Expedited Adverse Event Reporting Requirements

Protocol References Section Title 7.2 Safety-Related Data Collection 7.3 Expedited Adverse Event Reporting

Other References and Resources Manual for Expedited Reporting of Adverse Events to DAIDS (Version 2.0) DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1, dated March 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

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

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

The definition of adverse event provided in Version 2 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)

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

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.

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 I wonder if people will ask if pregnancy needs to be recorded on this form. From Katie – do you want to add it as a question so that everyone knows it does NOT need to be recorded on this form?

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 Protocol Section 7.3.2

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

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

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

Related or Not Related Related = There is a reasonable possibility that 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.

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

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)

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 Also mention the known epidemiology or typical frequency of the event occurring outside of the study – how common would this event be seen among pregnant/postpartum infants who are not receiving study drug?

Reminder of Random Assignments

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

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 trough breastfeeding

EAE Reporting Requirements for Infants Study Entry through Week 14 Postpartum Week 14 Postpartum through Study Exit Arm 1 SAEs SUSARs Arm 2 Arm 3

EAE Reporting Requirements for Mothers Study Entry through Week 14 Postpartum Week 14 Postpartum through Study Exit Arm 1 SAEs Arm 2 Arm 3 SUSARs Note that, for participants assigned to Arms 1 and 2, the requirements for mothers differ from the requirements for infants. For infants in these arms, after Week 14, SUSARs are required to be reported, rather than SAEs.

Additional EAE Reporting Requirements for Mothers Event Arm 1 Arm 2 Arm 3 Spontaneous abortions and fetal deaths Yes No Pregnancy complications that result in medically indicated and/or elective termination of the pregnancy

Additional EAE Reporting Requirements for Mothers Event Arm 1 Arm 2 Arm 3 Hepatic toxicities that result in discontinuation of DTG or EFV Yes Serious ABC hypersensitivity reactions in mothers switching from TDF or TAF to ABC

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? Yes No Maybe For mothers in Arm 1, all SAEs must be reported as EAEs (serious because of hospitalization) 0 of 0

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? Yes No Maybe For mothers in Arm 2, all SAEs must be reported as EAEs. 0 of 0

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? Yes No Maybe Th event is serious, but for mothers in Arm 3, EAE reportability depends on the site’s assessment of relationship and expectedness. REMINDER that regardless of EAE reportability, the event must be entered into eCRFs so that data are complete for comparisons across arms. 0 of 0

A pregnant woman randomized to Arm 1 at 22 weeks gestation experiences a still birth at 28 weeks gestation. Has a reportable EAE occurred? Yes No Maybe For mothers in Arm 1, all fetal deaths must be reported as EAEs. 0 of 0

A pregnant woman randomized to Arm 2 at 22 weeks gestation experiences a still birth at 28 weeks gestation. Has a reportable EAE occurred? Yes No Maybe For mothers in Arm 2, all fetal deaths must be reported as EAEs. 0 of 0

A pregnant woman randomized to Arm 3 at 22 weeks gestation experiences a still birth at 28 weeks gestation. Has a reportable EAE occurred? Yes No Maybe For mothers in Arm 3, fetal deaths are not required to be reported as EAEs. REMINDER that the pregnancy outcome must still be entered into pregnancy outcome eCRFs. In addition, all still births are considered grade 3 events per the DAIDS tox table so an adverse event eCRFs should also be completed. See next slide. 0 of 0

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? Yes No Maybe STOP HERE in BOTSWANA The intent of this description is to highlight the requirement to report “hepatic toxicities that result in discontinuation of DTG or EFV” in all three arms. The correct answer to the question will depend on how the woman’s symptoms are managed, and specifically whether DTG or EFV is discontinued. 0 of 0

What are your questions about EAE reporting?