Transcript Safety Workshop Part II - Expedited Reporting

Safety Workshop: Part II
Expedited Reporting & Assessment
Olu Ogunyankin, MD
DAIDS Regulatory Support Center (RSC)
Durban, South Africa
May 13, 2011
Objectives
• About Manual v2.0
• Definitions
• Assessment of Adverse Events
• Expedited Reporting Processes
2
Expedited Reporting Materials
• Manual for Expedited Reporting to DAIDS v2.0
• EAE Reporting Form 2.0
• EAE Reporting Form
Completion Instructions 2.0
• DAIDS AE Grading Table
(Clarification August 2009)
• Protocol
3
Manual for Expedited Reporting Version 2.0
• Manual v2.0 (dated Jan 2010) was issued and
posted on RSC website
• Primary goal for the revision from v1.0 to v2.0 is
to align expedited reporting to ICH-SAE
definition
• Fulfill DAIDS’ regulatory requirements to FDA
• Fulfill DAIDS’ obligations to industry collaborators
4
Definitions
Manual v2.0
Expedited Adverse Event (EAE)
• An adverse event that meets the criteria
•
•
•
for expedited reporting to Division of
AIDS (DAIDS).
In Manual v1.0, EAE did not map exactly
to SAE
In Manual v2.0, EAE was aligned to SAE
Protocol can specify additional reporting
to DAIDS
6
Expedited Adverse Event Reporting
to DAIDS
Two Reporting Categories:
SAE - All Serious Adverse Events
SUSAR - Only
Suspected, Unexpected, Serious
Adverse Reactions
• The protocol will specify which reporting
category will be used
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Expedited Adverse Event Reporting
to DAIDS
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
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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; regardless of who provides
the drugs/products
• Study agents will be specified in the protocol
9
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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Serious Adverse Event (SAE)
• Definition for SAE is per ICH E2A
• Certain DAIDS protocols will have expedited
reporting of all SAEs, prior to Manual v2.0
• E.g. A5241, MTN 003, P1066, P1060
• All protocols coming to SRCs after May 2010
are required to use Manual v2.0.
• Existing protocols with data collection beyond
May 31, 2011 required to switch to Manual v2.0
unless they have been approved by DAIDS for
an exemption
11
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
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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.
• Therefore life-threatening means immediatelly
life-threatening which is not the same as
potentially life-threatening.
13
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)
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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
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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; 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
16
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: 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.
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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
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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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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
Assessment of
Adverse Events
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 MOs provide
secondary review; consult with SPT prn
22
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
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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
24
Hospitalization
• 61 y.o. HIV-infected, African-American male,
enrolled Feb 15, 09, with Gr. 4 hospitalization
May 8, 09
• Feb 20, 09: subject was started on study agents
ABC and XYZ.
• May 8, 09: 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
25
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’
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Death
• Jan 14, 2009: 40-year-old HIV uninfected, Asian
female enrolled
• Jan 14, 2009: started on the study agent XYZ at
a dose of 32 mg, sublingually, 4 times a week
• May 6, 2009: Took last dose of XYZ; went for
clinic visit
• May 10, 2009: died due to sudden death
• Hx of illicit drug use [study target pop: drug use]
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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.”
• Follow-up for more details is necessary
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Seriousness
• Does primary AE meet criteria for an SAE?
• Use ICH-SAE definition provided in Manual v2.0
• Select appropriate SAE criteria
29
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
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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 grading table
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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 1.0 - December
2004 (Clarification dated August 2009)
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Estimating Severity Grade
Grade 1 – Mild
Symptoms causing no or minimal interference with usual social &
functional activities.
• When a subject experiences a chest pain which does not
interfere with the subjects’ activity of daily living; then it is graded
as 1.
Grade 2 – Moderate
Symptoms causing greater than minimal interference with usual
social and functional activities.
• When the chest pain is such that the subject, is unable to do
some of their activities of daily living.
33
Severity Grade
Grade 3 – Severe
Symptoms causing inability to perform usual social & functional activities.
• 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.
• 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
34
EXAMPLE FROM THE DIVISION OF AIDS
TABLE FOR GRADING THE SEVERITY OF
ADULT AND PEDIATRIC ADVERSE EVENTS
This table is used for estimating the severity grade of a
clinical AE not specifically listed in DAIDS Grading Table
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EXAMPLE FROM THE DIVISION OF AIDS
TABLE FOR GRADING THE SEVERITY OF
ADULT AND PEDIATRIC ADVERSE EVENTS
This table is used for grading a clinical AE specifically listed
in DAIDS Grading Table:
• E.g. grading by symptomatology
• E.g. grading by numerical ranges
36
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 0C, WBC: 14.0
with left shift
• Sent to hospital for sepsis workup and treatment
• AE term: neonatal sepsis, Severity: Grade 1
• Probable Sepsis is reasonable AE Term
• Basis for severity grade?
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Grading: Neonatal Sepsis cont’d
• Grading on basis of fever alone: Grade 1
• Grading on clinical basis of possible sepsis:
• at least Grade 3
• Grade 4 reasonable as well
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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, Birth Wt: 3.35 kg, Ht: 47.5, HC: 34 cm, HR:
140 bpm, RR: 62
• 12 hrs after birth: developed tachypnea and fussiness, RR: 62, 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?
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Grading: Respiratory Distress cont’d
40
Grading: Respiratory Distress cont’d
• Grading on basis of respiratory distress: at least
•
•
Grade 3
• Required CPAP at birth
• 12 hours later: tachypnea and RR:62
• Room air and 100% O2: 70-80%
Grading on basis of respiratory distress: Grade 4
• Need medical intervention beyond 100% O2
• Transferred to NICU
Grading on basis of alkalosis: Grade 2
• Not appropriate because it does not reflect
clinical picture in totality
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Issues With Grading
• Death = Grade 5; clarified in DAIDS Grading Table, August
2009
• Potentially life-threatening = Grade 4; per DAIDS grading table
• When lab values fall between two grades choose the higher
grade
• Grading abnormal laboratory values associated with a clinical
AE:
• Grade the clinical AE not the abnormal lab
• 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 SAE)
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Severity Grading: Grade 4
 In the DAIDS Grading Table, Grade 4 events are
referred to as potentially life-threatening events
 Thus a DAIDS Grading Table Grade 4 event
does not automatically imply that it meets SAE
criteria, if it is only potentially life-threatening
 Reminder: SAE criteria for LT refers to an
immediate timeframe, not at some point in the
future (potentially).
43
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).
44
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.
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Relationship Assessment cont’d
46
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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Expedited Reporting
Processes
Overview of Reporting Timelines
49
SAE Reporting Category Flowchart
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SUSAR Reporting Category Flowchart
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.
52
Reporting Fetal Loss
Manual Version 2.0
• SAE criteria: Congenital anomaly/birth defect
• DAIDS qualifier: Clinically insignificant physical
findings at birth, including those regarded as
normal variants, do not meet reporting criteria
• No fetal loss language in Manual v2.0
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New/Initial Reports
AEs that are reportable on New/Initial Reports:
• New AE
• Recurrent AE: only if the first AE has resolved, is
now reoccurring and meets expedited reporting
criteria
• Preexisting condition with increase in severity
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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)).
55
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
SAEs to DAIDS
56
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.
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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
• This physician makes the site’s final
assessment of the relationship to study agent(s)
58
Site Investigator Signature
Manual Version 2.0
• 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
59
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 SAEs 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
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Submitting Reports via DAERS
• DAERS URL: 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, include scan of signature page or FAX signature page
• DAERS will send a confirmation email for all SAE
reports submitted.
• It is the site’s responsibility to follow-up if they do not
receive a confirmation email.
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Where to Get Help
• RSC Safety Office:
•
E-mail:
[email protected]
•
Telephone:
+ 1-301-897-1709
or 1-800-537-9979 (US Only)
•
FAX:
+1-301-897-1710
or 1 -800-275-7619 (US Only)
• RSC Web Site:
http://rsc.tech-res.com
• DAIDS-ES Support:
•
E-mail:
[email protected]
•
Telephone:
+1-240-499-2239
or 1-866-337-1605 (US Only)
•
Fax:
+1-301-948-2242
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Questions?