1. EAE Training EAE Reporting and Assessment Overview DAIDS Regional Training Event, Regulatory Compliance Center Kampala, Uganda, September 2009 DAIDS Regional Training Event, Regulatory Compliance Center Kampala, Uganda, September 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. Definitions

5. 5 Expedited Adverse Event (EAE)  An adverse event that meets the criteria for expedited reporting to Division of AIDS (DAIDS).  DAIDS recognizes there are differences between events that require expedited reporting to DAIDS and SAEs as defined by ICH.

6. 6 Suspected Adverse Drug Reaction (SADR)  All noxious and unintended responses to a pharmaceutical product related to any dose, and to which a causal relationship between the product and the event cannot be ruled out.

7. Serious Adverse Event (SAE)  Definition for SAE is per ICH E2A  Certain DAIDS protocols will have expedited reporting of all SAEs  Protocols: A5241, MTN 003, P1066, P1060, to mention a few.  Protocols in development; pharma partners have reporting obligations as the MAHs of their drugs 7

8. Assessment of Adverse Events

9. 9 Assessment  Study physician listed on the 1572 / Investigator of Record (IoR) Agreement assesses the events: Seriousness Severity Relationship Expectedness (only applies to Targeted)

10. 10 Serious versus Severe  Seriousness is based on outcome of the AE and is a factor in determining reportability (this is a regulatory definition): Results in death or is life-threatening Hospitalization Disability or Congenital Anomaly Medically important  Severity refers to the intensity of the experience (this is a medical description of the AE): (e.g. Mild, moderate, or severe headache)

11. 11 Severity  Events are graded on a severity scale of 1-5: 1 = Mild 2 = Moderate 3 = Severe 4 = Potentially Life-threatening 5 = Death

12. 12 Grading Severity of Events  Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (Version 1.0) December 2004: Web Site: http://rcc.tech-res.comhttp://rcc.tech-res.com

13. 13 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

14. 14 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

15. 15 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)

16. 16 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

17. 17 Relatedness  Pending: Only for a death and while information about death is being obtained. Updated relationship assessment required within 3 business days or the event will automatically be coded as “Possibly Related.” Follow-up information should be submitted when available, especially if it results in a change to the relationship assessment.

18. 18  The protocol will specify one of three levels of adverse event reporting: Standard Intensive Targeted Levels of Adverse Event Reporting

19. 19 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 Adverse Event Reporting - Summary

20. 20 Additional Adverse Events To Be Reported  Serious Adverse Events associated with study participation or procedure.  SADRs that do not meet the protocol specific reporting criteria, but that the investigator believes are of significant concern to be reported on an expedited basis to DAIDS.

21. 21 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.

22. 22 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

23. 23 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.

24. 24 EAE Reporting Timeframe  Within 3 business days of site awareness that an event has occurred at a reportable level.

25. 25 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.

26. 26 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.

27. 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  If reporting via DAERS, no paper form needed 27

28. 28 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) RCCSafetyOffice@tech-res.com If e-mailing, scan or FAX signature page DAERS: via web

29. 29 Overview of Reporting Timelines

30. 30 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)  RCC Web Site: http://rcc.tech-res.comhttp://rcc.tech-res.com