# Presentation: 933174

## New Developments and CapabilitiesGLOBALLY 

**Dr. Barbara Law**
**Chief Vaccine Safety**
**Public Health Agency of Canada**

***Vaccine Safety Evaluation***
***Post Marketing Surveillance Conference***
***Bethesda, Maryland.  April 10-11, 2007***

## New Developments and Capabilities......GLOBALLY

**Potential for global synergies in postmarketing surveillance**
**Relevant Canadian Postmarketing Initiatives**** **

## Potential for global synergiesin postmarketing surveillance

**Standard AEFI Case Definitions **
**Brighton Collaboration**
**Vaccine Pharmacovigilance Terminology**
**CIOMS**
**Multi-Country Signal Detection**
**Uppsala Drug Monitoring**** ****Program**
**WHO Global Consultation**
**GACVS Workgroup**
**Global Networking and Communications**

## AEFI Reporting Harmonization/SynergiesVaccine Pharmacovigilance Terminology: CIOMS

**Council for International Organizations of Medical Sciences (CIOMS)**
**International, non-governmental, non-profit**
**Established jointly by WHO and UNESCO in 1949**
**Focus on drug development and use since early 1980’s**
**Safety requirements**
**Assessment and monitoring of adverse drug reactions**
**Reporting and terminology of adverse drug reactions**
**Ethical criteria for drug promotion**
**Joint WHO/CIOMS Working Group on Vaccine Pharmacovigilance - Nov, 2005**

## AEFI Reporting Harmonization/SynergiesJoint WHO/CIOMS Working Group on Vaccine Pharmacovigilance

**Meets twice yearly**
**Membership: **
**WHO - Global Advisory Committee on Vaccine Safety (2 members plus secretariat representation)**
**Vaccine experts/scientists from Regulatory Authorities, Industry and International organizations**** **
**Contribute to development, review, evaluation, approval, dissemination and wider adoption of Brighton Collaboration case definitions**
**Collaborate with other CIOMS working groups (eg standardised MedDRA Queries -for specific AEFI to manage clinical trial data)**** **

## AEFI Reporting Harmonization/SynergiesJoint WHO/CIOMS Working Group on Vaccine Pharmacovigilance

**Develop new definitions specific to vaccines**
**Vaccine pharmacovigilance: points out unique aspects of vaccines vis a vis safety**
**Signal**
**Adverse event following immunization**
**Immunization reaction versus temporal coincidence**
**Adverse vaccine reaction**
**Programme error**
**Injection site reaction**
**Anxiety reaction**
**? Immunization triggered reaction **
**Vaccine failure**
**Develop a position paper on causality assessment **

## AEFI Reporting Harmonization/SynergiesGlobal Vaccine Safety Signal Detection 

**Uppsala Monitoring**** ****Centre - WHO Collaborating Centre for International Drug Monitoring**
**known limitations for vaccine safety monitoring**
**Global Advisory Committee on Vaccine Safety called for a WHO Consultation - held in Geneva, Jan 9-10, 2006**
**Objectives:**
**Review / make recommendations for a high-quality system for reporting, detection, analysis and communication of vaccine-related adverse events at a global level**
**Identify concrete actions for strengthening system **

## AEFI Reporting Harmonization/SynergiesWHO Consultation on Improving Global AEFI Monitoring 

**Participants**
**WHO (Immunization Vaccines and Biologics, Medicines Policy and Standards, UMC, GACVS members) **
**Selected National Centre representatives**
**Regulators / Vaccine Industry**
**Brighton Collaboration and CIOMS/WHO working group**
**Immunization and vaccine safety experts**
**Key Recommendations**
**Improve AEFI reporting to UMC**
**NC preferred but other options considered**
**Work needed on determinants of AEFI reporting**
**Improve resources and methods for AEFI reporting / analysis**
**“****vaccine focal points”: recruit one to UMC; NCs if possible**
**Make UMC tools/resources available to AEFI programs**
**Review/revise ATC classification system for vaccines**
**Develop signal search strategies specific for vaccines**

## AEFI Reporting Harmonization/SynergiesWHO Consultation on Improving Global AEFI Monitoring 

**Key Recommendations (cont)**
**Improve resources and methods for AEFI reporting / analysis**
**Strengthen signal review panel (Sept 06: drug:vaccine = 40:1)**
**Promote harmonized terminology for vaccine safety monitoring**
**Joint training activities for AEFI and ADR groups**
**Improve Advocacy and Communication**
**Develop advocacy documents on vaccine safety monitoring**
**Establish collaboration between UMC and other international vaccine safety groups**
**Improve participation of immunization/AEFI staff in UMC annual National Centres meeting**
**Maintain and if possible increase cross appointment of drug and vaccine safety experts on GACVS and ACSoMP**

## AEFI Reporting Harmonization/SynergiesWHO Consultation on Improving Global AEFI Monitoring 

**Follow up Actions to date**
**June 06: GACVS subgroup established**
**Will meet twice yearly in conjunction with GACVS meeting**
**Sept 06: UMC visit (WHO IVB/GACVS)**
**No external funding support (must be self-sustaining)**
**Reports received electronically only (ICH E2B format)**
**Vigiflow - web-based data management system**
**Oct 06: Breakout session at annual NC mtg to share country experiences/further define needs**
**ATC review upcoming with working group to propose modifications**
**Nov 06: GACVS subgroup TOR/Deliverables**

## AEFI Reporting Harmonization/SynergiesWHO GACVS Subgroup on Global AEFI Monitoring 

**TOR**
**Advise how to increase countries submitting as well as quality of AEFI reports**
**Evaluate whether current UMC signal detection methods are appropriate to vaccines**
**Identify other international groups that collect vaccine safety information and advise on ways to exchange information/collaborate**
**Advise how to improve global communication on vaccine safety signals**
**Advise how principles and practice of pharmacovigilance can be made available to global immunization community**

## AEFI Reporting Harmonization/SynergiesWHO GACVS Subgroup on Global AEFI Monitoring 

**Deliverables**
**Summarize country specific processes for AEFI reporting**
**List groups other than NC’s/UMC collecting vaccine safety data**
**Reports on:**
**how to increase total countries reporting to UMC **
**extent to which appropriate methodologies for vaccine safety signal detection are applied at national, multinational levels **
**ways to enhance global vaccine safety communication**
**Facilitate expert meeting to assess most appropriate method(s) for vaccine safety signal detection**
**Identify ways to expand pool of UMC vaccine signal reviewers**
**Report on raised profile/awareness of pharmacovigilance in immunization community**

## AEFI Reporting Harmonization/SynergiesGlobal Networking and Communications 

**“****shots heard around the world” in the global village**
**Peruvian example of Rubella program delayed by thimerosal concerns**
**Canada: provincial HBV school based program impacted by French decision to cancel theirs**
**Deaths at start of 2006 Israeli influenza campaign led to concern/delays in other countries**
**Ideal post licensure vaccine safety system**
**Learn about international vaccine safety issues from an informed collegial network rather than the mass media**
**Synergistic approach to issues of mutual importance**
**Share the burden of gathering the evidence base needed for informed decision making    **

## Canada’s Postmarketing System

**Brief Overview**
**Relevant Initiatives**
**New AEFI report form incorporates BC definitions**
**IMPACT - active “syndromic” AEFI surveillance**
**Advisory Committee on Causality Assessment (ACCA)**
**Pandemic Preparedness Activities during annual influenza campaigns**
**National Vaccine Safety Alert Network **

## Canadian Context for Vaccine Pharmacovigilance Federal / Provincial / Territorial Activities “FPT” 

**Federal Vaccine Regulatory Activities:**
** ****Health Canada: oversees clinical trials, manufacturing facilities, laboratory assessment, notice of compliance, lot release **
** ****Public Health Agency of Canada: postmarketing surveillance  **

**Health is a PT responsibility**
**13 systems**
**vaccine providers 50:50 MD:RN  but one or other predominates in most P and Ts**
**Mix of publicly and privately funded vaccines**

## Adverse Event Following Immunization Reporting: Currently

- PHAC – IRID
- Vaccine Safety Section

- _PASSIVE SYSTEM_

**Vaccine **
**Providers**

**Healthcare**
**Providers**

**P/T Health**
**Local/Central**

**Vaccine **
**Manufacturers**

**Travel Clinics**

## Brighton definitions incorporated into revised AEFI report form, where possible

**Eg. Hypotonic-Hyporesponsive Episode (HHE) as an AEFI**
**• ****Level 1 of diagnostic certainty: The sudden onset of**
**Limpness (i.e. muscular hypotonia) *****AND***
**Reduced responsiveness(hypresponsiveness) or unresponsiveness *****AND***
**Pallor or cyanosis.**
**• ****Level 2 of diagnostic certainty: The sudden onset of**
**Two of the three inclusion criteria defining Level 1**
**• ****Level 3 of diagnostic certainty: The sudden onset of**
**Two of the three inclusion criteria defining Level 1 and**
**The third criterion noticed to be absent.**

**Revised Canadian AEFI Report Form****Incorporating Brighton Collaboration Definitions**** **

##  Canadian Vaccine Safety InitiativesHistorical Perspective  

**1989 - Vaccine injury compensation program under consideration but concern regarding unknowns **
**1990 -  special federal funding for the Vaccine Associated Adverse Events Initiative included**
**IMPACT active surveillance project **
**Initiation of an expert committee to advise on causality**

## IMPACT Network(Immunization Monitoring Program - ACTive)

* *_**Administered**__*** ***__**by**_***:***** Canadian Pediatric Society*****      ***

- IMPACT Network(Immunization Monitoring Program - ACTive)

**coast to coast network**
**12 hospitals with 85% 3****o**** care pediatric beds (~20% of Canadian children live near a centre)   **
**~90,000 annual admissions**

**Trained RN monitor on site**
**Standard reporting forms**
**Pre-selected targets: AEFI and VPD **
**Centralized data entry**

## IMPACT Network(Immunization Monitoring Program - ACTive)

* *_**Administered**__*** ***__**by**_***:***** Canadian Pediatric Society*****      ***

- IMPACT Network(Immunization Monitoring Program - ACTive)

**coast to coast network**
**12 hospitals with 85% 3****o**** care pediatric beds (~20% of Canadian children live near a centre)   **
**~90,000 annual admissions**

_**AEFI targets:(if plausible interval post immunization)**_
** ****Neurological events incl GBS **
** ****Thrombocytopenia**
** ****HHE**
** ****Severe Injection site reactions**
**Anaphylaxis, rashes**
**Other**

## IMPACT versus Passive Surveillance  Jan 1997 through Nov 2004 

- Male: 53%

**< 5 yr**
**(65%)**

**Notes:**
IMPAct
Nurse-monitors collect information on AEFI in children admitted to 12 paediatric centres across Canada. These centers represent about 90% of all tertiary care paediatric beds (approximately 75,000 admissions/year).
IMPAct
Nurse-monitors collect information on AEFI in children admitted to 12 paediatric centres across Canada. These centers represent about 90% of all tertiary care paediatric beds (approximately 75,000 admissions/year).

## Source of Adverse Event Reports  

- Other: Meningo-encephalitis/encephalopathy (4); ITP (1), Cardiac/pulmonary (2); Sudden death (1), URTI (1), vomiting (1)

**IMPACT**

## Advisory Committee on Causality Assessment:  1994 TO 2006.

** ****Initiated in 1994 by Health Canada’s Childhood Immunization Division**
** ****Purpose: **
** ****To analyze, classify and interpret selected serious or unusual adverse events following immunization (AEFI) **
** ****To recommend further investigations as needed**

## Causality Assessment in Canada  

**Selection criteria based on WHO criteria for seriousness**
**Fatal outcome**
**Hospitalized for AEFI**
**Life threatening event**
**Residual damage**
**In order to be reviewed additional case material required - not always available**
**Members: **
**Volunteers with expertise in clinical medicine, both pediatric and adult infectious disease, neurology, immunology and epidemiology**
** ****Annual 2 day meeting / monthly teleconferences**

**Notes:**
volunteers with expertise in clinical medicine, both pediatric and adult, infectious disease, neurology, 
immunology and epidemiology

## Causality Assessment in Canada  

**Standard form and process followed**
**Primary reason for reporting + ACCA focus for assessment**
**Frequency of occurrence of the event (in the population most representative of the subject of the AEFI report)**
**Do similar events occur with other diseases?**
**Is event known to be related to: **
**Act of vaccination?**
**Vaccine(s)?...If yes, strength of evidence for a causal relation**
**Is event biologically plausible?**
**Has patient had similar event and/or symptoms in past?**
**Concomitant / preceding drug therapy?**
**Concomitant / preceding condition?**
**Other contributing factors?**
**Causality association - using WHO defined terms **
**Consensus approach - if not reached, no causality assessment**

## Causality AssessmentDefinitions of Causality (“probability”) Terms  

| Causality | Adverse Event time relationship to vaccine administration is:  | Concurrent disease or other drugs/chemicals: |
| --- | --- | --- |
| Very likely | Plausible | Can’t explain AE |
| Probable | Reasonable | Unlikely to explain |
| Possible | Reasonable | Plausible cause of AE |
| Unlikely | Improbable | Plausible cause of AE |
| Unrelated | Incompatible | Can explain AE |
| Unclassifiable | Insufficient information to permit assessment and identification of cause |  |

## Causality AssessmentDefinitions of Causality (“probability”) Terms  

| Causality | Adverse Event time relationship to vaccine administration is:  | Concurrent disease or other drugs/chemicals: |
| --- | --- | --- |
| Very likely | Plausible | Can’t explain AE |
| Probable | Reasonable | Unlikely to explain |
| Possible | Reasonable | Plausible cause of AE |
| Unlikely | Improbable | Plausible cause of AE |
| Unrelated | Incompatible | Can explain AE |
| Unclassifiable | Insufficient information to permit assessment and identification of cause |  |

## ACCA Review: 1994-2006

**58,273 AEFI Reports**

**MEETS SELECTION CRITERIA?**

**Yes = 3420 (6%)**

**No = 54853 (94%)**

**SELECTED FOR REVIEW**

**No = 2270 (66%)**

**Yes = 1150 (34%)**

| Causality | Cases(%1150) |
| --- | --- |
| Very Likely | 80 (7.0%) |
| Probable | 85(7.4%) |
| Possible | 123(10.7%) |
| Unlikely | 118(10.3%) |
| Unrelated | 170(14.8%) |
| Unclassifiable | 30(2.6%) |
| Insufficient info | 260(22.6%) |
| Review unnecessary | 250(21.7%) |
| Review pending | 34(3.0%) |

## Causality Assessment By AEFI Source

- _IMPACT_
- 369 (68%) of 544 cases met selection criteria
- 137 (37%)  reviewed
-   3 (2.2%) judged to be unclassifiable

- _Passive Surveillance_
-  795(5%) of 15,020 met selection criteria
- 53 (6.7%) reviewed
- 6 (11.3%) judged to be unclassifiable

## Causality Assessment in CanadaSummary by AEFI (1994-2004)  

## Canadian Context for Vaccine Pharmacovigilance Annual Influenza Immunization Program 

**Target groups identified but encouraged for all Canadians**
**Ontario has a universal program**** **** **

**3 products used**
**Fluviral®(GSK/IBD)**
**Vaxigrip® (S-P) **
**Influvac® (Solvay)**** **

**Planning variety of enhanced postmarketing surveillance studies**
**Is annual vaccine behaving as expected? (~900 enrolled early)**
**Potential for telehealth / web reporting from large cohort (up to 10,000)**
**Vaccine safety data link -feasibility study **

**About 5 Million Doses/year**

## Canada’s Postmarketing System

**National Vaccine Safety Communication and Alert Network **

## Canadian Context for Vaccine Pharmacovigilance Federal / Provincial / Territorial Activities “FPT” 

**AEFI reporting not very timely at the national level**
**Need a rapid, reliable, secure system for two-way dialogue with P/Ts and health regions**

**Health is a PT responsibility**
**13 systems**
**vaccine providers 50:50 MD:RN  but one or other predominates in most P and Ts**
**Mix of publicly and privately funded vaccines**

## Canadian Context for Vaccine Pharmacovigilance Federal / Provincial / Territorial Activities “FPT” 

**AEFI reporting not very timely at the national level**
**Need a rapid, reliable, secure system for two-way dialogue with P/Ts and health regions**

- BC

- NT

- AB

- NU

- MB

- _SK_

- _QU_

- _ON_

- PEI

- _NB_

- NL

- NS

- YU

**Quebec “ESPRI” network**
**Designated Vaccine safety focus in each of 18 health regions and central health unit**
**Verifies/validates AEFI reports**
**Regular networked communication **
**Enables rapid communication and investigation of safety issues **

## Canadian Context for Vaccine Pharmacovigilance Federal / Provincial / Territorial Activities “FPT” 

**Established FPT Vaccine Pharmacovigilance Working Group may enable similar networks across Canada**
**Will be adding a technical Expert advisory group on vaccine safety **
**Hope to foster national network with potential for international ties**

- BC

- NT

- AB

- NU

- MB

- _SK_

- _QU_

- _ON_

- PEI

- _NB_

- NL

- NS

- YU

**Quebec “ESPRI” network**
**Designated Vaccine safety focus in each of 18 health regions and central health unit**
**Verifies/validates AEFI reports**
**Regular networked communication **
**Enables rapid communication of regional and central issues **

## Canadian Network for

**May 10, 2005**

*Reducing human illness associated with infectious disease by supporting intelligence exchange, surveillance activities and outbreak investigations*

**Secure web-based Collaborative resources to support group communication and planning **
**“****Collaboration Centre”**
**Discussion board**
**Documents Manager**
**Group notification**
**Meeting scheduler**
**News board**
**Can have multiple work groups each with different levels of access / privileges**

- Public Health Intelligence

**Canadian Network for Public Health Intelligence**

## Canadian Network for

**May 10, 2005**

*Reducing human illness associated with infectious disease by supporting intelligence exchange, surveillance activities and outbreak investigations*

**CIOSC: Canadian Integrated Outbreak Surveillance Centre**
**Web based secure alert system**
**Multiple users can have password protected access with variable privileges in terms of reading and posting alerts**

- Public Health Intelligence

**Canadian Network for Public Health Intelligence**

## Canadian Integrated outbreak Surveillance Centre (CIOSC): Alert Notification 

## Log in page

## Select from the Posted Alerts 

## Directly takes you to the alert

## Posting description

## CNPHI Users in Canada

**CNPHI Users in Canada**

**Over 1500 registered users.**
**Represents 100% of all Health Regions**

**Canadian Network for Public Health Intelligence**

**Notes:**
Our current CNPHI users within Canada include every province and territorial ministry of health and 98% of all health units across the country as well as federal/provincial/territorial laboratory services and the Public Health Agency of Canada.

All users are registered to gain access to CNPHIs web-based password protected applications. 

We have also recently engaged international users.

In total, in excess of 1400 registered users.

## Canadian Perspective on Ideal System for Vaccine Safety Communications 

**Rapid two/multi way dialogue possible across country via linked hubs in each P/T and Ottawa, with radiation to regional health units**
**International links built into system**
**Able to deal effectively and rapidly with perceived as well as real threats to vaccine safety**
**Enhance speed of preliminary AEFI reporting without compromising quality of final data**** **