1. Manual v2.0 Changes and DAERS Lawrence Allan (HJF – DAIDS) Dr. Oluwadamilola Ogunyankin (RSC Safety Office) Lawrence Allan (HJF – DAIDS) Dr. Oluwadamilola Ogunyankin (RSC Safety Office) November 15, 2010 HVTN Network Meeting. Seattle, WA November 15, 2010 HVTN Network Meeting. Seattle, WA

2. Objectives  Expedited Reporting Policy  Distinguish changes in Manual v2.0 Define key terms New algorithm for reportability Causality assessment  Distinguish DAERS changes for Manual v2.0 2

3. Manual for Expedited Reporting Version 2.0  Manual v2.0 (dated Jan 2010) has been issued and posted on Regulatory Support Center (RSC) website  Primary goal of this revision is to align expedited reporting to International Conference on Harmonization – Serious Adverse Event (ICH-SAE) definition Fulfill the DAIDS’ regulatory requirements to Federal Drug Administration (FDA) Fulfill the DAIDS’ obligations to industry collaborators 3

4. Highlights: Major Changes  Categories of expedited reporting  Clarification of Definitions  Terms used in the assessment of Relationship to Study Agent  Submission of updates Event resolution Increase in event severity of ongoing AEs  Timeframe for expedited AE reporting Reporting days Site investigator assessment and signature timeframe 4

5. Summary of Changes 5

6. 6

7. Expedited Reporting of Adverse Events to DAIDS Two Reporting Categories: The protocol (and any applicable Letter of Amendment) will specify which reporting category will be used 7

8. SAE Reporting Category 8

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 9

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)  Grade 4 events are referred to as potentially life-threatening events as defined in the DAIDS AE Grading Table; a Grade 4 event does not automatically meet SAE criteria Asymptomatic male subject presents with AST & ALT > 400 IU/L Asymptomatic female subject presents with a Hgb of 6.5 g/dL –Both events are Grade 4 events (per the AE grading table), but neither subject is “…at risk of death at the time of the event.” 10

11. Clarification on SAE Definition: Hospitalization 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 due to lack of a place to sleep)  Protocol-specified admission (e.g. for a procedure required by protocol)  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 NOTE: Hospitalization is not an AE, but is an outcome 11

12. 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 and 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. NOTE: DAIDS clarification 12

13. SUSAR Reporting Category 13

14. SUSAR Reporting Category Used for some non-Investigational New Drug (non- IND) studies/trials using U.S. FDA-approved agents with approved dosages for approved indications in typical populations  At the discretion of DAIDS NOTE: Since the majority of HVTN protocols are for unapproved vaccine products, the SAE reporting category would apply most of the time. 14

15. SUSAR Reporting Category For many HVTN studies, SUSAR reporting is used during the period of extended surveillance, after the main study reporting period has been completed  For a particular participant, “Main Study Reporting Period” typically means from study enrollment until completion of the main study or discontinuation from study participation  If the protocol specifies an extended period of surveillance via annual contacts, this period is known as the “Annual Health Contact Period” (after main study period, continuing for X years thereafter)  During the annual health contact period, only SUSARs are reported 15

16. SAE vs. SUSAR examples Hospitalization for lithium overdose, 9 months since last vaccination, 3 months after termination from the study. Assessed by site PI as not related. Identified during Annual Health Contact reporting period, SUSAR category of reporting  SAE: Yes (Hospitalization)  SUSAR: No  Category of reporting per protocol: SUSAR  Reportable: No 16

17. SAE vs. SUSAR examples Marked injection site muscle atrophy with arm weakness affecting ADLs reported during an annual health contact visit,1 year after last study visit, 18 months since last vaccination. Considered related due to anatomical location and an isolated similar finding in animal toxicity studies. Identified during Annual Health Contact reporting period  SAE: Yes (Important medical event)  SUSAR: Yes  Category of reporting per protocol: SUSAR  Reportable: Yes NOTE: All SUSARs are SAEs, NOT all SAEs are SUSARs 17

18. Reporting Category: SAE or SUSAR Additional reporting requirements:  A protocol may require other AEs to be reported on an expedited basis e.g. all liver toxicities (regardless of seriousness or severity)  The protocol will specify the additional AEs to be reported to DAIDS 18

19. 19 EXPEDITED REPORTING PROCESS

20. 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. 20

21. Updated Information Sites must follow each AE until the AE is resolved or stable. For each event reported to DAIDS, sites are required to submit an updated report 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] A change in the primary AE term from what was previously reported 21

22. New/Initial Report vs. Update

23. Reporting Timeframe Within 3 reporting days of site awareness that an event fulfills the protocol-defined criteria for expedited reporting to DAIDS  “Reporting Days” criteria: Starts at 12:00 a.m. and ends at 11:59 p.m. (local time) A day is counted as a reporting day regardless of the time of day that awareness occurred. Monday through Friday count as reporting days. Saturday and Sunday not considered reporting days. Any holiday (U.S. or in-country/local) that occurs on a Monday through Friday counts as a reporting day. 23

24. 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 NOTE: This physician makes the site’s final assessment of the relationship to study agent(s) 24

25. DAERS For sites where DAERS has been implemented, ALL expedited adverse events and supporting information MUST be submitted to DAIDS using DAERS  Use DAIDS EAE reporting form 2.0 if DAERS has not been implemented, or if the system is unavailable for technical reasons. 25

26. 26 ASSESSMENT OF ADVERSE EVENTS

27. Primary Adverse Event

28. Grading Severity of Events All events reported to DAIDS in an expedited timeframe must be graded for severity.  Grading does not determine reportability to DAIDS.  Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0 - December 2004 (Clarification dated August 2009) 28

29. Seriousness Versus Severity

30. Relationship Assessment The terms used to assess the relationship of an event to study agent are: 30

31. 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. 31

32. SCHARP’s AE Log CRFs SCHARP currently has 2 versions of the AE Log CRF. One has 5 relationship categories (Definelty, Probably, Possibly, Probably Not, or Not Related) The other has 2 relationship categories (Related or Not Related)  All ongoing studies will continue to use the five category AE Log CRF  All new studies (as well as HVTN 505 and LTFU), will use the two category AE Log CRF. 32

34. SCHARP’s AE Log CRFs For those studies using the five category AE Log CRF, but EAE Manual Version 2, please consider the following “mapping” guidance when documenting the SAE relationship in DAERS and on the AE Log CRF  “Mapping Strategy for Relationship Assessments Using Manual Version 2.0” Manual V1.0 Manual V2.0 Definitely relatedRelated Probably relatedRelated Possibly relatedRelated Probably not relatedNot Related Not relatedNot Related  This mapping strategy will be used during AE/EAE Reconciliation. 34

35. 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 (IB)  SAE reporting category: Sponsor to determine expectedness  SUSAR reporting category: Site physician to determine expectedness 35

36. Expectedness For unapproved products: Expected AEs are determined on the basis of the IB. Events are unexpected if:  Not listed in the IB  Occur at a specificity/severity that has not been previously observed  Expected based on the drug class, but not yet observed with the specific drug in this drug class  Occur at a greater frequency than anticipated 36

37. DAERS CASE REVIEW AND DEMONSTRATION

38.  10 Nov 2010 – Subject enrolled into the study and randomized; receives 1 st administration of study vaccine: MRKAd5 HIV-1 gag/pol/nef OR Placebo for MRKAd5  13 Nov 2010 – Subject presents to the ER complaining of sudden onset of severe abdominal pain (no previous history of GI issues or alcohol abuse), and is admitted for further testing and evaluation. Labs on admission were significant for elevated lipase (350 IU/L; normal 7 - 60 IU/L).  15 Nov 2010 – Subject contacts the site and notifies them that she was admitted, and remains hospitalized. 38 Case Study

39. Reporter and Site Information  Site Awareness Date: “…when the clinical research site recognizes that an event fulfills the protocol-defined criteria for expedited reporting to DAIDS.” Date serious adverse event (SAE) occurred –13 Nov 2010 Date site aware event occurred at a reportable level –15 Nov 2010 39

40. Must submit within 3 ‘reporting days’ of site awareness Timeline for Submission

41. Primary Adverse Event  Seriousness Criteria (select appropriate ICH-SAE criteria; more than one criteria can be selected) Requires inpatient hospitalization or prolongation of existing hospitalization  Primary Adverse Event Abdominal Pain  Severity Grade 4 – Potentially life-threatening 41

42. Primary Adverse Event (continued)  Onset Date: The date the primary adverse event first occurred at the level requiring expedited reporting 13 Nov 2010  Country of AE Origin: The country where the event occurred; may not necessarily be the same where the clinical site is located USA  Status Code at Most Recent Observation: The status code of the subject at the most recent observation Not Recovered/Not Resolved  Status Date: Date of the most recent observation of the subject 15 Nov 2010 42

43. Case Narrative Provide information on reported primary AE  Describe the clinical course, therapeutic measures, outcome, relevant past medical history, concomitant medication(s), alternative etiologies, any contributing factors, and all other relevant information. NOTE: Any significant information that doesn’t have a field in DAERS can be included in the case narrative (e.g., results of a re-challenge). 43

44. Study Agent  Not a free text field  Choose study agent from drop down menu MRKAd5 HIV-1 gag/pol/nef OR Placebo for MRKAd5  Exposure to and duration of use of study agent important information to assess the case Ensure accuracy of information If unsure, please note that the date is estimated 44

45. Study Agent (continued)  Relationship of Study Agent to Primary AE Related  Dose 1 milliliter  Date of First Dose 10 Nov 2010  Date of Last Dose: The date the subject took the last dose prior to onset of the adverse event 10 Nov 2010 45

46.  Action Taken: Enter the study physician’s action taken with the study agent after awareness of the SAE Temporarily Held  Action Date: Date has to be on or after the site awareness date (i.e., study physician can take action with study agent only after site is aware AE has occurred at a reportable level). If action taken is “Course Completed” or “Off Study Agent at AE Onset” action date can be left blank. 15 Nov 2010 46 Study Agent (continued)

47. Concomitant Medications: None Other Events: List other clinically significant signs and symptoms that more fully describe the nature, severity, and/or complications of the primary AE. None Laboratory Tests (include normal range, if known): Elevated lipase (350 IU/L; normal 7 – 60 IU/L) Diagnostic Tests: None 47 Concomitant medications Laboratory and Diagnostic tests

48. Reporter:  Completes and sends the report to submitter for final review Submitter:  Reviews and submits the report to DAIDS  Email notification of expedited report submission sent to CRS staff and other key stakeholders NOTE: It’s the site’s responsibility to confirm that the report was in fact submitted. 48 Review and Submission

49. Update  17 Nov 2010 – Subject is discharged from the hospital; event is ongoing.  18 Nov 2010 – Subject seen at the study clinic and provides a copy of discharge summary with diagnosis of acute pancreatitis. 49

50. Update (continued)  Primary Adverse Event Term: Acute pancreatitis Status Code: Recovering/Resolving Status Date: 18 Nov 2010  Case Narrative Do not delete previous narrative when updating  Additional Information Upload copy of the discharge summary 50

51. How to Report EAEs Reports must be submitted via DAERS: DAERS: via web https://daidses.niaid.nih.gov/Phoenix For emergency use only: –Fax: 1-301-897-1710 or 1-800-275-7619 (USA only) –Email: DAIDSRSCSafetyOffice@tech-res.comDAIDSRSCSafetyOffice@tech-res.com If e-mailing, scan or fax signature page 51

52. Where to Get Help  RSC Safety Office: E-mail: DAIDSRSCSafetyOffice@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.com/  DAIDS-ES Support: E-mail: DAIDS-ESSupport@niaid.nih.gov Telephone:+1-240-499-2239 or 1-866-337-1605 (US Only) Fax:+1-301-948-2242 52

53. QUESTIONS? 53