AEs, SAEs, and EAEs – An Overview

MTN 020 Training

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

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

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.

Definition: Pre-Existing Condition

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

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

Case 3

A participant has a positive pregnancy test result at her Month 7 visit.

Has an AE occurred? Yes No Not enough information

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?

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)

Definition: Reportable Adverse Event

Reportable Adverse Events

There are six types of AEs that are reportable in MTN 020.

Can you name them?

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

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

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.”

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

Describing AEs

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

Antepartum Bleeding

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

AE Severity

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

The relationship of each AE to study product must be assessed as:

Related Not Related

Relationship to Study Product

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

Factors to Consider

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

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

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

AE Outcome

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

Definition: Serious Adverse Event

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 ≠ 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 of Adverse Events

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

Expedited Adverse Event

Let’s Discuss More Adverse EventsSuppose a participant has a grade 3 decreased hemoglobin at her semi-annual visit

Is this an adverse event?

1. Yes

2. No

3. Not enough information to determine

Let’s Discuss More Adverse EventsSuppose a participant has a grade 4 decreased hemoglobin at her semi-annual visit

Is this serious?

1. Yes

2. No

3. Not enough information to determine

Let’s Discuss Adverse EventsSuppose 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. One

2. Two

3. None

Let’s Discuss Adverse EventsSuppose 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. One

2. Two

3. None

Let’s Discuss Adverse EventsSuppose 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?

1. Yes

2. No

3. Not enough information to determine

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”

Questions?