Comparability of Vaccine Safety Data Dr. med. Jan Bonhoeffer
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Transcript of Comparability of Vaccine Safety Data Dr. med. Jan Bonhoeffer
Comparability
of Vaccine Safety Data
Dr. med. Jan Bonhoeffer
Coordinator, The Brighton Collaboration
University Children’s Hospital Basel
2 Challenges To Comparability
• Safety assessed indirectly
• No standardization:
of Case definitions
of Guidelines
Lack of Standardized Case Definitions
• WHO and CIOMS definitions
- Not exaustive
- Not widely used
• Literature search
-Large diversity of safety methods
Temperature Cut-offsStudy protocols and surveillance systems
0
10
2030
40
50
6070
80
90Number of Studies (N=120)*
*Some studies with >1 cut off
37.5 38.0 38.3/ 38.5 39.0 39.5 40.0 40.5 “Fever” 37.8
Temperature (>=) °C
Cut-offs for Erythema & Swelling & Induration
Studies and Surveillance Systems
0
5
10
15
20
25
30Number of studies* (N=102)
*Some studies with >1 cut off
Cut off points in mm
The Brighton Collaboration Enables Comparability
• Develops case definitions for AEFI
• Promotes global implementation of case definitions
4 Step Process To Develop Case Definitions
1) Search for existing case definitions
2) Develop draft definitions
3) Review and evaluate draft definitions
4) Finalize and disseminate definitions
First Six AEFI Definitions
1) Fever
2) Local Reactions
3) Intussusception
4) Persistent Crying
5) Generalized Convulsive Seizure
6) Hypotonic - Hyporesponsive
Episode
Brighton Collaboration Case Definition Format
Level 1 of diagnostic certainty
Level 2 of diagnostic certainty
Level 3 of diagnostic certainty
Intussusception
Level 1 • Surgical criteria AND/OR • Radiological criteria AND/OR• Autopsy criteria
Level 2 Clinical criteria • 2 major OR 1 major & 3 minor criteria
Level 3 Clinical criteria • > 4 minor criteria
Fever
Level 1 Endogenous elevation of at least onemeasured body temperature of >38° C
Level 2 Not applicableLevel 3 Not applicable
4 Step Process To Develop Guidelines
1) Create draft definitions
2) Apply to real cases
3) Test for comparability
4) Formulate needed guidelines
Guidelines for Investigators
• Data collectione.g. vaccine, other medication, outcome
• Data Analysise.g. 5 categories, predefined increments
• Data Presentatione.g. numerator and denominator, distribution of data
Five Categories for Data Analysis
Level 1 of diagnostic certainty
Level 2 of diagnostic certainty
Level 3 of diagnostic certainty
Additional categories for data analysis
• Reported [AEFI] with insufficient evidence
to meet the case definition
• No, it is not a case of [AEFI]
Case definition
Structure of Brighton Collaboration
• Steering committee
• Working groups: Case definition
• Working group: Methods
• Reference group
Steering Committee
• Board
Elisabeth Loupi
Bob Chen
Phillippe Duclos
Ulrich Heininger
Harald Heijbel
Tom Jefferson
• Secretariat
Katrin Kohl
Jan Bonhoeffer
Bakary Drammeh
Next Steps
• Build reference group
• Build next 7 working groups
• Dissemination and Implementation
Smallpox AEFI
ParesthesiaCFS
MyalgiaITP
SIDSAllergic Reaction
Join the Collaboration !
• Use definitions, guidelines
• Be part of reference group
• Be part of working groups
We need aWorking Group Coordinator NOW!!
Funding
• Centers for Disease Control and Prevention
• EUSAFEVAC – European Research Program of Improved Vaccine Safety Surveillance
• World Health Organization
Fever
Level 1 Endogenous elevation of at least onemeasured body temperature of >38° C
Level 2 Not applicableLevel 3 Not applicable
Injection Site Nodule
Level 1 The presence of • Discrete or well demarcated soft tissue mass• Firm AND• At injection site
In the absence of • Abscess formation AND/OR• Warmth • Erythema
Level 2 Not applicableLevel 3 Not applicable
Abscess at injection site
Abscess is defined by• localized soft tissue collection of fluid • with or without fluctuance• at the site of immunization
The presence of• Spontaneous or surgical drainage of purulent
material from mass
AND
• Laboratory confirmation
Abscess of Infectious Etiology * Level 1
*may be accompanied by fever and/or regional lymphadenopathy.
Abscess of Infectious Etiology Level 2
The presence of• Spontaneous or surgical drainage of purulent
material from the mass
OR
• Fluid collection diagnosed by imaging technique
AND
• Localized sign(s) of inflammation AND/OR
• Prompt resolution with antimicrobial therapy
Swelling at injection site
Level 1* The presence of Measured enlargement of injection site / limb OR Visible enlargement of injection site / limb described as "joint to joint" or "crossing joints"
* the swelling may be accompanied by some erythema and tenderness
Swelling at injection site
Level 2* Reported visible enlargement of injection site/limb without objective measurement or specified anatomical description.
Level 3 not applicable
The following alone do not constitute 'swelling': An isolated injection site nodule, abscess, cellulites, induration
* the swelling may be accompanied by some erythema and tenderness
Cellulitis at injection site
Cellulitis is defined as an acute, infectious, expanding inflammatory condition of the skin that is characterized by ……
Cellulitis at injection siteLevel 1
The presence of (at least 3 of the following five)
● localized pain AND/OR
● tenderness to light touch AND/OR
● intense erythema AND/OR
● at least moderate induration AND/OR
● substantial local warmth
AND
● is at the injection site AND
● laboratory confirmation
Cellulitis at injection siteLevel 1 continued
In the absence of● spontaneous rapid resolution
AND/OR● fluctuance
ORThe presence of● a physician diagnosis of cellulitis AND● is at the injection site AND● laboratory confirmation
Cellulitis at injection siteLevel 2
The presence of (at least 3 of the following five)● localized pain AND● tenderness to light touch AND● intense erythema AND● at least moderate induration AND● substantial local warmth
AND● is at the injection site AND● health care provider diagnosis
In the absence of● spontaneous rapid resolution AND/OR● fluctuance
Cellulitis at injection siteLevel 3
The presence of (any of the following five)● localized pain AND/OR● tenderness to light touch AND/OR● intense erythema AND/OR● at least moderate induration AND/OR● substantial local warmth
AND● is at the injection site2 AND● health care provider diagnosis
In the absence of● spontaneous rapid resolution AND/OR● fluctuance
OR The presence of (at least 3 of the following five)● localized pain AND● tenderness to light touch AND● intense erythema AND● at least moderate induration AND● substantial local warmth
AND● is at the injection site AND● non health care provider report
Cellulitis at injection siteLevel 3 (continued)
Intussusception
Level 1 • Surgical criteria AND/OR • Radiological criteria AND/OR• Autopsy criteria
Level 2 Clinical criteria • 2 major OR 1 major & 3 minor criteria
Level 3 Clinical criteria • > 4 minor criteria
Inconsolable Crying
Level 1 The presence of Loud sustained vocalization, which is persistent, i.e.
continuous AND unaltered for > 3 hours
In the absence of Response to any attempt to console the crying (e.g.
by means of feeding, comforting, analgesics)
Level 2 Not applicableLevel 3 Not applicable
Generalized Convulsive Seizure
Level 1 • Witnessed sudden loss of consciousness AND• Generalized, tonic, clonic, tonic-clonic
or atonic motor manifestations
Generalized Convulsive Seizure
Level 2• History of unconsciousness AND• generalized tonic, clonic or tonic-clonic or
atonic motor manifestations
Level 3 • History of unconsciousness AND• Other generalized motor manifestations
HHE
Level 1 The sudden onset of
• Limpness (muscular hypotonia) AND
• Hypo-responsiveness or
unresponsiveness
AND
• Pallor or cyanosis
HHE
Level 2 The sudden onset of
Two of the three definite inclusion criteria
Level 3
The sudden onset of
Two of the three definite inclusion criteria AND
The third one noticed to be absent
Top 10 Serious* AEFI**, by Age Group
1 year
FEVER
CONVULSION
FEB SEIZURE
RASH
STUPOR
AGITATION
VOMIT
OTITIS MED
SOMNOLENCE
APNEA
0-12 months
FEVER
CONVULSION
AGITATION
SIDS
APNEA
STUPOR
HYPOTONIA
CYANOSIS
VOMIT
SOMNOLENCE
1
2
3
4
5
6
7
8
9
10
2-18 years
FEVER
CONVULSION
VOMIT
HEADACHE
RASH
ASTHENIA
STUPOR
SOMNOLENCE
DYSPNEA
HYPOKINESIA
>18years
FEVER
ASTHENIA
PARESTHESIA
GUILLAIN BARRE
PAIN
MYALGIA
ARTHRALGIA
HEADACHE
DYSPNEA
MYASTHENIA
* Per FDA criteria**Source: VAERS, 1991-2000Yellow = Currently included AEFI; Green = Next AEFI to be defined
0-12 months
FEVER
AGITATION
SCREAMING
CRY ABNORMAL
HYSN INJ SITE
EDEMA INJ SITE
SOMNOLENCE
RASH
VOMIT
HYPOTONIA
1 year
FEVER
RASH
AGITATION
HYSN INJ SITE
RASH MAC PAP
VASODILAT
CONVULSION
EDEMA INJ SITE
URTICARIA
RASH VESIC BULL
2-18 years
FEVER
HYSN INJ SITE
VASODILAT
EDEMA INJ SITE
RASH
URTICARIA
PRURITUS
PAIN INJ SITE
VOMIT
PAIN
>18years
HYSN INJ SITE
FEVER
VASODILAT
MYALGIA
PAIN INJ SITE
EDEMA INJ SITE
PAIN
PRURITUS
RASH
HEADACHE
1
2
3
4
5
6
7
8
9
10
Top 10 Non-Serious* AEFI**, by Age Group
* Per FDA criteria**Source: VAERS, 1991-2000Yellow = Currently included AEFI; Green = Next AEFI to be defined