Adverse Event Reporting & SAE Reporting for Investigators Trial Number: (POLO-AML-2) Date of training:23 February 2013 Trainer: Deepa Sachdev Venue:Investigator Meeting Toronto

Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 2 Importance of Safety Reporting Patient safety To fulfil our manufacturer’s responsibility towards patients and health care professionals To anticipate foreseeable risks and adapt accordingly Legal requirements To fulfil all regulatory requirements worldwide

Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 3 Participants will be able to: Understand Boehringer Ingelheim’s (BI’s) reporting timelines and follow-up reporting process Complete the SAE case form according to requirements Ensure that quality information is obtained and reported Training Objectives

Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 4 Agenda  Review of Definitions  Reporting Responsibilities  Pregnancy Reporting  Regulatory Reporting  Safety Reporting and Related Processes  Contact and Reference information

Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 5 A. Review of Definitions

6 Definitions: Adverse Event Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have to have a causal relationship with this treatment Any new illness or disease or a worsening of an existing illness or disease (after exposure to the medication or initiation of the clinical trial)

Vital signs, ECG, Physical Examination and Laboratory Test Results Changes in vital signs, ECG, physical examination and laboratory test results will be recorded as an (S)AE, if judged clinically relevant by the investigator. If serious, an SAE form has to be completed in addition Clinical relevance may be concluded, but is not limited to, if in response to the finding for example: the investigational drug is either discontinued, reduced or increased additional treatment is required, i.e. concomitant medication is added or changed any other intervention is performed Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 7

8 Definition: Serious Adverse Event (SAE) An AE is considered serious if any one of these conditions exists: Results in death Is immediately life-threatening Results in a persistent or significant disability or incapacity Requires or prolongs patient hospitalisation Is a congenital anomaly or a birth defect When based upon appropriate medical judgment, may jeopardise the patient and may require medical or surgical intervention to prevent more serious consequences, which may include death, illness or a worsening of an existing condition In addition, development of cancer is considered an SAE Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on:

Always Serious Adverse Events BI has defined a list of adverse events that are considered always serious by fulfilling the criteria for ‘medically important event’. Adverse events mentioned on the BI always serious AE list are deemed serious by virtue of the nature of the event. This list may be found on the GPV website and placed in the ISF for reference or included in RDC for direct access. Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 9

10 Hospitalisation: Criteria for SAE Reporting Hospitalisation is an overnight admission or stay An AE meets the SAE criteria for hospitalisation if: The event would have normally required hospitialisation but the patient was not hospitalised If the patient was already hospitalised when a new event occurred that required inpatient treatment but the event did not cause prolongation of the hospitalisation ( i.e. the patient would have been hospitalised if he was not in hospital already) If the patient is already in the hospital and an event occurs that causes prolongation of hospitalisation Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on:

11 Hospitalisation That Does NOT Meet SAE Criteria An AE does NOT meet the SAE criteria for hospitalisation if: The subject was treated in the emergency room but was not admitted for an overnight stay The hospitalisation is not accompanied by an event The hospitalisation is due to social circumstances Hospitalisation for diagnostic reasons without AE Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on:

12 Underlying Disease / Pre-Existing Conditions Worsening of the underlying disease or of other pre-existing conditions will be recorded as an (S)AE in the (e)CRF If serious, an SAE form has to be completed in addition Markers for a worsening could be but are not limited to: Fulfillment of SAE criteria Investigational drug is discontinued or the dose is reduced or increased Additional treatment is required, i.e. concomitant medication is added or changed Any other intervention is performed Judged clinically relevant by the investigator Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on:

13 Surgical Procedures That Are Considered AEs A surgical procedure is considered an AE if, after obtaining informed consent: An event emerges in a patient that requires a surgical procedure or medical intervention OR The decision is made to have surgery or a medical procedure on a pre-existing condition (by default, the decision to have a surgical procedure would be considered a marker of an exacerbation of a pre-existing condition) Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: These surgical procedures DO require reporting on the SAE case form

14 Surgical Procedures That Are NOT Considered AEs Pre-planned surgical procedures and medical interventions are NOT considered AEs if: The surgery or medical intervention was planned before obtaining informed consent or before trial medication was administered AND The condition for which the surgical procedure was scheduled has not worsened since the surgery or intervention was scheduled Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: These surgical procedures DO NOT require reporting on the SAE case form

15 Test Your Knowledge The following would be considered adverse events: Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 1. Patient was hospitalised to have surgery for a pre-existing event that worsened after informed consent 2. Patient was admitted for a surgical procedure planned prior to informed consent and the condition has not worsened 3. Patient had elevated white blood cell count (WBC) with no accompanying diagnosis and the patient was treated with antibiotics 4. Patient was diagnosed with pancreatic cancer after signed informed consent

16 Test Your Knowledge Which of these events would meet the SAE criteria for hospitalisation? Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 1. Emergency room treatment without an overnight stay 2. Prolongation of hospitalisation 3. Hospitalisation due to social circumstances 4. The event would have normally required hospitalisation but the patient was not hospitalised 5. Overnight admission to the hospital

17 Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: B. Reporting Responsibilities

18 AE Reporting Timeframe Upon trial initiation, report all AEs: Once informed consent has been obtained until the end of the observation period as specified in the protocol Regardless of whether or not study medication has been administered All SAEs/significant AEs and medically or temporally related non- serious AEs must be reported to Drug Safety within 24 hours of awareness or the next business day, whichever is shorter Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on:

19 Recording AEs and SAEs All AEs are to be recorded on the patient’s medical records and CRFs In addition, all SAEs are recorded on a separate BI SAE case form The SAE Report Form must also be completed for non-serious AEs if they: Occur at the same time as an SAE AND / OR Are medically related to the SAE AND/OR Are defined in the protocol as a significant event Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on:

20 Post-Study Events Post-study events are any SAEs that occur after the last observational period or after the patient’s participation in the trial is concluded, as defined in the trial protocol Post-study SAEs related to any of the study medications and / or study design are reportable by the investigator to the sponsor on the paper form only but should not be entered in RDC Deaths (unless considered drug- or trial-related) will not be reported as SAEs if occurring after the EoT visit, since death will be followed-up separately (key secondary endpoint). But death must be collected in RDC in any case.. Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on:

21 Test Your Knowledge Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 1. True 2. False False, AEs are collected once the pt has signed informed consent.

22 Test Your Knowledge Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 1. True 2. False False : Non-serious AE should be included on the SAE form if temporally or medically related to the SAE or if it is significant per protocol.

23 Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: C. Pregnancy Reporting

Pregnancy Reporting After obtaining informed consent, any pregnancy during / after exposure to study medication must be reported on the pregnancy monitoring form (paper form) Pregnancies themselves are NOT considered SAEs; however, they may be accompanied by an SAE If a pregnancy is accompanied by an SAE, an SAE case form must be completed Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 24 Pregnancy forms must be sent within 24 hours of awareness or next business day, whichever is shorter

Reporting Pregnancies With and Without an SAE Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 25 Patient is pregnant and has an accompanying SAE: Complete the Pregnancy Monitoring Form for Clinical Trials and fax to contact defined in ISF Complete the SAE case form: Mark the pregnancy box “yes” Record the weeks of gestation Patient is pregnant with no accompanying SAE: Complete the Pregnancy Monitoring Form for Clinical Trials and fax to contact defined in ISF immediately No SAE case form is required

Pregnancy Form The Pregnancy Form has two pages: Part A is completed and submitted upon first awareness of pregnancy in a female subject during or after exposure to trial medication Part B is completed and submitted upon delivery, termination or outcome of pregnancy Both Part A and Part B must be signed by the investigator 26 Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on:

27 Pregnancy Form: Part A RecordMaternalInformation Investigatorsignaturerequired Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on:

28 Pregnancy Form: Part B Recordpregnancyoutcomeinformation Recordinformationregarding thebaby Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: Investigatorsignaturerequired

29 Test Your Knowledge Which statements are true regarding the reporting of a pregnancy? Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 1. All pregnancies should be reported on the Pregnancy Monitoring Form and an SAE case form 2. The Pregnancy Monitoring Form is a paper form that must be completed and faxed to the sponsor 3. The investigator must sign both Part A and Part B of the Pregnancy Monitoring Form 4. The investigator is responsible for following up on the outcome of the pregnancy

30 Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: D. Regulatory Reporting

31 Variables That Determine Regulatory Reporting Seriousness / significance (assessed separately by investigator and BI) Causal relationship (assessed separately by investigator and BI) Listedness (assessed by BI only) Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on:  It is imperative that this information is collected for all (S)AE reports

Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: Expedited Reports BI prepares the safety reports required for the Regulatory Authorities to whom the report will be submitted: BI submits the reports to Health Authorities, investigators and central IRBs / IECs per local regulations 32 NEW: CIOMS reports for events from clinical trial source now contain all the information required by both regulators in the US and EU!

Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: Prepare for IND Safety Reports – US Only BI is responsible for submitting IND Safety Reports by day 15 to the FDA and participating investigators in the trial The GPVC US CSR (Central Safety Report) Group submits the IND Safety reports to the US investigators participating in IND trials for that product – IND Safety reports are submitted by BI to central IRBs – IND Safety reports are submitted by investigators to local IRBs 33 Investigators may receive IND Safety Reports for more than one trial and are obligated to review them, file them in the respective ISF and inform their IRB as applicable

Prepare for IND Safety Reports – Outside the US GPVC US Operations, Central Safety Reporting (CSR) continues to distribute the CIOMS included in the IND safety reports to CSOs who are responsible for distribution by day 15 The CSO distributes the CIOMS according to local regulations (may be distributed through CML) Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 34

Prepare for IND Safety Reports – Outside the US For those areas that have a local requirement to expedite SUSAR reports to all investigators participating in a trial for the IMP within 15 days: IND safety reports generated from a clinical trial source do not need to be sent in parallel to SUSAR reports IND safety reports generated for a marketed product classified as a spontaneous report (non-clinical trial source), must be submitted to all active IND investigators within 15 days For those areas that do not have local requirement to expedite SUSARs to investigators participating in a trial for the IMP within 15 days: All IND safety reports (clinical trial source and non-clinical trial source) must be submitted to all active IND investigators within 15 days Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 35

36 Test Your Knowledge The Investigator must make a causal assessment between the event and which of the following: Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 1. Study medication 2. Type of study blinding 3. Each concomitant medication 4. Study design

37 Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: E. Safety Reporting and Related Processes

SAE Form and Instructions Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 38

Page 1: Header and Fax Information Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 39 Patient number must be entered on every page

Page 1: Investigator Signature and Patient Demographics Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 40 Mark as initial or follow-up Investigator signature required

Page 2: Event Information Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 41 If known, provide diagnosis instead of signs / symptoms Record up to three events on each report

42 Reporting Signs and Symptoms If known diagnosis is preferred over signs and symptoms If diagnosis is NOT known, report all signs and symptoms Upon follow-up, if the diagnosis is known replace the signs and symptoms with diagnosis If the event is an exacerbation of pre-existing condition, record as “exacerbation of” the condition The event term must be specific enough to capture what the patient experienced as it was reported Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on:

Page 2: Event Information (Continued) Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 43 Indicate if therapy for the event was administered Mark serious criteria for event Mark during which trial phase(s) the event occurred

Significant Adverse Events Events classified as significant events are defined in the clinical trial protocol These events are to be reported on an SAE Form and forwarded to the sponsor and are handled by BI in the same manner as serious events Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 44

Page 2: Event Information (Continued) Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 45 Investigator must make a causality assessment

46 Causality Assessment The expression “reasonable causal relationship” is meant to convey, in general, that there are facts (evidence) or arguments to suggest a causal relationship Mark the “Yes” box if there is a reasonable causal relationship Mark the “No” box if there is not a reasonable causal relationship  Note: Medical judgment should be used when determining causality Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on:

47 Causality Assessment (continued) When completing the AE CRF, the investigator must provide a causal relationship assessment : Between each event and study medication In addition, on the SAE case form, the investigator must provide a causal relationship assessment between: Between each event and study design Between each event and concomitant medication (including Non-Investigational Medicinal Products (NIMPs) ) Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on:

AEs Associated With Study Design Capturing events associated with study design is a regulatory requirement in the EU / EEA and must be reported Study design includes, but is not limited to: Medication restrictions Medication washout periods Invasive procedures, (e.g. protocol-specified biopsy) NIMPs defined in the clinical trial protocol 48 Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on:

Page 2: Event Information (continued) Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 49 Mark death information if applicable Mark the outcome of each event Check box if additional information is provided and number additional pages 2a) 2b), etc.

Page 3: Rationale of Causality Assessment Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 50 List the event number from page 2 next to its description

Page 3: Description of Event(s) Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 51 List the event number from page 2 next to its description Check box if additional information is provided and number additional pages 3a) 3b), etc.

Page 4: Baseline Conditions Including Past Medical History Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 52 List baseline conditions. Tick ‘None’ if no concomitant or past diseases for the patient are available. Mark the “past” box if applicable

Page 4: Study Medication Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 53 Mark the action take for each event Mark if administration ofstudy medication was correct Mark if the blind was broken and enter date

Page 5: Relevant Past / Concomitant Therapy Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 54 Indicatecausalrelationship Check box ifadditionalinformation isprovided andnumber additionalpages 5a, 5b, etc. Include ONLYrelevant past /concomitant therapiesor NIMPs, e.g.background and / orrescue medications(NIMPs) Tick ‘None’ if noconcomitant / pastmedications weregiven

Relevant Past and/or Concomitant Therapies 55 Include: All relevant medications Past medication Medications being given at the onset of the AE Background medication if NOT related to any AE Do NOT include: Study medication Medications used to treat the AE Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on:

Follow-up Information on SAE Cases SAE reports should be updated following the same timeline for reporting the original SAE All changes must be initialed and dated In case of multiple changes, it is recommended to provide a new SAE Form with the previous information transcribed or copied to the new SAE Form If changes are made in Word to the SAE From, always copy the previous version and add changes; all versions must be saved and stored by the investigator Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 56

SAE Form: Documenting Follow up Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 57 Handwritten changes to form must be single-line crossed out, initialed and dated; add correct information

58 Test Your Knowledge Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 1.BI Trial Number 2.Country 3.Site Number 4.Patient Number All the information listed must be in the header on each page of the SAE case form.

59 Test Your Knowledge Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 1.Fever 2.Chills 3.Productive cough 4.Flu symptoms (diagnosis pending) Because a diagnosis has not been made, all signs and symptoms should be listed as separate events.

60 Test Your Knowledge Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 1.Each event and study medication 2.Each event and study design 3.Each event and concomitant medication 4.Only BI can make a causality assessment The investigator must make a causality assessment between each event and the study medication, study design and concomitant medication.

61 Test Your Knowledge Global Pharmacovigilance Training slides on the SAE Reporting Process Version 1.0 effective on: 1.Background medication if NOT related to the AE 2.Study medication 3.Medications being given at the onset of the AE 4.AE treatment medications Relevant past and/or concomitant therapies include anything that could potentially contribute to the AE or assessment of AE but do NOT include study medications or medications used to treat the AE.