Slide 2 2 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 Slide 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 3 Slide 4 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
http://www.niaid.nih.gov/LabsAndResources/resources/D
AIDSClinRsrch/Documents/eaereportpolicy.pdf 4 Slide 5 Highlights:
Major Changes Reporting Categories Categories of expedited
reporting Definitions Clarifications Assessment of Relationship to
study agent Terms 5 Slide 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 Slide 7
Definitions Manual v2.0 7 Slide 8 Expedited Reporting of Adverse
Events to DAIDS Two Reporting categories: The protocol will specify
which reporting category will be used 8 Slide 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 Slide 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) 10
Slide 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) 11 Slide 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. 12 Slide 13 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
Clarification on SAE Definition: Life-threatening Slide 14
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) Clarification on SAE Definition: Hospitalization 14 Slide
15 Clarification on SAE Definition: Hospitalization contd 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 Slide 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 Slide 17 Clarification on SAE Definition:
Congenital Anomaly/Birth Defect contd 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 sponsor notification 17 Slide
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 18 Slide 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 Slide 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
Slide 21 Assessment of Adverse Events 21 Slide 22 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 22 Slide 23 Serious
versus Severe Seriousness is NOT the same as Severity 23 Slide 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 1.0 - December 2004 (Clarification dated
August 2009) 24 Slide 25 25 Severity Grading 25 Slide 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 Slide 27 Relationship Assessment
contd 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. 27 Slide 28 Relationship Assessment contd 28 Slide 29
Expedited Reporting Processes 29 Slide 30 Determining Reportability
SAE Reporting Category Flowchart 30 Slide 31 Determining
Reportability SUSAR Reporting Category Flowchart 31 Slide 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 32 Slide 33 Reporting Fetal Loss 33
Slide 34 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)). 34 Slide 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 35 Slide 36 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 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. 36 Slide 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 sites final assessment of the relationship to study agent(s) 37
Slide 38 Site Investigator Signature contd 38 Slide 39 39 DAERS
(Phoenix) Release v1.60: Changes for Manual v2.0 Slide 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 40 Slide 41 DAERS Changes for Manual
v2.0 41 Slide 42 DAERS Changes for Manual v2.0 42 Slide 43 43 DAERS
(RELIANT) Release 1.6: Changes for Manual v2.0 Slide 44 44 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 Slide 45 45 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. Slide 46 46 DAERS EAE
Processing MO and SPT Screens 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 Slide 47 47 DAERS EAE Processing Slide 48
48 DAERS EAE Processing MO and SPT Screens 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) Slide 49 49 DAERS EAE Processing Slide 50 50 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 Slide 51 51 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. Slide 52 DAERS EAE Processing 52 Slide 53 Summary
of Changes 53 Slide 54 Summary of Changes 54 Slide 55 Summary of
Changes 55 Slide 56 New EAE Form and Instructions http://rcc.tech-
res.com/safetyandp harmacovigilance/ 56
