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Expedited Reporting of Adverse Events to the DAIDS. Version 2. Objectives . Expedited Reporting Policy Distinguish changes in Manual v2.0 Define key terms New algorithm for reportability Causality assessment Implementation Distinguish DAERS changes for Manual v2.0.

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  1. Expedited Reporting of Adverse Events to the DAIDS Version 2 Division of AIDS / NIAID

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

  3. Policy for Expedited Reporting of Adverse Events • 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 is posted at:http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/eaereportpolicy.pdf 3

  4. Expedited Reporting of Adverse Events: Reporting Materials • Manual for Expedited Reporting of Adverse Events to DAIDS Version 2.0 • EAE Reporting Form 2.0 • EAE Reporting Form Completion Instructions 2.0 • Division of AIDS (DAIDS) Adverse Event (AE) Grading Table (Clarification August 2009) • Protocol (and any applicable Letter of Amendment) • The Manual for Expedited Reporting of Adverse Events to DAIDS and the DAIDS AE Grading Table can be found on the RSC website at: http://rsc.tech-res.com/safetyandpharmacovigilance/ Division of AIDS / NIAID

  5. Manual for Expedited Reporting Version 2.0 • Manual v2.0 (dated Jan 2010) has been issued and posted on Regulatory Support Center (RSC) website • Primary goal of this revision is to align expedited reporting to International Conference on Harmonization – Serious Adverse Event (ICH-SAE) definition • Fulfill the DAIDS’ regulatory requirements to Federal Drug Administration (FDA) • Fulfill the DAIDS’ obligations to industry collaborators Division of AIDS / NIAID

  6. Highlights: Major Changes • Categories of expedited reporting • Clarification of Definitions • Terms used in the assessment of Relationship to Study Agent • Submission of updates • Event resolution • Increase in event severity of ongoing AEs • Timeframe for expedited AE reporting • Reporting days • Site investigator assessment and signature timeframe Division of AIDS / NIAID

  7. DefinitionsManual Version 2.0 Division of AIDS / NIAID

  8. Expedited Reporting of Adverse Events to DAIDS – Study Agents • 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. • Placebos are also considered to be study agents. • The protocol will specify what the study agent(s) are. Division of AIDS / NIAID

  9. Expedited Reporting of Adverse Events to DAIDS Two Reporting Categories: • The protocol (and any applicable Letter of Amendment) will specify which reporting category will be used SAE - All Serious Adverse Events SUSAR - OnlySuspected, Unexpected, Serious Adverse Reactions Division of AIDS / NIAID

  10. 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 Division of AIDS / NIAID

  11. 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) Division of AIDS / NIAID

  12. Clarification on SAE Definition: Life-Threatening • Grade 4 events are referred to as potentially life-threatening events as defined in the DAIDS Tox Table Therefore, a Grade 4 event does not automatically imply that it meets SAE criteria Division of AIDS / NIAID

  13. Clarification on SAE Definition: Hospitalization • 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 due to lack of a place to sleep) • Protocol-specified admission (e.g. for a procedure required by protocol) • 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 Division of AIDS / NIAID

  14. 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 and include all other findings (even if not individually significant). • For 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. Division of AIDS / NIAID

  15. Clarification on SAE Definition: Congenital Anomaly/Birth Defect • 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. Division of AIDS / NIAID

  16. Clarification on SAE Definition: Important Medical Events Examples of “Important Medical Events”: • 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 Division of AIDS / NIAID

  17. 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 Division of AIDS / NIAID

  18. SUSAR Reporting Category • For many HVTN studies, SUSAR reporting is used after the main study reporting period has been completed • For a particular participant, “main study reporting period” typically means from study enrollment until completion of the main study or discontinuation from study participation. Refer to each individual protocol for specifics on this timeframe. • Used for some non-Investigational New Drug (non-IND) studies/trials using U.S. FDA-approved agents with approved dosages for approved indications in typical populations • At the discretion of DAIDS Division of AIDS / NIAID

  19. Expedited Reporting of Adverse Events to DAIDS Additional reporting requirements: • A protocol may require other AEs to be reported on an expedited basis • e.g. all liver toxicities (regardless of seriousness or severity) • The protocol will specify the additional AEs to be reported to DAIDS Division of AIDS / NIAID

  20. 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). Division of AIDS / NIAID

  21. Assessment ofAdverse Events Division of AIDS / NIAID

  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 Medical Officers (MOs) provide secondary review Division of AIDS / NIAID

  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: Pneumonia Clinically significant event associated with primary AE: Fever Clinically significant event associated with primary AE: Cough Division of AIDS / NIAID

  24. Primary Adverse Event Is there an AE? If there are associated symptoms, what is the primary AE? How many primary AEs are there? Events that are not clearly associated with the primary AE should be reported as separate events Division of AIDS / NIAID

  25. Seriousness • Seriousness is based on the outcome of the AE • Examples: • Any death of a participant meets SAE criteria based on the outcome. • Gastroenteritis which required intervention and assessment at a hospital meets SAE criteria based on the outcome (hospitalization) • Use ICH-SAE definition provided in Manual v2.0 Division of AIDS / NIAID

  26. Severity • Severity refers to the intensity of a specific event. • Severity scales can be descriptive or numerical. For example, a headache can be described as: • Mild, moderate, or severe • Grade 1, 2, 3, or 4 Division of AIDS / NIAID

  27. Seriousness Versus Severity 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 Division of AIDS / NIAID

  28. 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) Division of AIDS / NIAID

  29. Take Home Messages re: Severity Grading • Potentially life-threatening = Grade 4 • Potentially life-threatening means at risk of death should the event occur in a more severe form • Grading needs to reflect the intensity of the event, not the outcome. • In the event a participant has a clinical condition (e.g. pneumonia) where different severity grades are involved (e.g. Grade 2 WBC count, Grade 3 fever and cough), grade the clinical AE as a whole as opposed to the individual lab abnormalities or associated signs and symptoms. Division of AIDS / NIAID

  30. Relationship Assessment • Relationship assessment changed from a five category to a two category classification • 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). Division of AIDS / NIAID

  31. SCHARP’s AE Log CRFs • SCHARP currently has two versions of the AE Log CRF. One has 5 relationship categories and one has 2. • All ongoing studies will continue to use the 5 category AE Log CRF • All new studies (as well as HVTN 505 and LTFU), will use the 2 category AE Log CRF. Division of AIDS / NIAID

  32. SCHARP’s AE Log CRFs • For those studies using the 5 category AE Log CRF, but EAE Manual Version 2, please consider the following “mapping” guidance SCHARP received from OPCRO (dated July 1, 2010) when documenting the SAE relationship in DAERS and on the AE Log CRF. • “Mapping Strategy for Relationship Assessments Using Version 2.0 of the DAIDS EAE Manual” EAE Manual V1.0 EAE Manual V2.0 Definitely related             Related Probably related              Related Possibly related               Related Probably not related         Not Related Not related                        Not Related • This mapping strategy will be used during AE/EAE Reconciliation. Division of AIDS / NIAID

  33. 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. • SCHARP also asks that this information be provided for ALL AEs on the AE Log CRF. • If new information becomes available, the relationship assessment of any AE should be reviewed again and updated as required. Division of AIDS / NIAID

  34. Relationship Assessment • When submitting an AE in DAERS for a study agent that is a fixed dose combination agent, an assessment of attribution will be made for each component and the combination agent. Division of AIDS / NIAID

  35. 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 Division of AIDS / NIAID

  36. Expedited reporting processes Division of AIDS / NIAID

  37. SAE Reporting Category Flowchart http://rsc.tech-res.com/Document/safetyandpharmacovigilance/Manual_for_Expedited_Reporting_AEs_to_DAIDS_v2.pdf Division of AIDS / NIAID

  38. SUSAR Reporting Category Flowchart http://rsc.tech-res.com/Document/safetyandpharmacovigilance/Manual_for_Expedited_Reporting_AEs_to_DAIDS_v2.pdf

  39. 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. Division of AIDS / NIAID

  40. New/Initial Reports AEs that are reportable on New/Initial Reports: • New AE • Recurrent AE: only if the first AE has been resolved, is now reoccurring, and meets expedited reporting criteria • Pre-existing condition with an increase in severity Division of AIDS / NIAID

  41. 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 • Additional significant information on a previously reported AE (e.g., cause of death, results of re-challenge with the study agent(s)) Division of AIDS / NIAID

  42. Reporting Timeframe • Within 3 reporting days of site awareness that an event fulfills the protocol-defined criteria for expedited reporting to DAIDS • “Reporting Days” criteria: • Starts at 12:00 a.m. and ends at 11:59 p.m. (local time) • A day is counted as a reporting day regardless of the time of day that awareness occurred. • 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. Division of AIDS / NIAID

  43. 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 • Sign the report • This physician makes the site’s final assessment of the relationship to study agent(s). Division of AIDS / NIAID

  44. Site Investigator Signature • In the rare event that such physician(s) are not available for signature, sites may submit without signature to meet the reporting timeframe. • However, the signature and any necessary corrections or additions must be submitted within the next three reporting days. • The IoR or designee is responsible for designating at least one other physician who can perform the assessment and signature so as to provide uninterrupted coverage of monitoring AEs that will require expedited reporting. Division of AIDS / NIAID

  45. Division of AIDS / NIAID

  46. DAERS • For sites where DAERS has been implemented, all expedited adverse events and supporting information will be submitted to DAIDS using DAERS, unless the system is unavailable for technical reasons. • Use DAIDS EAE reporting form 2.0 if DAERS is not implemented. Division of AIDS / NIAID

  47. How to Report EAEs Reports must be submitted via DAERS: • DAERS: via web https://daidses.niaid.nih.gov/Phoenix • For emergency use only: • Fax: 1-301-897-1710 or 1-800-275-7619 (USA only) • Email: DAIDSRSCSafetyOffice@tech-res.com • If e-mailing, scan or fax signature page Division of AIDS / NIAID

  48. Confirmation Of Receipt • DAERS will send a confirmation email for all SAE reports. • It is the site’s responsibility to follow-up if they do not receive a confirmation email. Division of AIDS / NIAID

  49. Where to Get Help • RSC Safety Office: • E-mail: DAIDSRSCSafetyOffice@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) • RSC Web Site: http://rsc.tech-res.com/ • DAIDS-ES Support: • E-mail: DAIDS-ESSupport@niaid.nih.gov • Telephone: +1-240-499-2239 or 1-866-337-1605 (US Only) • Fax: +1-301-948-2242 Division of AIDS / NIAID

  50. New Form for Expedited Reporting and Instructions • http://rsc.tech-res.com/safetyandpharmacovigilance/ 50

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