1. EAE Training PROTOCOL ­ SPECIFIC 2009

2. 2 Objectives  Definitions  Assessment of Adverse Events  EAE Reporting

3. 3 EAE Reporting Materials  EAE Manual  EAE Reporting Form  EAE Reporting Form Completion Instructions  AE Grading Table  Protocol

4. 4 Expedited Adverse Event (EAE)  An adverse event that meets the criteria for expedited reporting to Division of AIDS (DAIDS).

5. 5 Adverse Event Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. (ICH E2A)

6. 6 Serious Adverse Event (SAE) A serious adverse event (experience) or reaction is 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, or  Is a congenital anomaly/birth defect. In addition, “…important medical events that may not be immediately life- threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition above…should also usually be considered serious.” (ICH E2A)

7. 7 Adverse Event vs. Event Outcome Death  Death is an outcome and is not usually considered to be an AE. Example: If “death due to myocardial infarction” is reported, “myocardial infarction” can be selected and death should be captured as the outcome.  If the only information reported is death, then the most specific death term available should be selected. Example: If a reporter states only that “a study subject was found dead,” “found dead” can be selected. Example: If the autopsy report states, “the cause of death was natural”, “Death from natural causes” can be selected.

8. 8 Adverse Event vs. Event Outcome Hospitalization  Hospitalization is a consequence and is not usually considered an AE. Example: If “hospitalization due to congestive heart failure” is reported, “congestive heart failure” can be selected and hospitalization should be captured as the consequence of the event.  If the only information reported is the outcome term, then the most specific term available should be selected. Example: If a reporter states only that “a study subject was hospitalized,” “hospitalization” can be selected.

9. 9 Hospitalization: Exemptions from expedited reporting Hospitalization in the absence of a medical AE is not in itself an AE and does not need to be reported in an expedited time frame.  Admission unrelated to an AE (e.g. for labor/delivery, aging- related cosmetic surgery, administrative or social admission)  Protocol-specified admission (e.g. for procedure required by protocol)  Admission for diagnosis or treatment for pre-existing condition (unless it is worsening or increasing in frequency) A new AIDS-defining event in HIV-infected subject would be considered worsening of pre-existing condition of HIV infection

10. 10 Severity  Describes the intensity of the event  Events are graded on a severity scale  Events are graded on a severity scale of 1-5: 1 = Mild 2 = Moderate 3 = Severe 4 = Potentially Life-threatening 5 = Death

11. 11 Grading Severity of Events  Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (Version 1.0) December 2004 (Clarification August 2009): Web Site: http://rcc.tech-res.comhttp://rcc.tech-res.com

12. 12 EXAMPLE FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS CLINICAL PARAMETERGRADE 1 MILD GRADE 2 MODERATE GRADE 3 SEVERE GRADE 4 POTENTIALLY LIFE-THREATENING ESTIMATING SEVERITY GRADE Clinical adverse event NOT identified elsewhere in this DAIDS AE grading table Symptoms causing no or minimal interference with usual social & functional activities Symptoms causing greater than minimal interference with usual social & functional activities Symptoms causing inability to perform usual social & functional activities Symptoms causing inability to perform basic self-care functions OR Medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death Death = Grade 5

13. 13 EXAMPLE FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS SYSTEMIC PARAMETERGRADE 1 MILD GRADE 2 MODERATE GRADE 3 SEVERE GRADE 4 POTENTIALLY LIFE-THREATENING ChillsSymptoms causing no or minimal interference with usual social & functional activities Symptoms causing greater than minimal interference with usual social & functional activities Symptoms causing inability to perform usual social & functional activities N/A Fever (nonaxillary) 37.7 – 38.6  C38.7 – 39.3  C39.4 – 40.5  C> 40.5  C

14. 14 EXAMPLE FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS PARAMETERGRADE 1 MILD GRADE 2 MODERATE GRADE 3 SEVERE GRADE 4 POTENTIALLY LIFE-THREATENING INFECTION Infection (any other than HIV infection) Localized, no systemic antimicrobial treatment indicated AND Symptoms causing no or minimal interference with usual social & functional activities Systemic antimicrobial treatment indicated OR Symptoms causing greater than minimal interference with usual social & functional activities Systemic antimicrobial treatment indicated AND Symptoms causing inability to perform usual social & functional activities OR Operative intervention (other than simple incision and drainage) indicated Life-threatening consequences (e.g. septic shock)

15. 15 Severity vs. Serious  Severity is not the same as Serious  Severity = Intensity e.g., chest pain, moderate severity  Serious (SAE) = Based on patient/event outcome or action criteria Used to define regulatory reporting obligations  AE classification: must divorce usage of serious in a clinical sense from serious in a regulatory sense  For clinical connotations, use severity descriptors

16. 16 Action Taken with Drug  Action Taken with Drug: Withdrawn Dose reduced Dose increased Dose not changed Unknown Not applicable  ICH E2B (R3)  Action Taken with Drug: O: Course completed or Subject OFF study agent at AE C: Continued without change R: Dose or schedule reduced T: Temporarily held D: Permanently discontinued U: unknown  DAIDS EAE Form

17. 17 Outcome  Outcome of reaction/event at the time of last observation Recovered/resolved Recovering/resolving Not recovered/not resolved Recovered/resolved with sequelae Fatal Unknown  Outcome of subject in study Remains in Study Withdrawn Lost to follow-up Death

18. 18 Expectedness  Pertains to whether an event is expected or unexpected (on the basis of previous observation, not what might be anticipated from the pharmacological properties of the product)  Unexpected: the nature or severity of the adverse event is not consistent with the applicable product information (e.g. Investigator’s Brochure for unapproved product, Package Insert for approved product)

19. 19 Relatedness (Causality)  No standard international nomenclature  Conveys that a “causal relationship” between the study product and the adverse event is “at least a reasonable possibility” [ICH E2A] Facts (evidence) exist to suggest the relationship  Judged by: Reporting health professional Sponsor

20. 20  Standard determinations include: Is there [Drug Exposure] and [Temporal Association]? Is there [Dechallenge/Rechallenge] or [Dose Adjustments]? Any known association per [Investigator’s Brochure] or [Package Insert]? Is there [Biological Plausibility]? Any other possible [Etiology]? Determination of Relatedness

21. 21 Relatedness  Judgment of a relationship between AE and study agent.  An event is assessed as: Definitely related… Probably related… Possibly related… Probably not related… Not related… Pending relationship… …to the study agent

22. 22  Comprehensive, stand-alone “medical story” Written in logical time sequence Include key information from supplementary records Include relevant autopsy or post-mortem findings  Summarize all relevant clinical and related information, including: Study subject characteristics Therapy details Medical history Clinical course of the event(s) Diagnosis (workup, relevant tests/procedures, lab results) Other information that supports or refutes an AE > ICH E2D Narrative

23. 23 Assessment  Study physician listed on the 1572 / Investigator of Record (IoR) Agreement assesses the events: Seriousness Severity Relationship Expectedness (only applies to Targeted)

24. 24 Review and Assessment of EAE/SAE  Assemble all information available and use medical judgment  Standard for each AE: Select [Seriousness Criteria] Grade [Severity] per DAIDS Toxicity Table Specify [Actions Taken on Study Product] Specify [Outcome of SAE/EAE]. If Outcome is not resolved at time of evaluation, follow until resolution or stability at each study visit Is it [Expected]? Is it [Related]?

25. 25 New vs. Follow-up reports New  A reportable event first occurs.  An ongoing event increases in severity to a higher grade than previously reported.  An event fully resolves to baseline status and then recurs at a reportable level. Follow-up  DAIDS requests additional information.  Study physician changes assessment of relationship to study agent.  Additional significant information becomes available (e.g. autopsy report, death certificate).  Results of rechallenge.

26. 26  The protocol will specify one level of adverse event reporting: Standard Intensive Targeted Other: SAE (added 2008) Levels of Expedited Adverse Event Reporting

27. 27 Standard Level Intensive Level Targeted Level Deaths All Disabilities/ Incapacities All Congenital anomalies, birth defects, fetal losses All Hospitalization/ Intervention SADRs Unexpected SADRs Life-threatening Grade 4 SADRs Unexpected Clinical SADRs Other events Grade 3 SADRs Levels of Expedited Adverse Event Reporting - Summary

28. 28 EAE Reporting Period  Entire study duration for an individual subject (from enrollment until study completion or discontinuation for that particular subject).  …or as specified in the protocol.

29. 29 EAE Reporting Period  After the EAE Reporting Period, only the following should be reported: Unexpected, Serious, Clinical SADRs If the study staff becomes aware of their occurrence on a passive basis (i.e. through publicly available information, not active follow up) –Example: Obituary in the newspaper

30. 30 EAE Study Physician signature  Physician signature signifies physician review and sign off  The EAE report may be sent in without the study physician signature, if necessary. BUT  The completed signature page must be submitted to the RCC Safety Office within 3 business days of submitting the original EAE.

31. 31 EAE Reporting Timeframe  Within 3 business days of site awareness that an event has occurred at a reportable level.

32. 32 Confirmation Of Receipt  The RCC Safety Office sends a confirmation email for all new reports.  It is the site’s responsibility to follow-up if they do not receive a confirmation email.

33. How to Report EAEs  Reports must be submitted on the EAE form available on the RCC Web site http://rcc.tech-res.com/. http://rcc.tech-res.com/  DAERS: DAIDS AE Reporting System: web- based electronic submission https://daidses.niaid.nih.gov/Phoenix https://daidses.niaid.nih.gov/Phoenix If reporting via DAERS, no paper form needed 33

34. 34 How to Report EAEs  Reports may be submitted via FAX, E-mail or DAERS: FAX: 1-301-897-1710 or 1-800-275-7619 (USA only) Email: RCCSafetyOffice@tech-res.comRCCSafetyOffice@tech-res.com If e-mailing, scan or FAX signature page DAERS: https://daidses.niaid.nih.gov/Phoenixhttps://daidses.niaid.nih.gov/Phoenix

35. 35 Where to Get Help  RCC Safety Office: E-mail: RCCSafetyOffice@tech-res.comRCCSafetyOffice@tech-res.com Telephone: 1-301-897-1709 or 1-800-537-9979 (US Only) Fax: 1-301-897-1710 or 1 -800-275-7619 (US Only)  DAERS help: DAIDS-ESSupport@niaid.nih.govDAIDS-ESSupport@niaid.nih.gov Phone: 240-499-2239 (outside US), 866-337-1605 (US) Fax: 301-948-2242 (outside US), 866-337-1606 (US) Live assistance is available from 8:30 am to 5:30 pm EST, Monday to Friday (Excluding US Holidays)

36. 36 Overview of Reporting Timelines

37. Protocol ­ Specific Information