1. Comparability of Vaccine Safety Data Dr. med. Jan Bonhoeffer Coordinator, The Brighton Collaboration University Children’s Hospital Basel

2. 2 Challenges To Comparability Safety assessed indirectly No standardization: of Case definitions of Guidelines

3. Lack of Standardized Case Definitions WHO and CIOMS definitions - Not exaustive - Not widely used Literature search -Large diversity of safety methods

4. Temperature Cut-offs Study protocols and surveillance systems Number 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

5. Cut-offs for Erythema & Swelling & Induration Studies and Surveillance Systems Number of studies* (N=102) * Some studies with >1 cut off Cut off points in mm

6. The Brighton Collaboration Enables Comparability Develops case definitions for AEFI Promotes global implementation of case definitions

7. 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

8. First Six AEFI Definitions 1)Fever 2)Local Reactions 3)Intussusception 4)Persistent Crying 5)Generalized Convulsive Seizure 6)Hypotonic - Hyporesponsive Episode

9. Brighton Collaboration Case Definition Format Level 1 of diagnostic certainty Level 2 of diagnostic certainty Level 3 of diagnostic certainty

10. 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

11. Fever Level 1 Endogenous elevation of at least one measured body temperature of >38° C Level 2 Not applicable Level 3 Not applicable

12. 4 Step Process To Develop Guidelines 1)Create draft definitions 2)Apply to real cases 3)Test for comparability 4)Formulate needed guidelines

13. 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

14. 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

15. AEFI Definition Document Format Preamble Definition Guidelines

16. Structure of Brighton Collaboration Steering committee Working groups: Case definition Working group: Methods Reference group

17. Steering Committee Board Elisabeth Loupi Bob Chen Phillippe Duclos Ulrich Heininger Harald Heijbel Tom Jefferson Secretariat Katrin Kohl Jan Bonhoeffer Bakary Drammeh

18. Next Steps Build reference group Build next 7 working groups Dissemination and Implementation Smallpox AEFI ParesthesiaCFS MyalgiaITP SIDSAllergic Reaction

19. Country Distribution of Participants Date: October 2002 322 Participants 42 Countries

20. Join the Collaboration ! Use definitions, guidelines Be part of reference group Be part of working groups We need a Working Group Coordinator NOW!!

21. secretariat@brightoncollaboration.org http://brightoncollaboration.org

23. Funding Centers for Disease Control and Prevention EUSAFEVAC – European Research Program of Improved Vaccine Safety Surveillance World Health Organization

24. Fever Level 1 Endogenous elevation of at least one measured body temperature of >38° C Level 2 Not applicable Level 3 Not applicable

25. 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 2 Not applicable Level 3 Not applicable

26. Abscess at injection site Abscess is defined by localized soft tissue collection of fluid with or without fluctuance at the site of immunization

27. 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.

28. 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

29. Abscess of Infectious Etiology Level 3 Not applicable

30. 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

31. 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

32. Cellulitis at injection site Cellulitis is defined as an acute, infectious, expanding inflammatory condition of the skin that is characterized by ……

33. Cellulitis at injection site Level 1 The presence of (at least 3 of the following five) ● localized painAND/OR ● tenderness to light touchAND/OR ● intense erythemaAND/OR ● at least moderate induration AND/OR ● substantial local warmth AND ● is at the injection siteAND ● laboratory confirmation

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

35. Cellulitis at injection site Level 2 The presence of (at least 3 of the following five) ● localized painAND ● tenderness to light touchAND ● intense erythemaAND ● 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 resolutionAND/OR ● fluctuance

36. Cellulitis at injection site Level 3 The presence of (any of the following five) ● localized painAND/OR ● tenderness to light touchAND/OR ● intense erythemaAND/OR ● at least moderate indurationAND/OR ● substantial local warmth AND ● is at the injection site2AND ● health care provider diagnosis In the absence of ● spontaneous rapid resolutionAND/OR ● fluctuance

37. OR The presence of (at least 3 of the following five) ● localized painAND ● tenderness to light touchAND ● intense erythemaAND ● at least moderate indurationAND ● substantial local warmth AND ● is at the injection site AND ● non health care provider report Cellulitis at injection site Level 3 (continued)

38. 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

39. 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

40. Generalized Convulsive Seizure Level 1 Witnessed sudden loss of consciousness AND Generalized, tonic, clonic, tonic-clonic or atonic motor manifestations

41. 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

42. HHE Level 1 The sudden onset of Limpness (muscular hypotonia) AND Hypo-responsiveness or unresponsiveness AND Pallor or cyanosis

43. 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

44. 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, 1991-2000 Yellow = Currently included AEFI; Green = Next AEFI to be defined

45. 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