MTN-003 Study-Specific Training
Participant Safety
Monitoring and Reporting
Overview of Presentation












Participant safety monitoring
Adverse event definition
Reportable adverse event definition
AE terminology
AE severity
AE relationship to study product
AE outcome
AE recurrence
Serious adverse event definition
Expedited adverse event definition and reporting
Completion of adverse event case report forms
Examples
Participant Safety Monitoring

Participant safety is of utmost importance

Several layers of safety monitoring are in place for
MTN-003
 Study participants
 Study site staff team
 Clinical affairs staff at SCHARP
 MTN-003 Protocol Safety Review Team (PSRT)
 NIAID Vaccine and Prevention Data and Safety
Monitoring Board (DSMB)
Participant Safety Monitoring

Study Site Staff Team



Primary responsibility
for monitoring and
safeguarding participants
 IoR
 Clinical staff
 Non-clinical staff
Primary responsibility for submitting safety data to
SCHARP and DAIDS Safety Office
 Provides data for other layers of safety review
Alert Protocol Team if unexpected concerns arise
Participant Safety Monitoring

Clinical Affairs Staff at SCHARP



Review clinical and laboratory data received at
SCHARP
Issue clinical data QC notes (queries) for data
requiring confirmation, clarification, or further followup by site staff
Help prepare safety data reports for review by the
PSRT
Participant Safety Monitoring

MTN-003 PSRT





Routinely reviews MTN-003 safety data reports
prepared by SCHARP
Reviews data that are pooled across study treatment
groups
Meets via conference call to discuss safety data and
any potential safety concerns
Must be consulted on some clinical and product use
management issues, per protocol
Always available to consult on adverse event
management, product use management, and other
aspects of clinical management
PSRT Query Process
Site
submits
query
Email to mtn003safetymd@mtnstopshiv.org
Response
back to site
PSPs draft
response
72 hours
PSPs
finalize
response
PSRT
comments
PSRT Query Form
Instructions: Email completed form to MTN Safety Physicians: mtn003safetymd@mtnstopshiv.org
IMPORTANT: Complete all required fields so the PSRT has all information needed to respond to your
query.
Site:
Completed by:
Query Date (dd-MMM-yy):
Email address:
PTID:
Participant Age (in years):
Participant randomization assignment:
Reason for query:
vaginal gel
or
oral tablets
Product use consultation:
Should use of study product be temporarily discontinued?
Should use of study product be permanently discontinued?
Should use of study product be resumed?
Request for consultation on AE management
Request to withdraw participant from the study
Other, specify:
Is this query a request for the PSRT to consult on an adverse event (AE)?
form
posted on MTN-003 web page
Yes → continue completing this
page
Emergency Safety Phone





+001-412-641-8947 (toll call)
Staffed by Protocol Safety Physicians 24/7
Intended for emergency safety situations only
Questions that can wait should be addressed
through PSRT query process
 Usual response time 72 hours
 Urgent queries can be addressed within 1
working day if necessary
Contact form will be used to document each call
(initiated at site, completed by Safety Physician)
Participant Safety Monitoring

NIAID Vaccine and Prevention DSMB



Composed of independent medical, statistical,
and ethical experts
Routinely reviews MTN-003 safety data reports
prepared by SCHARP (approx every 8 months)
Data are presented by study treatment group
(unblinded)
Participant Safety Monitoring

NIAID Vaccine and Prevention DSMB


DSMB can recommend changes to study design
and operations related to:
 Study viability
 Product safety and/or effectiveness
 Results from other studies
Brief report from each review will be distributed to
Protocol Team and all study sites
 Must be submitted to IRBs/ECs
MTN-003 Study-Specific Training
Questions so far?
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: Adverse Event

For MTN-003, the ICH definition of adverse
event will be applied
 To all participants in all study groups
 Beginning at the time of randomization
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.
Let’s Discuss Adverse Events
Suppose a participant reports in her baseline medical
history that she has asthma.
Is this an adverse event?
1.
2.
3.
Yes
No
Not enough information
to determine
Let’s Discuss Adverse Events
Suppose a participant reports at her Month 1 visit that
she had abdominal menstrual cramping two weeks
before the visit.
Is this an adverse event?
1.
2.
3.
Yes
No
Not enough information
to determine
What more might you need to know to determine
whether this is an adverse event?
Let’s Discuss Adverse Events
Suppose a participant becomes pregnant while in the
study.
Is this an adverse event?
1.
2.
3.
Yes
No
Not enough information
to determine
Let’s Discuss Adverse Events
Suppose manipulation of the speculum during a pelvic
exam causes abrasion of the vaginal tissue.
Is this an adverse event?
1.
2.
3.
Yes
No
Not enough information
to determine
Let’s Discuss Adverse Events
Suppose a participant has a calculated creatinine clearance rate of
90 mL/min at Screening Part 1. At one of her study follow-up visits,
this participant’s calculated creatinine clearance rate is 81 mL/min.
The rate of 81 mL/min represents a 10% decrease from baseline.
Is this an adverse event?
1.
2.
3.
Yes
No
Not enough information
to determine
Let’s Discuss Adverse Events
Suppose a participant reports at her Month 11 visit that she has been
feeling very sad lately. Two of her family members passed away in
the past month and she and her partner are disagreeing about many
household matters. She has been so sad that she has not been able
to complete her household duties for the past 4 days; all she wants
to do is sleep.
Is this an adverse event?
1.
2.
3.
Yes
No
Not enough information
to determine
MTN-003 Study-Specific Training
Questions?
Definition: Reportable Adverse Event
An AE that meets criteria in the study protocol
for reporting on adverse event case report forms
(for VOICE, on the AE Log form)
Reportable Adverse Events
There are eight types of AEs
that are reportable in VOICE.
Can you name them?
Reportable AEs








All genital, genitourinary, and reproductive system AEs
except asymptomatic bacterial vaginosis
All fractures
All grade 2 or higher dizziness, headache, nausea, vomiting,
diarrhea, abdominal pain, rash
All grade 3 or higher AEs
All serious AEs, as defined by ICH GCP
All AEs that result in permanent discontinuation of study
product use
All lab test abnormalities not otherwise associated with a
reported clinical AE
AEs that do not meet the above criteria but meet expedited
reporting requirements
How does the listing of reportable AEs
change under Letter of Amendment #01?

All genital, genitourinary, and reproductive system AEs
except fetal losses


Fetal losses (e.g., spontaneous abortions,
spontaneous fetal deaths, still births) will not be
reported as AEs
However, untoward maternal conditions that either
result in or result from fetal losses will be reported as
reproductive system AEs.
Is this AE Reportable?
Grade 1 elevated ALT
1.
2.
Yes
No
Is this AE Reportable?
Grade 1 vulvovaginal itching
1.
2.
Yes
No
Is this AE Reportable?
Grade 1 headache
1.
2.
Yes
No
Is this AE Reportable?
Grade 2 musculoskeletal pain
1.
2.
Yes
No
Is this AE Reportable?
Grade 2 active hepatitis B infection
1.
2.
Yes
No
Is this AE Reportable?
Grade 2 malaria
1.
2.
Yes
No
MTN-003 Study-Specific Training
Questions?
Adverse Event Terminology






A term or description must be assigned to each AE
Whenever possible, assign a diagnosis
When not possible to assign a single diagnosis to
describe a cluster of signs and/or symptoms, each sign
and symptom must be documented as an individual AE
For genital and reproductive system AEs, assign terms
from the DAIDS Female Genital Grading Table
If an AE can occur in more than one anatomical location,
specify the location
See SSP Section 11.2 for tips and guidance
Let’s Discuss Adverse Events
Suppose a participant reports at her Month 1 visit that
she had fever, nasal congestion, cough, sore throat, and
sneezing two weeks before the visit.
Is this an adverse event and
if so, how many?
1.
2.
3.
4.
Yes, 5 AEs
Yes, 1 AE
No AE has occurred
Not enough information to
determine
What term would you use to describe this AE?
Let’s Discuss Adverse Events
Suppose a participant reports at her Month 1 visit that she had fever,
nasal congestion, cough, sore throat, and sneezing two weeks
before the visit. On one of the days when she had these symptoms,
she also had genital itching.
Is this an adverse event and
if so, how many?
1.
2.
3.
4.
5.
6.
Yes, 6 AEs
Yes, 5 AEs
Yes, 2 AEs
Yes, 1 AE
No AE has occurred
Not enough information to determine
What terms would you use to describe these AEs?
AE Terminology for Abdominal Pain





Abdominal pain that is gastrointestinal in nature must be
differentiated from abdominal pain that is genitourinary or
reproductive in nature
If gastrointestinal, report as “abdominal pain” or “lower
abdominal pain”
If genitourinary or reproductive, ideally localize the pain to
a genitourinary or reproductive organ and report as such,
e.g., adnexal pain, bladder pain
If unable to localize to a specific organ, report with terms
that identify a genitourinary or reproductive anatomical
location, e.g., pelvic pain, urinary tract pain
For pain associated with menstruation, report as
dysmenorrhea
MTN-003 Study-Specific Training
Questions?
Adverse
Experience
Log Form
• First form in training packet
• Form is “standard” (used in
MTN, HPTN, IMPAACT)
• Instructions on back
• Additional instructions in
SSP Section 14.6
• Let’s take a closer look at
the form items …
AE Log Form: Page Number
AE Log Form: Page Number



For each participant, assign page numbers starting
with “001” for the first AE reported
Continue assigning page numbers in sequential
ascending order (002, 003, 004, etc) through the
participant’s Termination Visit
 Do not start page numbers over at each visit
Once an AE Log page has been faxed, do not
change the page number or assign that page number
to another AE Log form for that participant
AE Log Form: Date Reported to Site
AE Log Form: Date Reported to Site




Date reported to site = date clinic staff became
aware of the AE
This could be
 Date of a clinic visit
 Date of a phone call in which a new symptom or
condition is reported
 Date clinic staff receive an abnormal lab test
result
Cannot be before the AE onset date (item 2)
Complete date (day, month, and year) is required
AE Log Form: Item 1
AE Log Form: Item 1

Report only one AE diagnosis or symptom per page
 Record a unifying diagnosis whenever possible
 Record signs and symptoms associated with a
diagnosis in comments at bottom of page
 E.g., “influenza” in item 1 and “with fever,
chills, and myalgia” in comments
 When a unifying diagnosis is not available, record
each reportable sign and symptom as a separate
AE on a separate AE Log form page
AE Log Form: Item 1


Include anatomical location when applicable
 Pain – location needed
 Headache – location not needed
Record as much detail as possible in the space
provided in item 1
 E.g., “red, itchy rash on both arms” rather than
“arm rash”
 The AE is coded using text in item 1 only
 If more details are available, record in comments
AE Log Form: Item 1
Pelvic Exam Finding AEs

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 Follow-up
Pelvic Exam CRF, whichever is more specific
 For example, do not report “genital sore”. Instead,
report “vaginal ulcer”.
AE Log Form: Item 1
Genital Bleeding AEs

Report only unexpected bleeding as AEs
 If bleeding associated with pelvic exam finding, report
finding as the AE
 If bleeding unexpected and not associated with pelvic
finding, use appropriate term in SSP Section 10.6
Menorrhaghia (menstrual)
 Menometrorrhagia (menstrual)
 Postcoital bleeding (non-menstrual)
 Metrorrhagia (non-menstrual)


Separate terms for pregnancy-related bleeding
AE Log Form: Item 1
Urinary Tract Infections (UTIs)

Only use term “Urinary Tract Infection” if participant




is symptomatic
tests positive for urine LE
tests positive for urine nitrites
If UTI suspected, but above criteria not met


Report each symptom as separate AE on separate AE Log
form
Do not report positive urine LE and positive nitrite results as
AEs
AE Log Form: Item 1



Do not report procedures or surgeries as AEs
 These are treatments, not AEs
 Treatments are collected in item 7
 E.g., c-section - do not record as AE
Do report the reason for a procedure and/or untoward
conditions resulting from a procedure as an AE
 E.g., cervical dystocia – report AE as “cephalo-pelvic
disproportion” (see SSP Figure 11-8)
 E.g., decreased hemoglobin post c-section – report
as AE
Include related diagnosis when available
 E.g., “edema related to congestive heart failure”
AE Log Form: Item 1


Do not use abbreviations
 Is “BOM” burning on micturition or bilateral otitis
media?
 Is “LAP” lower abdominal pain or laparotomy?
Review for correct spelling
 Variations in spelling can lead to differences in
AE coding, which means similar AEs will appear
in different places in AE safety reports
To QC or Not to QC?
Text recorded in item 1 on AE Log form is …
 candidiasis
 appendectomy
 lower abdominal pain
 UTI
 tingling in genital area
 feeling sad
 assault
 abnormal white cell count
AE Onset and Outcome Dates
AE Log Form: Items 2 and 6a



Onset and outcome dates can be based on
 Participant self-report
 Physical and/or pelvic exam dates
For laboratory AEs, onset date = specimen
collection date
Record a complete date whenever available,
at minimum, month and year required
MTN-003 Study-Specific Training
Questions?
Adverse Event Severity

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

Assign grades based on the DAIDS Female Genital
Grading Table (FGGT) and DAIDS Table for Grading
Adult and Pediatric Adverse Events (Toxicity Table)

See SSP Section 11.3 for tips and guidance
How does severity grading change under
Letter of Amendment #01?
Bleeding during pregnancy prior to the onset of
labor (regardless of trimester) will be graded per
the table below:
Severity Grading of Vaginal Candidiasis





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
AE Log Form: Item 3
MTN-003 Study-Specific Training
Questions?
Adverse Event Relationship

The relationship of all reportable AEs to
study product must be assessed as:
 Definitely related
 Probably related
 Possibly related
 Probably not related
 Not related
Likelihood AE is Related to Study Product
0%
1-49%
50%
51-99%
100%
Not
Related
Probably
Not Related
Possibly
Related
Probably
Related
Definitely
Related
AE
clearly
explained by
another cause
not related to
study product
Potential
relationship
cannot be
ruled out but
AE most likely
explained by
causes other
than study
product
AE
can be
explained
equally well by
causes other
than study
product
AE
more likely
explained by
study product
than other
causes
Direct
association
can be
demonstrated
between the
AE and study
product
Factors to Consider





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
Sample Case




A 24 year old VOICE participant who had no pre-existing
conditions and was randomized to vaginal gel presents
for an interim visit, 12 days after her enrollment visit.
This participant first started taking oral contraceptive
pills (OCPs) at her Screening Part 2 visit, which was five
days before her enrollment visit.
At her interim visit, she reports that she has been taking
her OCPs and inserting her study gel every day. She
also reports that she has been experiencing waves of
mild nausea off and on since her enrollment visit and
that is why she has come to the clinic today.
A pregnancy test done at the interim visit is negative.
Factors to Consider

Pre-clinical and clinical profile of the study
products: protocol, package inserts,
investigators brochures, other published
information
 What do we know about nausea from the
available sources?
Factors to Consider

Timing of product use relative to onset,
resolution, and/or recurrence of the AE
 What do we know about use of study gel
in relation to the participant’s nausea?
 What can we do to find out more?
Factors to Consider

Likelihood of observing the AE in the study
population in the absence of product use
 How common is nausea in the population
from which the study participants are drawn?
 If the participant was a patient of yours,
outside of the study, how likely is it that she
might experience nausea?
Factors to Consider

Presence of other conditions or exposures that
could have caused the AE
 What do we know about the presence or
absence of other possible causes of the
participant’s nausea? Consider other
medications, concomitant illnesses,
infectious diseases, etc …
 What can we do to find out more?
Factors to Consider

Clinical judgment
What if…


Instead the participant was randomized to oral
tablets and reports that she has been taking her
OCPs and her study tablets every day.
The participant was randomized to oral tablets,
but the participant first started taking oral
contraceptive pills (OCPs) about 9 months
before joining the study and she cannot
remember experiencing nausea like this since
she was a child.
MTN-003 Study-Specific Training
Questions?
Relationship to Study Product
AE Log Form: Item 4

If “not related” is marked, the cause of the AE
and/or other reason why the AE is not related
must be recorded in comments

For MTN-003, vaginal product = gel + applicator

If an AE is thought to be
related to the applicator,
report this by assigning
one of the “related”
categories and record in
comments that the
presumed relationship is
to the applicator
Study Product Administration
AE Log Form: Item 5



Mark “No change” if the AE does not result in product
hold/discontinuation (participant is on product and may
continue using it)
Mark “N/A” if product was already held or permanently
discontinued when the AE occurred
If multiple AEs are reported at a visit when product is held,
mark “Held” only for those AEs that required product to be held


All other AEs reported at the same visit should be marked “N/A”
If multiple AEs are reported at a visit when product is
permanently discontinued, mark “Permanently Discontinued”
only for those AEs that required permanent discontinuation

All other AEs reported at the same visit should be marked “N/A”
MTN-003 Study-Specific Training
Questions?
Adverse Event Outcome



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
Adverse Event Outcome



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
Adverse Event Outcome

If an AE increases in severity or frequency,
the higher grade AE must be documented
(and reported) as a new AE

If an AE completely resolves and then recurs
at a later date, the second occurrence must
be documented (and reported) as a new AE
Let’s Discuss Adverse Events
Suppose a participant has completely normal laboratory test results
at Screening Part 1. At Month 1, her hemoglobin level is grade 1. At
Month 2 her hemoglobin level is grade 2, and she is asked to return
in three days for another test. At that time her hemoglobin level has
returned to grade 1. At Month 3, her hemoglobin level is normal.
How many AEs have occurred?
1.
2.
3.
4.
1 AE
2 AEs
3 AEs
4 AEs
Let’s Discuss Adverse Events
Suppose a participant has completely normal laboratory test results
at Screening Part 1. At Month 1, her hemoglobin level is grade 1. At
Month 2 her hemoglobin level is grade 2, and she is asked to return
in three days for another test. At that time her hemoglobin level has
returned to grade 1. At Month 3, her hemoglobin level is normal.
Suppose this participant’s hemoglobin level is found to
be grade 2 at Month 6. Has another adverse event
occurred?
1.
2.
3.
Yes
No
Not enough
information
MTN-003 Study-Specific Training
Questions?
Status/Outcome and Date
AE Log Page: Items 6 and 6a


If AE outcome/status is “Continuing” when the AE
is first reported, leave item 6a blank
Later, after an AE outcome is determined





Line through the “Continuing” box
Mark the appropriate box for item 6
Record the appropriate outcome date in item 6a
Initial, date, and refax
When status/outcome = resolved, death or
severity/frequency increased, an outcome date
must be recorded in item 6a
AE Log Page: Items 6 and 6a


If a previously-reported AE increases in severity grade:
 Close out the previously-reported (lower grade) AE by
updating item 6 to “severity/frequency increased” and
recording in item 6a the date the AE increased in
severity. Initial, date, and refax.
 Complete a new AE Log page for the new (higher
grade) AE. Use the same text in item 1 as for the
lower grade AE. Record in item 2 (onset date) the
date the AE increased in severity. Initial, date, fax.
The date the AE increased in severity will be recorded as
the outcome date of the lower grade AE and the onset
date of the new AE
Example of Severity Increase



On 03-NOV-09, a participant has a grade 1 decreased
hemoglobin value. An AE Log form is completed with
status = continuing.
At the next visit on 01-DEC-09, the hemoglobin value is
still grade 1. Any updates to the AE Log form?
At the next visit on 05-JAN-10, the hemoglobin value is
grade 2. What do you do?


Update AE Log form for grade 1 decreased hemoglobin:
outcome = severity/frequency increased, outcome date =
05JAN10. Initial, date, refax.
Complete new AE Log form, item 1 = decreased
hemoglobin, onset date = 05-JAN-10, severity = grade 2,
status = continuing. Initial, date, fax.
AE Log Page: Items 6 and 6a


Improvements in AE severity – prior to resolution – do not
require changes to AE Log forms
E.g., Grade 2 rash identified at Month 6
 At an interim visit one week after the Month 6 visit,
the rash is re-assessed and found to have improved
to grade 1


Any updates to the AE form completed at Month 6?
Any new AE Log forms completed?
At Month 7, the rash has resolved


Any updates to the AE form completed at Month 6?
Any new AE Log forms completed?
AE Log Page: Items 6 and 6a


At each participant’s Termination Visit, review all
AEs marked as “continuing”
For any AEs continuing (ongoing) at the
Termination Visit, update item 6 to “continuing at
end of study participation” and initial, date, and
refax
Treatment
AE Log Form: Item 7



Record treatments that are clinically-indicated for the AE,
*regardless* of actual use
E.g., participant has an STI requiring treatment, but she
refuses the medication.

Mark item 7 as “Medications”
 In comments, record that the participant refused the
indicated treatment.
 Do not record the medication on the Concomitant
Medications Log (only document medications actually
taken/used by participant on the Con Meds Log)
Mark “Medications” if participant self-treated with
medications obtained on her own
MTN-003 Study-Specific Training
Questions?
Definition: Serious Adverse Event
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
Important medical events that may not be immediately
life-threatening 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




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
AE Log Form: Item 8
Definition: Expedited Adverse Event
AE that meets criteria in the study protocol
for additional reporting for rapid review and
assessment by DAIDS
VOICE protocol specifies “standard”
reporting per the Manual for Expedited
Reporting of Adverse Events to DAIDS
Expedited Adverse Events





EAE ≠ SAE
SAEs and EAEs are two different subsets of AEs
Some EAEs will be serious, some will not
All EAEs are reportable on AE Log forms
All AEs must be assessed by authorized study
staff to determine whether they meet criteria for
expedited reporting  source document and
record on AE Log form
AE Log Form: Item 9
EAE Reporting
Type of Adverse Event
Standard EAE Reporting
Results in death
Is a congenital anomaly or birth defect
or fetal loss
Report as EAE
regardless of relationship
Results in persistent or significant
disabilities or incapacities
Requires or prolongs hospitalization or
requires intervention to prevent
significant/permanent disability or
death
Is life-threatening
(includes all grade 4 AEs)
Other grade 1, grade 2, and grade 3
AEs
Report as EAE if:
 Definitely related
 Probably related
 Possibly related
 Probably not related
Do not report as EAE
More EAE Reporting



AEs that may be related to study product (definitely,
probably, possibly, or probably not related) that the IoR
believes are of sufficient concern to be reported on an
expedited basis to DAIDS; includes AEs that, based
upon appropriate medical judgment, may jeopardize the
participant and may require medical or surgical
intervention to prevent an SAE
SAEs that are not related to study product but could be
associated with study participation or procedures
Unexpected SAEs that may be related to study product
(definitely, probably, possibly, or probably not related)
and occur after the protocol-defined expedited reporting
period
How does EAE reporting change under
Letter of Amendment #01?
Type of Adverse Event
Standard EAE Reporting
Results in death
Is a congenital anomaly or birth defect
or fetal loss
Report as EAE regardless of
relationship
Results in persistent or significant
disabilities or incapacities
Requires or prolongs hospitalization or
Report as EAE if:
requires intervention to prevent
 Definitely related
significant/permanent disability or
 Probably related
death
 Possibly related
Is life-threatening
 Probably not related
(includes all grade 4 AEs)
Other grade 1, grade 2, and grade 3
AEs
Do not report as EAE
EAE Reporting

Report within 3 business days of site awareness







Check for consistency with AE Log case report form
Submit incomplete report if needed to meet timeframe
Follow up as quickly as possible
Use DAIDS Adverse Experience Reporting System
(DAERS) and DAERS Reference Guide for Site
Reporters and Study Physicians
Or submit paper EAE form if internet not available
Print and file all submitted EAE reports/forms, all
confirmations of receipt, any correspondence
Respond in a timely manner to any requests for more
information
MTN-003 Study-Specific Training
Questions?
Let’s Discuss Adverse Events
Suppose a participant is killed in a car accident after completing her
Month 7 study visit but before her Month 8 visit. It takes some effort
to find out exactly what happened, but you are able to obtain a verbal
report from the participant’s mother three weeks after the Month 7
visit and you obtain hospital records related to her injuries one week
after that.
Is this AE serious?
1.
2.
3.
Yes
No
Not enough information
to determine
Let’s Discuss Adverse Events
Suppose a participant reports at her Month 7 visit that she has fever,
nasal congestion, cough, sore throat, and sneezing. The Month 7
visit is completed per the protocol, including documentation of
upper respiratory tract infection as a grade 2 AE. Several days later,
a friend of the participant, who is also in the study, presents for a
study visit and reports that the participant has been hospitalized.
You contact the hospital, talk to the participant, and receive verbal
confirmation from the hospital physician that the participant has
been diagnosed with pneumonia.
How many AEs have occurred?
1.
2.
3.
One
Two
None
Let’s Discuss Adverse Events
Suppose a participant reports at her Month 7 visit that she has fever,
nasal congestion, cough, sore throat, and sneezing. The Month 7
visit is completed per the protocol, including documentation of
upper respiratory tract infection as a grade 2 AE. Several days later,
a friend of the participant, who is also in the study, presents for a
study visit and reports that the participant has been hospitalized.
You contact the hospital, talk to the participant, and receive verbal
confirmation from the hospital physician that the participant has
been diagnosed with pneumonia.
How many are serious?
1.
2.
3.
One
Two
None
Let’s Discuss Adverse Events
Suppose a participant reports at her Month 7 visit that she has fever,
nasal congestion, cough, sore throat, and sneezing. The Month 7
visit is completed per the protocol, including documentation of
upper respiratory tract infection as a grade 2 AE. Several days later,
a friend of the participant, who is also in the study, presents for a
study visit and reports that the participant has been hospitalized.
You contact the hospital, talk to the participant, and receive verbal
confirmation from the hospital physician that the participant has
been diagnosed with pneumonia.
How many are EAEs?
1.
2.
3.
One
Two
Not enough information
Let’s Discuss Adverse Events
Suppose a participant has a grade 4 decreased absolute neutrophil
count at her Month 9 visit.
Is this an adverse event?
1.
2.
3.
Yes
No
Not enough information
to determine
Let’s Discuss Adverse Events
Suppose a participant has a grade 4 decreased absolute neutrophil
count at her Month 9 visit.
82%
Is this AE serious?
1.
2.
3.
Yes
No
Not enough information
to determine
9%
1
2
9%
3
Let’s Discuss Adverse Events
Suppose a participant has a grade 4 decreased absolute neutrophil
count at her Month 9 visit.
Does the AE need to be reported as an EAE?
1.
2.
3.
Yes
No
Not enough information
to determine
Let’s Discuss Adverse Events
Suppose a participant has a positive pregnancy test at her Month 13
visit. At her Month 14 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?
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?
1.
2.
3.
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
MTN-003 Study-Specific Training
Questions?
AE Log Form: Item 10

The visit code in item 10 should match the
“Date Reported to Site” recorded in the upper
right corner of the AE Log form
AE Log Form: Item 11

Review the participant’s Pre-existing Conditions
form (and other documentation as needed) to
determine if the AE is a worsening of a preexisting condition
Adverse Event Documentation

Regardless of reporting on AE Log forms,
study staff must identify and document all AEs


For each AE, source documentation should
include AE term/diagnosis, severity grade, onset
date, outcome, outcome date, treatment
For reportable AEs, source documentation also
must include date reported to site, relationship to
study product, action taken with study product,
whether the AE is serious, whether the AE meets
criteria for expedited reporting (EAE)
Adverse Event Documentation

Site SOPs for source documentation should
reflect limited AE reporting:



Because some AEs will not be reported on an
AE Log form, this form cannot be designated as
source for all data elements
Identify in SOPs what documents will be source
Use AE tracking tools to ensure all AEs are
properly documented and all reportable AEs
are reported on the AE Log case report form
Adverse Event Reporting



Site delegation of duties documentation should
specify which study staff are authorized to complete
AE source documentation, AE Log forms, and EAE
report forms
All forms should be reviewed for completeness,
accuracy, and consistency of reporting by a clinician
listed on the FDA Form 1572  discuss review
finding as a team for ongoing training and QA
Re: consistency, ensure text in item 1 is not
contradicted by text in comments
MTN-003 Study-Specific Training
Questions?
For AEs Reported as EAEs




Review AE Log forms and EAE reports for consistency:
 Protocol and PTID
 AE term
 Onset date
 Severity
 Relationship to study product
Discrepancies will result in a clinical query
If a previously-reported EAE is updated, update the
matching AE Log form when applicable
Fax the AE Log form to SCHARP at the same time as
submitting the EAE report to the DAIDS Safety Office
Storage of AE Log Forms



Recommendation = store all AE Log forms for a
participant within one section of her study
notebook
Consider methods to identify AE Log pages that
have “continuing” AEs to help ensure these are
reviewed and updated as needed at each visit
until an AE has an outcome or the participant
terminates from the study
SCHARP will provide an “Unresolved AE” listing
that lists AEs that have been continuing for
several months
How to Mark AE Log Forms as Deleted




If you need to delete an AE (if, for example, an AE
was reported in error), draw a diagonal line across
the AE Log form page, write “delete due to _____”
and initial, date, and refax
Keep the AE Log form page in the participant’s
study notebook
Do not re-number the remaining AE Log pages for
the participant and do not “reassign” the page
number of the deleted AE
The deleted AE remains in DataFax but will not be
included in any reports or data analyses
References







Protocol Section 8 and SSP Section 11
DAIDS Toxicity Table and FGGT
Package Insert Viread
Package Insert for Truvada
Investigators Brochure for Tenofovir Gel
Manual for Expedited Reporting of Adverse Events
to DAIDS
DAERS Reference Guide for Site Reporters and
Study Physicians
MTN-003 Study-Specific Training
Questions?
AE Log Form
Data QC Examples
Do not use
abbreviations
Report
genital
bleeding
using
appropriate
term per SSP
section
10.6.4
Use term
“urinary tract
infection”
only if
symptoms
present AND
urine dipstick
is positive for
BOTH LE
and nitrites.
Otherwise,
report each
symptom as a
separate AE.
Refer to
SSP
section
11.3, Data
CQE #1
reminder
#2, and
Data
CQE #3
clarification #10.
Report each
genital
symptom on a
separate AE
Log form.
Specify
anatomical
location
(e.g., vulvar,
vaginal,
cervical)
Line through
“Continuing”
box, mark
“Resolved”
and
initial/date.
Specify
anatomical
location and
type of
finding. Use
appropriate
term in
FGGT or on
Pelvic Exam
CRF,
whichever is
more specific.
Wetness due
to study gel is
not an AE. It
could cause a
genital AE
though, such
as erythema,
which would
be a
reportable
AE.
Treatment was given
(dietary advice) and
documented correctly
as “Other” in item 7,
with description in
Comments.
AE term should be
“hypophosphatemia”
since treatment was
given.
See Data CQE #1
reminder #3.
Delete “Vaginal
Discharge” text and
document discharge
in Comments, if part
of the “symptomatic
bacterial vaginosis”
diagnosis, or as its
own separate AE.
Do not use
abbreviations.
Per protocol
section 8.2,
Grade 1 nausea
is not a
reportable AE.
This AE Log
form should be
marked for
deletion.
Only
Unexpected
Genital Bleeding
is an AE. If the
bleeding is
expected, this
AE Log form
should be
marked for
deletion.
Use more
specific
term(s) to
describe
what is
meant by
“difficulty”.
This will
help with
MedDRA
coding.
Do not use
symbols or
abbreviations.
Specify
anatomical
location.
Per protocol
Clarification
Memo #02,
cervical bleeding
associated with
speculum
insertion and/or
cervical
specimen
collection judged
to be within the
range of normal
is considered
expected nonmenstrual
bleeding (and is
not an AE).
Item 10
Visit
Code is
not valid.
Item 4 is
marked “Not
related”, but no
alternate
etiology is
provided in the
Comments
section.