1. Expedited Reporting of Adverse Events to the DAIDS
Version 2
Division of AIDS / NIAID 1

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

3. Policy for Expedited Reporting of Adverse Events
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 is posted at: 3 3

4. Expedited Reporting of Adverse Events: Reporting Materials
Manual for Expedited Reporting of Adverse Events to DAIDS Version 2.0
EAE Reporting Form 2.0
EAE Reporting Form Completion Instructions 2.0
Division of AIDS (DAIDS) Adverse Event (AE) Grading Table (Clarification August 2009)
Protocol (and any applicable Letter of Amendment)
The Manual for Expedited Reporting of Adverse Events to DAIDS and the DAIDS AE Grading Table can be found on the RSC website at:
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5. 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
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6. 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
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7. Definitions Manual Version 2.0
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8. Division of AIDS / NIAID
Expedited Reporting of Adverse Events to DAIDS – Study Agents
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.
Placebos are also considered to be study agents.
The protocol will specify what the study agent(s) are.
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9. 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
SAE - All Serious Adverse Events
SUSAR - Only Suspected, Unexpected, Serious Adverse Reactions
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10. 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
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11. 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)
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12. Clarification on SAE Definition: Life-Threatening
Grade 4 events are referred to as potentially life-threatening events as defined in the DAIDS Tox Table
Therefore, a Grade 4 event does not automatically imply that it meets SAE criteria
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13. 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 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
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14. 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).
For 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.
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15. 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:
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 the sponsor to know.
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16. Clarification on SAE Definition: Important Medical Events
Examples of “Important Medical Events”:
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
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17. Division of AIDS / NIAID
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
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18. SUSAR Reporting Category
For many HVTN studies, SUSAR reporting is used 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. Refer to each individual protocol for specifics on this timeframe.
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
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19. Expedited Reporting of Adverse Events to DAIDS
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
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20. Division of AIDS / NIAID
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).
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21. Assessment of Adverse Events
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22. Division of AIDS / NIAID
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 Medical Officers (MOs) provide secondary review
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23. Division of AIDS / NIAID
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: Pneumonia
Clinically significant event associated with primary AE: Fever
Clinically significant event associated with primary AE: Cough
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24. Division of AIDS / NIAID
Primary Adverse Event
Is there an AE?
If there are associated symptoms, what is the primary AE?
How many primary AEs are there?
Events that are not clearly associated with the primary AE should be reported as separate events
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25. Division of AIDS / NIAID
Seriousness
Seriousness is based on the outcome of the AE
Examples:
Any death of a participant meets SAE criteria based on the outcome.
Gastroenteritis which required intervention and assessment at a hospital meets SAE criteria based on the outcome (hospitalization)
Use ICH-SAE definition provided in Manual v2.0
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26. Division of AIDS / NIAID
Severity
Severity refers to the intensity of a specific event.
Severity scales can be descriptive or numerical. For example, a headache can be described as:
Mild, moderate, or severe
Grade 1, 2, 3, or 4
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27. Seriousness Versus Severity
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 descriptor)
Determined using the SAE criteria
Determined using the DAIDS grading table
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28. 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 December 2004 (Clarification dated August 2009)
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29. Take Home Messages re: Severity Grading
Potentially life-threatening = Grade 4
Potentially life-threatening means at risk of death should the event occur in a more severe form
Grading needs to reflect the intensity of the event, not the outcome.
In the event a participant has a clinical condition (e.g. pneumonia) where different severity grades are involved (e.g. Grade 2 WBC count, Grade 3 fever and cough), grade the clinical AE as a whole as opposed to the individual lab abnormalities or associated signs and symptoms.
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30. Relationship Assessment
Relationship assessment changed from a five category to a two category classification
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).
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31. Division of AIDS / NIAID
SCHARP’s AE Log CRFs
SCHARP currently has two versions of the AE Log CRF. One has 5 relationship categories and one has 2.
All ongoing studies will continue to use the 5 category AE Log CRF
All new studies (as well as HVTN 505 and LTFU), will use the 2 category AE Log CRF.
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32. Division of AIDS / NIAID
SCHARP’s AE Log CRFs
For those studies using the 5 category AE Log CRF, but EAE Manual Version 2, please consider the following “mapping” guidance SCHARP received from OPCRO (dated July 1, 2010) when documenting the SAE relationship in DAERS and on the AE Log CRF.
“Mapping Strategy for Relationship Assessments Using Version 2.0 of the DAIDS EAE Manual”
EAE Manual V1.0  EAE Manual V2.0
Definitely related             Related
Probably related              Related
Possibly related               Related
  Probably not related         Not Related
Not related                        Not Related
This mapping strategy will be used during AE/EAE Reconciliation.
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33. 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.
SCHARP also asks that this information be provided for ALL AEs on the AE Log CRF.
If new information becomes available, the relationship assessment of any AE should be reviewed again and updated as required.
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34. Relationship Assessment
When submitting an AE in DAERS for a study agent that is a fixed dose combination agent, an assessment of attribution will be made for each component and the combination agent.
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35. Division of AIDS / NIAID
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
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36. Expedited reporting processes
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37. SAE Reporting Category Flowchart
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38. SUSAR Reporting Category Flowchart

39. 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.
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40. Division of AIDS / NIAID
New/Initial Reports
AEs that are reportable on New/Initial Reports:
New AE
Recurrent AE: only if the first AE has been resolved, is now reoccurring, and meets expedited reporting criteria
Pre-existing condition with an increase in severity
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41. Division of AIDS / NIAID
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))
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42. Division of AIDS / NIAID
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 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.
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43. 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).
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44. Site Investigator Signature
In the rare event that such physician(s) are not available for signature, sites may submit without signature to meet the reporting timeframe.
However, the signature and any necessary corrections or additions must be submitted within the next three reporting days.
The IoR or designee is responsible for designating at least one other physician who can perform the assessment and signature so as to provide uninterrupted coverage of monitoring AEs that will require expedited reporting.
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45. Division of AIDS / NIAID

46. Division of AIDS / NIAID
DAERS
For sites where DAERS has been implemented, all expedited adverse events and supporting information will be submitted to DAIDS using DAERS, unless the system is unavailable for technical reasons.
Use DAIDS EAE reporting form 2.0 if DAERS is not implemented.
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47. Division of AIDS / NIAID
How to Report EAEs
Reports must be submitted via DAERS:
DAERS: via web
For emergency use only:
Fax: or
(USA only)
If ing, scan or fax signature page
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48. Confirmation Of Receipt
DAERS will send a confirmation for all SAE reports.
It is the site’s responsibility to follow-up if they do not receive a confirmation .
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49. Division of AIDS / NIAID
Where to Get Help
RSC Safety Office:
Telephone: or (US Only)
Fax: or (US Only)
RSC Web Site:
DAIDS-ES Support:
Telephone:
or (US Only)
Fax:
Division of AIDS / NIAID

50. New Form for Expedited Reporting and Instructions 50

51. Version 2 Definitions/Requirements Division of AIDS / NIAID
Summary of Changes
Major Changes
Version 2 Definitions/Requirements
Jan 2010
Reporting Categories
SAEs (Serious Adverse Events)
SUSARs (Suspected Unexpected Serious Adverse Reactions)
Relationship to study agent
Related (Reasonable possibility)
Not Related (No reasonable possibility)
Relationship assessment for a combination product
Each component separately as well as the combination
Division of AIDS / NIAID

52. Version 2 Definitions/Requirements Division of AIDS / NIAID
Summary of Changes
Major Changes
(Reportability)
Version 2 Definitions/Requirements
Jan 2010
SAEs
Report only if there is exposure to study agent
Life-threatening events
SAE level: Report regardless of relationship
SUSAR level: Report if related and unexpected
Hospitalizations
Report only if associated with an AE (See exceptions noted on Slide 15)
Important medical events
Part of ICH-SAE criteria
Report per category of expedited reporting
Fetal Loss
Not required unless clinically significant congenital anomaly detected, or specified by protocol (See Slide 16)
IRIS events
Do not report
Division of AIDS / NIAID

53. Version 2 Definitions/Requirements Division of AIDS / NIAID
Summary of Changes
Major Changes
Version 2 Definitions/Requirements
Jan 2010
Grading
Grade 4 events are referred to as potentially life threatening events. Therefore not all Grade 4 events will meet SAE reporting criteria
AE Resolution
Sites must follow each AE until resolved or stable. Provide as update
New events versus Updates
Report as an update if any ongoing event has a change in the severity grade
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54. Division of AIDS / NIAID
Conclusion
Q&A
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