# Presentation: 161253

## Vaccine Safety Evaluation: Post-marketing Surveillance Conference 

- New Zealand Experience with Meningococcal Vaccine  Post-marketing Surveillance
- Stewart Reid
- 11th April 2007

## Population  ~4M

- Maori       ~ 14%
- Pacific     ~ 7%
- Asian       ~ 9%
- European ~ 70%
- Location
- South Pacific
- Australia
- 3 hours West
- LA 12 hours
- North East

## Meningococcal disease isolate serogroup and dominant subtype 1990  -2005{not including PCR positive cases}

- Epidemiology of meningococcal disease in New Zealand 2005  ESR May 2006

## The problem

- Major epidemic
- Strain specific outer membrane vesicle (OMV) vaccine - MeNZBTM
-  Clinical trials in Auckland

## The Problem (cont)

- Licensure application - ~1100 recipients ~3300 doses*
- Substantial experience with other OMV vaccines – Norway, Cuba and Walter Reed outer membrane protein vaccine

- *Vaccine 23 (2005) 2191 -2196.

## The Problem (cont)

- Intention to vaccinate 1,000,000 New Zealanders aged 6m -19y
- No National Immunisation Register (NIR)
- Only monitoring - Centre for Adverse Reaction Monitoring (CARM) - passive reporting

## The Solution – Safety Monitoring System

- National Immunisation Register (NIR)
- -	with same patient identifier used in hospitals
- Several data sources

## Several data sources

- CARM
- 		Passive reporting system 		 		Intensive Vaccine Monitoring 			Programme (IVMP)
- Hospital based monitoring
- 		 		All event
- 					Rare event

## Slide 9

## Several data sources

- CARM
- 		Passive reporting system 		 		Intensive Vaccine Monitoring 			Programme (IVMP)
- Hospital based monitoring
- 		 		All event
- 					Rare event

## Rare events to be monitored

- Anaphylaxis
- Encephalopathy/encephalitis
- Flaccid paralysis
- Thrombocytopenia
- Hypotonic hypo-reponsive episodes
- Seizures
- Petechial rashes
- catch all categories e.g. all intensive care admissions within 7 days/ unusual events thought to be related to immunisation/deaths

## Hospital Based MonitoringRare Event

- Events of interest
*A priori* determined case definitions
- Independent case ascertainment – Clinical Review Committee (CRC)

## Hospital Based MonitoringRare Event (cont)

- Background disease rates
- Thresholds – stop/go points
- Minimum data sets

## Slide 14

## Under 5 ThresholdMinimum dataset 

- 	All 4 Northern District Health Boards to rest of country
- 	16 months – 4 years 	30,000 1st doses
- 	6-16 months 		7,500   1st doses
- 	6 weeks – 5 months	4,000   1st doses
- 	At each of these points substantial data was available on those vaccinated in Counties Manukau DHB.

## Independent Safety Monitoring Board

- Separation of data collection and analysis from assessment
- Independent assessment - Independent safety Monitoring Board (ISMB)

## Safety Monitoring Plan

- Discussed with Chair ISMB during development
- Reviewed and approved by ISMB
- Included
- monitoring methods,
- case definitions,
- background disease rates,
- cluster investigation protocol and
- causality assessment discussion

- http://www.moh.govt.nz/moh.nsf/pagesmh/5220/$File/safety-monitoring-plan.pdf

## Conclusion

- AS of June 2006 > 3,000,000 doses given
- ISMB review concluded –
- 	“outstanding programme of sensitive and objective safety monitoring”
- 	“no evidence of any significant adverse health event associated with the vaccine”

- http://www.moh.govt.nz/moh.nsf/pagesmh/5220?Open

## Acknowledgements

- Meningococcal Management Team (MMT) and Advisors
- 	Professor Diana Lennon, Dr Jane O’Hallahan, Dr Philipp Oster, Professor Kim Mulholland.
- 	Sue Crengle, Diana Martin, Liane Penney, Teuila Percival, Stewart Reid, Joanna Stewart
- MVS Trial Team, Auckland University
- Laboratory staff, Institute of Environmental Science and Research
- Independent Safety Monitoring Board and Clinical Review Committee
- MVS Safety Team, Ministry of Health
- 	Anne McNicholas, Yvonne Galloway, Paul Stehr-Green  et al,
- Centre for Adverse Reaction Monitoring (CARM) Dr Michael Tatley et al
- Safety monitoring teams at participating hospitals
- Rest of MVS team, Ministry of Health
- All vaccinators and others involved in the programme.

## References

**Strategy - **
- 	Sexton K, Lennon D, *et al.*  2 articles
- 	NZMJ 20 August 2004, Vol 117 No 1200
- http://www.nzma.org.nz/journal/117-1200/1026/
- http://www.immunise.moh.govt.nz/documents/nzmj-vaccinestrategy.pdf
**Safety Monitoring Plan – NZ Ministry of Health **
- http://www.moh.govt.nz/moh.nsf/pagesmh/5220/$File/safety-monitoring-plan.pdf

## Back up slides

## Observed vs expected cases

- Total population e.g. Acute flaccid paralysis

## Observed vs expected cases

- Vaccinees only e.g. seizures

## Immunisation Safety Surveillance

- A system that comprehensively monitors vaccine safety** **
- Should identify events caused by vaccination
- Enable causality assessment for events which may be caused by vaccination,
- Increase public confidence in vaccine programs  helping to avoid reductions in coverage caused by unsubstantiated fears of vaccine reactions.

## Independent Safety Monitoring Board

- Reviewed all safety data during the period of hospital based monitoring
- Independent with Australian chair and four other members, one from USA
- Advise on cessation of vaccination because of safety risk
- Advise on further investigation of possible safety risks

## Target population

- Reside in Counties Manukau, Auckland, Waitemata and Northland DHB’s.
- Target Cohorts
- 100,000 aged 5 – 19 years in CMDHB and Auckland DHB’s
- 100,000 aged 0 - 4 years in all 4 DHB’s

## Consent for MeNZBTM

**08 July 2004** 	consent for individuals aged 6 months or older valid for 2 	years
**03 February 2005**
- 		consent for individuals aged 6 weeks or older.
**12 January 2006**
- 		consent for 4th dose of the vaccine to infants who received 	the first dose when aged less than 6 months of age.
**21 July 2006**
- renewal of Provisional Consent under Section 23 of the
- Medicines Act 1981, valid for 2 years from 8 July 2006.

## Medicines Act 1981 – section 23

-    The Minister may, by notice in the Gazette, in accordance with this section, give his provisional consent to the sale or supply or use of a new medicine where s/he is of the opinion that it is desirable that the medicine be sold, supplied, or used on a restricted basis for the treatment of a limited number of patients.

## Intensive Vaccine Monitoring Programme

- Prospective observational cohort study of MeNZBTM vaccine

- Immunisation (s)

- incidents

- events

- reactions

- 6/52

- All health care visit details

*Sentinel Practices across  NZ*
*(primary health care providers)*

## IVMP sentinel practice monitoring

- Monitoring cohort
- Infants _*< 19 months*_ who have an immunisation in the practice
- All Immunisations

## IVMP sentinel practice monitoring

- Monitoring cohort
- Selection of practices
- 35 large medical centres (known as sentinel group practices)
- MedTech32® Practice Management Software
- Population geographically & socio-demographically diverse

## IVMP sentinel practice monitoring

- Monitoring cohort
- Selection of practices
- Data collection
- Software extraction from existing PMS data fields
- All immunisations (MeNZBTM & other)
- All health consultation details for the _*six weeks*_ following an immunisation
- Secure electronic transfer from PMS
- “Background mode”
- 		no additional work required at practice !!

## IVMP sentinel practice monitoring

- Monitoring cohort
- Selection of practices
- Data collection
- Events assessment
- Events assessed as unrelated (incidents) or related (reactions)
- Standardised coding and entry into IVMP database
- WHO National Centres causal relationship (after Karch & Lasagna)
- WHOART (event terminology)
- Grouped by related event terms (modified for clinical AEFI’s)

## IVMP Cohort groups

**assessed**

- 19,257 Vac-visits
- (10,308 vaccinees)
**analysed**

**< 6 month olds**
- 6, 749 vac-visits
- (3,156 vaccinees)

**6-<19 month olds**
- 4,474 vac-visits
- (2,368 vaccinees)

**19 month – 5 year olds**
- 8,034 vac-visits
- (4,784 vaccinees)

**MeNZB**
- Vac-visit
**1,166**

**Hybrid**
- Vac-visit
**2,452**

**Routine**
- Vac-visit
**3,131**

**MeNZB**
- Vac-visit
**3,540**

**Hybrid**
- Vac-visit
**441**

**Routine**
- Vac-visit
**493**

**Routine**
- Vac-visit
**209**

**Hybrid**
- Vac-visit
**304**

**MeNZB**
- Vac-visit
**7521**

- 52,754 Vac-visits
- (17,921 vaccinees)

**IVMP Cohort groups**

- 1 Outside of defined time periods:
- < 6 month olds, 03 Feb. 2005  - 30 Sep. 2005
- ≥ 6 month olds, 19 Jul. 2004 - 15 Nov. 2004

- 11,112 Vac-visits excluded1

- 22,385 Vac-visits not yet assessed

- 10 vaccinees opted out

- 19 July 2004 – 30 Sept 2005

## Key Findings

- Low opt-out rate (10/17921)
- No unexpected AEFI’s identified
- Low rate of reactogenicity
- Reaction profile similar to Routine immunisations

## ConclusionIVMP is a novel & valuable Pharmacovigilance tool

- Source of representative & unbiased data
- Minimal participant compliance burden
- EDT technologies result in resource savings and efficiencies
- Real life & real time vaccine campaign monitoring
- Feedback in real time to Programme leaders
- Reassurance to public
- Database available for long term follow-up