1. © Teva Pharmaceuticals Europe 02 October 2007 Pharmacovigilance and electronic reporting Background and procedures Wendy Huisman EU QP Teva Pharmaceuticals Europe

2. © Teva Pharmaceuticals Europe 02 October 2007 Content 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

3. © Teva Pharmaceuticals Europe 02 October 2007 Pharmacovigilance - Rescue dog

4. © Teva Pharmaceuticals Europe 02 October 2007

10. Pharmacovigilance 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

11. © 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 event An 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 Definitions

12. © Teva Pharmaceuticals Europe 02 October 2007 Adverse 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.

13. © Teva Pharmaceuticals Europe 02 October 2007 Sources of adverse events Receptionist Sales department Sales reps QA Medical information Legal Solicited programs Websites

14. © Teva Pharmaceuticals Europe 02 October 2007 How do we get them Phone calls Regular mail Fax Email Websites; general questions Visits sales reps

15. © Teva Pharmaceuticals Europe 02 October 2007 Terminology 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.

16. © Teva Pharmaceuticals Europe 02 October 2007 Terminology 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.

17. © Teva Pharmaceuticals Europe 02 October 2007 Terminology 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.

18. © Teva Pharmaceuticals Europe 02 October 2007 Terminology 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

19. © Teva Pharmaceuticals Europe 02 October 2007 Why do we need Pharmacovigilance? DrugEffectSpecies ContraceptivesBleeding of retinaMonkeys, mice ContraceptivesEye CancerMonkeys, mice DDT and phenobarbital Liver tumoursMice PenicillinRapid death after single dose Guinea pig AspirinFetal abnormalitiesrats Animal Adverse Reactions Not Seen in Humans

20. © Teva Pharmaceuticals Europe 02 October 2007 Why do we need Pharmacovigilance? DrugEffectSpecies where effect NOT seen ThalidomideFetotoxicityMost rat strains PractololEye lesionsAll species HalothaneLiver failureAll species ContraceptivesThrombosisAll Species AzauracilCNS effectsAll species ClioquinolOptic neuritisAll species PhenacetineNephrotoxicityAll species ChloramphenicolAplastic anemiaAll species Human adverse reactions Not Seen in Animals

21. © Teva Pharmaceuticals Europe 02 October 2007 Why 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”

22. © Teva Pharmaceuticals Europe 02 October 2007 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

23. © Teva Pharmaceuticals Europe 02 October 2007 Development Pre-authorisationAuthorisationPost-authorisation Clinical trials (Pharmaco)epidemiology Compassionate use Children Elderly Concomitant medication or diseases Statistics Short term Unauthorised indications Contraindications “safe drugs” No control

24. © Teva Pharmaceuticals Europe 02 October 2007 legislation 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

25. © Teva Pharmaceuticals Europe 02 October 2007 Guidance 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

26. © Teva Pharmaceuticals Europe 02 October 2007 Principle 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

27. © Teva Pharmaceuticals Europe 02 October 2007 Electronic 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

28. © Teva Pharmaceuticals Europe 02 October 2007 Eudravigilance 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.

29. © Teva Pharmaceuticals Europe 02 October 2007 Eudravigilance – 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".

30. © Teva Pharmaceuticals Europe 02 October 2007 Eudravigilance 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.

31. © Teva Pharmaceuticals Europe 02 October 2007 Eudravigilance database Source systems

32. © Teva Pharmaceuticals Europe 02 October 2007 Source 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

33. © Teva Pharmaceuticals Europe 02 October 2007 Source systems Data supporting Eudravigilance –Medicinal Product Dictionary (EVMPD) –Regulatory database (MAHs, Eudract) –Medical dictionary (MedDRA)

34. © Teva Pharmaceuticals Europe 02 October 2007 Eudravigilance database Extraction, transfer and loading

35. © Teva Pharmaceuticals Europe 02 October 2007 Extraction, 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.

36. © Teva Pharmaceuticals Europe 02 October 2007 Eudravigilance database Eudravigilance Data Warehouse

37. © Teva Pharmaceuticals Europe 02 October 2007 Datawarehouse 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).

38. © Teva Pharmaceuticals Europe 02 October 2007 Eudravigilance database Data Analysis

39. © Teva Pharmaceuticals Europe 02 October 2007 Eudravigilance 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.

40. © Teva Pharmaceuticals Europe 02 October 2007 Principle 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

41. © Teva Pharmaceuticals Europe 02 October 2007 Sending 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.

42. © Teva Pharmaceuticals Europe 02 October 2007 EMEA central gateway NCA MAH ICSR ACK Actual flow of information Receiver identifier is EMEA or NCA

43. © Teva Pharmaceuticals Europe 02 October 2007 ICH E2B

44. © Teva Pharmaceuticals Europe 02 October 2007 E2B

45. © Teva Pharmaceuticals Europe 02 October 2007 E2B format

46. © Teva Pharmaceuticals Europe 02 October 2007 Countries in production Czech Republic Denmark Finland Iceland Latvia Lichtenstein Lithuania Malta The Netherlands Norway Poland Slovenia Spain Sweden

47. © Teva Pharmaceuticals Europe 02 October 2007 MAH reporting Overall Reporting Period: 1 December 2001 – 18 July 2007 –247 MAH Headquarters have reported electronically to EVPM

48. © Teva Pharmaceuticals Europe 02 October 2007 MAHs’ Implementation status EVPM

49. © Teva Pharmaceuticals Europe 02 October 2007 Reporting by MAHs to EVPM

50. © Teva Pharmaceuticals Europe 02 October 2007 Number of ICSRs SENT

51. © Teva Pharmaceuticals Europe 02 October 2007 COMPLIANCE (EVPM)

52. © Teva Pharmaceuticals Europe 02 October 2007 Reporting by NCAs to EVPM

53. © Teva Pharmaceuticals Europe 02 October 2007 Number of ICSRs sent by NCAs

54. © Teva Pharmaceuticals Europe 02 October 2007 Clinical 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

55. © Teva Pharmaceuticals Europe 02 October 2007 Reporting by sponsors

56. © Teva Pharmaceuticals Europe 02 October 2007 Number of ICSRs sent by sponsors

57. © Teva Pharmaceuticals Europe 02 October 2007 Reporting by all stakeholders

58. © Teva Pharmaceuticals Europe 02 October 2007 BACKLOG REPORTING Number of Backlog ICSRs received per month from all stakeholders by 31 July 2007

59. © Teva Pharmaceuticals Europe 02 October 2007 BACKLOG REPORTING

60. © Teva Pharmaceuticals Europe 02 October 2007 Quality 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

61. © Teva Pharmaceuticals Europe 02 October 2007 Just 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

62. © 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.

63. © Teva Pharmaceuticals Europe 02 October 2007