1. Magnus Wallberg Senior Systems Architect M Sc Engineering Physics Dar Es Salaam November 26 th, 2009 magnus.wallberg@who-umc.org Tools for Pharmacovigilance and Cohort Event Monitoring

2. Magnus Wallberg, UMC Agenda Where does Cohort Event Monitoring fit –Walk through of other pharmacovigilance methods Spontaneous reporting –The “Vigis” - VigiBase, VigiSearch/VigiMine and VigiFlow Analysis of longitudinal data (patient records) Comparison, including CEM –Cohort Event Monitoring Method Tool requirements CemFlow

3. Magnus Wallberg, UMC Pharmacovigilance methods

4. Magnus Wallberg, UMC Spontaneous reporting The most common way of performing pharmacovigilance today …

5. Magnus Wallberg, UMC Analysis of patient records A project ongoing at the UMC to analyse longitudinal data (Clinical Insight) Based on patient record data –Method developed on different but similar datasets –Can be adapted for more generalized datasets Prototype already available in the UMC research and signal departments

6. Magnus Wallberg, UMC Cohort Event Monitoring …

7. Magnus Wallberg, UMC Different focus (simplified) Spontaneous reporting – VigiSearch/VigiMine/VigiFlow –Focus on ADRs Patient records –Focus on patients Cohort Event Monitoring – CemFlow –Focus on drugs –More about CemFlow soon…

8. Magnus Wallberg, UMC Different perspectives

9. Magnus Wallberg, UMC Cohort Event Monitoring

10. Magnus Wallberg, UMC Overall objective Achieve maximum benefit, least harm, for patients

11. Magnus Wallberg, UMC How? Monitor a specific medicine, substance or group of medicines by –Collecting: All data –Events, patient details, concomitant medications, outcomes… For “all” patients –In the Cohort –Analyze To get risk profiles and other statistical data –Produce recommendations

12. Magnus Wallberg, UMC What is Cohort Event Monitoring - CEM In Cohort Event Monitoring (CEM) a group (cohort) of patients are monitored while treated with a specific medicine (or group of medicines). All events in a control period before and during treatment shall be recorded.

13. Magnus Wallberg, UMC Why collect events before and after Events in the control period (before treatment) Events after treatment

14. Magnus Wallberg, UMC Why collect events before and after

15. Magnus Wallberg, UMC Objectives Should be fairly well known by now… but to summarize: Characterise known reactions Measure risk Detect signals of unrecognised reactions Detect Interactions Identify risk factors like Age, Gender, Dose… Assess safety in pregnancy & lactation Detect inefficacy

16. Magnus Wallberg, UMC Stratification possibilities

17. Magnus Wallberg, UMC Selection of cohort The cohort should be picked without biases among “all” patients being treated. –For example, all patients visiting the clinic on Tuesdays and Wednesdays that have been prescribed the monitored drug All patients, falling into the rules of the cohort setup, must be enrolled (to avoid biases) Continue the enrolment until the predefined size of the Cohort is reached

18. Magnus Wallberg, UMC This is a “cohort”…

19. Magnus Wallberg, UMC What to record All new Events even if common & minor Change in a pre-existing condition Abnormal changes in laboratory tests Accidents All deaths with date & cause Concomitant medications Concomitant diseases Lost to follow up!!

20. Magnus Wallberg, UMC Events = reactions + incidents Reactions –definite –probable –possible Incidents (background noise) –unlikely –Unclassified (conditional)

21. Magnus Wallberg, UMC A tool for CEM – web based IT support

22. Magnus Wallberg, UMC A tool for CEM – different focus The focus of a CEM tool is different from a spontaneous reporting tool like VigiFlow –Patient, not report More patient details –There is always at least one drug but usually not a reaction (however – many events) –There is more data to collect so the interface must be simple to use Preferably more information in each chapter and fewer chapters than in VigiFlow

23. Magnus Wallberg, UMC CemFlow CemFlow is a tool for: –Collection of CEM data On central level as well as primary reporter level Supports paper based data collection –Analysis of CEM data –Management of: Users reporters reporter organizations CEM programs CEM terminology

24. Magnus Wallberg, UMC CemFlow 1.0 structure CEM programs CEM settings Reporters Reporter Organizations CEM user CEM “report” Search and Statistics

25. Magnus Wallberg, UMC Reporter A reporter is added to the system and referenced on the report via a reporter lookup tool A reporter should belong to a reporter organization/clinic A reporter can not log on to the CemFlow system – is not a CemFlow user Shani Mwaluka – Mnazi Mmoja Health Centre, Dar es Salaam

26. Magnus Wallberg, UMC Reporter organization A reporter organization in CEM is for example a clinic/hospital where data for a CEM program is collected A reporter “should” be connected to a reporter organization A reporter organization belongs to a CEM program

27. Magnus Wallberg, UMC Search and Statistics The Search and Statistics tool provides standard analysis tools and export functionality Predefined filters and stratifications are available Will need further research when more data is available

28. Magnus Wallberg, UMC Filters and stratifications It is possible to stratify events based on –Sex –Age group –… and more will come In addition – statistics will be available based on –Concomitant medications –Concomitant diseases –…

29. Magnus Wallberg, UMC Search and Statistics – cont Search results are currently presented as figures In the near future statistics will also be: –Represented in graphs –Possible to export as Excel for local refinement

30. Magnus Wallberg, UMC Report-term list

31. Magnus Wallberg, UMC Summary by terms

32. Stratification by gender Magnus Wallberg, UMC

33. Administrative statistics A sub section of the Search and Statistics tool will provide administrative statistics like: –Reporting per clinic and reporter –Number of reports in the database –Number of assessed un-assessed reports –…

34. CEM terminology Magnus Wallberg, UMC

35. CemFlow structure – terminology CEM programs CEM settings Reporters Reporter Organizations CEM user CEM “report” Search and Statistics CEM terminology (and manager)

36. Magnus Wallberg, UMC CEM terminology A terminology to collect and code events occurring during a CEM program is being developed –Work is ongoing by David Coulter (via WHO) and UMC –The CEM terminology is derived from WHO-ART and IMMP used in New Zealand The structure is different from WHO-ART and MedDRA Different levels and groupings A number of Event terms included The terminology is available via CemFlow –For data entry and analysis

37. Magnus Wallberg, UMC Why another terminology One CEM terminology is needed so that different CEM programs can be compared Other terminologies like WHO-ART and MedDRA are reaction based – not event based –Many event terms needed can not be coded in WHO-ART or MedDRA Definitions needed When running a CEM program in Africa many new event terms will be needed and efficiently administered –Requires a flexible terminology

38. Magnus Wallberg, UMC CEM terminology and compatibility There is always a great concern when introducing a new terminology – measures will therefore be taken to map the CEM terminology to MedDRA Mapping will allow for: –Statistics being produced in the MedDRA terminology –Facilitates export of data to MedDRA compatible databases –Simplifies communication with for example manufacturers Mapping will primarily be done on PET level

39. Magnus Wallberg, UMC Structure of CEM termionology Clinical category (CC) Anatomic functional group (AFG) Clinical sub group (CG) Primary event term (PET) Secondary event term (SET) Mapped to MedDRA Statistics can theoretically be done on any terminology level

40. An example of the CEM terminology structure in CemFlow Magnus Wallberg, UMC

41. Why not use MedDRA or WHO-ART Another type of grouping is necessary –Different levels –One term can belong in different Clinical Cathegories And where it is placed is important Terms are ordered in a clinically meaningful way –Can highlight problem “areas” in a simple way The number of terms are kept low for simplicity

42. Magnus Wallberg, UMC CEM terminology The “same” term (same name) can appear in several “Clinical categories” –Therefore – when coding – the “correct” term must be selected Each individual term can have a definition attached to simplify the selection process –Definitions will be continuously added and modified

43. Magnus Wallberg, UMC CEM terminology The event will be entered as free text by the reporter and connected to a term in the events dictionary by an assessor or reviewer Coding of the free text events is crucial for the statistical methods to work It is important that events are coded in “the same way” by all assessors/reviewers

44. Magnus Wallberg, UMC Terminology manager To allow for easy maintenance and flexibility of the CEM terminology a terminology manager is available within CemFlow –Available for users with special access –Allows for: Restructuring of available terms Addition of new terms Mapping of terms to MedDRA Editing of definitions

45. Magnus Wallberg, UMC Terminology lookup tool

46. Magnus Wallberg, UMC Coding of “non event terms” To code other data items on the CEM report, apart from the event terms, MedDRA is used The places where MedDRA comes in are –Indications –Present or significant past medical conditions –Co-morbid conditions/concomitant diseases –Tests Often used MedDRA terms can be added to a quick list through the program manager –like standard tests and important concomitant diseases Default terms available

47. Hands on CemFlow Magnus Wallberg, UMC

48. Hands on Introduction and start up of the hands on section... Magnus Wallberg, UMC

50. CEM program A CEM program is the main “entity” of the CemFlow tool. –CemFlow supports many CEM programs in parallel –All “reports” and reporters belong to a specific program –Search and Statistics are made on reports for a specific program However, reports from other programs may be used as comparator/baseline data

51. Magnus Wallberg, UMC CEM program settings A CEM program has: –Organization (“owner” and contact person) –Description –Documents (like SOPs, Questionnaires and manuals) –Settings Program drug(s) Definition of control period Predefined laboratory tests Set up of visits –use of base line visit –multiple follow ups …

52. Magnus Wallberg, UMC We are in the “programs and users” module Select sub-tool Monitored drugs Standard tests Important co- morbid conditions

53. Hands on I will log on to CemFlow and set up a new CEM program for this session Magnus Wallberg, UMC

54. User The “users” of the CemFlow system register themselves and are assigned the access to a CEM program by an administrator. The users can be: –Assessors at the head organization –Data entry staff –Reporters at regional sites A user can have access to any number of CEM programs

55. Magnus Wallberg, UMC

56. Hands on Go to https://tools.who-umc.org/cemflowhttps://tools.who-umc.org/cemflow Register with your e-mail and password –Set your country to Andorra So that you will be easy to find! When you are registered: –Tell me and I will give you proper access! Magnus Wallberg, UMC

57. CEM “report” A CEM “report” is the CemFlow equivalent to the CEM questionnaires –All questionnaires collected in one CEM report Baseline, Pre, Post, Pregnancy and Pregnancy outcome questionnaires The equivalent to an individual questionnaire is entered as a “visit” with the events as the most important information items (except for baseline visits) CEM reports are managed through the Data Entry module of CemFlow

58. Magnus Wallberg, UMC List of CEM reports To be able to access old reports a report list with a filter is the first view in the data entry area There are several reasons to open “old reports” –Adding additional information (about for example a follow up visit) –Doing an assessment –Viewing a specific report –…

59. Magnus Wallberg, UMC We are in the “data entry” module Add a new report here!

60. Magnus Wallberg, UMC

61. Patient information Monitored medicine Other medicine Base line visit Treatment init. visit Follow up visit Past and current medical conditions General infoPregnancy info CEM report Assessment

62. Magnus Wallberg, UMC Patient details Name and address details are by default hidden There are a number of important mandatory fields If selecting female some additional fields will “pop up”

63. Magnus Wallberg, UMC More information for females

64. Hands on Create a new ”CEM report” Add patient information –The patient shall be a female –Note tha edditional fields for a female patient Add drugs with details to the drug list –One monitored drug –One other drug Collapse the entered drugs with the ”-”-sign Magnus Wallberg, UMC

65. Medicines taken Click here to get a list of all program drugs Open/close for edit with “+” and “-” List with concomitant medicines

66. Magnus Wallberg, UMC Visits There are three types of visits –Base line visit – only one Only used if “Use baseline visit” is ticked in the program administrator –Treatment initiation visit – only one –Follow up visit – more than one can be added The visits are grouped in tabs –Base line visit tab, treatment initiation visit tab and follow up visit(s) tab The most important is the follow up visit – shown on next slide

67. Magnus Wallberg, UMC Add a new event List of events for this visit “Outcomes” – only available at follow up visit Tick all drugs (from drug list) taken during treatment Reporters may differ from one visit to the other Patient weight may vary from one visit to another List of co-morbid conditions

68. Hands on Add one base line visit with data Add one treatment initiation visit with data –Add at least one test Add one follow up visit –Add at least two events Magnus Wallberg, UMC

69. Past and current medical conditions Present or significant past medical conditions Any number of conditions can be added Free text and coded values can be used Search for a MedDRA term or enter free text One button for past and one for current conditions

70. Hands on Add one past and one current medical condition Magnus Wallberg, UMC

71. What is happening now and onward Magnus Wallberg, UMC

72. Current CEM activities Two CEM programs are currently running –Tanzania Piloting of questionnaires and method CEM launch 17 th of Mars 2009 Adjustments done as result of lessons learnt from pilot The second phase has been initiated in Dar Es Salaam

73. Magnus Wallberg, UMC

74. Tanzania

75. Magnus Wallberg, UMC Current CEM activities Two CEM programs are currently running –Tanzania Piloting of questionnaires and method CEM launch 17 th of Mars 2009 Adjustments done as result of lessons learnt from pilot The second phase has been initiated in Dar Es Salaam –Nigeria A first pilot have been run with approximately 3000 patients A scale up is coming up

76. Magnus Wallberg, UMC

77. WHO Collaborating Centre for International Drug Monitoring Box 1051, SE - 751 40 Uppsala Sweden Tel +46 18 65 60 60, Fax +46 18 65 60 88 E-mail: info@who-umc.org Website: www.who-umc.org