1. Expedited Reporting/DAERS May 13, 2011 Oluwadamilola Ogunyankin, M.D. Chinedum Abanobi, M.D. DAIDS Regulatory Support Center (RSC) Oluwadamilola Ogunyankin, M.D. Chinedum Abanobi, M.D. DAIDS Regulatory Support Center (RSC)

2. DAERS Usage  6 month period (Oct 2010-Mar 2011)  Protocols: MTN-003, A5257, HPTN 058, iPrEx, P1070 85% submitted via DAERS 15% required data entry by proxy by RSC  PI signatures: 415 reports: 26 without signatures –Within 3 reporting days: 15% –Outside of 3 reporting days: 46% –Still pending: 38% 2

3. AEs Meeting Reportability Criteria  Total AEs received: 415 Meet reporting criteria: 340 (82%) Did not meet reporting criteria: 75 (18%)  Why? Important to bring to attention of DAIDS anyway Not sure, wanted to be on the safe side Only reason for submission is per protocol specifications for expedited reporting  RSC can assist with questions on whether an event is reportable or not  Sending in just to be sure results in additional work at RSC/DAIDS 3

4. Case Study: Acute Sinusitis CASE STUDY TO BE REVIEWED FOR 10 MINUTES 4

5. Case Study: Acute Sinusitis  January 16, 2011 subject enrolled into study and randomized to the oral arm.  On April18, 2011, subject experienced severe headache, nausea, dizziness, and loss of appetite. She took aspirin and was relieved.  On April 20, 2011, headache worsened, with fever, face pain, nasal congestion, nasal drainage, cough, and post nasal dripping. 5

6. Case Study: Acute Sinusitis  Lab work showed WBC of 15,700 cells/mm 3, frontal sinus x-rays showed air-fluid levels, and CT scan showed thickened mucous membrane.  She was admitted into the hospital for further work up and a diagnosis of grade 3 acute sinusitis was made.  She was started on pethidine, gentamycin, ibuprofen, and intravenous fluids. 6

7. Case Study: Acute Sinusitis  Reporter and Site Information Site Awareness Date: The date the site first became aware of the adverse event occurring at a reportable level -Date adverse event (AE) occurred - 18-Apr-2011 -Date serious adverse event (SAE) occurred - 20-Apr-2011 -Date site aware event occurred at a reportable level - 23-Apr-2011 7

8. Case Study: Acute Sinusitis  Timeline for Submission: Must submit within 3 ‘reporting days’ of site awareness 8 SundayMondayTuesdayWednesdayThursdayFridaySaturda y 1234567 891011121314 15161718192021 22232425262728 293031 Report Due (11: 59 PM Local Time) April 2011 Site Awareness (2 PM local time)

9. Case Study: Acute Sinusitis  Primary Adverse Event Seriousness Criteria –Select appropriate ICH-SAE criteria –More than one criteria can be selected –Requires inpatient hospitalization or prolongation of existing hospitalization Primary Adverse Event –Acute Sinusitis Severity Grade –3-Severe 9

10. Case Study: Acute Sinusitis  Primary Adverse Event (Cont’d) Onset Date: The date the primary adverse event first occurred at the level requiring expedited reporting –20-Apr-2011 Country of AE Origin: The country where the event occurred; may not necessarily be the same where the clinical site is located –South Africa 10

11. Case Study: Acute Sinusitis  Primary Adverse Event (Cont’d) Status Code at Most Recent Observation: The status code of the subject at the most recent observation –Not Recovered/Not Resolved Status Date: Date of the most recent observation of the subject –Date should be on or after site awareness date Date of most recent observation for subject status can be at or after site is aware of the occurrence of the event –23-Apr-2011 11

12. Case Study: Acute Sinusitis  Case Narrative: Provide information on reported primary AE –Describe the clinical course, therapeutic measures, outcome, relevant past medical history, concomitant medication(s), alternative etiologies, any contributing factors and all other relevant information 12

13. Case Study: Acute Sinusitis  Study Agents Not a free text field –Choices are available from the drop down menu To activate the drop down menu, start typing the first few letters of a study agent Choose the specific study agent you are working on –emtricitabine/tenofovir disoproxil fumarate –darunavir 13

14. Case Study: Acute Sinusitis emtricitabine/tenofovir disoproxil fumarate Study Agent 1 [oral formulation] darunavir Study Agent 2 [oral formulation] 14

15. Case Study: Acute Sinusitis  Study Agents (Cont’d) Relationship of Study Agent 1 to Primary AE –Not Related Dose –2 tablets per day Date of First Dose –16-Jan-2011 Date of Last Dose: The date the subject took the last dose prior to onset of the adverse event –Not provided 15

16. Case Study: Acute Sinusitis  Study Agents (Cont’d) Exposure to and duration of use of study agent important information to assess the case Ensure accuracy of information For dates, if you are unsure, please check that it is an estimated date. 16

17. Case Study: Acute Sinusitis  Study Agents (Cont’d) Action Taken: Enter the study physician’s action taken with the study agent after awareness of the SAE –Continued Without Change Action Date: Date has to be on or after the site awareness date i.e. study physician can take an action with the study agent only after the site is aware the AE has occurred at a reportable level –23-Apr-2010 –If action taken is “Course completed or Off Study Agent at AE Onset” action date can be left blank 17

18. Case Study: Acute Sinusitis  Concomitant Medications: Aspirin  Other Events: List other clinically significant signs and symptoms that more fully describe the nature, severity, and/or complications of the primary AE Headache Grade 3 Nasal congestion Grade 2 Cough Grade 2 Fever Grade 2 18

19. Case Study: Acute Sinusitis  Laboratory Tests White blood cell count = 15,700 cells/uL (Normal Range: 4,000-11,000)  Diagnostic Tests X-ray of sinuses (21-Apr-2011) –Frontal sinuses showed evidence of air-fluid levels Frontal CT scan (21-Apr-2011) –Thickened mucous membrane X-ray of sinuses (23-Apr-2011) –Result Pending 19

20. Case Study: Acute Sinusitis  Reporter: Completes and sends the report for final review  Submitter: Reviews and submits the report to DAIDS  Email notification of expedited report submission sent to CRS staff and other key stakeholders  Site responsibility to ascertain that the report was in fact submitted 20

21. Case Study: Acute Sinusitis UPDATE TO BE REVIEWED FOR 2 MINUTES 21

22. Case Study: Acute Sinusitis UPDATE  Subject’s condition improved  April 23, 2011, follow-up sinus x-ray results were normal.  Subject was discharged home from the hospital.  Subject seen at the study clinic on April 25, 2011, with no complaints and with her discharge summary. 22

23. Case Study: Acute Sinusitis  UPDATE Primary Adverse Event –Status Code: Recovered/Resolved –Status Date: 25-Apr-2011 Case Narrative Diagnostic Tests –X-ray (23-Apr-2011) Normal with absence of air-fluid levels Additional Information –Upload copy of the discharge summary (if available) 23

24. Case Study: Acute Sinusitis  Submission of UPDATE Update status code and status date Update case narrative –Provide information on subject’s clinical course in hospital –Provide information on subject’s assessment in clinic post- discharge –Provide information on action taken with study agents by the study physician post-discharge Additional Information –Upload discharge summary and other relevant records 24

25. Questions? 25

26. Examples of RSC Queries to Sites Ambiguous AE terms which are not codable The reporting of “hospitalization” as an adverse event instead of reason for hospitalization The reporting of “death” as an adverse event instead of cause of death. Wrong dates e.g. DOB, awareness, start, inconsistent with narrative Errors in the selection of the SAE criteria e.g. Life threatening anemia but assigned as Grade 2 Accurate information about study drugs e.g. dose, schedule, start, stop dates Missing information e.g. lab results, diagnostic test results, con meds, supporting information such as progress notes, death certificates 26