Comparability of Vaccine Safety Data Dr med Jan

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-offs Study protocols and surveillance systems Number of Studies (N=120)* 37. 5 38. 0 38. 3/ 38. 5 39. 0 39. 5 40. 0 37. 8 Temperature (>=) °C *Some studies with >1 cut off 40. 5 “Fever”

Cut-offs for Erythema & Swelling & Induration Studies 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 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 • • • 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 • Radiological criteria • Autopsy criteria AND/OR 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 2 Not applicable Level 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 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

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 Allergic Reaction SIDS ITP Myalgia CFS Paresthesia Smallpox AEFI • 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 a Working 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 formation • Warmth • Erythema Level 2 Not applicable Level 3 Not applicable AND/OR

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 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 site Level 1 The presence of (at least 3 of the following five) ● localized pain ● tenderness to light touch ● intense erythema ● at least moderate induration ● substantial local warmth AND ● is at the injection site ● laboratory confirmation AND/OR AND

Cellulitis at injection site Level 1 continued In the absence of ● spontaneous rapid resolution ● fluctuance OR The presence of ● a physician diagnosis of cellulitis ● is at the injection site ● laboratory confirmation AND/OR AND

Cellulitis at injection site Level 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 ● health care provider diagnosis AND In the absence of ● spontaneous rapid resolution ● fluctuance AND/OR

Cellulitis at injection site Level 3 The presence of (any of the following five) ● localized pain ● tenderness to light touch ● intense erythema ● at least moderate induration ● substantial local warmth AND/OR AND ● is at the injection site 2 ● health care provider diagnosis AND In the absence of ● spontaneous rapid resolution ● fluctuance AND/OR

Cellulitis at injection site Level 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 ● non health care provider report AND

Intussusception Level 1 • Surgical criteria • Radiological criteria • Autopsy criteria AND/OR 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 applicable Level 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 • Pallor or cyanosis AND

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 0 -12 months 1 year 2 -18 years >18 years 1 FEVER 2 CONVULSION ASTHENIA 3 AGITATION FEB SEIZURE VOMIT PARESTHESIA 4 SIDS RASH HEADACHE GUILLAIN BARRE 5 APNEA STUPOR RASH PAIN 6 STUPOR AGITATION ASTHENIA MYALGIA 7 HYPOTONIA VOMIT STUPOR ARTHRALGIA 8 CYANOSIS OTITIS MED SOMNOLENCE HEADACHE 9 VOMIT SOMNOLENCE DYSPNEA SOMNOLENCE APNEA MYASTHENIA 10 HYPOKINESIA * Per FDA criteria **Source: VAERS, 1991 -2000 Yellow = Currently included AEFI; Green = Next AEFI to be defined

Top 10 Non-Serious* AEFI**, by Age Group 0 -12 months 1 year 2 -18 years >18 years 1 FEVER HYSN INJ SITE 2 AGITATION RASH HYSN INJ SITE FEVER 3 SCREAMING AGITATION VASODILAT 4 CRY ABNORMAL HYSN INJ SITE EDEMA INJ SITE MYALGIA 5 HYSN INJ SITE RASH MAC PAP RASH PAIN INJ SITE 6 EDEMA INJ SITE VASODILAT URTICARIA EDEMA INJ SITE 7 SOMNOLENCE CONVULSION PRURITUS PAIN 8 RASH EDEMA INJ SITE PAIN INJ SITE PRURITUS 9 VOMIT URTICARIA VOMIT RASH 10 HYPOTONIA RASH VESIC BULL PAIN HEADACHE * Per FDA criteria **Source: VAERS, 1991 -2000 Yellow = Currently included AEFI; Green = Next AEFI to be defined