DAIDS Safety Workshop: Part II
Expedited Reporting & Assessment
Archita Chatterjee, M.S.
DAIDS RSC Safety Office
Johannesburg, South Africa
29 Aug 2012
Objectives
 Definitions
 Assessment of Adverse Events
 Expedited Reporting Processes
 About Manual v2.0
2
Expedited Reporting Materials
 Manual for Expedited Reporting to DAIDS v2.0
 DAIDS AE Grading Table
(Clarification Aug 2009)
 Protocol
 EAE Reporting Form 2.0
 EAE Reporting Form
Completion Instructions 2.0
3
Definitions
Manual v2.0
Expedited Adverse Event Reporting
to DAIDS
Two Reporting Categories:
SAE - All Serious Adverse Events
SUSAR - Only
Suspected, Unexpected, Serious
Adverse Reactions
5
Expedited Adverse Event Reporting
to DAIDS
The protocol will specify which reporting category
will be used
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
6
Expedited Adverse Event Reporting
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
 Study agents will be specified in the protocol
7
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)
8
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 lifethreatening 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
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
10
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)
11
Clarification on SAE Definition:
Hospitalization
 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
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; 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
13
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: 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
the sponsor to know.
14
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
15
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
16
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
17
Assessment of
Adverse Events
Assessment
 AEs are assessed for:

• Seriousness
• Severity
• Relationship
• Expectedness
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
19
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: Myocardial infarction
Clinically Significant Event
Associated with primary AE:
Chest pain
Clinically Significant Event
Associated with primary AE:
Dyspnea
20
Primary Adverse Event
How many primary AEs are there?
Events that are not clearly associated with the
primary AE should be reported as separate events.
Example: Acute renal failure and
Gastroesophageal reflux
Primary Adverse Event 1
Acute renal failure
Primary Adverse Event 2
Gastroesophageal reflux
21
Hospitalization
 8 May 2009: 61 year old HIV infected African
American male (enrolled 15 Feb 2009), with
Grade 4 hospitalization
 20 Feb 2009: subject was started on study
agents LMN and XYZ
 8 May 2009: 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
22
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”
 However, if you do not have any information about the
actual AE but the event is reportable you can report
“Hospitalization.” Submit an update when additional
significant information is available
23
Death
 14 Jan 2009: 40 year old HIV uninfected Asian



female enrolled; started on the study agent XYZ
at a dose of 32mg, sublingually, 4 times a week
6 May 2009: Took dose of XYZ; went for clinic
visit
10 May 2009: died due to sudden death (AE
term reported as “death”)
Hx of illicit drug use [study target pop: drug use]
24
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.” Submit an update when additional
significant information is available
25
Seriousness
Does primary AE meet criteria for an SAE?
 Use ICH-SAE definition provided in Manual v2.0
 Select appropriate SAE criteria
26
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
27
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 description)
Determined using the SAE
criteria
Determined using the DAIDS
AE grading table
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 DAIDS (DAIDS) Table for Grading
the Severity of the Adult and Pediatric Adverse
Events Version 1.0 – Dec 2004 (Clarification
dated Aug 2009)
29
Severity Grade
Grade 1 – Mild
 Symptoms causing no or minimal interference with usual
social & functional activities
• e.g., When a subject experiences a chest pain which does not interfere
with the subject’s activity of daily living
Grade 2 – Moderate
 Symptoms causing greater than minimal interference with
usual social and functional activities
• e.g., When the chest pain is such that the subject is unable to do some
of their activities of daily living
30
Severity Grade
Grade 3 – Severe
 Symptoms causing inability to perform usual social &
functional activities
• e.g., 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
• e.g., 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
31
EXAMPLE FROM THE DIVISION OF AIDS
TABLE FOR GRADING THE SEVERITY OF
ADULT AND PEDIATRIC ADVERSE EVENTS
CLINICAL
PARAMETER
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY
LIFE-THREATENING
ESTIMATING SEVERITY GRADE
Clinical adverse
event NOT identified
elsewhere in this
DAIDS AE grading
table
Symptoms causing
no or minimal
interference with
usual social &
functional activities
Symptoms causing
greater than minimal
interference with
usual social &
functional activities
Symptoms causing
inability to perform
usual social &
functional activities
Symptoms causing
inability to perform
basic self-care
functions OR Medical
or operative
intervention indicated
to prevent permanent
impairment, persistent
disability, or death
This table is used for estimating the severity grade of a
clinical AE not specifically listed in DAIDS Grading Table
32
EXAMPLE FROM THE DIVISION OF AIDS
TABLE FOR GRADING THE SEVERITY OF
ADULT AND PEDIATRIC ADVERSE EVENTS
SYSTEMIC
PARAMETER
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY
LIFE-THREATENING
Chills
Symptoms causing
no or minimal
interference with
usual social &
functional activities
Symptoms causing
greater than minimal
interference with
usual social &
functional activities
Symptoms causing
inability to perform
usual social &
functional activities
N/A
Fever (nonaxillary)
37.7 – 38.6C
38.7 – 39.3C
39.4 – 40.5C
> 40.5C
This table is used for grading a clinical AE specifically listed
in DAIDS AE Grading Table:
• e.g., grading by symptomatology
• e.g., grading by numerical ranges
33
Severity Grading
 Manual Version 2.0
• Grade 4 events are referred to as potentially lifethreatening events as defined in the DAIDS AE
Grading Table
• Thus a Grade 4 event per the DAIDS AE Grading
Table does not automatically imply that it meets SAE
criteria, if it is only potentially life-threatening
[SAE criteria for LT refers to immediate timeframe, not
potential at some point in the future, or if more severe]
34
Issues with Grading
 Death = Grade 5; clarified in DAIDS AE Grading Table Aug 2009
 Potentially life-threatening = Grade 4
• Potentially life-threatening means at risk of death should the event occur
in a more severe form. This is not the same as immediately lifethreatening
 Grading abnormal laboratory values associated with a clinical
AE:
• Does not correspond to grade provided in the DAIDS AE Grading Table
• When lab values fall between two grades choose the higher grade
 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 level of
SAE)
35
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°C, WBC:
14,000 with left shift
• Sent to hospital for sepsis workup
• AE term: Neonatal sepsis, Severity: Grade 1
 Neonatal Sepsis is reasonable AE Term
 Basis for severity grade?
36
Grading: Neonatal Sepsis
CLINICAL
PARAMETER
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY
LIFE-THREATENING
ESTIMATING SEVERITY GRADE
Clinical adverse
event NOT identified
elsewhere in this
DAIDS AE grading
table
Symptoms causing
no or minimal
interference with
usual social &
functional activities
Symptoms causing
greater than minimal
interference with
usual social &
functional activities
Symptoms causing
inability to perform
usual social &
functional activities
Symptoms causing
inability to perform
basic self-care
functions OR Medical
or operative
intervention indicated
to prevent permanent
impairment, persistent
disability, or death
37
Grading: Neonatal Sepsis
CLINICAL
PARAMETER
GRADE 1
GRADE 2
GRADE 3
GRADE 4
MILD
MODERATE
SEVERE
POTENTIALLY
LIFE-THREATENING
SYSTEMIC
Fever (nonaxillary)
37.7 – 38.6
Degrees Celsius
38.7 – 39.3
Degrees Celsius
39.4 – 40.5
Degrees Celsius
> 40.5
Degrees Celsius
 Grading on basis of fever alone: Grade 1
 Grading on clinical basis of possible sepsis:
•
•
at least Grade 3
Grade 4 reasonable as well
38
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, weight: 3.35 kg,
length: 47.5 cm, HR: 140 bpm, RR: 62 bpm
• 12 hrs after birth: developed tachypnea and fussiness, RR: 62 bpm,
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
Grading: Respiratory Distress
DYSPNEA OR RESPIRATORY DISTRESS
Pediatric < 14 years
Wheezing OR
minimal increase in
respiratory rate for
age
Nasal flaring OR
intercoastal retractions
OR Pulse oximetry 90
- 95%
Dyspnea at rest causing
inability to perform usual
social & functional
activities OR pulse
oximetry < 90%
Respiratory failure with
ventilatory support
indicated
Alkalosis
N/A
pH > 7.5 normal, but ≤
7.5
pH > 7.5 without lifethreatening
consequences
pH > 7.5 with lifethreatening
consequences
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
ESTIMATING SEVERITY GRADE
Clinical adverse event
NOT identified
elsewhere in this
DAIDS AE grading
table
Symptoms causing no
or minimal
interference with
usual social &
functional activities
Symptoms causing
greater than minimal
interference with usual
social & functional
activities
Symptoms causing
inability to perform usual
social & functional
activities
Symptoms causing
inability to perform basic
self-care functions OR
Medical or operative
intervention indicated to
prevent permanent
impairment, persistent
disability, or death
40
Grading: Respiratory Distress
 Grading on basis of respiratory distress: at least
Grade 3
• Required CPAP at birth
• 12 hours later: tachypnea and RR: 62 bpm
• Room air and 100% O2: 70-80%
 Grading on basis of respiratory distress: Grade 4
• Need medical intervention beyond O2 therapy
• Transferred to NICU
 Grading on basis of alkalosis: Grade 2
• Not appropriate because it does not reflect clinical picture
in totality
41
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)
*Per 21 CFR 312.32, “reasonable possibility” means there is evidence to
suggest a causal relationship between the drug and the adverse event.
42
Relationship Assessment
 When an SAE is assessed as “not related” to study
agent(s), an alternate 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
 When the study agent is a fixed dose combination
agent, an assessment of attribution will be made for
each component and the combination agent as a
whole
43
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
 SAE Reporting Category:
• Sponsor to determine expectedness
 SUSAR Reporting Category:
• Site physician and Sponsor to determine expectedness
44
Expedited Reporting
Processes
Overview of Reporting Timelines
46
SAE Reporting Category Flowchart
47
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
49
New/Initial Reports
AEs that are reportable on New/Initial Reports:
 New AE
 Recurrent AE: only if the initial AE has resolved,
is now reoccurring, and meets expedited
reporting criteria to DAIDS
 Pre-existing condition with increase in severity
50
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))
51
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 the reporting
of SAEs to DAIDS
52
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
53
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)
54
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
55
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
EAEs 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
56
How to Report SAEs
 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)
– E-mail: DAIDSRSCSafetyOffice@tech-res.com
– If e-mailing, scan or FAX signature page
57
Where to Get Help
 RSC Safety Office:
•
E-mail:
DAIDSRSCSafetyOffice@tech-res.com
•
Telephone:
+1-301-897-1709
or 1-800-537-9979 (USA only)
•
FAX:
+1-301-897-1710
or 1-800-275-7619 (USA only)
 RSC Website:
 DAIDS-ES Support:
https://rsc.tech-res.com
•
E-mail:
DAIDS-ESSupport@niaid.nih.gov
•
Telephone:
+1-240-499-2239
or 1-866-337-1605 (USA only)
•
FAX:
+1-301-948-2242
58
Questions?