Transcript Expedited Reporting-DAERS Cape Town

Manual v2.0 Changes and DAERS
Lawrence Allan (HJF – DAIDS)
Dr. Oluwadamilola Ogunyankin (RSC Safety Office)
November 15, 2010
HVTN Network Meeting. Seattle, WA
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
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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
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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Summary of Changes
5
Summary of Changes
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Expedited Reporting of Adverse
Events to DAIDS
Two Reporting Categories:
- All Serious Adverse Events
- Only Suspected, Unexpected, Serious
Adverse Reactions
The protocol (and any applicable Letter of Amendment) will
specify which reporting category will be used
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SAE Reporting Category
Report to DAIDS:
•
erious dverse vents
− Regardless of relationship
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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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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.”
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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
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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
SUSAR Reporting Category
Report to DAIDS:
•
erious Adverse Events
− that are nexpected
− and elated
13
SUSAR Reporting Category
Used for some non-Investigational New Drug (nonIND) 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.
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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
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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
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
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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
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EXPEDITED REPORTING
PROCESS
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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
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
New/Initial Report vs. Update
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.
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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)
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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.
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ASSESSMENT OF
ADVERSE EVENTS
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Primary Adverse Event
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)
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Seriousness Versus Severity
Relationship Assessment
The terms used to assess the relationship of an event
to study agent are:
– There is a reasonable possibility that the
AE may be related to the study agent(s).
– There is not a reasonable possibility
that the AE is related to the study agent(s).
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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
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.
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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 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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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
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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
DAERS CASE REVIEW
AND
DEMONSTRATION
Case Study
 10 Nov 2010 – Subject enrolled into the study and
randomized; receives 1st 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
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
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Timeline for Submission
Must submit within 3 ‘reporting days’ of site
awareness
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
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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
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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
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
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
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Study Agent (continued)
 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
Concomitant medications
Laboratory and Diagnostic tests
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
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Review and Submission
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
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
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
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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: [email protected]
• If e-mailing, scan or fax signature page
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Where to Get Help
 RSC Safety Office:
• E-mail:
• Telephone:
• Fax:
[email protected]
+ 1-301-897-1709
or 1-800-537-9979 (US Only)
+1-301-897-1710
or 1 -800-275-7619 (US Only)
 RSC Web Site: http://rsc.tech-res.com/
 DAIDS-ES Support:
•
•
E-mail:
Telephone:
•
Fax:
[email protected]
+1-240-499-2239
or 1-866-337-1605 (US Only)
+1-301-948-2242
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QUESTIONS?
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