Understanding Adverse Events - ICSSCHilgenbergWA)… · The Fundamentals of International Clinical...

The Fundamentals of The Fundamentals of International Clinical Research International Clinical Research WorkshopWorkshop

Understanding Adverse EventsUnderstanding Adverse EventsDeborah HilgenbergDeborah Hilgenberg

Family Health InternationalFamily Health International

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Goals of the PresentationGoals of the Presentation

Definition of Adverse Event (AE)Definition of Adverse Event (AE)Definitions of preDefinitions of pre--existing conditionsexisting conditionsIntensity of Adverse EventsIntensity of Adverse EventsDefinition of Definition of SERIOUSSERIOUS Adverse EventsAdverse EventsSeveritySeverity vs. vs. SeriousnessSeriousness of Adverse Eventsof Adverse EventsAssessment of Relatedness to Study ProductAssessment of Relatedness to Study ProductReporting of Adverse EventsReporting of Adverse Events

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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.

All clinical studies greater than minimal risk All clinical studies greater than minimal risk must have an AE reporting system in place.must have an AE reporting system in place.

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

Any untoward medical occurrence in a Any untoward medical occurrence in a study participant who has received study participant who has received study product / intervention that may or study product / intervention that may or may not have a causal relationship with may not have a causal relationship with this treatment / intervention.this treatment / intervention.

(ICH(ICH--E2A)E2A)

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An AE can therefore beAn AE can therefore beAny Any unfavorableunfavorable and and unintendedunintended sign sign

(including an abnormal lab finding), (including an abnormal lab finding), symptomsymptom or or diseasedisease, temporally , temporally associated with use of a medicinal associated with use of a medicinal (investigational) product / intervention, (investigational) product / intervention, whether or not related to the medicinal whether or not related to the medicinal (investigational) product / intervention(investigational) product / intervention

(ICH(ICH--E2A)E2A)

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Definition of interventionDefinition of intervention

Excerpt from 45CFR46.102Excerpt from 45CFR46.102““Intervention includes physical procedures Intervention includes physical procedures

by which data are gathered (for example, by which data are gathered (for example, venipuncture) and manipulation of the venipuncture) and manipulation of the participant or the participantparticipant or the participant’’s s environment that are performed for environment that are performed for research purposes.research purposes.””

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Not limited to DRUG Side effects. Not limited to DRUG Side effects. 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 illness or event, i.e., flu, Intercurrent illness or event, i.e., flu,

accidentaccident–– Events related or possibly related to Events related or possibly related to

concomitant medicationsconcomitant medications

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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

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What is Baseline?What is Baseline?

Protocol designated time point from Protocol designated time point from which changes in status are measured.which changes in status are measured.

Depends on the study design, but should Depends on the study design, but should be the same for all participants in the be the same for all participants in the study.study.

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PrePre--existing Conditionsexisting Conditions

Any chronic, recurring condition Any chronic, recurring condition identified prior to enrollment, whether identified prior to enrollment, whether present at enrollment or not.present at enrollment or not.

Example: diabetes, herpes, hypertensionExample: diabetes, herpes, hypertension

Do thorough screening to assess and Do thorough screening to assess and documentdocument prepre--existing conditions existing conditions

Document any concomitant meds at Document any concomitant meds at baselinebaseline

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PrePre--existing Conditionsexisting Conditions

PrePre--existing condition is not an AE existing condition is not an AE EXCEPT when it increases in severity or EXCEPT when it increases in severity or frequencyfrequency

Example: A patient at baseline with mild Example: A patient at baseline with mild asthma, continues to have mild asthma asthma, continues to have mild asthma throughout study period: throughout study period: notnot an AE.an AE.

Example: Same patient is hospitalized Example: Same patient is hospitalized with severe asthma: with severe asthma: isis a serious adverse a serious adverse eventevent

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Sample Protocol LanguageSample Protocol Language

““All adverse events occurring from initial study All adverse events occurring from initial study drug administration until 4 weeks post delivery drug administration until 4 weeks post delivery must be documented appropriately regardless of must be documented appropriately regardless of relationship . . . Any medical condition or relationship . . . Any medical condition or laboratory abnormality that is present at the time laboratory abnormality that is present at the time that the patient is screened should be that the patient is screened should be considered as baseline and not reported as an considered as baseline and not reported as an AE. However, if the medical condition AE. However, if the medical condition deteriorates at any time during the study it deteriorates at any time during the study it should be recorded as an AE. . . .should be recorded as an AE. . . .””

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Wherever possible, adverse events should be Wherever possible, adverse events should be described in terms of a described in terms of a change in the statuschange in the status or or diagnosis NOT the symptoms. diagnosis NOT the symptoms.

Example: Example: ““decrease in Hb from 10.1 to 7.3decrease in Hb from 10.1 to 7.3””

Example: Example: ““influenzainfluenza”” rather than stomach rather than stomach cramps, fever, chills.cramps, fever, chills.

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

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An An expectedexpected AE is any AE is any adverse reaction whose adverse reaction whose nature and intensity are nature and intensity are consistent with that consistent with that documented in the documented in the Investigators Brochure Investigators Brochure or the general or the general investigational plan.investigational plan.

Expected vs Unexpected AEExpected vs Unexpected AE

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Intensity of the Adverse EventIntensity of the Adverse Event

AEs assessed by the investigator AEs assessed by the investigator using protocol defined grading systemusing protocol defined grading system

If protocol has no defined grading If protocol has no defined grading system, use guidelines such as the system, use guidelines such as the following:following:

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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 and do not interfere with the required and do not interfere with the patientpatient’’s daily activitiess daily activities

–– ModerateModerate: : Some limitation in activity Some limitation in activity --some assistance may be needed; no or some assistance may be needed; no or minimal medical intervention/therapy minimal medical intervention/therapy requiredrequired

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Severity of the Adverse EventSeverity of the Adverse Event

–– SevereSevere:: Marked limitation in activity, Marked limitation in activity, interrupts participantinterrupts participant’’s usual daily s usual daily activity and may require medical activity and may require medical intervention/therapy, hospitalization intervention/therapy, hospitalization possiblepossible

–– 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 required; hospitalization or hospice care probablecare probable

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

SERIOUS Adverse Events (SAEs) are SERIOUS Adverse Events (SAEs) are defined as follows:defined as follows:

–– 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)

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

–– Requires inpatient Requires inpatient hospitalizationhospitalization or or prolongation of existing hospitalization prolongation of existing hospitalization during the period of protocol defined during the period of protocol defined surveillancesurveillance

–– 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

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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, may be or require hospitalization, may be considered a serious adverse event when, considered a serious adverse event when, based upon appropriate medical judgment, based upon appropriate medical judgment, the event may jeopardize the subject and the event may jeopardize the subject and maymay require medical or surgical require medical or surgical intervention to prevent one of the intervention to prevent one of the outcomes listed above.outcomes listed above.

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SeriousSerious vs Severevs Severe

SeriousSerious::““Serious AESerious AE”” is a regulatory definition (21 CFR is a regulatory definition (21 CFR 312.32)312.32)

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

Severe AE Severe AE ≠≠ Serious AESerious AE

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Assessment of RelatednessAssessment of Relatedness

In a clinical trial the study product/intervention In a clinical trial the study product/intervention must always be suspect. must always be suspect.

All SAEs must have their possible All SAEs must have their possible association/relationship to study product association/relationship to study product assessed by a binary system by using the assessed by a binary system by using the following question:following question:

–– Is there a reasonable possibility that the AE may Is there a reasonable possibility that the AE may have been caused by the investigational have been caused by the investigational product/intervention?product/intervention?

NONO-- not associatednot associatedYESYES-- associatedassociated

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AssociatedAssociated-- The event is The event is temporallytemporally relatedrelatedto the administration of the study to the administration of the study product/intervention and no other etiology product/intervention and no other etiology explains the event.explains the event.

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

Related = timing, product info, clinical Related = timing, product info, clinical judgmentjudgment

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ClinicianClinician’’s assessment s assessment ––part of part of documentationdocumentation

Consider other contributing factors:Consider other contributing factors:-- Medical historyMedical history-- Other MedicationOther Medication-- Lack of EfficacyLack of Efficacy

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Documentation of SAEDocumentation of SAE

SAE formSAE formAdverse Event Case Report FormAdverse Event Case Report FormSource documentsSource documentsALL must match and be completeALL must match and be completePrincipal Investigator (or other designated Principal Investigator (or other designated investigator) must sign SAE report.investigator) must sign SAE report.

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Expedited Reporting by Sponsor to Expedited Reporting by Sponsor to the FDA (IND)the FDA (IND)

If the SAE results in death or is If the SAE results in death or is considered by the PI to be lifeconsidered by the PI to be life--threateningthreateningAnd is unexpected (Not listed in the And is unexpected (Not listed in the Package insert or Investigational Package insert or Investigational Brochure)Brochure)And is related (reasonable suspected And is related (reasonable suspected causal relationship) between causal relationship) between administration of the drug and the eventadministration of the drug and the eventAn expedited report must go to the An expedited report must go to the FDA within 7 calendar daysFDA within 7 calendar days

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SAE FollowSAE Follow--upup

It is a rare occurrence when all details of a It is a rare occurrence when all details of a SAE are known when the initial report is SAE are known when the initial report is submitted.submitted.

Expect follow up with every SAE, Expect follow up with every SAE, especially those that contain new safety especially those that contain new safety information.information.

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Protocol DevelopmentProtocol Development

A well written clinical protocol addresses the A well written clinical protocol addresses the following issues:following issues:Careful identification of possible AEsCareful identification of possible AEsProper collection of preProper collection of pre--existing conditions and existing conditions and concomitant medsconcomitant medsDescription of procedures for monitoring the Description of procedures for monitoring the occurrence of AEsoccurrence of AEsAppropriate medical and toxicity management Appropriate medical and toxicity management for participants experiencing AEsfor participants experiencing AEsStandardized AE reportingStandardized AE reporting

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Case StudyCase Study

A thin 9 year old girl, Mary, is consented, A thin 9 year old girl, Mary, is consented, enrolled and is having her blood drawn using a enrolled and is having her blood drawn using a 21 gauge needle attached to a vacutainer.21 gauge needle attached to a vacutainer.

The startled child screams and moves, The startled child screams and moves, dislodging the needle. Pressure is immediately dislodging the needle. Pressure is immediately applied, but a hematoma 12 mm in diameter applied, but a hematoma 12 mm in diameter results. Distal pulses are intact, there is no results. Distal pulses are intact, there is no cyanosis, and movement of the extremities cyanosis, and movement of the extremities unimpairedunimpaired

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Is this an AE?Is this an AE?

Is This an SAE?Is This an SAE?

Intensity?Intensity?

Relatedness? Relatedness?

Site responsibility: Complete AE CRF, Site responsibility: Complete AE CRF, follow until AE is resolvedfollow until AE is resolved

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The team evaluates the child in 7 days. The team evaluates the child in 7 days. The lesion is purplish, but resolving. 14 The lesion is purplish, but resolving. 14 days later the lesion is completely healed.days later the lesion is completely healed.

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Site responsibility: Update AE CRF, Site responsibility: Update AE CRF, ensure source documents and CRFs ensure source documents and CRFs matchmatchAE is resolvedAE is resolved

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A thin 9 year old boy, John is consented, A thin 9 year old boy, John is consented, enrolled and is having his blood drawn using a enrolled and is having his blood drawn using a 21 gauge needle attached to a vacutainer.21 gauge needle attached to a vacutainer.

The startled child screams and moves, The startled child screams and moves, dislodging the needle. Pressure is immediately dislodging the needle. Pressure is immediately applied, but a hematoma 12 mm in diameter applied, but a hematoma 12 mm in diameter results. Distal pulses are intact, there is no results. Distal pulses are intact, there is no cyanosis, and movement of the extremities cyanosis, and movement of the extremities unimpairedunimpaired

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Mother brings the child back in 5 days Mother brings the child back in 5 days with fever. Lesion at puncture site is hot, with fever. Lesion at puncture site is hot, swollen, red and tender. The hematoma swollen, red and tender. The hematoma site has abcessed and the child is site has abcessed and the child is hospitalized for incision and drainage and hospitalized for incision and drainage and intravenous antibiotics.intravenous antibiotics.

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Is this an AE?Is this an AE?

Is this an SAE?Is this an SAE?

Intensity?Intensity?

Relatedness?Relatedness?

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Site responsibility: Site responsibility: –– Continue to treat with best clinical Continue to treat with best clinical

managementmanagement–– Complete Adverse Event CRFComplete Adverse Event CRF–– Complete DMID SAE form, report to Complete DMID SAE form, report to

sponsor, IRBsponsor, IRB–– Follow until resolutionFollow until resolution–– Update SAE form when resolvedUpdate SAE form when resolved

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SummarySummaryAdverse Event defined as an untoward medical event during Adverse Event defined as an untoward medical event during enrollment in a clinical study.enrollment in a clinical study.Chronic, recurring condition at baseline is not an AE if it recuChronic, recurring condition at baseline is not an AE if it recurs rs during study, i.e. asthma, herpes, arthritis, unless increase induring study, i.e. asthma, herpes, arthritis, unless increase inseverity or frequencyseverity or frequencyPI or designated PI or designated clinicianclinician must assess intensity and relatednessmust assess intensity and relatednessSerious Adverse EventsSerious Adverse Events well defined in regulationswell defined in regulationsManagement of AEs based on best clinical practice availableManagement of AEs based on best clinical practice availableEnsure source documentation and CRFs and SAE form match Ensure source documentation and CRFs and SAE form match Patient safety is paramountPatient safety is paramount

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