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

Version 2

Expedited Reporting of Adverse Events to the DAIDS

1Division 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

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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

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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 4

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


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


DEFINITIONSMANUAL VERSION 2.0


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.


Expedited Reporting of Adverse Events to DAIDS – Study Agents

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 - Only Suspected, Unexpected, Serious Adverse Reactions

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


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)


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


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


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.


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.


Clarification on SAE Definition: Important Medical Events

Examples of “Important Medical Events”:

Intensive treatment in an emergency room or at home for allergic bronchospasmBlood dyscrasias or convulsions that do not result in hospitalizationDevelopment of drug dependency or drug abuse


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


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


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


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).


ASSESSMENT OFADVERSE EVENTS


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 22

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


Primary Adverse Event

How many primary AEs are there?


Is there an AE?

Events that are not clearly associated with the primary AE should be reported as separate events

If there are associated symptoms, what is the primary AE?

Seriousness

Seriousness is based on the outcome of the AEExamples:• 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


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


Seriousness Versus Severity


Seriousness is NOT the same as Severity

Seriousness

Based on outcome of the AE and is a factor in

determining reportability (regulatory definition)

Determined using the SAE criteria

Severity

Based on the intensity of the AE and is not a factor in determining reportability

(clinical descriptor)

Determined using the DAIDS grading table

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)


Take Home Messages re: Severity Grading

Potentially life-threatening = Grade 4Potentially 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.


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).


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.


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.



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.



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.


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


EXPEDITED REPORTING PROCESSES


SAE Reporting Category Flowchart

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

SUSAR Reporting Category Flowchart

38http://rsc.tech-res.com/Document/safetyandpharmacovigilance/Manual_for_Expedited_Reporting_AEs_to_DAIDS_v2.pdf

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.


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


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))


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.


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).


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.



Overview of Reporting TimelinesOverview of Reporting Timelines

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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.


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: [email protected]

– If e-mailing, scan or fax signature page


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.


Where to Get Help

RSC Safety Office:E-mail: [email protected]: + 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: [email protected]: +1-240-499-2239

or 1-866-337-1605 (US Only)Fax: +1-301-948-2242


New Form for Expedited

Reporting and Instructions

http://rsc.tech-res.com/safetyandpharmacovigilance/

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Summary of Changes


Major ChangesVersion 2 Definitions/Requirements

Jan 2010

Reporting Categories

• SAEs (Serious Adverse Events)

• SUSARs (Suspected Unexpected Serious Adverse Reactions)

Relationship to study agent• Related (Reasonable possibility)

• Not Related (No reasonable possibility)

Relationship assessment for a combination product

Each component separately as well as the combination

Summary of Changes


Major Changes(Reportability)

Version 2 Definitions/RequirementsJan 2010

SAEs Report only if there is exposure to study agent

Life-threatening events

SAE level: Report regardless of relationshipSUSAR level: Report if related and unexpected

Hospitalizations

SAE level: Report regardless of relationshipSUSAR level: Report if related and unexpectedReport only if associated with an AE (See exceptions noted on Slide 15)

Important medical events

Part of ICH-SAE criteriaReport per category of expedited reporting

Fetal Loss Not required unless clinically significant congenital anomaly detected, or specified by protocol (See Slide 16)

IRIS events Do not report

Summary of Changes


Major Changes Version 2 Definitions/RequirementsJan 2010

GradingGrade 4 events are referred to as potentially life threatening events. Therefore not all Grade 4 events will meet SAE reporting criteria

AE Resolution Sites must follow each AE until resolved or stable. Provide as update

New events versus Updates

Report as an update if any ongoing event has a change in the severity grade

Conclusion

Q&A


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

Documents

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