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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.
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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 Number of Studies (N=120)* 37.5 38.0 38.3/ 38.5 39.0 39.5 40.0 40.5 “Fever” 37.8 Temperature (>=) °C *Some studies with >1 cut off
Cut-offs for Erythema & Swelling & IndurationStudies and Surveillance Systems Number of studies* (N=102) Cut off points in mm *Some studies with >1 cut off
The Brighton Collaboration Enables Comparability • Develops case definitions for AEFI • Promotes global implementation of case definitions
4 Step Process To Develop Case Definitions • Search for existing case definitions • Develop draft definitions • Review and evaluate draft definitions 4) Finalize and disseminate definitions
First Six AEFI Definitions • Fever • Local Reactions • Intussusception • Persistent Crying • Generalized Convulsive Seizure • 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 one measured body temperature of >38° C Level 2Not applicable Level 3Not applicable
4 Step Process To Develop Guidelines • Create draft definitions • Apply to real cases • Test for comparability • Formulate needed guidelines
Guidelines for Investigators • Data collection e.g. vaccine, other medication, outcome • Data Analysis e.g. 5 categories, predefined increments • Data Presentation e.g. numerator and denominator, distribution of data
Five Categories for Data Analysis Case definition 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]
AEFI Definition Document Format • Preamble • Definition • Guidelines
Structure of Brighton Collaboration • Steering committee • Working groups: Case definition • Working group: Methods • Reference group
Board Elisabeth Loupi Bob Chen Phillippe Duclos Ulrich Heininger Harald Heijbel Tom Jefferson Secretariat Katrin Kohl Jan Bonhoeffer Bakary Drammeh Steering Committee
Allergic Reaction SIDS ITP Myalgia CFS Paresthesia Smallpox AEFI Next Steps • Build reference group • Build next 7 working groups • Dissemination and Implementation
Country Distribution of Participants Date: October 2002 322 Participants 42 Countries
Join the Collaboration ! • Use definitions, guidelines • Be part of reference group • Be part of working groups We need aWorking Group Coordinator NOW!!
secretariat@brightoncollaboration.org http://brightoncollaboration.org
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 one measured body temperature of >38° C Level 2 Not applicable Level 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 formationAND/OR • Warmth • Erythema • Level 2Not applicable • Level 3Not applicable
Abscess at injection site Abscess is defined by • localized soft tissue collection of fluid • with or without fluctuance • at the site of immunization
Abscess of Infectious Etiology *Level 1 The presence of • Spontaneous or surgical drainage of purulent material from mass AND • Laboratory confirmation *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
Abscess of Infectious Etiology Level 3 • Not applicable
Swelling at injection site Level 1* The presence of Measured enlargement of injection site / limb ORVisible 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 OR The 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
Cellulitis at injection siteLevel 3 (continued) 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
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 ispersistent, 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 2Not applicable Level 3Not 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
0-12 months FEVER CONVULSION AGITATION SIDS APNEA STUPOR HYPOTONIA CYANOSIS VOMIT SOMNOLENCE 1 year FEVER CONVULSION FEB SEIZURE RASH STUPOR AGITATION VOMIT OTITIS MED SOMNOLENCE APNEA 2-18 years FEVER CONVULSION VOMIT HEADACHE RASH ASTHENIA STUPOR SOMNOLENCE DYSPNEA HYPOKINESIA 1 2 3 4 5 6 7 8 9 10 Top 10 Serious* AEFI**, by Age Group >18years FEVER ASTHENIA PARESTHESIA GUILLAIN BARRE PAIN MYALGIA ARTHRALGIA HEADACHE DYSPNEA MYASTHENIA * Per FDA criteria **Source: VAERS, 1991-2000 Yellow = 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, 1991-2000 Yellow = Currently included AEFI; Green = Next AEFI to be defined