DAIDS Safety Workshop: Part IIExpedited Reporting & Assessment

DAIDS Safety Workshop: Part IIExpedited Reporting & Assessment

Archita Chatterjee, M.S.DAIDS RSC Safety Office

Johannesburg, South Africa

29 Aug 2012

Archita Chatterjee, M.S.DAIDS RSC Safety Office

Johannesburg, South Africa

29 Aug 2012

ObjectivesObjectives

Definitions

Assessment of Adverse Events

Expedited Reporting Processes

About Manual v2.0

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Expedited Reporting MaterialsExpedited Reporting Materials

Manual for Expedited Reporting to DAIDS v2.0

DAIDS AE Grading Table (Clarification Aug 2009)

Protocol

EAE Reporting Form 2.0

EAE Reporting Form Completion Instructions 2.0

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DefinitionsManual v2.0

DefinitionsManual v2.0

Two Reporting Categories:

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Expedited Adverse Event Reporting to DAIDSExpedited Adverse Event Reporting to DAIDS

Expedited Adverse Event Reporting to DAIDSExpedited Adverse Event Reporting to DAIDS

The protocol will specify which reporting category will be used

Additional reporting requirements:

The protocol may require other AEs to be reported on an expedited basis; may or may not meet SAE criteria

These other AEs that are required to be reported to DAIDS will be specified in the protocol

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Expedited Adverse Event Reporting to DAIDSExpedited 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

Study agents will be specified in the protocol

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Reporting PeriodReporting 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)

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SAE Definition (ICH E2A)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

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Clarification on SAE Definition:Life-threateningClarification 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

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Clarification on SAE Definition:HospitalizationClarification 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)

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Clarification on SAE Definition:HospitalizationClarification on SAE Definition:Hospitalization

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

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Clarification on SAE Definition:Congenital Anomaly/Birth DefectClarification 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

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Clarification on SAE Definition:Congenital Anomaly/Birth DefectClarification 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.

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Clarification on SAE Definition:Important Medical EventsClarification 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

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SUSAR DefinitionSUSAR 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

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SUSAR Reporting CategorySUSAR 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

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Assessment ofAdverse EventsAssessment ofAdverse Events

AssessmentAssessment

AEs are assessed for:

• Seriousness• Severity• Relationship• Expectedness

Study physician listed on the 1572/ Investigator of Record (IoR) Agreement is responsible for the assessment of AEs

Sponsor Level: DAIDS MOs provide secondary review

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Primary Adverse EventPrimary Adverse Event

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Example: Primary AE: Myocardial infarctionExample: Primary AE: Myocardial infarction

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

Report only one primary AE per report.Report only one primary AE per report.

Clinically Significant Event Associated with primary AE:

Chest pain

Clinically Significant Event Associated with primary AE:

Chest pain

Clinically Significant Event Associated with primary AE:

Dyspnea

Clinically Significant Event Associated with primary AE:

Dyspnea

Is there an AE?Is there an AE?

Primary Adverse EventPrimary Adverse Event

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Example: Acute renal failure and Gastroesophageal reflux

Example: Acute renal failure and Gastroesophageal reflux

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

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

Primary Adverse Event 1 Acute renal failure

Primary Adverse Event 1 Acute renal failure

Primary Adverse Event 2 Gastroesophageal refluxPrimary Adverse Event 2

Gastroesophageal reflux

How many primary AEs are there?How many primary AEs are there?

HospitalizationHospitalization

8 May 2009: 61 year old HIV infected African American male (enrolled 15 Feb 2009), with Grade 4 hospitalization

20 Feb 2009: subject was started on study agents LMN and XYZ

8 May 2009: 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

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Teaching PointsTeaching 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.” Submit an update when additional significant information is available

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DeathDeath

14 Jan 2009: 40 year old HIV uninfected Asian female enrolled; started on the study agent XYZ at a dose of 32mg, sublingually, 4 times a week

6 May 2009: Took dose of XYZ; went for clinic visit

10 May 2009: died due to sudden death (AE term reported as “death”)

Hx of illicit drug use [study target pop: drug use]

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Teaching PointsTeaching 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: Drug overdose (although not enough info provided for this)

However, if you do not have any information about the actual AE but the event is reportable you can report “Death unknown cause.” Submit an update when additional significant information is available

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SeriousnessSeriousness

Does primary AE meet criteria for an SAE?

Use ICH-SAE definition provided in Manual v2.0

Select appropriate SAE criteria

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SeveritySeverity

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

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Seriousness is NOT the same as SeveritySeriousness is NOT the same as Severity

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Based on the intensity of the AE and is not a factor in determining reportability (clinical description)

Based on the intensity of the AE and is not a factor in determining reportability (clinical description)

Based on outcome of the AE and is a factor in determining reportability (regulatory definition)

Based on outcome of the AE and is a factor in determining reportability (regulatory definition)

SeriousnessSeriousness SeveritySeverity

Determined using the SAE criteriaDetermined using the SAE criteria

Determined using the DAIDS AE grading tableDetermined using the DAIDS AE grading table

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Grading Severity of EventsGrading Severity of Events

All events reported to DAIDS in an expedited timeframe must be graded for severity

• Grading does not determine reportability

Division of DAIDS (DAIDS) Table for Grading the Severity of the Adult and Pediatric Adverse Events Version 1.0 – Dec 2004 (Clarification dated Aug 2009)

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Severity GradeSeverity Grade

Grade 1 – Mild

Symptoms causing no or minimal interference with usual social & functional activities

• e.g., When a subject experiences a chest pain which does not interfere with the subject’s activity of daily living

Grade 2 – Moderate

Symptoms causing greater than minimal interference with usual social and functional activities

• e.g., When the chest pain is such that the subject is unable to do some of their activities of daily living

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Severity GradeSeverity Grade

Grade 3 – Severe

Symptoms causing inability to perform usual social & functional activities

• e.g., When the chest pain is such that the subject is unable to 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

• e.g., When the chest pain makes the subject unable to perform basic functions and is at risk of permanent impairment/persistent disability/death if no surgical or medical intervention is done

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This table is used for estimating the severity grade of a clinical AE not specifically listed in DAIDS Grading Table

EXAMPLEEXAMPLE FROM THE DIVISION OF AIDS FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTSADULT AND PEDIATRIC ADVERSE EVENTS

EXAMPLEEXAMPLE FROM THE DIVISION OF AIDS FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTSADULT AND PEDIATRIC ADVERSE EVENTS

EXAMPLEEXAMPLE FROM THE DIVISION OF AIDS FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTSADULT AND PEDIATRIC ADVERSE EVENTS

EXAMPLEEXAMPLE FROM THE DIVISION OF AIDS FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTSADULT AND PEDIATRIC ADVERSE EVENTS

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This table is used for grading a clinical AE specifically listed in DAIDS AE Grading Table:

• e.g., grading by symptomatology• e.g., grading by numerical ranges

Severity GradingSeverity Grading

Manual Version 2.0

• Grade 4 events are referred to as potentially life-threatening events as defined in the DAIDS AE Grading Table

• Thus a Grade 4 event per the DAIDS AE Grading Table does not automatically imply that it meets SAE criteria, if it is only potentially life-threatening

[SAE criteria for LT refers to immediate timeframe, not potential at some point in the future, or if more severe]

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Issues with GradingIssues with Grading

Death = Grade 5; clarified in DAIDS AE Grading Table Aug 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 AE Grading 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)

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Grading: Neonatal SepsisGrading: 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°C, WBC:

14,000 with left shift• Sent to hospital for sepsis workup• AE term: Neonatal sepsis, Severity: Grade 1

Neonatal Sepsis is reasonable AE Term

Basis for severity grade?

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Grading: Neonatal Sepsis Grading: Neonatal Sepsis

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Grading: Neonatal SepsisGrading: Neonatal Sepsis

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Grading on basis of fever alone: Grade 1

Grading on clinical basis of possible sepsis:

• at least Grade 3

• Grade 4 reasonable as well

Grading: Respiratory DistressGrading: 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, weight: 3.35 kg, length: 47.5 cm, HR: 140 bpm, RR: 62 bpm

• 12 hrs after birth: developed tachypnea and fussiness, RR: 62 bpm, 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?

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Grading: Respiratory Distress Grading: Respiratory Distress

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Grading: Respiratory DistressGrading: Respiratory Distress

Grading on basis of respiratory distress: at least Grade 3• Required CPAP at birth• 12 hours later: tachypnea and RR: 62 bpm• Room air and 100% O2: 70-80%

Grading on basis of respiratory distress: Grade 4• Need medical intervention beyond O2 therapy• Transferred to NICU

Grading on basis of alkalosis: Grade 2• Not appropriate because it does not reflect clinical picture

in totality

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Relationship AssessmentRelationship 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)*Per 21 CFR 312.32, “reasonable possibility” means there is evidence to suggest a causal relationship between the drug and the adverse event.

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Relationship AssessmentRelationship Assessment

When an SAE is assessed as “not related” to study agent(s), an alternate 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

When the study agent is a fixed dose combination agent, an assessment of attribution will be made for each component and the combination agent as a whole

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ExpectednessExpectedness

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

SAE Reporting Category:

• Sponsor to determine expectedness

SUSAR Reporting Category:

• Site physician and Sponsor to determine expectedness

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Expedited Reporting Processes

Expedited Reporting Processes

Overview of Reporting TimelinesOverview of Reporting Timelines

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SAE Reporting Category FlowchartSAE Reporting Category Flowchart

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Adverse Events Not Requiring Expedited Reporting to DAIDSAdverse 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

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New/Initial ReportsNew/Initial Reports

AEs that are reportable on New/Initial Reports:

New AE

Recurrent AE: only if the initial AE has resolved, is now reoccurring, and meets expedited reporting criteria to DAIDS

Pre-existing condition with increase in severity

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Updated InformationUpdated 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))

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Reporting TimeframeReporting 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 the reporting of SAEs to DAIDS

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Reporting DaysReporting 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 timeA 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 SAE 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 1Monday through Friday count as reporting daysSaturday and Sunday are not considered reporting daysAny holiday (U.S. or in-country/local) that occurs on a Monday through Friday counts as a reporting day

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Site Investigator SignatureSite 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)

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Site Investigator SignatureSite 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

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DAERSDAERS

DAERS: DAIDS Adverse Experience Reporting System:

An integrated module that is part of the DAIDS Enterprise System (DAIDS-ES)

A secure, confidential, web-based system through which sites are required to submit expedited reports to DAIDS

For sites where DAERS has been implemented, all EAEs and supporting information will be submitted to DAIDS using the DAERS, unless the system is unavailable for technical reasons

• Use DAIDS EAE reporting form if DAERS not implemented

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How to Report SAEsHow to Report SAEs

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)

– E-mail: DAIDSRSCSafetyOffice@tech-res.com

– If e-mailing, scan or FAX signature page

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Where to Get HelpWhere to Get Help

RSC Safety Office:

• E-mail: DAIDSRSCSafetyOffice@tech-res.com

• Telephone: +1-301-897-1709

or 1-800-537-9979 (USA only)

• FAX: +1-301-897-1710

or 1-800-275-7619 (USA only)

RSC Website: https://rsc.tech-res.com

DAIDS-ES Support:

• E-mail: DAIDS-ESSupport@niaid.nih.gov

• Telephone: +1-240-499-2239

or 1-866-337-1605 (USA only)

• FAX: +1-301-948-2242

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Questions?