AEFI Revised Concepts and Definitions

AEFI Revised Concepts and Definitions

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AEFI CausalityAssessmentAEFI CausalityAssessment

Session ASession A

Causality Assessment of AEFIs Module F | October 2012 | 1AEFI Causality Assessment Revised WHO Classification | August 2012 | 1


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Photo: WHO

AEFI CausalityAssessment

Madhav Ram

What is pharmacovigilance?What is pharmacovigilance?

• The science and activities relating to thedetection, assessment, understanding andprevention of adverse effects or any other drug-related problems.

• Vaccine pharmacovigilance* is defined as thescience and activities relating to the detection,assessment, understanding and communicationof adverse events following immunization andother vaccine- or immunization-related issues,and to the prevention of untoward effects of thevaccine or immunization.

Causality Assessment of AEFIs Module F | October 2012 | 2


• Vaccine pharmacovigilance* is defined as thescience and activities relating to the detection,assessment, understanding and communicationof adverse events following immunization andother vaccine- or immunization-related issues,and to the prevention of untoward effects of thevaccine or immunization.

* Source: Report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance, 2012

What is pharmacovigilance? (previous)What is pharmacovigilance? (previous)


• Vaccine pharmacovigilance is defined as thescience and activities relating to the detection,assessment, understanding and prevention ofadverse events following immunization, or anyother vaccine- or immunization-related issues.



• Vaccine pharmacovigilance is defined as thescience and activities relating to the detection,assessment, understanding and prevention ofadverse events following immunization, or anyother vaccine- or immunization-related issues.

Definition of AEFIDefinition of AEFI

An Adverse Event Following Immunization is any untowardmedical occurrence which follows immunization and whichdoes not necessarily have a causal relationship with theusage of the vaccine.

The adverse event may be any unfavorable or unintendedsign, abnormal laboratory finding, symptom or disease.

Report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance, 2012


An Adverse Event Following Immunization is any untowardmedical occurrence which follows immunization and whichdoes not necessarily have a causal relationship with theusage of the vaccine.

The adverse event may be any unfavorable or unintendedsign, abnormal laboratory finding, symptom or disease.

Report of CIOMS/WHO Working Group on Vaccine Pharmacovigilance, 2012

Definition of AEFI (previous)Definition of AEFI (previous)

An adverse event following immunizationis a medical incident that takes placeafter an immunization, causes concernand is believed to be caused bythe immunization.

WHO Aide Memoire: AEFI Investigation, 2004www.who.int/immunization_safety/en/


An adverse event following immunizationis a medical incident that takes placeafter an immunization, causes concernand is believed to be caused bythe immunization.

WHO Aide Memoire: AEFI Investigation, 2004www.who.int/immunization_safety/en/

CIOMS/ WHO classification of AEFICIOMS/ WHO classification of AEFI

• Product• Quality• Immunization Error• Immunization anxiety-related

Related to Vaccine / Vaccination



Coincidental

Cause-specific definitions of AEFICause-specific definitions of AEFI

1. Vaccine product-related reaction: An AEFI that is caused or precipitated by a vaccine due toone or more of the inherent properties of the vaccine product.

2. Vaccine quality defect-related reaction: An AEFI that is caused or precipitated by a vaccinethat is due to one or more quality defects* of the vaccine product including its administration device asprovided by the manufacturer.

3. Immunization error-related reaction: An AEFI that is caused by inappropriate** vaccinehandling, prescribing or administration and thus by its nature is preventable.

4. Immunization anxiety-related reaction: An AEFI arising from anxiety about theimmunization.

5. Coincidental event: An AEFI that is caused by something other than the vaccine product,immunization error or immunization anxiety


1. Vaccine product-related reaction: An AEFI that is caused or precipitated by a vaccine due toone or more of the inherent properties of the vaccine product.

2. Vaccine quality defect-related reaction: An AEFI that is caused or precipitated by a vaccinethat is due to one or more quality defects* of the vaccine product including its administration device asprovided by the manufacturer.

3. Immunization error-related reaction: An AEFI that is caused by inappropriate** vaccinehandling, prescribing or administration and thus by its nature is preventable.

4. Immunization anxiety-related reaction: An AEFI arising from anxiety about theimmunization.

5. Coincidental event: An AEFI that is caused by something other than the vaccine product,immunization error or immunization anxiety

* a vaccine quality defect is defined as any deviation of the vaccine product as manufactured from its set quality specifications** “Inappropriate” refers to usage (handling, prescribing and administration) other than what is licensed and recommended in a given jurisdictionbased on scientific evidence or expert recommendations

AEFICausalityAssessment

Revised WHO Classification



Causality Assessment of AEFIs Module F | October 2012 | 8AEFI Causality Assessment Revised WHO Classification | August 2012 | 8





Causality Assessment of Adverse Events Following Immunization

August 2012

Photo: WHO

WHO causality assessment criteria (Previous)WHO causality assessment criteria (Previous)


A. Consistent causalassociation to immunization


A1. Vaccine product-relatedreaction (As per published

literature)

A2. Vaccine quality relatedreaction

A3. Immunization error-relatedreaction

B. IndeterminateB. Indeterminate

B1. *Temporal relationship isconsistent but there isinsufficient definitive

evidence for vaccine causingevent (may be new vaccine-

linked event)

C. Inconsistent causalassociation to immunization

(Coincidental)


(Coincidental)

C1. Underlying or emergingcondition(s)

C2. Conditions caused byexposure to something other

than vaccine

AdequateInformation

available

Step 4: ClassificationStep 4: Classification

B2. Qualifying factors result inconflicting trends of

consistency and inconsistencywith causal association to

immunization




A4. Immunization anxietyrelated reaction

B. Indeterminate C. Inconsistent causalassociation to immunization

(Coincidental)


than vaccine

UnclassifiableUnclassifiable

Specify the additional information required for classificationSpecify the additional information required for classification

AdequateInformationnot available

*B1 : Potential signal and maybe considered for investigation



immunization

Why causality assessment for AEFI?Why causality assessment for AEFI?

To avoid faulty logic of “event happened aftervaccination, therefore it happened because ofvaccination”…we need good evidence.

Best evidence is randomized trial comparingAEFI in vaccinated and non vaccinated groups.

But…never large enough to detect rare events.

Therefore, other forms of evidence are needed.


To avoid faulty logic of “event happened aftervaccination, therefore it happened because ofvaccination”…we need good evidence.

Best evidence is randomized trial comparingAEFI in vaccinated and non vaccinated groups.

But…never large enough to detect rare events.

Therefore, other forms of evidence are needed.

Why separate causality assessment for VaccinesWhy separate causality assessment for Vaccines

• Reports in children > > > than in adults

• AEs occur on background of health

• Serious adverse events are rare

• Complex products

• Short duration exposure but long effect; no “washout”

• Vaccine may cause disease being prevented(VAPP and OPV)

• Vaccine preventable disease may occur at sametime as vaccine being given


• Reports in children > > > than in adults

• AEs occur on background of health

• Serious adverse events are rare

• Complex products

• Short duration exposure but long effect; no “washout”

• Vaccine may cause disease being prevented(VAPP and OPV)

• Vaccine preventable disease may occur at sametime as vaccine being given

Causality and Causality assessmentCausality and Causality assessment

• Is the relationship between two events(the cause and the effect), where thesecond event is a consequence of thefirst.

• A direct cause is a factor in absence of which the effect would notoccur (necessary cause).

• Sometimes, there are multiple factors that can precipitate orfunction as co-factors for the effect (event) to occur.

Causality


• Is the relationship between two events(the cause and the effect), where thesecond event is a consequence of thefirst.

• A direct cause is a factor in absence of which the effect would notoccur (necessary cause).

• Sometimes, there are multiple factors that can precipitate orfunction as co-factors for the effect (event) to occur.

• Determining if such a relationshipexists and if so to what extent

CausalityAssessment

What is the outcome of AEFI Causality Assessment?What is the outcome of AEFI Causality Assessment?


Related to Vaccine / Vaccination

Helps to determine if the AEFI is



Coincidental

Unsure

Outcome of AEFI Causality Assessment: Sub categoriesOutcome of AEFI Causality Assessment: Sub categories

1. Vaccine product-related: Caused or precipitated by a vaccine due to one or more of theinherent properties of the vaccine product.

2. Vaccine quality defect-related: Caused or precipitated by a vaccine due to one ormore quality defects* of the vaccine product including its administration device

3. Immunization error-related: Caused by inappropriate** vaccine handling, prescribing oradministration and thus by its nature is preventable.

4. Immunization anxiety-related: Arising from anxiety about the immunization.

5. Coincidental event: Caused by something other than the vaccine product, immunizationerror or immunization anxiety Underlying or emerging condition(s) or Conditions caused by exposure to something other than vaccine

Vaccine & Vaccination


1. Vaccine product-related: Caused or precipitated by a vaccine due to one or more of theinherent properties of the vaccine product.

2. Vaccine quality defect-related: Caused or precipitated by a vaccine due to one ormore quality defects* of the vaccine product including its administration device

3. Immunization error-related: Caused by inappropriate** vaccine handling, prescribing oradministration and thus by its nature is preventable.

4. Immunization anxiety-related: Arising from anxiety about the immunization.

5. Coincidental event: Caused by something other than the vaccine product, immunizationerror or immunization anxiety Underlying or emerging condition(s) or Conditions caused by exposure to something other than vaccine

Coincidence

Outcome of AEFI Causality Assessment: Sub categoriesOutcome of AEFI Causality Assessment: Sub categories

1. Temporal relationship is consistent but there is insufficient definitiveevidence for vaccine causing the event (may be new vaccine-linkedevent).

2. Reviewing factors result in conflicting trends of consistency andinconsistency with causal association to immunization (i.e. may bevaccine associated as well as coincidental and can’t clearly favour oneor the other)

Unsure (Indeterminate)


1. Temporal relationship is consistent but there is insufficient definitiveevidence for vaccine causing the event (may be new vaccine-linkedevent).

2. Reviewing factors result in conflicting trends of consistency andinconsistency with causal association to immunization (i.e. may bevaccine associated as well as coincidental and can’t clearly favour oneor the other)

Factors influencing good assessmentFactors influencing good assessment

• Causality assessment is done by systematicallyreviewing data about an AEFI case to determine thelikelihood of a causal association between the event andthe vaccine(s) received.

• The quality of the causality assessment depends upon:– The performance of the AEFI reporting system in terms of

responsiveness, effectiveness and quality of investigation andreports.

– Availability of adequate medical and laboratory services andaccess to background information

– The quality of the causality review process


• Causality assessment is done by systematicallyreviewing data about an AEFI case to determine thelikelihood of a causal association between the event andthe vaccine(s) received.

• The quality of the causality assessment depends upon:– The performance of the AEFI reporting system in terms of

responsiveness, effectiveness and quality of investigation andreports.

– Availability of adequate medical and laboratory services andaccess to background information

– The quality of the causality review process

Steps in review process checklist for AEFISteps in review process checklist for AEFI

1. Screen all AEFI: verify reason for reporting

2. Do routine systematic review for minor and well knownAEFI

3. Collate and analyze data to detect any decrease orincrease in frequency and/or severity of events

4. Determine if AEFI meets preset criteria (next slide)for selection and referral to Expert Committee forformal causality assessment.

5. Store data on all AEFIs in a retrievable manner.Causality Assessment of AEFIs Module F | October 2012 | 18

1. Screen all AEFI: verify reason for reporting

2. Do routine systematic review for minor and well knownAEFI

3. Collate and analyze data to detect any decrease orincrease in frequency and/or severity of events

4. Determine if AEFI meets preset criteria (next slide)for selection and referral to Expert Committee forformal causality assessment.

5. Store data on all AEFIs in a retrievable manner.

• Serious AEFIs*

• Clusters and events aboveexpected rate or severity

• Signals

• Other AEFIs if the reviewing team / committee decides as a specialcase or to conduct special studies

− AEFIs that may have been caused by immunization error(e.g. bacterial abscess, severe local reaction,high fever or sepsis, BCG lymphadenitis, toxic shocksyndrome)

− Significant events of unexplained cause occurring within30 days after a vaccination (and not listed in product label)

− Events causing significant parental or community concern (e.g.Hypotonic Hyporesponsive Episode (HHE), febrile seizures)

Case selection forformal causality assessmentCase selection forformal causality assessment *Death

Hospitalization

Significant disability

Life threatening

Congenital anomaly/birthdefect

*Death

Hospitalization

Significant disability

Life threatening

Congenital anomaly/birthdefect


• Serious AEFIs*

• Clusters and events aboveexpected rate or severity

• Signals

• Other AEFIs if the reviewing team / committee decides as a specialcase or to conduct special studies

− AEFIs that may have been caused by immunization error(e.g. bacterial abscess, severe local reaction,high fever or sepsis, BCG lymphadenitis, toxic shocksyndrome)

− Significant events of unexplained cause occurring within30 days after a vaccination (and not listed in product label)

− Events causing significant parental or community concern (e.g.Hypotonic Hyporesponsive Episode (HHE), febrile seizures)

Preparing for Causality AssessmentPreparing for Causality Assessment

1. Ensure that the AEFI investigation is completed, alldetails of the case is available (investigation; laboratoryand autopsy reports) and there is a valid diagnosis*

2. Prepare documents for causality assessment by theExpert Committee including anonymizing information(block out patient name, hospital name, etc.) .



1. Ensure that the AEFI investigation is completed, alldetails of the case is available (investigation; laboratoryand autopsy reports) and there is a valid diagnosis*

2. Prepare documents for causality assessment by theExpert Committee including anonymizing information(block out patient name, hospital name, etc.) .


* unfavorable or unintended sign, abnormal laboratory finding, symptom or disease.

Who should assess AEFI causalityWho should assess AEFI causality

• To ensure broader acceptance of the findings; by areviewing team/committee that should– Be Independent

• free of real or perceived government, industry conflicts of interest– Have broad range of expertise

• infectious diseases, epidemiology, microbiology, pathology, immunology,neurology, vaccine program expertise, other…

– Have written terms of reference (ToR)

• Can make use of an existing drugcausality assessment team BUTmodify and adapt to fit vaccines.


• To ensure broader acceptance of the findings; by areviewing team/committee that should– Be Independent

• free of real or perceived government, industry conflicts of interest– Have broad range of expertise

• infectious diseases, epidemiology, microbiology, pathology, immunology,neurology, vaccine program expertise, other…

– Have written terms of reference (ToR)

• Can make use of an existing drugcausality assessment team BUTmodify and adapt to fit vaccines.

ToR for committee’s formal causality assessmentToR for committee’s formal causality assessment

• Criteria (including case definitions) for formal assessment

• Method of causality assessment

• System for classifying causality

– Consistent, inconsistent (coincidental), indeterminate,unclassifiable

• System for communicating on findings• Liaise with AEFI secretariat ensuring links with

– investigative team– administrative support

• Provide recommendations for taking action


• Criteria (including case definitions) for formal assessment

• Method of causality assessment

• System for classifying causality

– Consistent, inconsistent (coincidental), indeterminate,unclassifiable

• System for communicating on findings• Liaise with AEFI secretariat ensuring links with

– investigative team– administrative support

• Provide recommendations for taking action

Causality Assessment StepsCausality Assessment Steps

Algorithm

Classification


Eligibility

Checklist

• Step 1: Eligibility: To determine if the AEFI case satisfies theminimum criteria for causality assessment

• Step 2: Checklist: To systematically review the relevant andavailable information to address possible causal aspects ofthe AEFI

• Step 3: Algorithm: To obtain a direction as to the causality withthe information gathered in the checklist

• Step 4: Classification: To categorize the AEFI’s association tothe vaccine / vaccination based on the direction determined inthe algorithm

Why 4 steps


• Step 1: Eligibility: To determine if the AEFI case satisfies theminimum criteria for causality assessment

• Step 2: Checklist: To systematically review the relevant andavailable information to address possible causal aspects ofthe AEFI

• Step 3: Algorithm: To obtain a direction as to the causality withthe information gathered in the checklist

• Step 4: Classification: To categorize the AEFI’s association tothe vaccine / vaccination based on the direction determined inthe algorithm

One or morevaccinesadministeredbefore thisevent clearlyidentified?

Does thereportedevent have avaliddiagnosis*?

Does thediagnosismeet a casedefinition

Now thecase is readyfor thechecklist

Yes

Yes

YesYesAEFI

databaseAEFI

database

Periodicdata mining

Periodicdata mining

• Brighton Collaboration defn• Standard literature defn• National defn• Other approved defn

• Brighton Collaboration defn• Standard literature defn• National defn• Other approved defn

Step 1: EligibilityStep 1: Eligibility


…*the adverse event may be anyunfavorable or unintended sign, abnormallaboratory finding, symptom or disease.

ReportedAEFI Case

One or morevaccinesadministeredbefore thisevent clearlyidentified?

Does thereportedevent have avaliddiagnosis*?

Does thediagnosismeet a casedefinition

No

Case review necessaryCase review necessary

No

AEFIdatabase

AEFIdatabase

Creating a causality questionCreating a causality question

• At this stage it is also essential for the reviewers todefine the “causality question” to address theunfavorable or unintended sign, laboratory finding,symptom or disease.

• Examples of causality questions− “Has the vaccine A caused hepatomegaly?” (An example of an

unfavorable or unintended sign) or

− “Has the vaccine B caused thrombocytopenia?” (An example ofa laboratory finding) or

− “Has the patient complained that the vaccine C caused itchingand redness?” (An example of a symptom) or

− “Has the vaccine D caused meningitis?” (An example of adisease).


• At this stage it is also essential for the reviewers todefine the “causality question” to address theunfavorable or unintended sign, laboratory finding,symptom or disease.

• Examples of causality questions− “Has the vaccine A caused hepatomegaly?” (An example of an

unfavorable or unintended sign) or

− “Has the vaccine B caused thrombocytopenia?” (An example ofa laboratory finding) or

− “Has the patient complained that the vaccine C caused itchingand redness?” (An example of a symptom) or

− “Has the vaccine D caused meningitis?” (An example of adisease).

ChecklistChecklist

I. Is there strong evidence for other causes?

• Relationship with vaccine ingredients• Immunization error• Relationship with vaccine administration

II. Is there a known causal association with the Vaccine / Vaccination

Step 2: ChecklistStep 2: Checklist


II (Time). Was the event within the time window of increased risk?

III. Is there a strong evidence against a causal association?

IV. Other Qualifying Factors

ChecklistChecklist

I. Is there strong evidence for other causes?


Y N UK NA


• Does a clinical examination or laboratory tests on thepatient confirm another cause?

Y N UK NAYes No Unknown Not Applicable

ChecklistChecklist

• Relationship with vaccine ingredients• Is there evidence in literature that this vaccine (s) may cause the reported event even if

administered correctly?• Did a specific test demonstrate the causal role of the vaccine or any of the ingredients?

• Immunization Error• Was there an error in prescribing or non-adherence to recommendations for use of the vaccine

(e.g. usage beyond expiry date, wrong recipient etc)?• Was the vaccine (ingredients) administered unsterile?• Was the vaccine's physical condition (e.g. colour, turbidity, foreign substances etc.) abnormal at

the time of administration ?• Was there an error in vaccine constitution / preparation by the vaccinator (e.g., wrong product,

wrong diluent, improper mixing, improper syringe filling etc)?• Was there an error in vaccine handling? (e.g. Break in cold chain during transport, storage

and/or immunization session etc)?• Was the vaccine administered incorrectly (e.g. wrong dose, site or route of administration;

wrong needle size etc)?• Immunization Anxiety

• Could the event have been caused by anxiety about the immunization (e.g. vasovagal,hyperventilation or stress-related disorder)?

II. Is there a known causal association with the Vaccine / Vaccination


Y N UK NA


• Relationship with vaccine ingredients• Is there evidence in literature that this vaccine (s) may cause the reported event even if

administered correctly?• Did a specific test demonstrate the causal role of the vaccine or any of the ingredients?

• Immunization Error• Was there an error in prescribing or non-adherence to recommendations for use of the vaccine

(e.g. usage beyond expiry date, wrong recipient etc)?• Was the vaccine (ingredients) administered unsterile?• Was the vaccine's physical condition (e.g. colour, turbidity, foreign substances etc.) abnormal at

the time of administration ?• Was there an error in vaccine constitution / preparation by the vaccinator (e.g., wrong product,

wrong diluent, improper mixing, improper syringe filling etc)?• Was there an error in vaccine handling? (e.g. Break in cold chain during transport, storage

and/or immunization session etc)?• Was the vaccine administered incorrectly (e.g. wrong dose, site or route of administration;

wrong needle size etc)?• Immunization Anxiety

• Could the event have been caused by anxiety about the immunization (e.g. vasovagal,hyperventilation or stress-related disorder)?

• Did the event occur in an appropriate time window after vaccine administration?

II (Time). If “yes” to any question in II, was the event within the timewindow of increased risk?


ChecklistChecklistStep 2: ChecklistStep 2: Checklist

• Is there a strong evidence against a causal association?

III. Is there a strong evidence against a causal association?

• Could the event occur independent of vaccination (background rate)• Could the event be a manifestation of another health condition?• Did a comparable event occur after a previous dose of a similar vaccine?• Was there exposure to a potential risk factor / toxin prior to the event?• Was there acute illness prior to the event?• Did the event occur in the past independent of vaccination ?• Was the patient taking any medication prior to vaccination?• Is there a biological plausibility that the vaccine could cause the event?

IV. Other qualifying factors (in the patient)

Y N UK NA



• Could the event occur independent of vaccination (background rate)• Could the event be a manifestation of another health condition?• Did a comparable event occur after a previous dose of a similar vaccine?• Was there exposure to a potential risk factor / toxin prior to the event?• Was there acute illness prior to the event?• Did the event occur in the past independent of vaccination ?• Was the patient taking any medication prior to vaccination?• Is there a biological plausibility that the vaccine could cause the event?

I A. Inconsistentcausal

association toimmunization

I A. Inconsistentcausal


IV D.Unclassifiable

II. Is there aknown causal

association withthe vaccine/vaccination

II. Is there aknown causal

association withthe vaccine/vaccination

Yes

Yes

III A. Inconsistentcausal


III A. Inconsistentcausal


Yes

Review otherqualifying

factors

Review otherqualifying

factors

IV. Is the eventclassifiable?

III. Is there astrong evidenceagainst a causal

association?

III. Is there astrong evidenceagainst a causal

association?

I. Is there strongevidence for

other causes?

I. Is there strongevidence for

other causes?

Step 3: AlgorithmStep 3: Algorithm


II A. Consistentcausal


II A. Consistentcausal


IV B.Indeterminate

IV B.Indeterminate

IV D.Unclassifiable

IV D.Unclassifiable

IV C. Inconsistentcausal


IV C. Inconsistentcausal


IV A. Consistentcausal


IV A. Consistentcausal


Yes

Yes

NoNo



II (Time). Was theevent within thetime window ofincreased risk?

II (Time). Was theevent within thetime window ofincreased risk?



A1. Vaccine product-relatedreaction (As per published

literature)

A2. Vaccine quality relatedreaction


B. IndeterminateB. Indeterminate

B1. *Temporal relationship isconsistent but there isinsufficient definitive

evidence for vaccine causingevent (may be new vaccine-

linked event)


(Coincidental)


(Coincidental)

C1. Underlying or emergingcondition(s)


than vaccine

AdequateInformation

available

Step 4: ClassificationStep 4: Classification



immunization




A4. Immunization anxietyrelated reaction

B. Indeterminate C. Inconsistent causalassociation to immunization

(Coincidental)


than vaccine

UnclassifiableUnclassifiable

Specify the additional information required for classificationSpecify the additional information required for classification

AdequateInformationnot available

*B1 : Potential signal and maybe considered for investigation



immunization

AEFI causality of a single case - The Scientific BasisAEFI causality of a single case - The Scientific Basis


Assessing causality: Temporal relationshipAssessing causality: Temporal relationship

• “Cause” must precede effect.

• Receipt of the vaccineshould precede the earliestmanifestation of the eventor a clear exacerbation ofthe condition.

• Examples:− NOT rash 2 days post MMR

vaccine – too soon after immunization− NOT “anaphylactic” reaction within less

than a minute of receiving influenza vaccine


• “Cause” must precede effect.

• Receipt of the vaccineshould precede the earliestmanifestation of the eventor a clear exacerbation ofthe condition.

• Examples:− NOT rash 2 days post MMR

vaccine – too soon after immunization− NOT “anaphylactic” reaction within less

than a minute of receiving influenza vaccine

Photo: WHO

Assessing causality: Alternate explanationsAssessing causality: Alternate explanations

• ‘Coincidental AEFI’ – i.e. an AEFI due to something otherthan the vaccine product, immunization error orimmunization anxiety.– Preexisting illness– Newly acquired illness– Spontaneous occurrence of an event without known risk factors– Emergence of a genetically programmed disease– Other exposures to drugs or toxins prior to event– Surgical or other trauma that leads to a complication– A manifestation of, or complication of, a coincidental infection

that was present before or at immunization or incubating but notapparent at the time of immunization


• ‘Coincidental AEFI’ – i.e. an AEFI due to something otherthan the vaccine product, immunization error orimmunization anxiety.– Preexisting illness– Newly acquired illness– Spontaneous occurrence of an event without known risk factors– Emergence of a genetically programmed disease– Other exposures to drugs or toxins prior to event– Surgical or other trauma that leads to a complication– A manifestation of, or complication of, a coincidental infection

that was present before or at immunization or incubating but notapparent at the time of immunization

Assessing causality: Alternate explanations(Continued)Assessing causality: Alternate explanations(Continued)

Coincidental deaths/year in selected South Asiacountries: After DPT vaccine

Month Week Day

Australia 331 76 11

Cambodia 8,199 1,892 270


Cambodia 8,199 1,892 270

China 170,202 39,277 5,596

Japan 1,154 266 38

Laos 4,427 1,022 146

New Zealand 86 20 3

Assessing causality: Prior evidenceAssessing causality: Prior evidence

Previously known reaction• Literature

• Pre-licensure studies

• Post-marketing surveillancedatabases– E.g., intussusception with

rotavirus vaccine

• Post-licensure studies


Previously known reaction• Literature

• Pre-licensure studies

• Post-marketing surveillancedatabases– E.g., intussusception with

rotavirus vaccine

• Post-licensure studies

Assessing causality: Biological plausibilityAssessing causality: Biological plausibility

• The association should becoherent – can be explainedby one (or more) of:– Natural history– Biology of the disease– Laboratory evidence– Animal studies

• Least strong of the criteria; helpfulif present but not useful if absent− E.g., fever 8 to 10 days after MMR


• The association should becoherent – can be explainedby one (or more) of:– Natural history– Biology of the disease– Laboratory evidence– Animal studies

• Least strong of the criteria; helpfulif present but not useful if absent− E.g., fever 8 to 10 days after MMR Photo: WHO

Assessing causality: Proof of associationAssessing causality: Proof of association

• Clinical or laboratory proof thatthe vaccine caused the event(most often found for liveattenuated vaccines).– a case of aseptic meningitis after

immunization with Urabe mumpsvaccine virus and recovery of theUrabe virus from the CSF

– recovery of the BCG agent from afocus of osteomyelitis).


• Clinical or laboratory proof thatthe vaccine caused the event(most often found for liveattenuated vaccines).– a case of aseptic meningitis after

immunization with Urabe mumpsvaccine virus and recovery of theUrabe virus from the CSF

– recovery of the BCG agent from afocus of osteomyelitis).

Photo: WHO

Assessing causality: Population based evidenceAssessing causality: Population based evidenceThe aim is to determine if there is a

causal association between theusage of a vaccine and a particularAEFI in the population

ie“Is there evidence in literature that this

vaccine(s) may cause the reportedevent even if administered correctly?”


The aim is to determine if there is acausal association between theusage of a vaccine and a particularAEFI in the population

ie“Is there evidence in literature that this

vaccine(s) may cause the reportedevent even if administered correctly?”

Photo: A Bentsi-Enchill/WHO

An online guide to WHO information sheets on observed rates of vaccine reactionsthat summarizes the AEFI on a single antigen vaccine or combination product isavailable at http://www.who.int/vaccine_safety/initiative/tools/Guide_Vaccine_rates_information_sheet_.pdf

What does this evolved process facilitateWhat does this evolved process facilitate• Ensures that AEFI cases are classified according to the CIOMS/ WHO

guidelines

• Incorporates major criteria affecting causality

• Flexible approach that evolves as more information becomes available

• Minimizes errors

• Simple – no technology involved; can be used in settings with differentlevels of experience and specialization.

• Can be adapted to computer logic if necessary

• A convenient tool to teach and learn


• Ensures that AEFI cases are classified according to the CIOMS/ WHOguidelines

• Incorporates major criteria affecting causality

• Flexible approach that evolves as more information becomes available

• Minimizes errors

• Simple – no technology involved; can be used in settings with differentlevels of experience and specialization.

• Can be adapted to computer logic if necessary

• A convenient tool to teach and learn

The Constraints…The Constraints…

• The "critical" part is the valid diagnosis.

• The first conclusion may not be final: as moreinformation becomes available, the causality canchange


• The "critical" part is the valid diagnosis.

• The first conclusion may not be final: as moreinformation becomes available, the causality canchange

Single Case

Proving causality is hard unlessAEFI already known to berelated.

May be possible to prove theimmunization error related

Unclassifiable is commonbecause of insufficient data.

The critical factor is determiningthe “indeterminate” and“coincidental.”

Can impact population

Cluster

• May be able to provecausality

• Need to determine rate

• Extremely important fordetecting immunizationerrors, but

• Often clusters are not trueclusters, rather concurrentevents, unrelated to eachother.

When clusters are investigated, each case in the cluster should beinvestigated separately. The data should be linelisted to see if there is apattern. If a new pattern is identified, a signal should be suspected

Causality assessment of a single case vs a cluster / signalCausality assessment of a single case vs a cluster / signal


Single Case

Proving causality is hard unlessAEFI already known to berelated.

May be possible to prove theimmunization error related

Unclassifiable is commonbecause of insufficient data.

The critical factor is determiningthe “indeterminate” and“coincidental.”

Can impact population

Cluster

• May be able to provecausality

• Need to determine rate

• Extremely important fordetecting immunizationerrors, but

• Often clusters are not trueclusters, rather concurrentevents, unrelated to eachother.

Single casereports Single case

reports Single casereports

Nationaldatabase

Signalling processData analysisReview of all relevantsources of data

Evaluation of single case, cluster and signalEvaluation of single case, cluster and signal


NationaldatabaseCluster case

reportsCluster casereports

Signalling processData analysisReview of all relevantsources of data

Causality assessmentand decision on

further studies to confirmcausal association

Challenges to causality assessmentChallenges to causality assessment

1. Causality assessment not done, not systematic, not done bytrained personnel and/or not done timely

2. Information in AEFI report is so limited that causality assessmentcannot be done

3. Lack of expertise and/or independence of the review committeeresponsible for formal causality assessment undermines credibility

4. Non analysis of the AEFI in context after causality assessment maydelay recognition of clusters and possible programme errors

5. Lack of skilled communication of findings, not addressing all targetaudiences, or lack of diplomacy and/or cultural sensitivity


1. Causality assessment not done, not systematic, not done bytrained personnel and/or not done timely

2. Information in AEFI report is so limited that causality assessmentcannot be done

3. Lack of expertise and/or independence of the review committeeresponsible for formal causality assessment undermines credibility

4. Non analysis of the AEFI in context after causality assessment maydelay recognition of clusters and possible programme errors

5. Lack of skilled communication of findings, not addressing all targetaudiences, or lack of diplomacy and/or cultural sensitivity

Summary and discussions: Key conceptsSummary and discussions: Key concepts

• Which types of AEFI should be selected for formalcausality assessment?

• What are the prerequisites before starting causalityassessment?

• What are the 4 steps for a formal AEFI causalityassessment process?

• Based on the CA conclusions, what are the key actionpoints?


• Which types of AEFI should be selected for formalcausality assessment?

• What are the prerequisites before starting causalityassessment?

• What are the 4 steps for a formal AEFI causalityassessment process?

• Based on the CA conclusions, what are the key actionpoints?

Documents

AEFI Revised Concepts and Definitions