comparability of vaccine safety data dr. med. jan bonhoeffer coordinator, the brighton collaboration...

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



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




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

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

• Dissemination and Implementation

Smallpox AEFI

ParesthesiaCFS

MyalgiaITP

SIDSAllergic Reaction

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!!

[email protected]

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 onemeasured body temperature of >38° C


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


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

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 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


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


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)


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

comparability of vaccine safety data dr. med. jan bonhoeffer coordinator, the brighton collaboration...

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