Safety Workshop: Part II Expedited Reporting & Assessment

1. Safety Workshop: Part IIExpedited Reporting & Assessment Olu Ogunyankin, MD DAIDS Regulatory Support Center (RSC) Durban, South Africa May 13, 2011

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

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

4. Manual for Expedited Reporting Version 2.0 • Manual v2.0 (dated Jan 2010) was issued and posted on RSC website • Primary goal for the revision from v1.0 to v2.0 is to align expedited reporting to ICH-SAE definition • Fulfill DAIDS’ regulatory requirements to FDA • Fulfill DAIDS’ obligations to industry collaborators

5. DefinitionsManual v2.0

6. Expedited Adverse Event (EAE) • An adverse event that meets the criteria for expedited reporting to Division of AIDS (DAIDS). • In Manual v1.0, EAE did not map exactly to SAE • In Manual v2.0, EAE was aligned to SAE • Protocol can specify additional reporting to DAIDS

7. SUSAR - OnlySuspected, Unexpected, Serious Adverse Reactions Expedited Adverse Event Reporting to DAIDS • SAE - All Serious Adverse Events Two Reporting Categories: • The protocol will specify which reporting category will be used

8. Expedited Adverse Event Reporting to DAIDS 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

9. 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; regardless of who provides the drugs/products • Study agents will be specified in the protocol

10. Reporting Period • Protocol specified reporting period: from enrollment to end of trial follow-up for that participant • After the protocol-defined AE 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).

11. Serious Adverse Event (SAE) • Definition for SAE is per ICH E2A • Certain DAIDS protocols will have expedited reporting of all SAEs, prior to Manual v2.0 • E.g. A5241, MTN 003, P1066, P1060 • All protocols coming to SRCs after May 2010 are required to use Manual v2.0. • Existing protocols with data collection beyond May 31, 2011 required to switch to Manual v2.0 unless they have been approved by DAIDS for an exemption

12. 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

13. 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. • Therefore life-threatening means immediatelly life-threatening which is not the same as potentially life-threatening.

14. 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)

15. Clarification on SAE Definition: Hospitalization cont’d • 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

16. 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) • Example: 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

17. Clarification on SAE Definition: Congenital anomaly/birth defect cont’d • 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.

18. 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

19. 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

20. 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

21. Assessment ofAdverse Events

22. Assessment • AEs are assessed for: • Seriousness • Severity • Expectedness • Relationship • Study physician listed on the1572 / Investigator of Record (IoR) Agreement is responsible for the assessment of AEs • Sponsor Level: DAIDS MOs provide secondary review; consult with SPT prn

23. 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

24. 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 Gastroesophageal Reflux • Primary Adverse Event 1 Acute Renal Failure • Primary Adverse Event 2 Gastroesophageal Reflux

25. Hospitalization • 61 y.o. HIV-infected, African-American male, enrolled Feb 15, 09, with Gr. 4 hospitalization May 8, 09 • Feb 20, 09: subject was started on study agents ABC and XYZ. • May 8, 09: 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

26. 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’

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

28. 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.” • Follow-up for more details is necessary

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

30. 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

31. 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 grading table

32. 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 AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0 - December 2004 (Clarification dated August 2009)

33. Estimating Severity Grade Grade 1 – Mild Symptoms causing no or minimal interference with usual social & functional activities. • When a subject experiences a chest pain which does not interfere with the subjects’ activity of daily living; then it is graded as 1. Grade 2 – Moderate Symptoms causing greater than minimal interference with usual social and functional activities. • When the chest pain is such that the subject, is unableto do someof their activities of daily living.

34. Severity Grade Grade 3 – Severe Symptoms causing inability to perform usual social & functional activities. • When the chest pain is such that the subject is unableto 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. • When the chest pain makes the subject unable to perform basicfunctions and is at riskof permanent impairment/persistent disability/death if no surgical or medical intervention is done

35. 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

36. 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 Grading Table: • E.g. grading by symptomatology • E.g. grading by numerical ranges

37. 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 0C, WBC: 14.0 with left shift • Sent to hospital for sepsis workup and treatment • AE term: neonatal sepsis, Severity: Grade 1 • Probable Sepsis is reasonable AE Term • Basis for severity grade?

38. Grading: Neonatal Sepsis cont’d • 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, Birth Wt: 3.35 kg, Ht: 47.5, HC: 34 cm, HR: 140 bpm, RR: 62 • 12 hrs after birth: developed tachypnea and fussiness, RR: 62, 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 cont’d

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

42. Issues With Grading • Death = Grade 5; clarified in DAIDS Grading Table, August 2009 • Potentially life-threatening = Grade 4; per DAIDS grading table • When lab values fall between two grades choose the higher grade • Grading abnormal laboratory values associated with a clinical AE: • Grade the clinical AE not the abnormal lab • 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 SAE)

43. Severity Grading: Grade 4 In the DAIDS Grading Table, Grade 4 events are referred to as potentially life-threatening events Thus a DAIDS Grading Table Grade 4 event does not automatically imply that it meets SAE criteria, if it is only potentially life-threatening Reminder: SAE criteria for LT refers to an immediate timeframe, not at some point in the future (potentially).

44. 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).

45. Relationship Assessment • When an SAE is assessed as “not related” to study agent(s), an alternative 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.

46. Relationship Assessment cont’d

47. 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 • SUSAR Reporting Category: • Site physician to determine expectedness • SAE Reporting Category: • Sponsor to determine expectedness

48. Expedited Reporting Processes

49. Overview of Reporting Timelines

50. SAE Reporting Category Flowchart