Follow-up Medical History and Clinical Considerations

1. Follow-up Medical History and Clinical Considerations MTN 025 Training

2. Outline • Medical Menstrual History Update • Specific Clinical Management Considerations

3. Follow-Up Medical/Menstrual History • An updated participant self reported medical/menstrual history is required at each scheduled visit • Two objectives of the follow-up history • Determine whether previously documented conditions have changed • Determine whether new AEs have occurred since the last history was obtained • History should also be obtained at interim visits, as clinically indicated

4. Possible Approaches • General questions about current health • How are you feeling today? • Have you had any issues since your last visit? • Targeted gynecologic questions • Any gynecologic problems since your last visit- like abnormal discharge or irregular bleeding? • Targeted questions about ongoing baseline medical conditions and previously reported AEs • At your last visit you reported X. Is this still ongoing?

5. Follow-Up Medical/Menstrual History Documentation • “How have things changed since your last visit with us?” • Chart note • Review Baseline Medical History Log CRF • Follow-up on ppt-reported baseline symptoms/conditions still ongoing • Document resolution of ppt-reported items by updating form • Review AE and GAE CRFs • Follow up on and update, as needed, ppt-reported conditions on AE and GAE CRFs that are continuing; add new events as needed • Cross-check with Con Meds Log as needed

6. Follow-up Medical History Documentation and Considerations • Documentation of review is required in a chart note, even if nothing has changed • Example: “Ppt reported no changes in conditions or symptoms since last visit” • Participants will see a number of staff members throughout the visit and may report different or varying symptoms during the visit • How will the team ensure that documentation is consistent in the chart notes? How will discrepancies be addressed?

7. Baseline Condition Identified • If a baseline condition is identified in follow-up (That is, the participant did not report it at screening or enrollment), add the information to the Baseline Medical History Log CRF • Explain the addition in a chart note

8. Last Menstrual Period • Last menstrual period will be recorded on the Pregnancy Test Result CRF. • Menstrual-like bleeding • Use clinical discretion to determine if bleeding is menstrual like • LMP recording does not need to be consistent with AE reporting terms. • Genital bleeding that is not considered to be menses, should not be documented on the Pregnancy Test Result CRF. • Record on other source documents as applicable (e.g. chart notes) as well as AE Log CRF, if AE reporting requirements are met.

9. Self-Collection of Vaginal Fluid • At Enrollment and all scheduled follow-up visits, participants will collect vaginal fluid for biomarker analysis (**instructions on website) • Collect PRIOR to removal of the last month’s ring • Collect even if the participant chose not to wear the ring or had a hold • Collect even during menses • The participant or clinician can collect

10. AEs, SAEs, and EAEs – An Overview MTN 025 Training

11. Layers of Safety • Study participants • Study site staff team • Clinical affairs staff at SCHARP • MTN-025 Protocol Safety Review Team (PSRT)

12. 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

13. Definition: Baseline Medical Condition Any medical condition, problem, sign, symptom, or finding identified as ongoing in a study participant at the time of enrollment Baseline Medical conditions are not AEs. However, if a baseline condition worsens in severity and/or frequency after enrollment , the worsened condition is an AE. If a baseline condition resolves after enrollment, but then recurs at a later date, the recurrence is considered an AE.

14. Case 1 • A participant reports that she has asthma during her baseline medical history • Has an AE occurred? • No • Yes • Not enough information to determine

15. Case 2 • A participant reports a migraine headache occurring two weeks before her Month 3 visit. • Has an AE occurred? • No • Yes • Not enough information to determine

16. Case 3 • A participant has a positive pregnancy test result at her Month 6 visit. • Has an AE occurred? • Yes • No • Not enough information

17. Case 4 • A participant reports new vulvar erythema at her Month 3 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?

18. Definition: Reportable Adverse Event An AE that meets study protocol criteria for reporting on adverse event case report forms For MTN 025, 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)

19. Reportable Adverse Events There are six types of AEs that are reportable in MTN 025. Can you name them?

20. Reportable AEs • All genital, genitourinary, and reproductive system AEs except • Fetal losses • Expected genital bleeding per clinical assessment • All AEs of severity Grade 2 or higher • All serious AEs • All AEs that results in product hold • All lab test abnormalities not otherwise associated with a reported clinical AE • AEs that meet expedited reporting requirement • Any AE not covered above will go on a Grade 1 AE Log form

21. AE Log or Grade 1 AE Log CRF? • Grade 1 vaginal erythema • Grade 3 headache • Grade 1 diarrhea • Grade 1 urinary tract infection • Grade 1 weakness prompting hospital admission to rule out stroke • Grade 1 allergic reaction to the vaginal ring

22. 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.”

23. Pelvic Exam Terminology

24. Well-Defined Terms • Makes communication between investigators easier • Can be used to double-check what is recorded regarding intactness of the epithelium and blood vessels

25. Pelvic Exam Terminology • To document findings, use terms from the pelvic exam case report form or FGGT • These terms largely match the FGGT • Ecchymosis is listed on CRF but not on FGGT • Petechiae is listed neither place but is referenced in protocol • Always grade 1 per SSP • Use routine QC/QA opportunities to help ensure consistency of terminology across staff and exams

26. Common Pelvic Finding Terms • Erythema • Edema • Petechiae • Ecchymosis • Peeling • Ulceration • Abrasion • Laceration

27. Pelvic Exam Findings Review Epithelial Disruption Erythema Edema ALL IMPACT PRODUCT USE

28. Epithelial Disruption • Extent of epithelial disruption helps to distinguish between findings • Superficial epithelial disruption • Does not penetrate into the subepithelial tissue • Deep epithelial disruption • Penetrates into and exposes subepithelial tissue and possibly vessels

29. Epithelial Disruption • If bleeding from finding is present, disruption should be recorded as deep when in doubt • Assessment of disruption depth is subjective, even with magnification of colposcopy

30. Normal Cervix • Mucosa • Typically uniformly pink • Epithelium intact • Vessels intact • Normal variants are not lesions • Ectropion • Gland openings • Scarring from cone biopsies

31. Normal Findings • Ectopy

32. Normal Findings • Nabothian cysts

33. Erythema • Reddened areas • Margins may or may not be clearly defined • Epithelium intact • Vessels intact

34. Edema • Epithelium • Intact • Swollen • Vessels • Intact • Color • Normal or pale white

35. Petechiae • Punctate red areas • Individual or group • Epithelium intact • Vessels disrupted • Diameter ≤3mm • Color of finding is red or purple

36. Ecchymosis • Epithelium intact • Vessels disrupted • Size >3mm • Color is red or purple

37. Peeling • Epithelium disrupted but superficially • Vessels intact • Fragment may remain attached to area of peeling • Generally well-demarcated • Underlying epithelium appears normal

38. Ulceration • Disrupted epithelium • Superficial or deep • Vessels intact or disrupted • May include sloughing • Sharply demarcated outline

39. Abrasion • Epithelium disrupted • Superficial or deep • Vessels intact or disrupted • Diffuse or poorly demarcated outline

40. Laceration • A “cut” or “fissure” • Epithelium disrupted • Superficial or deep • Vessels intact or disrupted • Appears to be linear “pulling apart” or wearing away of tissue

41. Reporting Recurring Events • If an AE previously reported within an AE log CRF resolves and then recurs at a later date, the second occurrence must be reported as a new AE on a new AE or GAE Log CRF • Regular occurrences of the same adverse event that are expected are not considered separate adverse events • Headaches, for example

42. 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)

43. 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

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

45. 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

46. Relationship Rationale • Sites must include text in the “Comments” field to explain why the AE has been judged “related” or “not related“ • “No other explanation” is not adequate

47. 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 months

48. 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

49. 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

50. 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.