1. 1 US Investigator Meeting DIAS-4, San Diego, January 2011 Pharmacovigilance & Adverse Event Reporting 15-JUL-2011 Meredin Stoltenberg MD, PhD, DMSC Medical Safety Advisor Global Pharmacovigilance HQ

2. US Investigator Meeting DIAS-4, San Diego, January 2011 2 Agenda Context What will you get from this session? Safety and Pharmacovigilance at Lundbeck Working in partnership Getting it right first time Definitions of Adverse Events and Serious Adverse Events Ensuring correct diagnosis From diagnosis to coding Identifying causality Using the study reporting tools

3. US Investigator Meeting DIAS-4, San Diego, January 2011 3 Voting pads

4. 4 US Investigator Meeting DIAS-4, San Diego, January 2011 Context

5. US Investigator Meeting DIAS-4, San Diego, January 2011 5 Your patients, our reputation Why we are here: A new medicine that may help doctors and patients So far, so good, but this is still something new Our first duty: the safety of trial participants You are our eyes and ears What we do will affect how this medicine benefits patients

6. US Investigator Meeting DIAS-4, San Diego, January 2011 6 60 minutes, to safeguard study participants What you will get from this presentation: How we will work together How to save time and avoid rework How to report How to use the reporting tools Opportunity to ask questions

7. How many safety/ pharmacovigilance presentations have you been to? 7 Interactive question 1.This is my first 2.A few 3.A lot 4.Far more than you can imagine 5.I could probably give this presentation myself

8. US Investigator Meeting DIAS-4, San Diego, January 2011 8 Please give us your undivided attention

9. US Investigator Meeting DIAS-4, San Diego, January 2011 9 Pharmacovigilance: The science of safety Understanding and preventing adverse events by: Monitoring and reporting the use of the drug Detecting and assessing any adverse effects Assessing frequency, risk factors, levels of risk Assessing risk versus benefit

10. US Investigator Meeting DIAS-4, San Diego, January 2011 10 Working together First point: the patient comes first Partners in an investigative process Simplicity, accuracy and right first time Unclear or incomplete data will be followed up Every report is followed up appropriately

11. 11 US Investigator Meeting DIAS-4, San Diego, January 2011 Getting it right first time

12. US Investigator Meeting DIAS-4, San Diego, January 2011 12 Adverse events What is an Adverse Event? Untoward, or out of place, medical event during the clinical trial Patients included when they sign the consent form Events before first administration ARE included Does not need to be caused by the drug Unchanged pre-existing conditions are not AEs

13. 13 Interactive question Which of the events shown should you report as an Adverse Event or Serious Adverse Event?

14. 14 Interactive question 1.All 3 events should be reported 2.Only event number 3 should be reported 3.Events number 2 & 3 should be reported Which of the events shown should you report as an Adverse Event or Serious Adverse Event?

15. US Investigator Meeting DIAS-4, San Diego, January 2011 15 Laboratory abnormalities can also indicate an Adverse Event If the investigator believes they are clinically significant If they lead to a change or discontinuation of treatment If they fulfil a seriousness criteria If they indicate a potential safety risk to the patient Other things to note

16. US Investigator Meeting DIAS-4, San Diego, January 2011 16 Other things to note Overdose At minimum, should be reported as an AE, stating whether intentional or accidental If intentional, please add the reason Any symptoms resulting from the overdose should also be declared as AEs Medication errors, drug abuse, drug interactions, quality issues with the drug Medical or surgical procedures The reason for the procedure should be reported as an AE

17. US Investigator Meeting DIAS-4, San Diego, January 2011 17 Other things to note Pregnancy Should be reported as an AE within 24 hours using the Pregnancy form and entered as an AE in the eCRF Any untoward event, such as spontaneous abortion, congenital anomaly or foetal death should be reported as a Serious Adverse Event Report the outcome to Lundbeck, even if study has ended

18. US Investigator Meeting DIAS-4, San Diego, January 2011 18 What is a serious adverse event? Death Life-threatening Results in persistent or permanent disability or incapacity Results in birth defect/ congenital anomaly Requires hospitalisation Medically important

19. US Investigator Meeting DIAS-4, San Diego, January 2011 19 Serious adverse events All SAEs should be reported immediately, then tracked and updated until there is an outcome: Recovering Recovered Recovered with sequelae Died Did not recover (for chronic conditions)

20. Which of the following are serious adverse events? 20 Interactive question Which of the following are serious adverse events? 1.Patient died after being stabbed with a knife 2.Patient broke leg and was admitted to hospital 3.Patient suffered anaphylactic shock 4.Patient gave birth to a healthy baby 5.Patient admitted for scheduled surgery to remove gall bladder

21. Which of the following are serious adverse events? 21 Interactive question Which of the following are serious adverse events? 1.Patient died after being stabbed with a knife 2.Patient broke leg and was admitted to hospital 3.Patient suffered anaphylactic shock 4.Patient gave birth to a healthy baby 5.Patient admitted for scheduled surgery to remove gall bladder 1.Events 1,2, 3 are SAEs 2.Events 1,2,3,5 are SAEs 3.Events 2,3 are SAEs 4.All 5 events are SAEs Press one of the following options:

22. US Investigator Meeting DIAS-4, San Diego, January 2011 22 Reporting AEs and SAEs Reports should include: Symptoms and/or diagnosis Their intensity Cause (if known) Causality assessment Action taken Outcome Be specific about cause and sequence: Patient took an extra tablet because he forgot the previous dose Patient presented with an arm fracture after falling over due to dizziness

23. US Investigator Meeting DIAS-4, San Diego, January 2011 23 Symptoms and diagnosis

24. US Investigator Meeting DIAS-4, San Diego, January 2011 24 Symptoms and diagnosis Ensure that cumulative symptoms are reported correctly: Together, chest pain, dyspnoea, diaphoresis and ECG changes can indicate a myocardial infarction The symptoms should be reported as AEs or SAEs as they occur but should be connected when the link becomes clear

25. US Investigator Meeting DIAS-4, San Diego, January 2011 25 Coding and why we do it

26. US Investigator Meeting DIAS-4, San Diego, January 2011 26 Causality Is the AE or SAE linked to the study drug? Probably: There is a reasonable time relationship between the AE/SAE and drug administration, or the AE/SAE recurs when the drug is taken again. Is unlikely to be caused by disease or other drugs. Possibly: There is a suggested time relationship between the AE/SAE and drug administration, however, it could also be caused by disease or other drugs. Not related: There is no time relationship between the AE/SAE and drug administration, or AE/SAE is caused by disease or other drugs.

27. How many different CRF systems have you been trained in over the years? 27 Interactive question 1. None 2. 1-3 3. 4 or 5 4. 6-10 5. More than 10

28. US Investigator Meeting DIAS-4, San Diego, January 2011 28 Recording using the eCRF

29. US Investigator Meeting DIAS-4, San Diego, January 2011 29 Recording using the eCRF Our goals: Simple to use Necessary, but not excessive, data Clear purpose and subsequent outcomes Your goals: Devote adequate time CRF completion as a priority task Consistent and, where appropriate, report diagnosis instead of signs and symptoms

30. US Investigator Meeting DIAS-4, San Diego, January 2011 30 Sample entry: reporting a sequence of linked AEs If possible combine signs and symptoms into a single diagnosis Ensure the initially reported AEs (symptoms) are inactivated Note whether the adverse event is serious

31. US Investigator Meeting DIAS-4, San Diego, January 2011 31 Sample entry: reporting an AE

32. US Investigator Meeting DIAS-4, San Diego, January 2011 32 Sample entry: reporting an AE

33. US Investigator Meeting DIAS-4, San Diego, January 2011 33 Sample entry: reporting an AE

34. US Investigator Meeting DIAS-4, San Diego, January 2011 34 Sample entry: reporting an AE

35. US Investigator Meeting DIAS-4, San Diego, January 2011 35 Sample entry: reporting a sequence of linked AEs If possible combine signs and symptoms into a single diagnosis Ensure the initially reported AEs (symptoms) are inactivated Note whether the adverse event is serious

36. US Investigator Meeting DIAS-4, San Diego, January 2011 36 Sample entry: reporting a sequence of linked AEs If possible combine signs and symptoms into a single diagnosis Ensure the initially reported AEs (symptoms) are inactivated Note whether the adverse event is serious

37. US Investigator Meeting DIAS-4, San Diego, January 2011 37 Sample entry: reporting a sequence of linked AEs

38. US Investigator Meeting DIAS-4, San Diego, January 2011 38 Sample entry: reporting a sequence of linked AEs

39. US Investigator Meeting DIAS-4, San Diego, January 2011 39 Sample entry: narrative reports

40. US Investigator Meeting DIAS-4, San Diego, January 2011 40 Sample entry: narrative reports Narrative reports can be pasted into a free text field Give detail about the events leading to the AE Describe investigations and treatments Ensure the outcome is included A good example: On 12 October the patient was shovelling snow. The path was slippery and he fell and hit his head. He had not ingested alcohol and was not dizzy. He was hospitalised to be investigated (CT scan) and monitored for neurological injury. None was found and, on 14 October he was discharged with only a mild headache.

41. US Investigator Meeting DIAS-4, San Diego, January 2011 41 Sample entry: reporting a sequence of linked AEs

42. US Investigator Meeting DIAS-4, San Diego, January 2011 42 Sample entry: reporting a sequence of linked AEs

43. US Investigator Meeting DIAS-4, San Diego, January 2011 43 Back-up procedure If it is not possible to use the eCRF, record SAEs on emergency worksheets If necessary, continue to use these for follow-up assessments and reports Send them to the contact details shown at the end Update the eCRF at the earliest opportunity

44. 44 US Investigator Meeting DIAS-4, San Diego, January 2011 Summary

45. US Investigator Meeting DIAS-4, San Diego, January 2011 45 Summary You are our eyes and ears -- we, and the study participants, are in your hands Familiarise yourselves with the definitions of AEs and SAEs Familiarise yourselves with the reporting tools Getting it right, first time, will prevent follow-up contact and save you time There is a support network to help answer any queries

46. Has this session been: 46 Interactive question 1.Unnecessary 2.Necessary but nothing new 3.Useful 4.Useful and engaging 5.So good, Id like to sit through it again right now

47. US Investigator Meeting DIAS-4, San Diego, January 2011 47 For further information All information in this presentation is summarised in the study protocol: Section 9, pages 47-73 Ask your CRA or international/regional study manager Ask your Safety Advisor: fpe@lundbeck.comfpe@lundbeck.com Contact Details: For reporting, always use the eCRF Backup options: Fax +45 36 30 99 67 or email safety@lundbeck.comsafety@lundbeck.com

48. US Investigator Meeting DIAS-4, San Diego, January 2011 48

49. 49 US Investigator Meeting DIAS-4, San Diego, January 2011 Data Monitoring Committee (DMC)

50. US Investigator Meeting DIAS-4, San Diego, January 2011 50 DMC The Data Monitoring Committee (DMC) is an independent expert advisory group Combined DMC for 12402A (DIAS-3) study and 12649A (DIAS 4) Purpose and functions: Monitoring the safety of patients Conduct a predefined interim futility analysis when half of the patients have been evaluated in either one of the studies.

51. US Investigator Meeting DIAS-4, San Diego, January 2011 51 DMC Members: 3 external experts Chairman Deputy Chairman Third member Meetings Throughout the studies when a predefined number of patients have been enrolled and followed up for 90 days. First meeting: Feb 2010, 50 patients Second Meeting: 09 Feb 2011, 150 patients Thereafter for 250, 400, 550 and 700 patients

52. US Investigator Meeting DIAS-4, San Diego, January 2011 52 DMC members Prof. Kennedy R. Lees, MD DMC Chair and Stroke Specialist Department of Medicine Western Infirmary Glasgow, UK Dr Lawrence R. Wechsler, MD Deputy DMC Chair and Stroke Specialist University of Pittsburgh, Stroke Institute Pittsburgh, USA Dr Michael Eliasziw, PhD DMC member and Biostatistics Specialist DavLar Biostats Calgary, Canada Lundbeck personnel involved: Meredin Stoltenberg MD, PhD, DMSc DMC secretary H. Lundbeck A/S, Denmark

53. US Investigator Meeting DIAS-4, San Diego, January 2011 53

54. What should you report when a patient presents with a series of symptoms which are later linked? 54 Interactive question 1.Report each symptom as an adverse event 2.Report each symptom as an adverse event and the diagnosis as a serious adverse event 3.Report each symptom as an adverse event but inactivate the initial reports when you realise that the previously reported symptoms are covered by one diagnosis 10

55. US Investigator Meeting DIAS-4, San Diego, January 2011 55 Sample entry: narrative reports

56. US Investigator Meeting DIAS-4, San Diego, January 2011 56 How many safety/ pharmacovigilance presentations have you been to? This is my first A few A lot Far more than you can imagine I could probably give this presentation myself

57. US Investigator Meeting DIAS-4, San Diego, January 2011 57 Interactive question Which of the events shown should you report as an Adverse Event or Serious Adverse Event?

58. US Investigator Meeting DIAS-4, San Diego, January 2011 58 Interactive question Which of the following are serious adverse events? 1.Patient died after being stabbed with a knife 2.Patient broke leg and was admitted to hospital 3.Patient suffered anaphylactic shock 4.Patient gave birth to a healthy baby 5.Patient admitted for scheduled surgery to remove gall bladder

59. US Investigator Meeting DIAS-4, San Diego, January 2011 59 Interactive question How many different CRF systems have you been trained in over the years? 1.None 2.1-3 3.4 or 5 4.6-10 5.More than 10

60. US Investigator Meeting DIAS-4, San Diego, January 2011 60 Interactive question What should you report when a patient presents with a series of symptoms which are later linked? 1.Report each symptom as an adverse event 2.Report each symptom as an adverse event and the diagnosis as a serious adverse event 3.Report each symptom as an adverse event but inactivate the initial reports when you realise that the previously reported symptoms are covered by one diagnosis

61. US Investigator Meeting DIAS-4, San Diego, January 2011 61 Interactive question Has this session been: 1.Unnecessary 2.Necessary but nothing new 3.Useful 4.Useful and engaging 5.So good, Id like to sit through it again right now