1. Safety Workshop: Part II Expedited Reporting & Assessment Olu Ogunyankin, MD DAIDS Regulatory Support Center (RSC) Durban, South Africa May 13, 2011 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 2

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

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 4

5. Definitions Manual v2.0

6. 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 6 Expedited Adverse Event (EAE)

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

8. 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 8 Expedited Adverse Event Reporting to DAIDS

9. 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 9 Expedited Adverse Event Reporting to DAIDS

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). 10

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 11

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 12

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. 13

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) 14

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 15

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 16

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.htmhttp://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 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. 17

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 18

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 19

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 20

21. Assessment of Adverse Events

22. Assessment AEs are assessed for: Seriousness Severity Expectedness Relationship 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; consult with SPT prn 22

23. Primary Adverse Event 23 Example: Primary AE: Myocardial Infarction If there are associated symptoms, what is the primary AE? Report only one primary AE per report. Clinically Significant Event Associated with primary AE: Chest Pain Clinically Significant Event Associated with primary AE: Dyspnea Is there an AE?

24. Primary Adverse Event 24 Example: Acute Renal Failure and Gastroesophageal Reflux Events that are not clearly associated with the primary AE should be reported as separate events. Events that are not clearly associated with the primary AE should be reported as separate events. Primary Adverse Event 1 Acute Renal Failure Primary Adverse Event 2 Gastroesophageal Reflux How many primary AEs are there?

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 25

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’ 26

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] 27

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 28

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

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 30

31. Seriousness is NOT the same as Severity Based on outcome of the AE and is a factor in determining reportability (regulatory definition) Seriousness Determined using the SAE criteria Determined using the SAE criteria Based on the intensity of the AE and is not a factor in determining reportability (clinical description) Based on the intensity of the AE and is not a factor in determining reportability (clinical description) Severity Determined using the DAIDS grading table 31

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) 32

33. Estimating Severity Grade 33 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 unable to do some of their activities of daily living.

34. Severity Grade 34 Grade 3 – Severe Symptoms causing inability to perform usual social & functional activities. 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. 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

35. 35 This table is used for estimating the severity grade of a clinical AE not specifically listed in DAIDS Grading Table EXAMPLE FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS

36. 36 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 0 C, 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? 37

38. Grading: Neonatal Sepsis cont’d 38 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? 39

40. Grading: Respiratory Distress cont’d 40

41. 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% O 2 : 70-80% Grading on basis of respiratory distress: Grade 4 Need medical intervention beyond 100% O 2 Transferred to NICU Grading on basis of alkalosis: Grade 2 Not appropriate because it does not reflect clinical picture in totality 41 Grading: Respiratory Distress cont’d

42. Issues With Grading 42 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). 43

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). 44

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. 45

46. Relationship Assessment cont’d 46

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 47

48. Expedited Reporting Processes

49. Overview of Reporting Timelines 49

50. SAE Reporting Category Flowchart 50

51. SUSAR Reporting Category Flowchart

52. 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. 52

53. Reporting Fetal Loss 53

54. New/Initial Reports AEs that are reportable on New/Initial Reports: New AE Recurrent AE: only if the first AE has resolved, is now reoccurring and meets expedited reporting criteria Preexisting condition with increase in severity 54

55. Updated Information Sites must follow each AE until the AE is resolved or stable For each AE reported to DAIDS, sites are required to submit an updated report to DAIDS as soon as significant additional information becomes available. The following are examples that must be submitted: An updated report documenting the stable or resolved outcome of the AE, unless the initial report included a final outcome Any change in the assessment of the severity grade of the AE or the relationship between the AE and the study agent Additional significant information on a previously reported AE (e.g., cause of death, results of re-challenge with the study agent(s)). 55

56. Reporting Timeframe Within 3 reporting days of site awareness that an event has occurred at a reportable level “Reporting days” are those that count toward the 3-day timeline provided for reporting of SAEs to DAIDS 56

57. Reporting Days The criteria used to determine reporting days are as follows: A reporting day starts at 12:00 AM (midnight) and ends at 11:59 PM local time. A day is counted as a reporting day regardless of the time of day that awareness occurred. The day a site indicates that site personnel became aware of an SAE that meets reporting criteria shall count as day 1 if that day occurs on a reporting day (i.e., Monday through Friday). If that day occurs on a non-reporting day (i.e., Saturday or Sunday), then the next reporting day shall count as day 1. Monday through Friday count as reporting days. Saturday and Sunday are not considered reporting days. Any holiday (U.S. or in-country/local) that occurs on a Monday through Friday counts as a reporting day. 57

58. Site Investigator Signature A site physician investigator or sub-investigator listed on the 1572 or the IoR Agreement must: Review and verify the completed report for accuracy and completeness Sign the report This physician makes the site’s final assessment of the relationship to study agent(s) 58

59. Site Investigator Signature 59

60. DAERS DAERS: DAIDS Adverse Experience Reporting System: An integrated module that is part of the DAIDS Enterprise System (DAIDS-ES) A secure, confidential, web-based system through which sites are required to submit expedited reports to DAIDS For sites where DAERS has been implemented, all SAEs and supporting information will be submitted to DAIDS using the DAERS, unless the system is unavailable for technical reasons Use DAIDS EAE reporting form if DAERS not implemented 60

61. Submitting Reports via DAERS DAERS URL: https://daidses.niaid.nih.gov/Phoenixhttps://daidses.niaid.nih.gov/Phoenix For emergency use only: FAX: 1-301-897-1710 or 1-800-275-7619 (USA only) Email: RSCSafetyOffice@tech-res.comRSCSafetyOffice@tech-res.com If e-mailing, include scan of signature page or FAX signature page DAERS will send a confirmation email for all SAE reports submitted. It is the site’s responsibility to follow-up if they do not receive a confirmation email. 61

62. Where to Get Help RSC Safety Office: E-mail: DAIDSRSCSafetyOffice@tech-res.comDAIDSRSCSafetyOffice@tech-res.com Telephone:+ 1-301-897-1709 or 1-800-537-9979 (US Only) FAX: +1-301-897-1710 or 1 -800-275-7619 (US Only) RSC Web Site: http://rsc.tech-res.comhttp://rsc.tech-res.com DAIDS-ES Support: E-mail: DAIDS-ESSupport@niaid.nih.govDAIDS-ESSupport@niaid.nih.gov Telephone: +1-240-499-2239 or 1-866-337-1605 (US Only) Fax: +1-301-948-2242 62

63. Questions?