1. AEs, SAEs, and EAEs – An Overview
MTN 020 Training

2. Layers of Safety 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

3. 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

4. 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.

5. Case 1
A participant reports that she has hypertension during her baseline medical history
Has an AE occurred? No
Yes
Not enough information to determine
No. Hypertension was present before randomization; therefore, it is not an AE

6. Case 2
A participant reports a migraine headache occurring two weeks before her Month 4 visit.
Has an AE occurred? No
Yes
Not enough information to determine
Not enough information. Where would you look for more information? Ask participant and look on PRE

7. Case 3
A participant has a positive pregnancy test result at her Month 7 visit.
Has an AE occurred?
Yes No
Not enough information
No. pregnancy is not an AE

8. Case 4
A participant reports new vulvar erythema at her Month 10 visit. You note erythema on pelvic exam that covers approximately 30% of her vulva.
Is this an AE?
Yes No
Not enough information
What if the vulvar erythema had not been seen on exam – does this change your answer?
Yes, Grade 1 AE for vulvar erythema

9. 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)

10. Reportable Adverse Events
There are six types of AEs
that are reportable in MTN 020.
Can you name them?

11. Reportable AEs
All genital, genitourinary, and reproductive system AEs except
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

12. AE Log or Grade 1 AE Log CRF?
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
The only AEs NOT on the AE log CRF is grade 1 nausea. This goes on GAE

13. Pelvic Exam Finding AEs
Describing AEs
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 Pelvic Exam CRF, whichever is more specific
For example, do not report “genital sore.” Instead, report “vaginal ulcer.”

14. Describing AEs Genital Bleeding AEs
Report only bleeding that is different from baseline
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
The bleeding is a sign of the finding, - comment on in Comments field

15. Antepartum Bleeding
Bleeding during pregnancy prior to the onset of labor (regardless of trimester) will be graded per the table below:

16. AE 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
Severity reflects the intensity of the AE.
AEs listed in both the Tox Table and the FGGT should be graded per the FGGT.
AEs not listed in the FGGT should be graded per the Tox Table.
AEs not listed in the FGGT or the Tox Table should be graded per the “estimating severity grade row” on page 1 of the Tox Table.

17. 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
This slide is included because questions often arise on how to deal with symptomatic and asymptomatic yeast. See FGGT for a guide.

18. Relationship to Study Product
The relationship of each AE to study product must be assessed as:
Related
Not Related

19. 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
If not related, specify reason you made this judgement on line provided (not in Comments)

20. AE 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

21. AE 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

22. AE 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

23. 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.

24. 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
Seriousness is based on the outcome or action associated with an AE, whereas severity reflects the intensity of the AE

25. 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

26. Let’s Discuss More Adverse Events
Suppose a participant has a grade 3 decreased hemoglobin at her semi-annual visit
Is this an adverse event?
Yes No
Not enough information to determine
Yes.
Follow-up: Is it reportable? (Yes)

27. Let’s Discuss More Adverse Events
Suppose a participant has a grade 4 decreased hemoglobin at her semi-annual visit
Is this serious?
Yes No
Not enough information to determine
Although most Grade 4 events fall into a category of “potentially life threatening” on DAIDS, they are NOT necessarily considered serious events.

28. 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?
Two AEs have occurred: laceration on forehead and broken collarbone
Follow-up: Are they both serious? (Based on the description given, only the laceration is serious, because it resulted in hospitalization.)
One
Two
None

29. 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?
Yes – Laceration is EAE.
One
Two
None

30. 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?
Yes No
Not enough information to determine
Fetal losses are not considered AEs (therefore no AE, no reportable AE, no SAE)

31. A Few Extra Reporting Tips
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”

32. Questions?