Expedited Adverse Event Reporting Requirements

1. Expedited Adverse Event Reporting Requirements

2. Protocol References

3. Other References and Resources • Manual for Expedited Reporting of Adverse Eventsto DAIDS (Version 2.0) • DAIDS Table for Grading the Severity ofAdult and Pediatric Adverse Events,Corrected Version 2.1, dated July 2017 • Study drug package inserts • DAERS user and reference guides • DAIDS safety training resources https://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids https://rsc.tech-res.com/clinical-research-sites/safety-reporting/safety-training-resources

4. Overview of Presentation • Terms and definitions • Protocol specifications for expedited adverse event reporting • Relationship assessment • Case examples

5. Adverse Event Protocol Section 7.2 The definition of the term adverse event provided in Version 2.0 of the DAIDS EAE Manual will be used in this study

6. The definition of adverse event provided in Version 2.0 of the DAIDS EAE Manual will be used in this study. Adverse event = any untoward medical occurrence in a patient or clinical investigation subject administered a study agent which does not necessarily have a causal relationship with this treatment. An adverse event can therefore by any unfavorable and unintended sign (including an abnormal laboratory finding, symptom, or disease) temporally associated with the use of a medicinal (investigational) agent, whether or not related to the medicinal (investigational) agent. (ICH E2A)

7. Adverse Event So for each mother-infant pair, we start identifying adverse events immediately after they are randomized in the Subject Enrollment System • The same definition applies to all participants • Beginning at the time of enrollment • Regardless of the ARVs the mother takes or does not take

8. Pre-Existing Condition Pre-existing condition = untoward medical occurrence identified in a study participant prior to enrollment. Pre-existing conditions are not adverse events. However, if a pre-existing condition worsens in severity or frequency after enrollment, the worsened condition is an adverse event.

9. Pre-Existing Conditions Protocol Section 7.2.1 All pre-existing conditions identified among mothers during the 28 days prior to study entry will be entered into maternal medical history eCRFs

10. Expedited Adverse Events The following types of adverse events must be reported in an expedited manner in IMPAACT 2010: • Serious adverse events (SAEs) • Suspected unexpected serious adverse reactions (SUSARs) • Pregnancy complications that result in medically indicated and/or elective termination of pregnancy • Spontaneous abortions and fetal deaths • Hepatic toxicities that result in discontinuation of DTG or EFV • Serious ABC hypersensitivity reactions in mothers switching from TDF or TAF to ABC

11. Serious Adverse Event Serious adverse event = an adverse event that ... • Results in death • Is life-threatening* • Requires inpatient hospitalization* or prolongation of existing hospitalization • Results in persistent or significant disability/incapacity • In a congenital anomaly/birth defect* • Is an important medical event 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 other outcomes listed above *See helpful clarifications of these terms in the DAIDS EAE Manual

12. Congenital anomaly/birth defect

13. Do you have any questions about the definition of SAE for this study?

14. SUSAR Suspected = Related to use of study drug Unexpected = Nature or severity is not consistent with the study drug’s current package insert Serious adverse reaction = SAE

15. Related or Not Related Related = There is a reasonable possibilitythat the event may be related to study drug. Not related = There is not a reasonable possibility that the event may be related to study drug.

16. Reasonable Possibility Reasonable possibility is intended to convey that there are facts, evidence, or arguments to suggest a causal relationship between the event and study drug

17. Facts, Evidence, or Arguments to Suggest a Causal Relationship • A temporal relationship between the event and use of study drug • A plausible biologic mechanism for study drug to cause the event • Previous reports of similar events associated with study drug (or drugs of the same class) • Resolution of the event after de-challenge (hold/discontinuation of study drug) • Recurrence of the event after re-challenge (resumption of study drug after a hold)

18. Related or Not Related • In addition to considering the possibility of a causal relationship with study drug, consider other potential causes of the event, e.g., • Past medical history • Concurrent illness • Concomitant medications • For events assessed as not related, document an alternative etiology, diagnosis, or explanation in study records

19. Reminder of Random Assignments

20. Related or Not Related • For EAEs reported for participants in Arm 1 • Relationship assessments are required for DTG, FTC, and TAF • For EAEs reported for participants in Arm 2 • Relationship assessments are required for DTG, FTC, and TDF • For EAEs reported for in Arm 3 • Relationship assessments are required for EFV, FTC, and TDF

21. Related or Not Related • For mothers, assess relationship to each ARV received (ingested) • For infants, assess relationship to each ARV received by the mother to which the infant may have been exposed in utero or through breastfeeding

22. EAE Reporting Requirementsfor Infants

23. EAE Reporting Requirementsfor Mothers Modified in Protocol Version 2.0 X X SAEs SAEs If a mother in Arm 3 switches to a DTG-containing or TAF-containing regimen, then switch to the same reporting as for mothers in Arms 1 and 2

24. Additional EAE Reporting Requirements for Mothers Modified in Protocol Version 2.0 X Yes X Yes If a mother in Arm 3 switches to a DTG-containing or TAF-containing regimen, then switch to the same reporting as for mothers in Arms 1 and 2

25. Additional EAE Reporting Requirements for Mothers Modified in Protocol Version 2.0

26. Yes No Maybe 26 A pregnant woman randomized to Arm 1 at 18 weeks gestation is hospitalized at 20 weeks gestation with a febrile illness. Has a reportable EAE occurred?

27. Yes No Maybe 27 A pregnant woman randomized to Arm 2 at 18 weeks gestation is hospitalized at 20 weeks gestation with a febrile illness. Has a reportable EAE occurred?

28. Yes No Maybe 28 A pregnant woman randomized to Arm 3 at 18 weeks gestation is hospitalized at 20 weeks gestation with a febrile illness. Has a reportable EAE occurred?

29. Yes No Maybe A pregnant woman randomized to Arm 1 at22 weeks gestation experiences a still birth at 28 weeks gestation. Has a reportable EAE occurred?

30. Yes No Maybe A pregnant woman randomized to Arm 2 at 22 weeks gestation experiences a still birth at 28 weeks gestation. Has a reportable EAE occurred?

31. Yes No Maybe A pregnant woman randomized to Arm 3 at22 weeks gestation experiences a still birth at 28 weeks gestation. Has a reportable EAE occurred?

33. Yes No Maybe 33 An enrolled pregnant woman reports to the clinic for her antepartum Week 4 visit complaining of severe fatigue, nausea, vomiting, and abdominal pain. Lab testing provides grade 4 ALT and AST results. Has a reportable EAE occurred?

34. What are your questions about EAE reporting?