MTN-003 Study-Specific Training

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 follow-up 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 Email to mtn003safetymd@mtnstopshiv.org 72 hours

PSRT Query Form form posted on MTN-003 web 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? • 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? • 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? • 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? • 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? • 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? • 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?

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 Reportable AEs

All genital, genitourinary, and reproductive system AEs How does the listing of reportable AEs change under Letter of Amendment #01? 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 • Yes • No

Is this AE Reportable? Grade 1 vulvovaginal itching • Yes • No

Is this AE Reportable? Grade 1 headache • Yes • No

Is this AE Reportable? Grade 2 musculoskeletal pain • Yes • No

Is this AE Reportable? Grade 2 active hepatitis B infection • Yes • No

Is this AE Reportable? Grade 2 malaria • Yes • No

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? • 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? • 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

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 notstart 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”.

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

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”

MTN-003 Study-Specific Training