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2 Objectives Distinguish changes in Manual v2.0 Define key terms New algorithm for reportability Causality assessment Implementation Distinguish DAERS.

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Presentation on theme: "2 Objectives Distinguish changes in Manual v2.0 Define key terms New algorithm for reportability Causality assessment Implementation Distinguish DAERS."— Presentation transcript:


2 2 Objectives Distinguish changes in Manual v2.0 Define key terms New algorithm for reportability Causality assessment Implementation Distinguish DAERS changes for Manual v2.0 Phoenix v1.6 Reliant v1.6

3 Development of Manual v2.0 for Expedited Reporting to DAIDS SAEC WG: Safety and Adverse Events Core Working Group Members: Vaccines: Libby Adams (SME) Prevention: Jeanna Piper (SME) Therapeutics: Karin Klingman (SME), Kathy Smith Pediatrics: Ed Handelsman, Renee Browning RCC Safety: Anu Jasti, Sandy Butler SPT: Ling Chin  Jing Bao, Larry Allan, David Diwa OPCRO: Richard Hafner, Scott Proestel DAERS: Peter Kim Primary goal is to align expedited reporting to ICH-SAE definition. Fulfill DAIDS’ regulatory requirements to FDA Fulfill DAIDS’ obligations to industry collaborators 3

4 4 EAE Policy and Location Purpose: To describe requirements for reporting adverse events in an expedited timeframe to DAIDS Scope: This policy applies to all NIAID (DAIDS) supported and/or sponsored clinical trials Revised policy will be posted on or before May 3 AIDSClinRsrch/Documents/eaereportpolicy.pdf 4

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 Definitions Manual v2.0 7

8 Expedited Reporting of Adverse Events to DAIDS Two Reporting categories: The protocol will specify which reporting category will be used 8

9 Expedited Reporting of Adverse Events 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 9

10 Expedited Reporting of Adverse Events 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 the study agents(s) 10

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) 11

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, or 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. 12

13 “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 13 Clarification on SAE Definition: Life-threatening

14 Hospitalization is 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) Clarification on SAE Definition: Hospitalization 14

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 15

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) E.g. 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 16

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: Guidelines for Conducting Birth Defects Surveillance, National Birth Defects Prevention Network (NBDPN), appendix 3.1. Direct link to document: This website listing should not restrict the reporting of anomalies that the site investigator deems important for sponsor notification 17

18 Clarification on SAE Definition: Important Medical Events 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 18

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 19

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 20

21 Assessment of Adverse Events 21

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

23 Serious versus Severe Seriousness is NOT the same as Severity 23

24 Grading Severity of Events All events reported to DAIDS in an expedited timeframe must be graded for severity Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0 - December 2004 (Clarification dated August 2009) 24

25 25 Severity Grading 25

26 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). 26

27 Relationship Assessment cont’d 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. 27

28 Relationship Assessment cont’d 28

29 Expedited Reporting Processes 29

30 Determining Reportability SAE Reporting Category Flowchart 30

31 Determining Reportability SUSAR Reporting Category Flowchart 31

32 Adverse Events Not Requiring Expedited Reporting to DAIDS An SAE occurring before exposure to a study agent Immune reconstitution inflammatory syndrome (IRIS), even if the event otherwise meets the reporting criteria. IRIS is an intense immune reaction that may result from a response to HIV treatment and is an anticipated event for antiretroviral therapies 32

33 Reporting Fetal Loss 33

34 Updated Information Sites must follow each AE until the AE is resolved or stable For each AE reported to DAIDS, sites are required to submit an updated report to DAIDS as soon as significant additional information becomes available. The following are examples that must be submitted: An updated report documenting the stable or resolved outcome of the AE, unless the initial report included a final outcome, Any change in the assessment of the severity grade of the AE or the relationship between the AE and the study agent, or Additional significant information on a previously reported AE (e.g., cause of death, results of re-challenge with the study agent(s)). 34

35 Reporting Timeframe Within 3 reporting days of site awareness that an event has occurred at a reportable level “Reporting days” are those that count toward the 3-day timeline provided for reporting of EAEs to DAIDS 35

36 Reporting Days The criteria used to determine reporting days are as follows: A reporting day starts at 12:00 AM (midnight) and ends at 11:59 PM local time. A day is counted as a reporting day regardless of the time of day that awareness occurred. The day a site indicates that site personnel became aware of an EAE that meets reporting criteria shall count as day 1 if that day occurs on a reporting day (i.e., Monday through Friday). If that day occurs on a non-reporting day (i.e., Saturday or Sunday), then the next reporting day shall count as day 1. Monday through Friday count as reporting days. Saturday and Sunday are not considered reporting days. Any holiday (U.S. or in-country/local) that occurs on a Monday through Friday counts as a reporting day. 36

37 Site Investigator Signature A site physician investigator or sub-investigator listed on the 1572 or the IoR Agreement must: Review and verify the completed report for accuracy and completeness and Sign the report This physician makes the site’s final assessment of the relationship to study agent(s) 37

38 Site Investigator Signature cont’d 38

39 39 DAERS (Phoenix) Release v1.60: Changes for Manual v2.0

40 DAERS Changes for Manual v2.0 DAERS will automatically reflect the changes in specified fields once a protocol using the EAE Manual Version 2.0 is selected After a protocol has switched to the EAE Manual Version 2.0: New EAEs will use EAE Manual Version 2.0 Updates to EAE reports created prior to the switch will continue using EAE Manual Version 1.0 40

41 DAERS Changes for Manual v2.0 41

42 DAERS Changes for Manual v2.0 42

43 43 DAERS (RELIANT) Release 1.6: Changes for Manual v2.0

44 44 DAERS EAE Processing Medical Officer Safety Assessment Screen “Safety Report Required” Business Rules For IND Studies Case 1: –Site or MO assessment evaluation is Serious, and, –Site or MO relationship assessment is NOT “Not Related”, and –MO expectedness evaluation is “Unexpected” Case 2: –Grade 5 (Death) and, –Site or MO relationship assessment is NOT “Not Related”

45 45 DAERS EAE Processing Medical Officer Safety Assessment Screen For Non-IND Studies The product will not enforce a safety report required decision. The RCC will enforce the current policy as required.

46 46 DAERS EAE Processing MO and SPT Screens Search Screen Enabled user to open older EAEs in Read Only Mode Users can review Safety Report document history Resolution History Pop-up window added to show the history of: –Participant Status –Observation Date History is shown for the life of the EAE

47 47 DAERS EAE Processing

48 48 DAERS EAE Processing MO and SPT Screens Screen Header Updates Reporting Manual: Displays full manual name, version, and version date Reporting Category: Shows reporting method and level as appropriate –Reporting Manual: Manual for Expedited Reporting of Adverse Events to DAIDS, 1.0, 06-May-2004 –Reporting Category: EAE (Standard)

49 49 DAERS EAE Processing

50 50 DAERS EAE Processing Medical Officer Safety Report Review Screen Added field to collect action that will be taken as a result of reviewing the Safety Report Need to check on one of the questions One question requires comments A response is required to complete the Safety Report Review

51 51 DAERS EAE Processing Medical Officer Safety Report Review Screen Based on review of this adverse event report: DAIDS does not believe that changes to the conduct of this trial are warranted at this time. Discussions are underway to determine whether changes will be made to the conduct of this trial. DAIDS will inform the FDA and other appropriate authorities if any changes will be made. The following changes to the conduct of this trial will be taken (please specify): –This response will require comments.

52 DAERS EAE Processing 52

53 Summary of Changes 53

54 Summary of Changes 54

55 Summary of Changes 55

56 New EAE Form and Instructions harmacovigilance/ 56

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