© teva pharmaceuticals europe 02 october 2007 pharmacovigilance and electronic reporting background...

© Teva Pharmaceuticals Europe 02 October 2007

Pharmacovigilance and electronic reporting

Background and procedures

Wendy HuismanEU QP Teva Pharmaceuticals Europe


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


Pharmacovigilance - Rescue dogPharmacovigilance - Rescue dog


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


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


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.


Sources of adverse eventsSources of adverse events

• Receptionist• Sales department• Sales reps• QA• Medical information• Legal• Solicited programs• Websites


How do we get themHow do we get them

• Phone calls

• Regular mail

• Fax

• Email

• Websites; general questions

• Visits sales reps


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.



• 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.



• 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.



• 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


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


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


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”


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


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


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


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


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


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


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.


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".


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.


Eudravigilance databaseEudravigilance database

Source systems


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


Source systemsSource systems

• Data supporting Eudravigilance– Medicinal Product

Dictionary (EVMPD)– Regulatory database

(MAHs, Eudract)– Medical dictionary

(MedDRA)



Extraction, transfer and loading


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.



Eudravigilance Data Warehouse


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).



Data Analysis


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.


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


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.


EMEA central gateway

NCAMAH

ICSR ICSR

ACKACK

Actual flow of informationActual flow of information

Receiver identifier is EMEA or NCA


ICH E2BICH E2B


E2BE2B


E2B formatE2B format


Countries in productionCountries in production

• Czech Republic • Denmark • Finland • Iceland • Latvia • Lichtenstein • Lithuania

• Malta • The Netherlands • Norway • Poland • Slovenia • Spain • Sweden


MAH reportingMAH reporting

• Overall Reporting Period: 1 December 2001 – 18 July 2007– 247 MAH Headquarters have reported electronically to

EVPM


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


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


Number of ICSRs SENTNumber of ICSRs SENT


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%


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


Number of ICSRs sent by NCAsNumber of ICSRs sent by NCAs


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


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


Number of ICSRs sent by sponsorsNumber of ICSRs sent by sponsors


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


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


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


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


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


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 pharmacovigilance and electronic reporting background...

Documents

adverse reactions

adverse drug reaction

terminology spc

spc available

reporting hcp

safety profile

periodic safety update

terminology psur