The Fundamentals of The Fundamentals of International Clinical ResearchInternational Clinical Research

Understanding Adverse EventsUnderstanding Adverse EventsTracy Tracy NewboldNewbold

Family Health InternationalFamily Health International

Reason for Adverse Event Reason for Adverse Event Collection and ReportingCollection and Reporting

The most important responsibilities of The most important responsibilities of investigators and sponsors of clinical investigators and sponsors of clinical research studies:research studies:

–– Protection of human subjectsProtection of human subjects..–– Collection of clean and reproducible data.Collection of clean and reproducible data.

Goals of the PresentationGoals of the Presentation

UNDERSTANDINGUNDERSTANDING::Definition of Adverse EventDefinition of Adverse EventExpected vs. Unexpected Adverse EventExpected vs. Unexpected Adverse EventDefinition of Definition of SERIOUSSERIOUS Adverse EventsAdverse EventsIntensityIntensity vs. vs. SeriousnessSeriousness of Adverse Eventsof Adverse EventsRelationship of Adverse Event to Study ProductRelationship of Adverse Event to Study ProductReporting of Adverse EventsReporting of Adverse Events

What is an Adverse Event (AE)?What is an Adverse Event (AE)?

Any untoward medical occurrence in a Any untoward medical occurrence in a patient or clinical investigation subject patient or clinical investigation subject administered a pharmaceutical product administered a pharmaceutical product that does not necessarily have a causal that does not necessarily have a causal relationship with this treatment.relationship with this treatment.

(ICH(ICH--E2A)E2A)

What is an Adverse Event (AE)?What is an Adverse Event (AE)?

Any Any unfavorableunfavorable and and unintendedunintended sign sign (including an abnormal lab finding)(including an abnormal lab finding)

SymptomSymptom or or diseasedisease, , temporally associated with use of a temporally associated with use of a medicinal (investigational) product, medicinal (investigational) product, whether or not related to the medicinal whether or not related to the medicinal (investigational) product (investigational) product

(ICH(ICH--E2A)E2A)

What is an Adverse Event (AE)?What is an Adverse Event (AE)?

Unfavorable deviation from baseline Unfavorable deviation from baseline health, which includes:health, which includes:

–– Worsening of conditions present at onset of Worsening of conditions present at onset of the studythe study

–– Patient deterioration due to primary diseasePatient deterioration due to primary disease–– Intercurrent illnessIntercurrent illness–– Events related or possibly related to Events related or possibly related to

concomitant medicationsconcomitant medications

What is an Adverse Event (AE)?What is an Adverse Event (AE)?

Unwanted Unwanted EffectsEffects

–– Symptoms Symptoms (headache, nausea)(headache, nausea)

–– Syndromes of diseaseSyndromes of disease–– Physical findings Physical findings

(elevated BP, lump)(elevated BP, lump)–– Abnormal lab valuesAbnormal lab values–– OverdosesOverdoses–– ToxicitiesToxicities

An An expectedexpected AE is any AE is any adverse reaction whose adverse reaction whose nature and intensity nature and intensity have been previously have been previously observed and observed and documented for the documented for the study product study product (e.g. in the investigator (e.g. in the investigator brochure, product brochure, product information).information).

Expected vs Unexpected AEExpected vs Unexpected AE

Expected vs Unexpected AEExpected vs Unexpected AEAn An unexpectedunexpected AE is any adverse AE is any adverse reaction not reaction not observedobserved, whether or not it , whether or not it has been anticipated because of the has been anticipated because of the pharmacologic properties of the study pharmacologic properties of the study agent.agent.

Unexpected Unexpected adverse drug experienceadverse drug experience: : Any adverse drug experience, the Any adverse drug experience, the specificity or severity of which is not specificity or severity of which is not previously consistent with the current previously consistent with the current investigator brochure; or, if an investigator brochure; or, if an investigator brochure is not required or investigator brochure is not required or available, the specificity or severity of available, the specificity or severity of which is not consistent with the risk which is not consistent with the risk information described in the general information described in the general investigational plan or elsewhere in the investigational plan or elsewhere in the current application, as amended. current application, as amended. 21 CFR 312.3221 CFR 312.32

Wherever possible, adverse events Wherever possible, adverse events should be described in terms of a should be described in terms of a change in the statuschange in the status of patientof patient’’s health, s health, NOT the action taken or outcome. NOT the action taken or outcome.

How Would You Describe an AE?How Would You Describe an AE?

How Would You Describe an AE?How Would You Describe an AE?

Example:Example:A patient experiences a bleeding A patient experiences a bleeding stomach ulcer that requires stomach ulcer that requires hospitalization. hospitalization.

–– Question:Question: What event(s) should be listed on What event(s) should be listed on the Case Report Form (CRF)?the Case Report Form (CRF)?

–– Answer:Answer: Bleeding ulcerBleeding ulcer

What Is a What Is a SeriousSerious Adverse Event?Adverse Event?

A SERIOUS Adverse Event (SAE) is A SERIOUS Adverse Event (SAE) is defined as an AE meeting one of the defined as an AE meeting one of the following conditions:following conditions:

–– DeathDeath during the period of protocol defined during the period of protocol defined surveillancesurveillance

–– Life threateningLife threatening (defined as a subject at (defined as a subject at immediate risk of death at the time of the immediate risk of death at the time of the event)event)

What is a What is a SeriousSerious Adverse Event?Adverse Event?

–– Hospital admissionHospital admission during the period of during the period of protocol defined surveillanceprotocol defined surveillance

–– Any event that results inAny event that results in congenital congenital anomaly or birth defectanomaly or birth defect

–– Any event that results in aAny event that results in a persistent or persistent or significant disability/incapacitysignificant disability/incapacity

What is a What is a SeriousSerious Adverse Event?Adverse Event?

–– Any other important medical eventAny other important medical event that that may not result in death, be life threatening, may not result in death, be life threatening, or require hospitalization, or require hospitalization, may be may be considered a serious adverse eventconsidered a serious adverse eventwhenwhen, based upon appropriate medical , based upon appropriate medical judgment, judgment, the event may jeopardize the the event may jeopardize the subject and may require medical or subject and may require medical or surgical intervention to prevent one of surgical intervention to prevent one of the outcomes listed above.the outcomes listed above.

Intensity of the Adverse EventIntensity of the Adverse Event

All adverse events will be assessed by All adverse events will be assessed by the investigator using the protocol the investigator using the protocol defined grading system. defined grading system.

If the protocol has no defined grading If the protocol has no defined grading system, then guidelines such as the system, then guidelines such as the following will be used to quantify following will be used to quantify intensity:intensity:

Intensity of the Adverse EventIntensity of the Adverse Event

–– MildMild:: Transient or mild discomfort (<48 Transient or mild discomfort (<48 hours); no medical intervention/therapy hours); no medical intervention/therapy required required

–– ModerateModerate: : Mild to moderate limitation Mild to moderate limitation in activity in activity -- some assistance may be some assistance may be needed; no or minimal medical needed; no or minimal medical intervention/therapy requiredintervention/therapy required

Intensity of the Adverse EventIntensity of the Adverse Event

–– SevereSevere:: Marked limitation in activity, Marked limitation in activity, some assistance usually required; some assistance usually required; medical intervention/therapy required, medical intervention/therapy required, hospitalization possiblehospitalization possible

–– Life threateningLife threatening:: Extreme limitation in Extreme limitation in activity, significant assistance required; activity, significant assistance required; significant medical intervention/therapy significant medical intervention/therapy required, hospitalization or hospice care required, hospitalization or hospice care possiblepossible

SeriousSerious vs Severevs Severe

SeriousSerious::Serious is defined as a regulatory Serious is defined as a regulatory definitiondefinition

SevereSevere::Severe is defined as an intensity Severe is defined as an intensity classification (mild, moderate, severe)classification (mild, moderate, severe)

Adverse Event Relationship Adverse Event Relationship to Study Productsto Study Products

All All AEsAEs must have their possible must have their possible relationship to study product assessed relationship to study product assessed by a system such as the following:by a system such as the following:

Adverse Event Relationship Adverse Event Relationship to Study Productsto Study Products

– Associated – The event is temporally related to the administration of the study product and no other etiology explains the event.

– Not Associated - The event is temporally independent of study product and/or the event appears to be explained by another etiology.

Reporting Adverse EventsReporting Adverse Events

NonNon--serious serious AEsAEs–– ROUTINE REPORTING ROUTINE REPORTING

(e.g. annual report, AE form, CRF)(e.g. annual report, AE form, CRF)

Reporting Adverse EventsReporting Adverse Events

ANY ANY SeriousSerious AEAE–– Complete DMID SAE form and send to Complete DMID SAE form and send to

PPD or PPD or send to DMID via PPDFor For fatal/ lifefatal/ life--threatening threatening SAEsSAEs::Within Within 24 hours 24 hours of site awarenessof site awarenessFor For all otherall other SAEsSAEs::WithinWithin 72 hours (3 days) 72 hours (3 days) of site awarenessof site awareness

–– ROUTINE REPORTING ROUTINE REPORTING (e.g. annual report)(e.g. annual report)

Goals of the PresentationGoals of the Presentation……

Definition of AEDefinition of AEExpected vs. Unexpected AEExpected vs. Unexpected AEDefinition of SERIOUS AEDefinition of SERIOUS AEIntensity vs. Seriousness of Intensity vs. Seriousness of AEsAEsRelationship of AE to Study ProductRelationship of AE to Study ProductReporting of Reporting of AEsAEs

……AchievedAchieved??

Breakout SessionBreakout Session

Does the scenario constitute an AE?Does the scenario constitute an AE?–– If yes, is it an SAE?If yes, is it an SAE?–– Why or why not?Why or why not?

For For AEsAEs, please discuss the following:, please discuss the following:–– IntensityIntensity–– RelatednessRelatedness–– Site responsibilitiesSite responsibilities

Reporting Reporting Clinical followClinical follow--upup