Updated SPC– Updated patient information
• Agreed on at approval• Liability
© Teva Pharmaceuticals Europe 02 October 2007
DevelopmentDevelopment
Pre-authorisation Authorisation Post-authorisation
Clinical trials
(Pharmaco)epidemiology
Compassionate use
Children
Elderly
Concomitant medication or diseases
Statistics
Short term
Unauthorised indications
Contraindications
“safe drugs”
No control
© Teva Pharmaceuticals Europe 02 October 2007
legislationlegislation
• Initially local and different among the EU countries• Harmonisation is ongoing
• European legislation– Valid for 30 countries
– Regulations/Directives/Guidelines
• Clinical trials: Directive 2001/20/EC
• MRPs/DCPs registered products; Directive 2001/83/EC• Centrally authorised products: Regulation 726/2004
© Teva Pharmaceuticals Europe 02 October 2007
Guidance documentsGuidance documents
• Volume 9A of the notice to applicants– Registered products– Guideline on the
monitoring of compliance with PhV
– Guideline on the EU risk management plan
• Volume 10– Investigational products
© Teva Pharmaceuticals Europe 02 October 2007
Principle of reporting in the EEAPrinciple of reporting in the EEA
• Registered products– Serious adverse events originating from the EEA
have to be reported only locally.– Serious unexpected adverse events resulting from
non EEA have to be reported to all countries in the EEA where the company has a license (all MAH)
– Only HCP reports
• Clinical trial products– Serious unexpected reports of the IMP have to be
reported– Also on comparator– Unblind
© Teva Pharmaceuticals Europe 02 October 2007
Electronic reportingElectronic reporting
• Where are the reported all adverse events?– Company database is very complete in the innovative
phase– Authority database contains only reported reactions
– Serious unexpected from trials– Solicited?– Non serious?– Other countries?
• EMEA database?– Electronic reporting mandatory as of 20 November 2005– Eudravigilance database
© Teva Pharmaceuticals Europe 02 October 2007
EudravigilanceEudravigilance
• EudraVigilance supports in particular the:
– Electronic exchange of suspected adverse reaction reports (referred to as Individual Case Safety Reports) between the European Medicines Agency (EMEA), national Competent Authorities, marketing authorisation holders, and sponsors of clinical trials in the EEA;
– Early detection of possible safety signals associated with medicinal products for Human Use;
– Continuous monitoring and evaluation of potential safety issues in relation to reported adverse reactions;
– Decision making process, based on a broader knowledge of the adverse reaction profile of medicinal products especially in the frame of Risk Management.
© Teva Pharmaceuticals Europe 02 October 2007
Eudravigilance – 2 databasesEudravigilance – 2 databases
• The EudraVigilance Clinical Trial Module (EVCTM) to facilitate the electronic reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) as required by Directive 2001/20/EC.
• The EudraVigilance Post-Authorisation Module (EVPM) designed for post-authorisation ICSRs, Regulation (EC) No 726/2004, Directive 2001/83/EC as amended, and Volume 9A of the "Rules Governing Medicinal Products in the European Union: Pharmacovigilance for medicinal products for human use".
© Teva Pharmaceuticals Europe 02 October 2007
EudravigilanceEudravigilance
• One of the main pillars of the European Risk Management Strategy, a joint effort between the EMEA and national Competent Authorities to strengthen the conduct of pharmacovigilance in the EEA.
• Facilitates the process of risk management at several levels including aspects of risk detection, risk assessment, risk minimisation and risk communication.
• Contributes to the protection and promotion of public health in the EEA and provides a powerful tool for the EMEA and national Competent Authorities in monitoring the safety of medicinal products and in minimising potential risks related to suspected adverse reactions.
© Teva Pharmaceuticals Europe 02 October 2007
Eudravigilance databaseEudravigilance database
Source systems
© Teva Pharmaceuticals Europe 02 October 2007
Source systemsSource systems
• Source systems capture and store the data that are reported to or used by EudraVigilance
• Data reported to Eudravigilance– PM-ICSRs: Individual Case Safety Reports transmitted to
the EudraVigilance Post-Authorisation Module (EVPM) – CT-ICSRs (SUSARs): Individual Case Safety Reports
transmitted to the EudraVigilance Clinical Trial module (EVCTM)
– PSUR-ICSRs: Individual Case Safety Reports from Periodic Safety Update Reports transmitted to the EVPM
– ASR-ICSRs: Individual Case Safety Reports from Annual Safety Reports transmitted to the EVCTM
– BACKLOG-ICSRs: Individual Case Safety Reports transmitted retrospectively to the EVPM or EVCTM
© Teva Pharmaceuticals Europe 02 October 2007
Source systemsSource systems
• Data supporting Eudravigilance– Medicinal Product
Dictionary (EVMPD)– Regulatory database
(MAHs, Eudract)– Medical dictionary
(MedDRA)
© Teva Pharmaceuticals Europe 02 October 2007
Eudravigilance databaseEudravigilance database
Extraction, transfer and loading
© Teva Pharmaceuticals Europe 02 October 2007
Extraction, transfer and loadingExtraction, transfer and loading
• the means by which data are transferred from source systems and loaded into the EudraVigilance Data Warehouse.
• Specifically, the ETL process does the following:– Stores information about the structure and contents of
source systems and the Data Warehouse – Correlates the source systems structure and contents to
the structure and contents of the Data Warehouse – Provides information to the data extraction tools that
physically execute the transfer of data from source systems to the Data Warehouse
• The ETL process is performed nightly so that every day the EudraVigilance Data Warehouse is populated with data updated to the day before.
© Teva Pharmaceuticals Europe 02 October 2007
Eudravigilance databaseEudravigilance database
Eudravigilance Data Warehouse
© Teva Pharmaceuticals Europe 02 October 2007
DatawarehouseDatawarehouse
• The repository for storing all of the information required to analyse data
• Optimized for enabling users to report on and manipulate data (includes transformation of variables, filtering and tabulation).
© Teva Pharmaceuticals Europe 02 October 2007
Eudravigilance databaseEudravigilance database
Data Analysis
© Teva Pharmaceuticals Europe 02 October 2007
Eudravigilance data analysis toolkitEudravigilance data analysis toolkit
• Provides many predefined table and graph formats for report presentation.
• Users can customise formatting to suit particular needs, and have a variety of functions available for the manipulation of report results.
• Interaction with the EudraVigilance Data Analysis Toolkit is through a graphical user interface (GUI), which will be available via a common web browser and can be accessed from any place, requiring only an Internet connection.
• A training course to use the EudraVigilance Data Analysis System is being developed.
© Teva Pharmaceuticals Europe 02 October 2007
Principle of reportingPrinciple of reporting
• Registered products– Serious adverse events originating from the EEA have to be
reported only locally.– Serious unexpected adverse events resulting from non EEA have
to be reported to all countries in the EEA where the company has a license (all MAH)
MAH
NCA
EMEA
local
foreign
© Teva Pharmaceuticals Europe 02 October 2007
Sending a reportSending a report
• To acknowledge the receipt of a safety or medicinal product report message the receiver must generate an acknowledgement message.
• In order to transport a safety or acknowledgement message to the correct receiver it is required to correctly specify the message sender identifier and the message receiver identifier.
• The EudraVigilance Gateway reads the sender and receiver information specified in the safety, acknowledgement or medicinal product report messages and routes the message to the appropriate receiver.
© Teva Pharmaceuticals Europe 02 October 2007
EMEA central gateway
NCAMAH
ICSR ICSR
ACKACK
Actual flow of informationActual flow of information
Receiver identifier is EMEA or NCA
© Teva Pharmaceuticals Europe 02 October 2007
ICH E2BICH E2B
© Teva Pharmaceuticals Europe 02 October 2007
E2BE2B
© Teva Pharmaceuticals Europe 02 October 2007
E2B formatE2B format
© Teva Pharmaceuticals Europe 02 October 2007
Countries in productionCountries in production
• Czech Republic • Denmark • Finland • Iceland • Latvia • Lichtenstein • Lithuania
• Malta • The Netherlands • Norway • Poland • Slovenia • Spain • Sweden
© Teva Pharmaceuticals Europe 02 October 2007
MAH reportingMAH reporting
• Overall Reporting Period: 1 December 2001 – 18 July 2007– 247 MAH Headquarters have reported electronically to
EVPM
© Teva Pharmaceuticals Europe 02 October 2007
MAHs’ Implementation status EVPMMAHs’ Implementation status EVPM
Reports
Cases
Non-EEAEEA
69,576
41,628
419,572
246,720
0
50,000
100,000
150,000
200,000
250,000
300,000
350,000
400,000
450,000
Number of ICH ICSRs and Cases Reported by MAHs to EVPM1 December 2001 - 18 July 2007
© Teva Pharmaceuticals Europe 02 October 2007
Reporting by MAHs to EVPMReporting by MAHs to EVPM
0
20
40
60
80
100
120
140
160
Nov-05
Dec-05
Jan-06
Feb-06
Mar-06
Apr-06
May-06
Jun-06
Jul-06
Aug-06
Sep-06
Oct-06
Nov-06
Dec-06
Jan-07
Feb-07
Mar-07
Apr-07
May-07
Jun-07
Jul-07
Number of MAHs reporting to EVPM 20 Nov 2005 - 18 July 2007
© Teva Pharmaceuticals Europe 02 October 2007
Number of ICSRs SENTNumber of ICSRs SENT
© Teva Pharmaceuticals Europe 02 October 2007
COMPLIANCE (EVPM)COMPLIANCE (EVPM)
Within Outside% ICSRs % ICSRs
15 Days Reporting Compliance0 0.28% 0.00%1 1.01% 0.00%2 2.19% 0.00%3 2.73% 0.00%4 3.19% 0.00%5 3.90% 0.00%6 6.59% 0.00%7 10.06% 0.00%8 10.49% 0.00%9 10.16% 0.00%10 8.99% 0.00%11 9.28% 0.00%12 8.92% 0.00%13 8.37% 0.00%14 4.93% 0.00%15 2.19% 0.00%>15 0.00% 6.71%Total 93.29% 6.71%
© Teva Pharmaceuticals Europe 02 October 2007
Reporting by NCAs to EVPMReporting by NCAs to EVPM
0
5
10
15
20
25
Nov-05
Dec-05
Jan-06
Feb-06
Mar-06
Apr-06
May-06
Jun-06
Jul-06
Aug-06
Sep-06
Oct-06
Nov-06
Dec-06
Jan-07
Feb-07
Mar-07
Apr-07
May-07
Jun-07
Jul-07
Number of NCAs reporting to EVPM 20 Nov 2005 - 18 July 2007
© Teva Pharmaceuticals Europe 02 October 2007
Number of ICSRs sent by NCAsNumber of ICSRs sent by NCAs
© Teva Pharmaceuticals Europe 02 October 2007
Clinical trials registered in EudraCTClinical trials registered in EudraCT
• 11,204 distinct clinical trials recorded in EudraCT– 21,001 clinical trial applications to individual Member
States• 80.5% commercial sponsors• 19% non-commercial sponsors• 0.5% Not Specified
• Number of unique sponsors cannot be queried directly in EudraCT
• Overall Reporting Period: 1 May 2004 – 18 July 2007– 198 Sponsor Headquarters have reported electronically to
EVCTM
© Teva Pharmaceuticals Europe 02 October 2007
Reporting by sponsorsReporting by sponsors
0
20
40
60
80
100
120
Jul-04A
ug-04S
ep-04O
ct-04N
ov-04D
ec-04Jan-05Feb-05M
ar-05A
pr-05M
ay-05Jun-05Jul-05A
ug-05S
ep-05O
ct-05N
ov-05D
ec-05Jan-06Feb-06M
ar-06A
pr-06M
ay-06Jun-06Jul-06A
ug-06S
ep-06O
ct-06N
ov-06D
ec-06Jan-07Feb-07M
ar-07A
pr-07M
ay-07Jun-07Jul-07
Number of Sponsors reporting to EVCTM 01 May 2004 - 18 July 2007
© Teva Pharmaceuticals Europe 02 October 2007
Number of ICSRs sent by sponsorsNumber of ICSRs sent by sponsors
© Teva Pharmaceuticals Europe 02 October 2007
Reporting by all stakeholdersReporting by all stakeholders
Reports
Cases
Non-EEAEEA
68,130
29,066
62,254
28,271
0
10,000
20,000
30,000
40,000
50,000
60,000
70,000
Number of SUSAR reports and Cases Reported by all Stakeholders to EVCTM1 December 2001 - 18 July 2007
© Teva Pharmaceuticals Europe 02 October 2007
BACKLOG REPORTINGBACKLOG REPORTING
Number of Backlog ICSRs received per month from all stakeholders by 31 July Number of Backlog ICSRs received per month from all stakeholders by 31 July 20072007
© Teva Pharmaceuticals Europe 02 October 2007
BACKLOG REPORTINGBACKLOG REPORTING
0
10
20
30
40
50
60
70
80
90
1stQtr
2ndQtr
3rdQtr
4thQtr
EastWestNorth
EVPM
EVCTMMAHs/Sponsors
NCAs
24,869
0
37,609
597
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
Number of Backlog Cases Transmitted to EudraVigilance by all Stakeholders by 31/07/2007
MAHs/Sponsors
NCAs
© Teva Pharmaceuticals Europe 02 October 2007
Quality of dataQuality of data
• Rubbish in – rubbish out….
• Business rules will be updated
• Companies will be informed on the quality of their data.
• Language– Companies to report in
English– NCA may report partly
in lcoal language
© Teva Pharmaceuticals Europe 02 October 2007
Just some thougthsJust some thougths
• Start in november 2005. Still not all NCAs and MAHs are compliant
• The EVMPD is not filled• Signal detection has not
yet started
© Teva Pharmaceuticals Europe 02 October 2007
When it works and everyone is compliant I think we will have a very good European system to monitor the safety of the medicinal products on the EU market.
This gives industry and authorities a perfect tool to monitor the products.
© Teva Pharmaceuticals Europe 02 October 2007