Transcript Microbicides 2008

AEs, SAEs, and EAEs –
An Overview
MTN 020 Training
Layers of Safety
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Study participants
Study site staff team
Clinical affairs staff at SCHARP
MTN-020 Protocol Safety Review Team
(PSRT)
NIAID Vaccine and Prevention Data and
Safety Monitoring Board (DSMB) site
Definition: Adverse Event
Any untoward medical occurrence in a clinical
research participant administered an investigational
product that does not necessarily have a causal
relationship with the investigational product.
An AE can therefore be an unfavorable or unintended
sign (including an abnormal laboratory finding),
symptom, or disease temporally associated with the
use of an investigational product, whether or not
considered related to the investigational product.
ICH E6, Glossary 1.2
Definition: Pre-Existing Condition
Any medical condition, problem, sign, symptom, or
finding identified as ongoing in a study participant at
the time of enrollment (prior to randomization).
Pre-existing conditions are not AEs.
However, if a pre-existing condition worsens in
severity and/or frequency after randomization, the
worsened condition is an AE.
Case 1
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A participant reports that she has
hypertension during her baseline medical
history
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Has an AE occurred?
 No
 Yes
 Not enough information to determine
Case 2
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A participant reports a migraine headache
occurring two weeks before her Month 4
visit.
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Has an AE occurred?
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No
Yes
Not enough information to determine
Case 3
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A participant has a positive pregnancy
test result at her Month 7 visit.
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Has an AE occurred?
 Yes
 No
 Not enough information
Case 4
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A participant reports new vulvar erythema at her
Month 10 visit. You note erythema on pelvic exam
that covers approximately 30% of her vulva.
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Is this an AE?
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Yes
No
Not enough information
What if the vulvar erythema had not been seen on
exam – does this change your answer?
Definition: Reportable Adverse Event
An AE that meets study protocol criteria for
reporting on adverse event case report forms
For MTN 020, this means reportable on an
Adverse Experience (AE) Log CRF
AEs that do not meet the protocol criteria for
reporting on adverse event forms will be
recorded on the Grade 1 AE Log CRF (GAE
Log)
Reportable Adverse Events
There are six types of AEs
that are reportable in MTN 020.
Can you name them?
Reportable AEs
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All genital, genitourinary, and reproductive
system AEs except
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Fetal losses
All AEs of severity Grade 2 or higher
All serious AEs
All AEs that results in permanent discontinuation
of study product use
All lab test abnormalities
AEs that meet expedited reporting requirement
Any AE not covered above will go on a Grade
1 AE Log form
AE Log or Grade 1 AE Log CRF?
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Grade 1 vaginal itching
Grade 3 headache
Grade 1 nausea
Grade 1 urinary tract infection
Grade 1 weakness prompting hospital
admission to rule out stroke
Grade 1 allergic reaction to the vaginal
ring
Describing AEs
Pelvic Exam Finding AEs
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Report any and all new abnormal findings as AEs
 Specify anatomical location (e.g., vulvar, vaginal,
cervical)
 Use finding term as it appears in FGGT or Pelvic
Exam CRF, whichever is more specific
 For example, do not report “genital sore.” Instead,
report “vaginal ulcer.”
Describing AEs
Genital Bleeding AEs
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Report only bleeding that is different from baseline
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May be expected (due to menses or contraceptive use) or
unexpected
Use appropriate term from FGGT/SSP
Use separate terms for pregnancy-related bleeding – SSP
Section 10.6
If bleeding associated with pelvic exam finding, report
finding as the AE
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The bleeding is a sign of the finding, - comment on in
Comments field
Antepartum Bleeding
Bleeding during pregnancy prior to the onset of
labor (regardless of trimester) will be graded per
the table below:
AE Severity
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The severity of all AEs must be graded as
 Grade 1 = Mild
 Grade 2 = Moderate
 Grade 3 = Severe
 Grade 4 = Potentially Life-Threatening
 Grade 5 = Death
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Assign grades based on the DAIDS Female Genital
Grading Table (FGGT) and DAIDS Table for Grading
Adult and Pediatric Adverse Events (Toxicity Table)
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See SSP Section 11.3 for tips and guidance
Severity Grading of Vaginal Candidiasis
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Normal = absence of symptoms regardless of
candida test results
Grade 1 = positive wet mount or other laboratory
test for yeast, with mild symptoms
Grade 2 = positive wet mount or other laboratory
test for yeast, with moderate to severe symptoms
Grade 3: Not applicable
Grade 4: Not applicable
Relationship to Study Product
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The relationship of each AE to study product
must be assessed as:
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Related
Not Related
Factors to Consider
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Pre-clinical and clinical profile of the study products:
protocol, package inserts, investigators brochures, other
published information
Timing of product use relative to onset, resolution, and/or
recurrence of the AE
Likelihood of observing the AE in the study population in
the absence of product use
Presence of other conditions or exposures that could
have caused the AE
Clinical judgment, including judgment of biologic
plausibility
AE Outcome
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All AEs – reportable and not reportable – must
be followed clinically until the AE resolves or
stabilizes
Resolution = return to baseline severity grade
Stabilization = persistence at a severity grade
above baseline for 3 consecutive monthly
evaluations
AE Outcome
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At each visit, an authorized study clinician
should review all previously reported ongoing
AEs to evaluate their current status
Oftentimes the outcome of an AE will not be
available when the AE is first documented
In such cases, documentation should be
updated when the final outcome becomes
available
AE Outcome
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If an AE increases in severity or frequency,
the higher grade AE must be documented
(and reported) as a new AE
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If an AE completely resolves and then recurs
at a later date, the second occurrence must
be documented (and reported) as a new AE
Definition: Serious Adverse Event
Any untoward medical occurrence that at any dose:
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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
Important medical events that may not be immediately lifethreatening or result in death or hospitalization, but may
jeopardize the participant or may require intervention to
prevent one of the above-listed outcomes, also may be
considered serious.
Seriousness of Adverse Events
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Seriousness ≠ severity
SAEs are a subset of all AEs
All SAEs are reportable on AE Log forms
All AEs must be assessed by authorized study
staff to determine whether they meet the
definition of serious  source document and
record on AE Log form
Expedited Adverse Event
AE that meets criteria in the study protocol for
additional reporting for rapid review and
assessment by DAIDS
Reporting period begins once the participant is
randomized and continues through the final
study visit (Study Exit/Termination Visit)
Only suspected, unexpected serious adverse
reactions (SUSARs) as defined in Version 2.0 of
the EAE Manual will be reported to DAIDS
NEED TO CHECK ABOVE
Let’s Discuss More Adverse Events
Suppose a participant has a grade 3 decreased hemoglobin at her semiannual visit
Is this an adverse event?
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2.
3.
Yes
No
Not enough information
to determine
Let’s Discuss More Adverse Events
Suppose a participant has a grade 4 decreased hemoglobin at her semiannual visit
Is this serious?
1.
2.
3.
Yes
No
Not enough information
to determine
Let’s Discuss Adverse Events
Suppose a participant has an argument with her partner related to her
participation in the study. She was late meeting him because a study visit
took longer than expected. He thinks the study is taking up too much of
her time and he does not want to hear any more from her about safe sex
and using condoms. The argument escalates and he pushes her to the
floor, resulting in a laceration on her forehead and a broken collarbone.
She is treated in the emergency department and then admitted to the
hospital for observation related to her head injury.
How many AEs have occurred?
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2.
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One
Two
None
Let’s Discuss Adverse Events
Suppose a participant has an argument with her partner related to her
participation in the study. She was late meeting him because a study visit
took longer than expected. He thinks the study is taking up too much of
her time and he does not want to hear any more from her about safe sex
and using condoms. The argument escalates and he pushes her to the
floor, resulting in a laceration on her forehead and a broken collarbone.
She is treated in the emergency department and then admitted to the
hospital for observation related to her head injury.
How many AEs are EAEs?
1.
2.
3.
One
Two
None
Let’s Discuss Adverse Events
Suppose a participant has a positive pregnancy test at her Month 6 visit.
At her Month 7 visit, her pregnancy test is negative. She reports having
no symptoms between visits and is surprised that she is no longer
pregnant.
Is this an adverse event?
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2.
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Yes
No
Not enough information
to determine
A Few Extra Reporting Tips
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Only symptomatic BV confirmed by wet mount
should be reported as an AE
Only report symptomatic candida infections
confirmed by wet mount should be reported as
an AE
Chlamydia should be “genitourinary chlamydia
infection”
Gonorrhea should be “genitourinary gonorrhea
infection”
Suspected herpes lesions should be captured
as “ulcers”
Questions?