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

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 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

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

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

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

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 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 The only AEs NOT on the AE log CRF is grade 1 nausea. This goes on GAE

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.”

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

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

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.

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.

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

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)

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

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

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

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 semi-annual visit Is this an adverse event? Yes No Not enough information to determine Yes. Follow-up: Is it reportable? (Yes)

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.

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

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

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)

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?