# Presentation: 177131

## Roundtable: Cutting edge safety systems A global perspective

**Vaccine Safety Evaluation: **
**Post Marketing Surveillance Conference**
**Bethesda, MD**
**10 April,2007**
**Adwoa Bentsi-Enchill ****Quality, Safety and Standards**
**Immunization Vaccines and Biologicals**
**WHO**

##  Outline

- Background
- WHO Programme for International Drug Monitoring
- Overview
- Potential for strengthening vaccine pharmacovigilance
- WHO's Global Network for Post-marketing Surveillance of New Vaccines
- Selected country examples of new methodologies

##  Background

- Global impact of real or perceived safety concerns
- Challenges for ensuring effective safety monitoring systems in non-industrialized countries
- Relative lack of resources
- Communication, cultural and other local factors
- What would an ideal post licensure vaccine safety system be ........ globally?
- How can we build more effective systems in non-industrialized  countries?

##  WHO Programme for International Drug Monitoring

- Network of National Pharmacovigilance Centres, WHO HQ, and the WHO Collaborating Centre for International Drug Monitoring (the ***Uppsala Monitoring Centre (UMC)***)
- Established in 1968 and at UMC since 1978
- Jan 2007: 82 member countries (+ 17 associate members)
- Approx. 3.7 million case reports in database
- Only approx. 10% of database relates to vaccine reports (82% of vaccine reports from 3 countries) – M Letourneau, 2005; publication pending

##  Functions of the WHO Programme

- Identification and analysis of **new adverse reaction signals**
**WHO database as reference source** for signal strengthening and ad hoc investigations.
**Information exchange** between WHO and National Centres (Vigimed)
**Periodical newsletters**, **guidelines etc. **in PhV and risk management
**Tools for management of clinical information** (WHO Drug Dictionary and the WHO Adverse Reaction Terminology; WHO-ART to MedDRA mapping)
- T**raining and consultancy support** to National Centres
**Software for case report management** (VigiFlow)
- Annual **meetings for representatives of National Centres**
**Methodological research**

##  Steps in UMC signalling

**Global reporting** (from National Centres) of safety data to UMC
- Quarterly **analysis of data** using a Bayesian Confidence Propagation Neural Network (BCPNN) method
- Generates **Combinations Database** (all Drug-ADR combinations)
**Triage** algorithms applied to prioritize **associations** of interest (potential signals) for review by clinical "signal reviewers"
- based on an **Information Component** (IC) value; unexpected drug-ADR pairs
- based on special terms of interest
**Signal review** (including review of literature)
**Publication** in *Signal* document
- Additional **pattern recognition** to generate hypotheses for further study (e.g., specific events or ADR risk factors)

## UMC: Signal Detection & Follow-up

**Combinations**.db
- (reported quarterly)

**Triage** **(filter)**

- Quarterly analysis
- BCPNN

- Vigibase

**Review **
**panel**

- SIGNAL

- Yes

- No

- National Centres

- Pharma
- Company

- Follow-up

- Source: the Uppsala Monitoring Centre

##  Improving vaccine safety monitoring through the WHO Programme for International Drug Monitoring

- WHO consultation on improving global AEFI monitoring (9-10 Jan 2006)
- _[http://www.who.int/wer/2006/wer8127.pdf](http://www.who.int/wer/2006/wer8127.pdf)_
- Improving AEFI reporting to UMC
- understanding  determinants for AEFI reporting
- Improving UMC resources and methods for reporting and analysis of vaccine safety data
- Improving advocacy and communication
- Linkages with international vaccine safety groups/experts

- AEFI = adverse events following immunization

##  Global Network for Post-marketing Surveillance of New Vaccines

- To support WHO vaccine prequalification system (supply by UN agencies) with safety data in post-marketing phase
**Objectives:**
- Ensure standardised approach to monitoring serious adverse events
- Identify/address potential safety signals in timely manner
- Ensure adequate safety information to support vaccination policy and recommendations
- may include recommendations for more controlled studies

##  Global PMS Network: Surveillance methods

- Start with 10-12 countries
- Core/standard PMS guidelines
- adaptation to local resources and systems
- improve use of standardised terminology and case definitions (e.g., Brighton Collaboration)
- Case detection
- public AND private sector
- stimulated passive system (based on existing systems)
- active sentinel surveillance for selected events and vaccines
- monitoring in campaign settings (e.g., JE)
- Strengthen data analysis, investigation & causality assessment for serious AEs
- reporting to UMC to enhance signal detection

## Proposed functional structure

- *

- *

**UMC**
- (Signal detection)

**Network management group: **Member countries, WHO (RO + HQ), experts/advisors
- (extended analyses and specific studies)

-  *  Monthly, or “ad hoc” reporting

- ** Quarterly feed-back

- **

- **

## A new way to monitor vaccine safety in South Australia

## First pilot study in Australia to evaluate 	  technical feasibility	  effectiveness	  acceptability
of linking Commonwealth and State health records to monitor vaccine safety.

- of linking Commonwealth and State health records to monitor vaccine safety.

- SAVeS study

- Linkage of 1997-2002 data from:
- Australian Childhood Immunisation Register
- OACIS
- Women’s and Children’s Hospital HAS-ED
- SA passive AEFI reporting system

**Notes:**
We received HSRIP funding in 2004

## Effective?Demographic data for linking

**Data Linkage Officers in SA Department of Health**

**ACIR**
- Name
- Date of birth
- Gender
- Address
- Local ID (eg: ACIR 1)

**SA passive system**
- Name
- Date of birth
- Gender
- Address
- Local ID (eg: SAVeS 9)

**OACIS CRR**
- Name
- Date of birth
- Gender
- Address
- Local ID (eg: OACIS 5)

**WCH HAS-ED**
- Name
- Date of birth
- Gender
- Address
- Local ID (eg: HAS 31)

- Effective?Demographic data for linking

## Effective?Clinical data for analysis

**Analyst at Curtin University, WA**

**ACIR**
- .
- .
- .
- .
- .
- .
- .
- Immunisation history
- Local ID (eg: ACIR 1)

**SA passive system**
- Date of admission
- Date of discharge
- .
- .
- .
- .
- Length of stay
- Immunisation history
- Local ID (eg: SAVeS 9)

**OACIS CRR**
- Date of admission
- Date of discharge
- ICD principal dx code
- ICD 2nd ry dx code
- External cause code
- ED presentation code
- Length of stay
- .
- Local ID (eg: OACIS 5)

**WCH HAS-ED**
- Date of admission
- Date of discharge
- ICD principal dx code
- .
- .
- .
- .
- .
- Local ID (eg: HAS 31)

- Effective?Clinical data for analysis

## Effective?Sensitivity of SA passive system

| MMR | Actual Events | Attributable to MMR vaccine | Events reported as convulsions |
| --- | --- | --- | --- |
| Baseline | 832 | - | 5 |
| -14 to 0 days | 14 | 0 | 0 |
| 6 to 11 days | 30 | 15 | 0 |
| 15 to 35 days | 48 | 0 | 0 |

- Effective?Sensitivity of SA passive system

- Actual events = identified through data linkage;
- Events reported as convulsions = identified through SA passive system

## Q4. How comfortable are you with data linkage for general health research?

- Q4. How comfortable are you with data linkage for general health research?

## Q6. Under what circumstances should data linkage be allowed for vaccine safety research?

- Q6. Under what circumstances should data linkage be allowed for vaccine safety research?

## Next steps include: 

- Plans for assessing national feasibility and acceptability of data linkage for vaccine safety surveillance.

**Notes:**
We received HSRIP funding in 2004

## Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute
Istituto Superiore di Sanità
Italy

***Istituto Superiore di Sanità***
***Italy***

**The Italian H****era study ****on the risk of death due to unknown or ill defined causes during the first two years of life**

## Italian Hera study: safety of hexavalent vaccine

- 2003: signal of possible association between hexavalent product and sudden unexpected deaths raised in Germany
- Hexavalent vaccines widely used in Italy since 2001
- Coverage in Italy for three doses (ICONA 2003, on a sample of 4,602 children from the 2001 birth cohort; Ciofi degli Atti, 2005)
- >78% by 12th month; >95% by 24th month
**Case series method** used to evaluate risk of death due to unknown or ill defined causes during the first two years of life following vaccination

## Objectives

- To evaluate whether the incidence density of unexpected deaths during the first two years of life is higher in periods of time close to vaccine administration (i.e. vaccinations are associated with an increased short term risk of SIDS-SUD)
- To compare the incidence density following the administration of one of the two available hexavalent vaccines, and to compare hexavalent vaccines with products previously used in Italy

## Study design and analysis

- Five annual cohorts of newborns in Italy (> 500,000 newborns per year); 1 Jan 1999 - 31 Dec 2003
- Only vaccinated cases included in analysis
- For each case, the observation period following each vaccine dose was divided into:
- Three **risk periods** following vaccination were considered: 0-1; 0-7; and 0-14 days
**Control period** between the 14th day and the subsequent vaccination or death
- Confounding factors adjusted by age (≤80; 81-100; 101-120; 121-180; 181-360; >360 days)

## Computation of person-time during at risk- and control-periods

- _Classes in days_
- 31-80   81-100  101-120 121-180  181-360  >360

- P-T stratified by 		- class of age
- 			- vaccine
- Other available covariates : 	- mother citizenships
- 				- place of death (home or not)
- 				- calendar year
- 				- last dose

**Risk period**

**Control period**

**Risk period**

**Control period**

_**Any vaccine**_

- Death

**Risk period, Vac Y**

**Risk period, Vac X**

**Control period**

- Death

_**By vaccine**_

## Conclusions

- No increased risk
- for 0-1 days following vaccination
- by dose
- for 2nd year of life
- For the risk periods 0-7 and 0-14 days most RR estimates were slightly greater than 1 with non-significant confidence intervals
- At 14 days both hexavalent vaccines had the same estimated risk
- The RRs concerning concomitant administration of six antigens do not differ from the estimates of the two hexavalent products
**Manuscript in preparation for publication**

##  How can we ensure "ideal post licensure vaccine safety systems" in the WHO Programme?

- Improving reporting by National Centres to UMC and use of UMC resources and methods for reporting and analysis of vaccine safety data
- Networks of non-industrialized countries for post-marketing surveillance (incl. data linkage, epidemiological studies etc.)
- Linkages with international vaccine safety groups and experts
- Capitalize on experiences from advanced monitoring systems
- Subgroup of *Global Advisory Committee on Vaccine Safety* established in Jun 06 to advise on global AEFI monitoring
- CIOMS/WHO Working Group on Vaccine Pharmacovigilance

##  Acknowledgements

- the Uppsala Monitoring Centre/WHO Programme for International Drug Monitoring
- Mike Gold, Sarah Dugdale et al (South Australia Vaccine Safety Study)
- Stefania Salmaso et al (Istituto Superiore di Sanità, Italy)