Safety Workshop: Part II Expedited Reporting & Assessment Training

1. Safety Workshop: Part IIExpedited Reporting & Assessment Training August 19, 2010 Albert Yoyin, M.D. DAIDS Regulatory Support Center (RSC)

2. Objectives • Definitions • Assessment of Adverse Events • Expedited Reporting Processes • Moving from Manual v1.0 to v2.0

3. Expedited Reporting Materials • Manual for Expedited Reporting to DAIDS v2.0 • SAE Reporting Form 2.0 • SAE Reporting FormCompletion Instructions 2.0 • DAIDS AE Grading Table • (Clarification August 2009) • Protocol

4. Manual for Expedited Reporting Version 2.0 • Manual v2.0 (dated Jan 2010) has been issued and posted on RSC website • Primary goal is to align expedited reporting to ICH-SAE definition • Fulfill DAIDS’ regulatory requirements to FDA • Fulfill DAIDS’ obligations to industry collaborators

5. Highlights: Major Changes • Reporting Categories • Categories of expedited reporting • Definitions • Clarifications • Assessment of Relationship to study agent • Terms 5

6. Highlights: Major Changes • Submission of updates • Event resolution • Increase in event severity of ongoing AEs • Timeframe for expedited adverse event reporting • Reporting days • Site investigator assessment and signature timeframe 6

7. DefinitionsManual v2.0

8. Expedited Adverse Event Reporting to DAIDS SAE - All Serious Adverse Events SUSAR - Only Suspected, Unexpected, Serious Adverse Reactions Two Reporting Categories: • The protocol will specify which reporting category will be used

9. Expedited Adverse Event Reporting to DAIDS Additional reporting requirements: • In addition, a protocol may require other AEs to be reported on an expedited basis • The protocol will specify the additional AEs to be reported to DAIDS

10. Expedited Adverse Event Reporting to DAIDS • Study agent(s) – drugs, biological agents, combination of drugs and biological agents or devices (approved or investigational) defined in the protocol for which expedited reporting to DAIDS is required; regardless of who provides the drugs/products • The protocol will specify what the study agent(s) are

11. Reporting Period • Protocol specified reporting period: from enrollment to end of trial follow-up for that participant • After the protocol-defined AE reporting period, unless otherwise noted, only SUSARs will be reported to DAIDS if the study staff becomes aware of the events on a passive basis (from publicly available information).

12. SAE Definition (ICH E2A) A serious adverse event (SAE) is defined as 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 • Is 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 patient or may require intervention to prevent one of the other outcomes listed in the definition above

13. Clarification on SAE Definition: Life-threatening Life-threatening refers to an event in which the patient was at risk of death at the time of the event • It does not refer to an event which hypothetically might have caused death if it were more severe • E.g. malignancy

14. Clarification on SAE Definition: Hospitalization Not an AE, but is an outcome of the AE The following types of hospitalization do not require expedited reporting to DAIDS: • Any admission unrelated to an AE (e.g., for labor/delivery, cosmetic surgery, administrative or social admission for temporary placement for lack of a place to sleep) • Protocol-specified admission (e.g., for a procedure required by protocol)

15. Clarification on SAE Definition: Hospitalization cont’d • Admission for diagnosis or therapy of a condition that existed before receipt of study agent(s) and has not increased in severity or frequency as judged by the clinical investigator. • A new AIDS-defining event in a subject already known to be HIV-infected would be considered an increase in severity of a pre-existing condition [HIV infection] and would be reportable as an expedited AE

16. Clarification on SAE Definition: Congenital anomaly/birth defect Do not report clinically insignificant physical findings at birth, including those regarded as normal variants • Report clinically significant anomalies; include all other findings (even if not individually significant) • Example: an isolated finding of polydactyly or Mongolian spot in an infant with no other findings would not be reported, but polydactyly or Mongolian spot occurring with a major cardiac defect would be included in the SAE report of the major cardiac defect

17. Clarification on SAE Definition: Congenital anomaly/birth defect cont’d • Information about congenital anomalies can be found on the Centers for Disease Control and Prevention (CDC) website: http://www.cdc.gov/ncbddd/bd/monitoring.htm • Guidelines for Conducting Birth Defects Surveillance, National Birth Defects Prevention Network (NBDPN), appendix 3.1. Direct link to document: www.nbdpn.org/current/resources/sgm/appendix3-1.pdf • This website listing should not restrict the reporting of anomalies that the site investigator deems important for the sponsor to know.

18. Clarification on SAE Definition: Important Medical Events • Events considered as important medical events can meet SAE criteria. • Examples: • Intensive treatment in an emergency room or at home for allergic bronchospasm • Blood dyscrasias or convulsions that do not result in hospitalization • Development of drug dependency or drug abuse

19. SUSAR Definition • SUSAR is defined as an adverse event that is a Suspected Unexpected Serious Adverse Reaction • For the SUSAR reporting category, an SAE will be reported if it fulfills the following criteria: • Related and • Unexpected

20. SUSAR Reporting Category • Used for some non-IND studies/trials using U.S. FDA-approved agents with approved dosages for approved indications in typical populations • At the discretion of DAIDS

21. Assessment ofAdverse Events

22. Assessment • AEs are assessed for: • Seriousness • Severity • Expectedness • Relationship • Study physician listed on the1572 / Investigator of Record (IoR) Agreement is responsible for the assessment of AEs • Sponsor Level: DAIDS MOs provide secondary review

23. Primary Adverse Event Is there an AE? If there are associated symptoms, what is the primary AE? Report only one primary AE per report. Example: Primary AE: Myocardial Infraction Clinically Significant Event Associated with primary AE: CHEST PAIN Clinically Significant Event Associated with primary AE: DYSPNEA

24. Primary Adverse Event How many primary AEs are there? Events that are not clearly associated with the primary AE should be reported as separate events. Example “Acute Renal Failure and Gastroesophageal Reflux” Primary Adverse Event 1 “Acute Renal Failure” Primary Adverse Event 2 “Gastroesophageal Reflux”

25. Hospitalization • 61 y.o. HIV-infected, African-American male, enrolled Feb 15, 09, with Gr. 4 hospitalization May 8, 09 • Feb 20, 09: subject was started on study agents ABC and XYZ. • May 8, 09: subject visited study clinic with complaints of abdominal pain and non-bloody diarrhea for the past one week • Vomited three times on the day of clinic visit

26. Hospitalization • PE: moderately dehydrated aged man with vague generalized abdominal tenderness. No guarding or rebound tenderness. BP: 109/71 mmHg and HR: 69 beats/min • Given IV Ringers lactate and IM diclofenac, 75 mg • Sent to hospital for further work up • Hospital lab results: K+ 2.1 mEq/L (3.5–5.2 mEq/L) • KCL 20 mmol, was added to each liter of Ringers lactate • Results for stool culture pending • May 9, 2009: stable, awaiting discharge

27. Teaching Points • Hospitalization in and of itself is not an AE term; it is an outcome of the AE • Grading should be on the AE, not the outcome of the AE • Primary AE: ? • Abdominal pain, non-bloody diarrhea, vomiting, vague generalized abdominal tenderness • Possible AE Term: gastroenteritis, NOT ‘Hospitalization’ • However, if you do not have any information about the actual AE but the event is reportable you can report “Hospitalization”

28. Death • Jan 14, 2009: 40-year-old HIV uninfected, Asian female enrolled • Jan 14, 2009: started on the study agent XYZ at a dose of 32 mg, sublingually, 4 times a week • May 6, 2009: Took last dose of XYZ; went for clinic visit • May 10, 2009: died due to sudden death (AE term reported as death)

29. Death • May 11, 2009: subject’s younger brother called to inform site that subject died on May 10, 2009, at home. • According to the site, there is a hx of illicit drug use. [Note: study population is a drug addicted population]. No recent sickness, hospital admission, self-inflicting injury, violent attack, falls or family history of sudden death. • The site has provided a death certificate which gives the cause of death as “sudden death (cause unknown)”. • The Site Principal Investigator has assessed the event of death as not related to the study agent XYZ

30. Teaching Points • Death in and of itself is not an AE term; it is an outcome of the AE • Primary AE: • Sudden death (per death certificate) • Possible AE Term: Death unknown cause • However, if you do not have any information about the actual AE but the event is reportable you can report “Death unknown cause.”

31. Seriousness • Does primary AE meet criteria for an SAE? • Use ICH-SAE definition provided in Manual v2.0 • Select appropriate SAE criteria

32. Severity • Severity refers to the intensity of a specific event • Events are graded on a severity scale of 1-5: • 1 = Mild • 2 = Moderate • 3 = Severe • 4 = Potentially Life-threatening • 5 = Death

33. Seriousness is NOT the same as Severity Seriousness Severity • Based on outcome of the AE and is a factor in determining reportability (regulatory definition) • Based on the intensity of the AE and is not a factor in determining reportability (clinical descriptor) • Determined using the • SAE criteria • Determined using the DAIDS grading table

34. Grading Severity of Events • All events reported to DAIDS in an expedited timeframe must be graded for severity • Grading does not determine reportability • Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0 - December 2004 (Clarification dated August 2009)

35. Estimating Severity Grade Grade 1 – Mild Symptoms causing no or minimal interference with usual social & functional activities. • When a subject experiences a chest pain which does notinterfere with the subjects’ activity of daily living; then it is graded as 1. Grade 2 – Moderate Symptoms causing greater than minimal interference with usual social and functional activities. • When the chest pain is such that the subject, is unableto do someof their activities of daily living.

36. Severity Grade Grade 3 – Severe Symptoms causing inability to perform usual social & functional activities. • When the chest pain is such that the subject is unableto carry out activities of daily living. • Grade 4 – Potentially Life Threatening Symptoms causing inability to perform basic self-care functions OR medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death. • When the chest pain makes the subject unable to perform basicfunctions and is at riskof permanent impairment/persistent disability/death if no surgical or medical intervention is done

37. EXAMPLE FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS This table is used for estimating the severity grade of a clinical AE not specifically listed in DAIDS Grading Table

38. EXAMPLE FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS • This table is used for grading a clinical AE specifically listed in DAIDS Grading Table: • E.g. grading by symptomatology • E.g. grading by numerical ranges

39. Severity Grading

40. Issues With Grading • Death = Grade 5; clarified in DAIDS Grading Table, August 2009 • Potentially life-threatening = Grade 4 • Potentially life-threatening means at risk of death should the event occur in a more severe form. This is not the same as immediately life-threatening. • Grading abnormal laboratory values associated with a clinical AE: • Does not correspond to grade provided in the DAIDS toxicity table • When lab values fall between two grades choose the higher grade • Grading does not appear to reflect the event: • Event led to hospitalization, but graded as “Grade 1” or “Grade 2” • Grade the SAE not the initial AE (initial AE had progressed to level of SAE)

41. Grading: Neonatal Sepsis Neonatal Sepsis Grade 1 • 27 day-old, male infant, normal delivery, breastfed, nevirapine • 2-week visit: crying on urination, amoxicillin for 7 days • 3-week visit: refusing feed, brought back to clinic • PE: lethargic, HR: 140 bpm, RR: 58 bpm, T: 37.7 0C, WBC: 14.0 with left shift • Sent to hospital for sepsis workup • AE term: neonatal sepsis, Severity: Grade 1 • R/O Sepsis is reasonable AE Term • Basis for severity grade?

42. Grading: Neonatal Sepsis cont’d • Grading on basis of fever alone: Grade 1 • Grading on clinical basis of possible sepsis: • at least Grade 3 • Grade 4 reasonable as well

43. Grading: Respiratory Distress Respiratory Distress Grade 2 • 2 day-old male, delivered at 39 wks GA by C/S, started on oral zidovudine • PE: pale, flexed, not crying, given CPAP with improvement, APGAR: 6 at 5 minutes and 9 at 10 minutes, Birth Wt: 3.35 kg, Ht: 47.5, HC: 34 cm, HR: 140 bpm, RR: 62 • 12 hrs after birth: developed tachypnea and fussiness, RR: 62, Pulse Ox on room air: 70% • Transferred to NICU, 100% oxyhood, Pulse Ox: 80%, pH: 7.48, pCO2: 27, pO2: 251, HCO3: 20. • PE: systolic murmur heard along left sternal border • Echo: Moderate PDA, ASD, patent foramen, mild TR, trivial MR • Respiratory Distress is reasonable AE Term • Basis for severity grade?

44. Grading: Respiratory Distress cont’d

45. Grading: Respiratory Distress cont’d • Grading on basis of respiratory distress: at least Grade 3 • Required CPAP at birth • 12 hours later: tachypnea and RR:62 • Room air and 100% O2: 70-80% • Grading on basis of respiratory distress: Grade 4 • Need medical intervention beyond 100% O2 • Transferred to NICU • Grading on basis of alkalosis: Grade 2 • Not appropriate because it does not reflect clinical picture in totality

46. Relationship Assessment The terms used to assess the relationship of an event to study agent are: • Related– There is a reasonable possibility that the AE may be related to the study agent(s). • Not Related– There is not a reasonable possibility that the AE is related to the study agent(s).

47. Relationship Assessment • When an SAE is assessed as “not related” to study agent(s), an alternative etiology, diagnosis, or explanation for the SAE should be provided. • If new information becomes available, the relationship assessment of any AE should be reviewed again and updated, as required.

48. Relationship Assessment cont’d

49. Expectedness • Expected AEs are events that have been previously observed with use of the study agent(s). It is not based on what might be anticipated from the pharmacological properties of the study agent • Listed in the Investigator’s Brochure or Package Insert • SUSAR Reporting Category: • Site physician to determine expectedness • SAE Reporting Category: • Sponsor to determine expectedness

50. Expedited Reporting Processes