1. 1

2. Distinguish changes in Manual v2.0
Objectives
Distinguish changes in Manual v2.0
Define key terms
New algorithm for reportability
Causality assessment
Implementation
Distinguish DAERS changes for Manual v2.0
Phoenix v1.6
Reliant v1.6 2

3. Development of Manual v2.0 for Expedited Reporting to DAIDS
SAEC WG: Safety and Adverse Events Core Working Group
Members:
Vaccines: Libby Adams (SME)
Prevention: Jeanna Piper (SME)
Therapeutics: Karin Klingman (SME), Kathy Smith
Pediatrics: Ed Handelsman, Renee Browning
RCC Safety: Anu Jasti, Sandy Butler
SPT: Ling Chin  Jing Bao, Larry Allan, David Diwa
OPCRO: Richard Hafner, Scott Proestel
DAERS: Peter Kim
Primary goal is to align expedited reporting to ICH-SAE definition.
Fulfill DAIDS’ regulatory requirements to FDA
Fulfill DAIDS’ obligations to industry collaborators

4. EAE Policy and Location
Purpose:
To describe requirements for reporting adverse events in an expedited timeframe to DAIDS
Scope:
This policy applies to all NIAID (DAIDS) supported and/or sponsored clinical trials
Revised policy will be posted on or before May 3 4 4

5. Highlights: Major Changes
Reporting Categories
Categories of expedited reporting
Definitions
Clarifications
Assessment of Relationship to study agent
Terms 5 5

6. Highlights: Major Changes
Submission of updates
Event Resolution
Increase in event severity of ongoing AEs
Timeframe for expedited adverse event reporting
Reporting days
Site investigator assessment and signature timeframe 6

7. Definitions Manual v2.0 7

8. Expedited Reporting of Adverse Events to DAIDS
Two Reporting categories:
The protocol will specify which reporting category will be used 8

9. Expedited Reporting of Adverse Events to DAIDS
Additional reporting requirements:
In addition, a protocol may require other AEs to be reported on an expedited basis
The protocol will specify the additional AEs to be reported to DAIDS 9

10. Expedited Reporting of Adverse Events 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
The protocol will specify the study agents(s)

11. 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)

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, or
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 13 13

14. Clarification on SAE Definition: Hospitalization
Hospitalization is 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)
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 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:
Guidelines for Conducting Birth Defects Surveillance, National Birth Defects Prevention Network (NBDPN), appendix Direct link to document:
This website listing should not restrict the reporting of anomalies that the site investigator deems important for sponsor notification
Jeanna Piper: This is just one of many reference materials the site might choose to use to assist with classification of anomalies. None of those reference materials should override site investigator judgment.

18. Clarification on SAE Definition: Important Medical Events
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 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
Not anticipated to be used frequently

21. Assessment of Adverse Events21

22. Sponsor Level: DAIDS MOs provide secondary review
Assessment
AEs are assessed for:
Seriousness
Relationship
Expectedness
Severity
Site Level: Study physician listed on the1572/IoR (Investigator of Record) Agreement is responsible for the assessment of AEs
Sponsor Level: DAIDS MOs provide secondary review
Order of AE assessment is based on the order specified in the manual. 22

23. Seriousness is NOT the same as Severity
Serious versus Severe
Seriousness is NOT the same as Severity
Make sure you emphasize the first bullet.
Spend a little more time on this slide. 23

24. Grading Severity of Events
All events reported to DAIDS in an expedited timeframe must be graded for severity
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events Version December (Clarification dated August 2009)
To sites: grading is not used to determine reportability 24

25. Severity Grading 25 25

26. 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). 26

27. Relationship Assessment cont’d
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.
In the absence of a proven diagnosis, investigator judgment is respected but there needs to be sufficient information to support their assessment for causality. 27

28. Relationship Assessment cont’d28

29. Expedited Reporting Processes

30. Determining Reportability SAE Reporting Category Flowchart

31. Determining Reportability SUSAR Reporting Category Flowchart

32. 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

33. Reporting Fetal Loss

34. Sites must follow each AE until the AE is resolved or stable
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, or
Additional significant information on a previously reported AE (e.g., cause of death, results of re-challenge with the study agent(s)).

35. 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 EAEs to DAIDS 
Mention the EAE submission timing calculator on the RCC website. 35

36. 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 EAE 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.

37. 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 and
Sign the report
This physician makes the site’s final assessment of the relationship to study agent(s) 37

38. Site Investigator Signature cont’d

39. DAERS (Phoenix) Release v1.60: Changes for Manual v2.039 39

40. DAERS Changes for Manual v2.0
DAERS will automatically reflect the changes in specified fields once a protocol using the EAE Manual Version 2.0 is selected
After a protocol has switched to the EAE Manual Version 2.0:
New EAEs will use EAE Manual Version 2.0
Updates to EAE reports created prior to the switch will continue using EAE Manual Version 1.0

41. DAERS Changes for Manual v2.041 41

42. DAERS Changes for Manual v2.042 42

43. DAERS (RELIANT) Release 1.6: Changes for Manual v2.043 43

44. Medical Officer Safety Assessment Screen
DAERS EAE Processing
Medical Officer Safety Assessment Screen
“Safety Report Required” Business Rules
For IND Studies
Case 1:
Site or MO assessment evaluation is Serious, and,
Site or MO relationship assessment is NOT “Not Related”, and
MO expectedness evaluation is “Unexpected”
Case 2:
Grade 5 (Death) and,
Site or MO relationship assessment is NOT “Not Related” 44

45. Medical Officer Safety Assessment Screen
DAERS EAE Processing
Medical Officer Safety Assessment Screen
For Non-IND Studies
The product will not enforce a safety report required decision. The RCC will enforce the current policy as required. 45

46. MO and SPT Screens DAERS EAE Processing Search Screen
Enabled user to open older EAEs in Read Only Mode
Users can review Safety Report document history
Resolution History
Pop-up window added to show the history of:
Participant Status
Observation Date
History is shown for the life of the EAE 46

47. DAERS EAE Processing 47

48. MO and SPT Screens DAERS EAE Processing Screen Header Updates
Reporting Manual: Displays full manual name, version, and version date
Reporting Category: Shows reporting method and level as appropriate
Reporting Manual: Manual for Expedited Reporting of Adverse Events to DAIDS, 1.0, 06-May-2004
Reporting Category: EAE (Standard) 48

49. DAERS EAE Processing 49

50. Medical Officer Safety Report Review Screen
DAERS EAE Processing
Medical Officer Safety Report Review Screen
Added field to collect action that will be taken as a result of reviewing the Safety Report
Need to check on one of the questions
One question requires comments
A response is required to complete the Safety Report Review 50

51. Medical Officer Safety Report Review Screen
DAERS EAE Processing
Medical Officer Safety Report Review Screen
Based on review of this adverse event report:
DAIDS does not believe that changes to the conduct of this trial are warranted at this time.
Discussions are underway to determine whether changes will be made to the conduct of this trial. DAIDS will inform the FDA and other appropriate authorities if any changes will be made.
The following changes to the conduct of this trial will be taken (please specify):
This response will require comments. 51

52. DAERS EAE Processing

53. Summary of Changes

54. Summary of Changes

55. Summary of Changes

56. New EAE Form and Instructions 56