DAIDS Safety Workshop: Part II Expedited Reporting & Assessment

1. DAIDS Safety Workshop: Part IIExpedited Reporting & Assessment Archita Chatterjee, M.S. DAIDS RSC Safety Office Johannesburg, South Africa 29 Aug 2012

2. Objectives • Definitions • Assessment of Adverse Events • Expedited Reporting Processes • About Manual v2.0

3. Expedited Reporting Materials • Manual for Expedited Reporting to DAIDS v2.0 • DAIDS AE Grading Table (Clarification Aug 2009) • Protocol • EAE Reporting Form 2.0 • EAE Reporting Form Completion Instructions 2.0

4. DefinitionsManual v2.0

5. SUSAR - Only Suspected, Unexpected, Serious Adverse Reactions Expedited Adverse Event Reporting to DAIDS SAE - All Serious Adverse Events Two Reporting Categories:

6. Expedited Adverse Event Reporting to DAIDS The protocol will specify which reporting category will be used Additional reporting requirements: • The protocol may require other AEs to be reported on an expedited basis; may or may not meet SAE criteria • These other AEs that are required to be reported to DAIDS will be specified in the protocol

7. Expedited Adverse Event Reporting to DAIDS • Study agent(s) – drugs biological agents, combination of drugs and biological agents or devices (approved or investigational) defined in the protocol for which expedited reporting to DAIDS is required • Study agents will be specified in the protocol

8. Reporting Period • Protocol specified reporting period: from enrollment to end of trial follow-up for that participant • After the protocol-definedAE reporting period, unless otherwise noted, only SUSARs will be reported to DAIDS if the study staff becomes aware of the events on a passive basis (from publicly available information)

9. SAE Definition (ICH E2A) A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: • Results in death • Is life-threatening • Requires inpatient hospitalization or prolongation of existing hospitalization • Results in persistent or significant disability/incapacity • Is a congenital anomaly/birth defect • Is an important medical event that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition above

10. Clarification on SAE Definition:Life-threatening Life-threatening refers to an event in which the patient was at risk of death at the time of the event • It does not refer to an event which hypothetically might have caused death if it were more severe • e.g., malignancy

11. Clarification on SAE Definition:Hospitalization Not an AE, but is an outcome of the AE • The following types of hospitalization do not require expedited reporting to DAIDS: • Any admission unrelated to an AE (e.g., for labor/delivery, cosmetic surgery, administrative or social admission for temporary placement for lack of a place to sleep) • Protocol-specified admission (e.g., for a procedure required by protocol)

12. Clarification on SAE Definition:Hospitalization • Admission for diagnosis or therapy of a condition that existed before receipt of study agent(s) and has not increased in severity or frequency as judged by the clinical investigator • A new AIDS-defining event in a subject already known to be HIV-infected would be considered an increase in severity of a pre-existing condition [HIV infection] and would be reportable as an expedited AE

13. Clarification on SAE Definition:Congenital Anomaly/Birth Defect Do not report clinically insignificant physical findings at birth, including those regarded as normal variants • Report clinically significant anomalies; include all other findings (even if not individually significant) • e.g., an isolated finding of polydactyly or Mongolian spot in an infant with no other findings would not be reported, but polydactyly or Mongolian spot occurring with a major cardiac defect would be included in the SAE report of the major cardiac defect

14. Clarification on SAE Definition:Congenital Anomaly/Birth Defect • Information about congenital anomalies can be found on the Centers for Disease Control and Prevention (CDC) website: http://www.cdc.gov/ncbddd/bd/monitoring.htm • Guidelines for Conducting Birth Defects Surveillance, National Birth Defects Prevention Network (NBDPN), appendix 3.1. Direct link to document: www.nbdpn.org/current/resources/sgm/appendix3-1.pdf • This website listing should not restrict the reporting of anomalies that the site investigator deems important for the sponsor to know.

15. Clarification on SAE Definition:Important Medical Events • Events considered as important medical events can meet SAE criteria • Examples: • Intensive treatment in an emergency room or at home for allergic bronchospasm • Blood dyscrasias or convulsions that do not result in hospitalization • Development of drug dependency or drug abuse

16. SUSAR Definition • SUSAR is defined as an adverse event that is a Suspected Unexpected Serious Adverse Reaction • For the SUSAR reporting category, an SAE will be reported if it fulfills the following criteria: • Related and • Unexpected

17. SUSAR Reporting Category • Used for some non-IND studies/trials using U.S. FDA-approved agents with approved dosages for approved indications in typical populations • At the discretion of DAIDS

18. Assessment ofAdverse Events

19. Assessment • AEs are assessed for: • Seriousness • Severity • Relationship • Expectedness • Study physician listed on the 1572/ Investigator of Record (IoR) Agreement is responsible for the assessment of AEs • Sponsor Level: DAIDS MOs provide secondary review

20. Primary Adverse Event Is there an AE? If there are associated symptoms, what is the primary AE? Report only one primary AE per report. Example: Primary AE: Myocardial infarction Clinically Significant Event Associated with primary AE: Chest pain Clinically Significant Event Associated with primary AE: Dyspnea

21. Primary Adverse Event How many primary AEs are there? Events that are not clearly associated with the primary AE should be reported as separate events. Example: Acute renal failure and Gastroesophagealreflux Primary Adverse Event 1 Acute renal failure Primary Adverse Event 2 Gastroesophagealreflux

22. Hospitalization • 8 May 2009: 61 year old HIV infected African American male (enrolled 15 Feb 2009), with Grade 4 hospitalization • 20 Feb 2009: subject was started on study agents LMN and XYZ • 8 May 2009: subject visited study clinic with complaints of abdominal pain and non-bloody diarrhea for the past one week • Vomited three times on the day of clinic visit

23. Teaching Points • Hospitalization in and of itself is not an AE term; it is an outcome of the AE • Grading should be on the AE, not the outcome of the AE • Primary AE: ? • Abdominal pain, non-bloody diarrhea, vomiting, vague generalized abdominal tenderness • Possible AE term: “Gastroenteritis,” NOT “Hospitalization” • However, if you do not have any information about the actual AE but the event is reportable you can report “Hospitalization.” Submit an update when additional significant information is available

24. Death • 14 Jan 2009: 40 year old HIV uninfected Asian female enrolled; started on the study agent XYZ at a dose of 32mg, sublingually, 4 times a week • 6 May 2009: Took dose of XYZ; went for clinic visit • 10 May 2009: died due to sudden death (AE term reported as “death”) • Hx of illicit drug use [study target pop: drug use]

25. Teaching Points • Death in and of itself is not an AE term; it is an outcome of the AE • Primary AE: • Sudden death (per death certificate) • Possible AE Term: Drug overdose (although not enough info provided for this) • However, if you do not have any information about the actual AE but the event is reportable you can report “Death unknown cause.” Submit an update when additional significant information is available

26. Seriousness Does primary AE meet criteria for an SAE? • Use ICH-SAE definition provided in Manual v2.0 • Select appropriate SAE criteria

27. Severity • Severity refers to the intensity of a specific event • Events are graded on a severity scale of 1-5: • 1 – Mild • 2 – Moderate • 3 – Severe • 4 – Potentially Life-threatening • 5 – Death

28. Seriousness is NOT the same as Severity ≠ Seriousness Severity • Based on outcome of the AE and is a factor in determining reportability (regulatory definition) • Based on the intensity of the AE and is not a factor in determining reportability (clinical description) • Determined using the SAE criteria • Determined using the DAIDS AE grading table

29. Grading Severity of Events • All events reported to DAIDS in an expedited timeframe must be graded for severity • Grading does not determine reportability • Division of DAIDS (DAIDS) Table for Grading the Severity of the Adult and Pediatric Adverse Events Version 1.0 – Dec 2004 (Clarification dated Aug 2009)

30. Severity Grade Grade 1 – Mild • Symptoms causing no or minimal interference with usual social & functional activities • e.g., When a subject experiences a chest pain which does not interfere with the subject’s activity of daily living Grade 2 – Moderate • Symptoms causing greater than minimal interference with usual social and functional activities • e.g., When the chest pain is such that the subject is unable to do some of their activities of daily living

31. Severity Grade Grade 3 – Severe • Symptoms causing inability to perform usual social & functional activities • e.g., When the chest pain is such that the subject is unable to carry out activities of daily living Grade 4 – Potentially Life-Threatening • Symptoms causing inability to perform basic self-care functions OR medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death • e.g., When the chest pain makes the subject unable to perform basic functions and is at risk of permanent impairment/persistent disability/death if no surgical or medical intervention is done

32. EXAMPLE FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS This table is used for estimating the severity grade of a clinical AE not specifically listed in DAIDS Grading Table

33. EXAMPLE FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS • This table is used for grading a clinical AE specifically listed in DAIDS AE Grading Table: • e.g., grading by symptomatology • e.g., grading by numerical ranges

34. Severity Grading • Manual Version 2.0 • Grade 4 events are referred to as potentially life-threatening events as defined in the DAIDS AE Grading Table • Thus a Grade 4 event per the DAIDS AE Grading Table does not automatically imply that it meets SAE criteria, if it is only potentially life-threatening [SAE criteria for LT refers to immediate timeframe, not potential at some point in the future, or if more severe]

35. Issues with Grading • Death = Grade 5; clarified in DAIDS AE Grading Table Aug 2009 • Potentially life-threatening = Grade 4 • Potentially life-threatening means at risk of death should the event occur in a more severe form. This is not the same as immediately life-threatening • Grading abnormal laboratory values associated with a clinical AE: • Does not correspond to grade provided in the DAIDS AE Grading Table • When lab values fall between two grades choose the higher grade • Grading does not appear to reflect the event: • Event led to hospitalization, but graded as “Grade 1” or “Grade 2” • Grade the SAE not the initial AE (initial AE had progressed to level of SAE)

36. Grading: Neonatal Sepsis Neonatal Sepsis Grade 1 • 27 day old, male infant, normal delivery, breastfed, nevirapine • 2 week visit: crying on urination, amoxicillin for 7 days • 3 week visit: refusing feed, brought back to clinic • PE: lethargic, HR: 140 bpm, RR: 58 bpm, T: 37.7°C, WBC: 14,000 with left shift • Sent to hospital for sepsis workup • AE term: Neonatal sepsis, Severity: Grade 1 • Neonatal Sepsis is reasonable AE Term • Basis for severity grade?

37. Grading: Neonatal Sepsis

38. Grading: Neonatal Sepsis • Grading on basis of fever alone: Grade 1 • Grading on clinical basis of possible sepsis: • at least Grade 3 • Grade 4 reasonable as well

39. Grading: Respiratory Distress Respiratory Distress Grade 2 • 2 day old male, delivered at 39 wks GA by C/S, started on oral zidovudine • PE: pale, flexed, not crying, given CPAP with improvement, APGAR: 6 at 5 minutes and 9 at 10 minutes, weight: 3.35 kg, length: 47.5 cm, HR: 140 bpm, RR: 62 bpm • 12 hrs after birth: developed tachypnea and fussiness, RR: 62 bpm, Pulse Ox on room air: 70% • Transferred to NICU, 100% oxyhood, Pulse Ox: 80%, pH: 7.48, pCO2: 27, pO2: 251, HCO3: 20 • PE: systolic murmur heard along left sternal border • Echo: Moderate PDA, ASD, patent foramen, mild TR, trivial MR • Respiratory Distress is reasonable AE Term • Basis for severity grade?

40. Grading: Respiratory Distress

41. Grading: Respiratory Distress • Grading on basis of respiratory distress: at least Grade 3 • Required CPAP at birth • 12 hours later: tachypnea and RR: 62 bpm • Room air and 100% O2: 70-80% • Grading on basis of respiratory distress: Grade 4 • Need medical intervention beyond O2 therapy • Transferred to NICU • Grading on basis of alkalosis: Grade 2 • Not appropriate because it does not reflect clinical picture in totality

42. Relationship Assessment The terms used to assess the relationship of an event to study agent are: • Related – There is a reasonable possibility* that the AE may be related to the study agent(s) • Not Related – There is not a reasonable possibility that the AE is related to the study agent(s) *Per 21 CFR 312.32, “reasonable possibility” means there is evidence to suggest a causal relationship between the drug and the adverse event.

43. Relationship Assessment • When an SAE is assessed as “not related” to study agent(s), an alternate etiology, diagnosis, or explanation for the SAE should be provided • If new information becomes available, the relationship assessment of any AE should be reviewed again and updated, as required • When the study agent is a fixed dose combination agent, an assessment of attribution will be made for each component and the combination agent as a whole

44. Expectedness • Expected AEs are events that have been previously observed with use of the study agent(s). It is not based on what might be anticipated from the pharmacological properties of the study agent • Listed in the Investigator’s Brochure or Package Insert • SAE Reporting Category: • Sponsor to determine expectedness • SUSAR Reporting Category: • Site physician and Sponsor to determine expectedness

45. Expedited Reporting Processes

46. Overview of Reporting Timelines

47. SAE Reporting Category Flowchart

49. Adverse Events Not Requiring Expedited Reporting to DAIDS • An SAE occurring before exposure to a study agent • Immune reconstitution inflammatory syndrome (IRIS), even if the event otherwise meets the reporting criteria. IRIS is an intense immune reaction that may result from a response to HIV treatment and is an anticipated event for antiretroviral therapies

50. New/Initial Reports AEs that are reportable on New/Initial Reports: • New AE • Recurrent AE: only if the initial AE has resolved, is now reoccurring, and meets expedited reporting criteria to DAIDS • Pre-existing condition with increase in severity