Pharmacovigilance & Adverse Event Reporting Meredin Stoltenberg MD, PhD, DMSC Medical Safety Advisor Global Pharmacovigilance HQ 1

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 2

Voting pads 3

Context 4

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 5

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 6

Interactive question 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 7

Please give us your undivided attention 8

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 9

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 10

Getting it ‘right first time’ 11

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 12

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

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

Other things to note 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 15

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 16

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 17

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 18

Serious adverse events All SAEs should be reported immediately, then tracked and updated until there is an outcome: “Recovered” “Recovered with sequelae” “Died” “Did not recover” (for chronic conditions) 19

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

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

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” 22

Symptoms and diagnosis 23

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 24

Coding and why we do it 25

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. 26

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

Recording using the eCRF 28

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 29

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 30

Sample entry: reporting an AE 31

Sample entry: reporting an AE 32

Sample entry: reporting an AE 33

Sample entry: reporting an AE 34

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 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

Sample entry: reporting a sequence of linked AEs 37

Sample entry: reporting a sequence of linked AEs 38

Sample entry: narrative reports 39

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. 40

Sample entry: reporting a sequence of linked AEs 41

Sample entry: reporting a sequence of linked AEs 42

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 43

Summary 44

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 45

Interactive question Has this session been: Unnecessary   Unnecessary Necessary but nothing new Useful Useful and engaging So good, I’d like to sit through it again right now 46

For further information All information in this presentation is summarised in the study protocol: Section 9, pages 46 to 51 Ask your CRA or international/regional study manager Ask your Safety Advisor: fpe@lundbeck.com stol@lundbeck.com   Contact Details: For reporting, always use the eCRF Backup options: Fax US: 866 832 0540 ( Fax DK: +45 36 30 99 67) or email safety@lundbeck.com 47

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Data Monitoring Committee (DMC) 49

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.

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

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

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